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By Stuart Fox, 2010
-Article describes possible outcomes if synthetic biology was to become more prevalent and how it could be utilized for biological warfare and many other plausible scenarios.

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The announcement last week of the first synthetic living cell generated sensational headlines and thinly sourced reports that its creator, J. Craig Venter, is "playing God." But most experts in the field would say otherwise, suggesting the creation is somewhat run-of-the-mill.

Ethicists and other researchers do point out real reasons for concern that don't involve a devout being, however.

Scientists and others worry that if the synthetic organism escapes, it could mutate into a deadly pathogen or affect the environment adversely in some way. They're also worried the technology might be used to make biological weapons. With these potential risks, scientists are urging agencies to regulate the safe handling of any synthetic organism.

"If the upside is that we can potentially genetically engineer algae to produce biofuels, for example, the downside is that we could inadvertently create an environmental hazard we cannot easily control and correct for," said William FitzPatrick, an associate professor of philosophy at Virginia Tech and a specialist in bioethics. "Simple prudence therefore recommends caution and sufficient regulation to guard against potential dangers."

Making of a genome controversy?

The study scientists essentially transplanted a genome they had constructed from the bacterium Mycoplasma mycoides into a M. capricolum cell (now the first cell with a complete synthetic genome) that had been emptied of its own genome. Once the DNA "booted up," the bacteria began to function and reproduce in the same manner as naturally occurring M. mycoides.

The breakthrough could help scientists with many research efforts, from pursuing cancer treatments to figuring out the origin of life.

Advances in cloning and legislation involving stem cells inevitably generate conflict between proponents of the technology and those who believe tampering with the raw material of life amounts to playing God.

The Venter creation, however, shouldn't amount to such philosophical bickering for a number of reasons, experts say, including the low complexity of the organism in question, and the limited scope of the specific experiment in particular. Additionally, years of research and genetic experimentation has made these discoveries commonplace, and thus less likely to shock the public.

"If Venter had created the first synthetic human, you would expect a lot more controversy, but I don't think this rises to that level. What he has done is not that distinct in the moral categories used by people in the United States," said John Evans, a professor of sociology at the University of California, San Diego, and author of "Playing God?: Human Genetic Engineering and the Rationalization of Public Bioethical Debate" (University of Chicago Press, 2002).

What would cause controversy

To provoke a fervent response, Venter would have to create a new life form that resembles an animal the public knows, like engineering a cat that has wings, or creating a synthetic human being, Evans said. Bacteria are invisible and mostly abstract to most Americans, making it difficult for people to connect viscerally with the news, Evans said.

This new technology also doesn't seem to generate new concerns that differ enough from previous experiments to instigate a new round of outrage, said Adina Roskies, a professor of philosophy, and bioethics specialist, at Dartmouth College. Society has already wrestled with the consequences of genetic engineering, and this new advance falls squarely within the morality constructed by those earlier debates, Roskies said.

"I don't think there's anything on the face of it that's particularly troubling. It doesn't seem different, really, than fiddling with genomes, which we've been able to do for a while." Roskies said.

Additionally, the public has acclimated to scientific discoveries and engineering advances with profound implications, said Peter Godfrey-Smith, a professor of philosophy at Harvard University and author of "Theory and Reality: An Introduction to the Philosophy of Science" (University of Chicago Press, 2003).

Starting with the atomic bomb, Americans have lived under the shadow of potentially dangerous scientific advances for so long that announcements like Venter's no longer produce the same level of dread, Godfrey-Smith said.

Real risks of synthetic life

However, like the atomic bomb, synthetic biology poses a number of practical risks. For instance this technology could produce devastating biological weapons, or escape, mutate and cause unforeseeable damage to the ecosystem, Evans and Godfrey-Smith both pointed out.

"What would happen if he took this thing and threw it out in the grass behind his lab? I don't think anyone knows for sure, and you want to have regulation to prevent that kind of behavior," Evans said. "Someone needs to do that for the same reason that I'm not allowed to have toxic waste in my garage."

Venter and genetics watchdog organizations like the ETC Group differ on which regulatory scheme strikes the best balance between safety and business, but even those opponents agree that the technology does not violate any deeper ethical boundaries.

Venter and his opponents, as well as Evans, Godfrey-Smith and Roskies, all agreed that like every technological advance since fire and the sharpened stick, the ethical concerns surrounding synthetic biology rest not with the tool itself, but the hand that wields it.

"It's how you use it, and what you use it for, that matters," Roskies said.

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The announcement last week of the first synthetic living cell generated sensational headlines and thinly sourced reports that its creator, J. Craig Venter, is "playing God." But most experts in the field would say otherwise, suggesting the creation is somewhat run-of-the-mill. Ethicists and other researchers do point out real reasons for concern that don't involve a devout being, however.

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By Mark Shwartz, no date

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Clinical trial

The proposed Stanford clinical trial will focus on the stem cells in our bone marrow that produce red blood cells.

People with sickle-cell disease have two defective hemoglobin genes in their stem cells, one from each parent. Together, the two defective genes are what cause red blood cells, which are normally disc-shaped and flexible, to become stiff and sticky as they mature.

People who inherit one defective gene and one normal gene have what is known as sickle-cell trait, a condition that affects about 3 million Americans. Most of their red blood cells are normal, allowing them to lead healthy lives free of sickle-cell disease. However, the abnormal hemoglobin gene in their DNA can be passed on to their children.

In his trial, Porteus plans to repair and replace defective blood stem cells in patients with sickle-cell disease. The idea is to transform the patients into healthy people with sickle-cell trait by converting their defective stem cells with two abnormal hemoglobin genes into stem cells with just a single abnormal gene.

CRISPR's job will be to remove the mutated DNA sequence from one of the genes.

"Our first step will be to design CRISPR-Cas9 to locate and delete the DNA mutation," says Porteus. "But that won't fix anything. We also have to engineer a virus to deliver the correct sequence of normal DNA."

Once the gene has been repaired, the newly modified stem cells with sickle-cell trait will be injected back into the patient's bloodstream. Ideally, some will find their way into the bone marrow and start cranking out millions of healthy red blood cells.

"We'll probably have to use chemotherapy to create a space in the patient's bone marrow for the corrected stem cells to be taken up," says Porteus."The repaired stem cells could create enough normal red blood cells for the patient to be symptom-free for life," he adds. "That's the ultimate goal."

70 percent threshold

The CRISPR process doesn't have to be perfect to be effective, says Porteus. That's because symptoms of the disease occur only if the proportion of sickled cells in the bloodstream is above 30 percent. If at least 70 percent of the red blood cells are healthy, the patient is symptom-free.

"Having 20 percent corrected stem cells in the bone marrow will probably be sufficient for most patients to get above the 70 percent threshold," explains Porteus. "That's because healthy red blood cells live about five times longer than diseased cells and quickly outnumber them."

Monitoring the modified stem cells to make sure they are producing enough healthy red blood cells will be crucial, he adds.

"The proof will come when we follow the patients over time and see whether they have any symptoms of the disease," says Porteus. "They could remain symptom-free, or they might need additional treatments. Some things we'll know in a month, others in 10 years."

Patients like David are well aware of the 70 percent target. Every Monday he undergoes a blood test at a hospital clinic to measure his sickle-cell count. The results determine how much healthy donor blood he will receive at his next infusion, which is part of a three-hour procedure known as apheresis, where David's diseased red blood cells are removed and replaced with normal donor cells.

But the benefits of the infusion last only about a month, during which time his defective stem cells continue to function, producing more diseased red blood cells.

Prior to his infusion last November, David's count had risen to 24 percent, slightly below the level that triggers new symptoms. But after the infusion, the proportion of sickled cells dropped to just 12 percent.

Staying above the 70 percent threshold has reduced many of David's symptoms. But last spring, intense headaches forced him to withdraw from school. He was diagnosed with moya-moya disease, a potentially lethal condition caused by blockage in the arteries to his brain. He had surgery at Packard Children's to bypass the blocked arteries and restore blood flow.

"The brain surgery saved his life," says Jennifer Andrews, MD, MSc, David's primary doctor, a clinical associate professor of pathology and of pediatrics. "Without it, he could have had a major stroke."

His grandmother recalls the day of the procedure: "Before he went into surgery I said, 'Baby, aren't you scared?'" she says. "He said, 'No, Nana, would you rather take care of me like I am now, or after I have a stroke?' He's a very compassionate child."

David recovered from the surgery and has enrolled as a freshman in an online high school that lets him study at his own pace. That way he doesn't have to worry about missing class because of lengthy medical procedures or when symptoms recur.

If the CRISPR clinical trial at Stanford is successful, monthly infusions of donor red blood cells for people with sickle-cell disease could be a thing of the past.

"I think it's great that people are working with CRISPR to cure sickle cell and other diseases," says David. "It's really cool that they could come up with something like this. So many people have lives that could be so much better."

Designer babies

Clinical trials of CRISPR like the one Porteus is proposing have broad public support, in part because using CRISPR in adults and children would alter their DNA, but not that of their offspring.

Editing human embryos to repair disease-causing genes is far more controversial. One concern is that CRISPR occasionally targets and removes the wrong gene. One off-target event could have serious consequences for newborns and their descendants.

"The idea of editing human embryos makes a lot of people queasy, and it should," says Mercola. "CRISPR isn't perfect, and when you alter embryonic DNA, the results are passed from one generation to the next."

Public anxiety was heightened in 2015 when scientists in China used CRISPR to edit human embryos for the first time. Although the experimental embryos were not viable, some worried that fertility clinics would start using CRISPR to genetically engineer children with traits parents might want, like making them stronger, taller or smarter.

"People are most worried about enhancement, using CRISPR to give babies superpowers," says Greely. "But we don't know now any genes that give people superpowers. For practical and regulatory reasons, we're not going to be CRISPRing embryos and making designer babies any time soon."

Greely also sees little justification for using CRISPR in embryos to prevent disease. "Very few people will need to do gene editing to have healthy babies," he argues. "Almost every genetic disease can be avoided using preimplantation genetic diagnosis. Rather than changing genes in an embryo, you just select an embryo that doesn't have the dangerous genes. PGD has been around for almost 30 years. It's safe and effective."

In a 2017 report, the National Academy of Sciences recommended that, for now, CRISPR and other gene-editing tools be permitted only in human clinical trials aimed at curing and preventing serious diseases, not enhancing babies.

Proceed with caution

Sickle-cell disease seems well-suited for CRISPR gene therapy because it targets a specific type of cell, according to the 2017 NAS report. Other inherited diseases such as cystic fibrosis and muscular dystrophy may be more difficult to treat because they affect different cell types in different organs. Despite these challenges, a number of labs are using CRISPR to find cures for these and other genetic diseases in adults and children.

"For what we're doing, CRISPR has made things easier," says Porteus, who served on the NAS report committee. "The momentum for developing new gene therapies is incredible. We want to move fast because the patients deserve that, but we want to move carefully. We don't want to do something that causes a huge setback."

Gene therapy did suffer a major setback in 1999 when an 18-year-old man with an inherited liver disease died during a clinical trial at the University of Pennsylvania. Researchers had injected what was thought to be a harmless virus carrying a modified gene into the man's liver. But the virus ran amok, triggering a severe immune response, and the young man died four days later.

'For treating classic genetic diseases like sickle cell, I think CRISPR will be transformative, and that's a great thing.'

Before then, gene therapy had been considered a promising, breakthrough treatment for many diseases, but the clinical-trial death stopped other researchers in their tracks. Fast forward to 2016, when a different group from the University of Pennsylvania asked a federal panel to green-light the first-ever clinical trial using CRISPR. The trial was designed to genetically alter immune cells in cancer patients, then reinject the modified cells to see if they improve the immune system's ability to fight off the disease.

Hearings were held before the Recombinant DNA Advisory Committee, a panel of experts that advises the director of the National Institutes of Health on whether to approve federally funded gene-transfer trials.

"There was a lot of trepidation at the hearings, in part because the cancer protocol is so complex," says Stanford bioethicist Mildred Cho, PhD, who is a member of the advisory committee. "It requires manipulating lots of different systems at the same time, especially the immune system, which is not fully predictable."

Unresolved questions about the 1999 fatality persisted throughout the hearings, but the committee ultimately recommended that the clinical trial proceed using CRISPR.

"In the 1999 case, a genetically altered virus was infused directly into the patient's liver, so there was little control on where it spread through the bloodstream," says Cho, a professor of pediatrics and of medicine. "But most CRISPR protocols are ex vivo - they take the cells out of the body, manipulate them and then put them back. That, at least, allows for some kind of risk assessment to see if there are any off-target gene modifications, or if they've turned the immune cells into cancer cells by accident."

Even if CRISPR proves successful, Cho worries that for many patients, the financial cost will be prohibitive.

"Gene therapy is not the same as taking a pill from the pharmacy," she says. "It's more like getting an organ transplant. It's a very complex procedure. Cancer immunotherapy already costs in the hundreds of thousands of dollars per year. There's no way that gene-edited treatments are going to be any less expensive."

Runaway evolution

Cho is also concerned about using CRISPR to control entire populations of disease-spreading animals, like mosquitoes that carry malaria and mice that transmit Lyme disease. Researchers are exploring ways of altering the DNA in these and other fast-breeding species so that future generations cannot spread disease.

But attempts to manipulate nature, though well-meaning, sometimes backfire.

"We don't have the ability to control runaway evolutionary changes to wild populations," says Cho. "There's no regulatory framework to test mosquitoes and other modified organisms. Once they're released in the wild, it's hard to reverse any inadvertent effects."

CRISPR also makes it easier for people with bad intentions to do harm, adds Greely.

"Smallpox has been eradicated in the wild," he says. "But if you want to make a biological weapon, you can use CRISPR to turn ordinary cowpox virus into smallpox."

What's needed, Greely says, are well-thought-out, well-enforced federal regulations that make it difficult for CRISPR to be misused accidentally or intentionally.

"The Obama administration listed gene editing as one of the four biggest threats to the country," he says. "It might be ISIS or North Korea. I guarantee that there are people in Washington, D.C., very worried about this."

CRISPR Model T

Still, the promise that CRISPR offers keeps researchers focused on the future. Beyond treating individual patients, the most important application of CRISPR may lie in the discovery of new drugs for dozens of intractable diseases, says Mercola.

"We're just scratching the surface in the drug-target space," he says. "For me, that's where this field is going. CRISPR is a great example of how basic research can lead to something of tremendous utility in a record amount of time."

At Stanford, recruitment of participants for the sickle-cell clinical trial could begin early next year. But more work is needed to demonstrate that stem cells altered with CRISPR are ready to be tested in people. Last year, Porteus received a $5.2 million grant from the California Institute for Regenerative Medicine to fund that additional research.

Donated human stem cells are now being processed at the Stanford Laboratory for Cell and Gene Medicine, a large facility dedicated to making biological materials that meet the rigorous federal standards for clinical trials, including a high level of sterility and a strict protocol for chain of custody.

"Before the lab opened in 2016, there was no way for us to conduct an entire clinical trial at Stanford," says Porteus. "We'd have to send the stem cells to a company off campus for processing. But the new lab demonstrates a major commitment by Stanford to be at the forefront of gene therapy just as this promising field is emerging."

Greely compares the invention of CRISPR today to the rollout of the Ford Model T a century ago."The Model T was cheap and reliable, and before long everybody had a car and the world changed," he says. "CRISPR has made gene editing cheap, easy and accessible, and therefore more common. I think it's going to change the world. Exactly how beats me."

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CRISPR is a gene-editing tool that's revolutionary, though not without risk

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The proposed Stanford clinical trial will focus on the stem cells in our bone marrow that produce red blood cells. People with sickle-cell disease have two defective hemoglobin genes in their stem cells, one from each parent. Together, the two defective genes are what cause red blood cells, which are normally disc-shaped and flexible, to become stiff and sticky as they mature.

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2014-  Alex Reis, Ph.D., Bitesize Bio
Breton Hornblower, Ph.D., Brett Robb, Ph.D. and George Tzertzinis, Ph.D., New England
Biolabs, Inc.

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The development of efficient and reliable ways to make precise, targeted changes to the genome of living cells is a long-standing goal for biomedical researchers. Recently, a new tool based on a bacterial CRISPR-associated protein-9 nuclease (Cas9) from Streptococcus pyogenes has generated considerable excitement (1). This follows several attempts over the years to manipulate gene function, including homologous recombination (2) and RNA interference (RNAi) (3). RNAi, in particular, became a laboratory staple enabling inexpensive and high-throughput interrogation of gene function (4, 5), but it is hampered by providing only temporary inhibition of gene function and unpredictable off-target effects (6). Other recent approaches to targeted genome modification - zinc-finger nucleases [ZFNs, (7)] and transcription-activator like effector nucleases [TALENs (8)]- enable researchers to generate permanent mutations by introducing doublestranded breaks to activate repair pathways. These approaches are costly and time-consuming to engineer, limiting their widespread use, particularly for large scale, high-throughput studies.

What is CRISPR/Cas9?

The functions of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and CRISPR-associated (Cas) genes are essential in adaptive immunity in select bacteria and archaea, enabling the organisms to respond to and eliminate invading genetic material. These repeats were initially discovered in the 1980s in E. coli (9), but their function wasn't confirmed until 2007 by Barrangou and colleagues, who demonstrated that S. thermophilus can acquire resistance against a bacteriophage by integrating a genome fragment of an infectious virus into its CRISPR locus (10).

Three types of CRISPR mechanisms have been identified, of which type II is the most studied. In this case, invading DNA from viruses or plasmids is cut into small fragments and incorporated into a CRISPR locus amidst a series of short repeats (around 20 bps). The loci are transcribed, and transcripts are then processed to generate small RNAs (crRNA - CRISPR RNA), which are used to guide effector endonucleases that target invading DNA based on sequence complementarity (Figure 1) (11).

Figure 1. Cas9 in vivo: Bacterial Adaptive Immunity

In the acquisition phase, foreign DNA is incorporated into the bacterial genome at the CRISPR loci. CRISPR loci is then transcribed and processed into crRNA during crRNA biogenesis. During interference, Cas9 endonuclease complexed with a crRNA and separate tracrRNA cleaves foreign DNA containing a 20-nucleotide crRNA complementary sequence adjacent to the PAM sequence. (Figure not drawn to scale.)

One Cas protein, Cas9 (also known as Csn1), has been shown, through knockdown and rescue experiments to be a key player in certain CRISPR mechanisms (specifically type II CRISPR systems). The type II CRISPR mechanism is unique compared to other CRISPR systems, as only one Cas protein (Cas9) is required for gene silencing (12). In type II systems, Cas9 participates in the processing of crRNAs (12), and is responsible for the destruction of the target DNA (11). Cas9's function in both of these steps relies on the presence of two nuclease domains, a RuvC-like nuclease domain located at the amino terminus and a HNH-like nuclease domain that resides in the mid-region of the protein (13).

To achieve site-specific DNA recognition and cleavage, Cas9 must be complexed with both a crRNA and a separate trans-activating crRNA (tracrRNA or trRNA), that is partially complementary to the crRNA (11). The tracrRNA is required for crRNA maturation from a primary transcript encoding multiple pre-crRNAs. This occurs in the presence of RNase III and Cas9 (12).

During the destruction of target DNA, the HNH and RuvC-like nuclease domains cut both DNA strands, generating double-stranded breaks (DSBs) at sites defined by a 20-nucleotide target sequence within an associated crRNA transcript (11, 14). The HNH domain cleaves the complementary strand, while the RuvC domain cleaves the noncomplementary strand.

The double-stranded endonuclease activity of Cas9 also requires that a short conserved sequence, (2-5 nts) known as protospacer-associated motif (PAM), follows immediately 3´- of the crRNA complementary sequence (15). In fact, even fully complementary sequences are ignored by Cas9-RNA in the absence of a PAM sequence (16).

Cas9 and CRISPR as a New Tool in Molecular Biology

The simplicity of the type II CRISPR nuclease, with only three required components (Cas9 along with the crRNA and trRNA) makes this system amenable to adaptation for genome editing. This potential was realized in 2012 by the Doudna and Charpentier labs (11). Based on the type II CRISPR system described previously, the authors developed a simplified two-component system by combining trRNA and crRNA into a single synthetic single guide RNA (sgRNA). sgRNAprogrammed Cas9 was shown to be as effective as Cas9 programmed with separate trRNA and crRNA in guiding targeted gene alterations (Figure 2A).

To date, three different variants of the Cas9 nuclease have been adopted in genome-editing protocols. The first is wild-type Cas9, which can site-specifically cleave double-stranded DNA, resulting in the activation of the doublestrand break (DSB) repair machinery. DSBs can be repaired by the cellular Non-Homologous End Joining (NHEJ) pathway (17), resulting in insertions and/or deletions (indels) which disrupt the targeted locus. Alternatively, if a donor template with homology to the targeted locus is supplied, the DSB may be repaired by the homology-directed repair (HDR) pathway allowing for precise replacement mutations to be made (Figure 2A) (17, 18).

Cong and colleagues (1) took the Cas9 system a step further towards increased precision by developing a mutant form, known as Cas9D10A, with only nickase activity. This means it cleaves only one DNA strand, and does not activate NHEJ. Instead, when provided with a homologous repair template, DNA repairs are conducted via the high-fidelity HDR pathway only, resulting in reduced indel mutations (1, 11, 19). Cas9D10A is even more appealing in terms of target specificity when loci are targeted by paired Cas9 complexes designed to generate adjacent DNA nicks (20) (see further details about "paired nickases" in Figure 2B).

The third variant is a nuclease-deficient Cas9 (dCas9, Figure 2C) (21). Mutations H840A in the HNH domain and D10A in the RuvC domain inactivate cleavage activity, but do not prevent DNA binding (11, 22). Therefore, this variant can be used to sequence-specifically target any region of the genome without cleavage. Instead, by fusing with various effector domains, dCas9 can be used either as a gene silencing or activation tool (21, 23-26). Furthermore, it can be used as a visualization tool. For instance, Chen and colleagues used dCas9 fused to Enhanced Green Fluorescent Protein (EGFP) to visualize repetitive DNA sequences with a single sgRNA or nonrepetitive loci using multiple sgRNAs (27).

Figure 2. CRISPR/Cas9 System Applications

A. Wild-type Cas9 nuclease site specifically cleaves double-stranded DNA activating double-strand break repair machinery. In the absence of a homologous repair template non-homologous end joining can result in indels disrupting the target sequence. Alternatively, precise mutations and knock-ins can be made by providing a homologous repair template and exploiting the homology directed repair pathway.
B. Mutated Cas9 makes a site specific single-strand nick. Two sgRNA can be used to introduce a staggered double-stranded break which can then undergo homology directed repair.
C. Nuclease-deficient Cas9 can be fused with various effector domains allowing specific localization. For example, transcriptional activators, repressors, and fluorescent proteins.

Targeting Efficiency and Off-target Mutations

Targeting efficiency, or the percentage of desired mutation achieved, is one of the most important parameters by which to assess a genome-editing tool. The targeting efficiency of Cas9 compares favorably with more established methods, such as TALENs or ZFNs (8). For example, in human cells, custom-designed ZFNs and TALENs could only achieve efficiencies ranging from 1% to 50% (29-31). In contrast, the Cas9 system has been reported to have efficiencies up to >70% in zebrafish (32) and plants (33), and ranging from 2-5% in induced pluripotent stem cells (34). In addition, Zhou and colleagues were able to improve genome targeting up to 78% in one-cell mouse embryos, and achieved effective germline transmission through the use of dual sgRNAs to simultaneously target an individual gene (35).

A widely used method to identify mutations is the T7 Endonuclease I mutation detection assay (36, 37) (Figure 3). This assay detects heteroduplex DNA that results from the annealing of a DNA strand, including desired mutations, with a wildtype DNA strand (37).

Figure 3. T7 Endonuclease I Targeting Efficiency Assay

Genomic DNA is amplified with primers bracketing the modified locus. PCR products are then denatured and re-annealed yielding 3 possible structures. Duplexes containing a mismatch are digested by T7 Endonuclease I. The DNA is then electrophoretically separated and fragment analysis is used to calculate targeting efficiency.

Another important parameter is the incidence of off-target mutations. Such mutations are likely to appear in sites that have differences of only a few nucleotides compared to the original sequence, as long as they are adjacent to a PAM sequence. This occurs as Cas9 can tolerate up to 5 base mismatches within the protospacer region (36) or a single base difference in the PAM sequence (38). Off-target mutations are generally more difficult to detect, requiring whole-genome sequencing to rule them out completely.

Recent improvements to the CRISPR system for reducing off-target mutations have been made through the use of truncated gRNA (truncated within the crRNA-derived sequence) or by adding two extra guanine (G) nucleotides to the 5´ end (28, 37). Another way researchers have attempted to minimize off-target effects is with the use of "paired nickases" (20). This strategy uses D10A Cas9 and two sgRNAs complementary to the adjacent area on opposite strands of the target site (Figure 2B). While this induces DSBs in the target DNA, it is expected to create only single nicks in off-target locations and, therefore, result in minimal off-target mutations.

By leveraging computation to reduce off-target mutations, several groups have developed webbased tools to facilitate the identification of potential CRISPR target sites and assess their potential for off-target cleavage. Examples include the CRISPR Design Tool (38) and the ZiFiT Targeter, Version 4.2 (39, 40).

Applications as a Genome-editing and Genome Targeting Tool

Following its initial demonstration in 2012 (9), the CRISPR/Cas9 system has been widely adopted. This has already been successfully used to target important genes in many cell lines and organisms, including human (34), bacteria (41), zebrafish (32), C. elegans (42), plants (34), Xenopus tropicalis (43), yeast (44), Drosophila (45), monkeys (46), rabbits (47), pigs (42), rats (48) and mice (49). Several groups have now taken advantage of this method to introduce single point mutations (deletions or insertions) in a particular target gene, via a single gRNA (14, 21, 29). Using a pair of gRNA-directed Cas9 nucleases instead, it is also possible to induce large deletions or genomic rearrangements, such as inversions or translocations (50). A recent exciting development is the use of the dCas9 version of the CRISPR/Cas9 system to target protein domains for transcriptional regulation (26, 51, 52), epigenetic modification (25), and microscopic visualization of specific genome loci (27).

The CRISPR/Cas9 system requires only the redesign of the crRNA to change target specificity. This contrasts with other genome editing tools, including zinc finger and TALENs, where redesign of the protein-DNA interface is required. Furthermore, CRISPR/Cas9 enables rapid genome-wide interrogation of gene function by generating large gRNA libraries (51, 53) for genomic screening.

The future of CRISPR/Cas9

The rapid progress in developing Cas9 into a set of tools for cell and molecular biology research has been remarkable, likely due to the simplicity, high efficiency and versatility of the system. Of the designer nuclease systems currently available for precision genome engineering, the CRISPR/Cas system is by far the most user friendly. It is now also clear that Cas9's potential reaches beyond DNA cleavage, and its usefulness for genome locus-specific recruitment of proteins will likely only be limited by our imagination.
View NEB's Genome Editing Products

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From NEB expressions Issue I, 2014
Article by Alex Reis, Ph.D., Bitesize Bio
Breton Hornblower, Ph.D., Brett Robb, Ph.D. and George Tzertzinis, Ph.D., New England
Biolabs, Inc.

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CRISPR/Cas9 and Targeted Genome Editing: A New Era in Molecular Biology

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The development of efficient and reliable ways to make precise, targeted changes to the genome of living cells is a long-standing goal for biomedical researchers. Recently, a new tool based on a bacterial CRISPR-associated protein-9 nuclease (Cas9) from Streptococcus pyogenes has generated considerable excitement (1).

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Oxford Geoengineering Programme // What is Geoengineering?

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Geoengineering is the deliberate large-scale intervention in the Earth's natural systems to counteract climate change. There is wide range of proposed geoengineering techniques. Generally, these can be grouped into two categories: solar radiation management (SRM), and carbon dioxide removal (CDR).

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Resistance is Futile: Cognitive dissonance, temporal refusal, and the e-learning environment as cyborg

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Resistance is Futile: Cognitive dissonance, temporal refusal, and the e-learning environment as cyborg

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By Linda Rose, Published 23 February 2015. The source describes how pop culture has normalized the idea of Cyborgs and how E-learners could potentially turn into cyborgs and replace traditional learning environments.

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This study uses interpretive sociological methods to explore parallels between fictional accounts of cyborgs and educational technology-based practices currently present in some e-learning environments. Specifically, the cyborg in fictional accounts ( Star Trek and Doctor Who) and the cyborg in academic accounts (Donna Haraway's A Cyborg Manifesto) are used to frame an analysis of the potential of regarding e-learners as cyborgs. Two social scientific concepts are revisited in this analysis: cognitive dissonance (social psychology) and temporal refusal (critical sociology). These conceptual lenses reveal that the various modes of operating in the online classroom have assimilating tendencies threatening to draw us into a mass social delusion. Considering the science fiction trope, "Resistance is Futile", the author proposes that the promotion of "best practices" sublimates us into the domination of a particular educational philosophy. Recognizing this type of oppression provides space for temporal refusal - withdrawing from the potentially assimilating "Borg" when it threatens to be disadvantageous to education. Her conclusions lead the author to suggest the need for a critical reflexivity in teachers to identify and take advantage of opportunities to resist the absorption of distinctiveness in the online educational environment.

We are the Borg. Lower your shields and surrender your ships. We will add your biological and technological distinctiveness to our own. Your culture will adapt to service us. Resistance is futile. ( Star Trek: First Contact, 1996 Movie)

As I read the call for papers for this special issue on "Networked Realms and Hoped for Futures", I took to heart the editors' invitation "to step back from the never-ending quest for new concepts and ideas and to revisit past insights into the relationships between education and technologies". I was instantly transported to the 1990s, during my own early days as a theorist, entrenched in a relationship involving education, technology, and a "hoped for future". In the 1990s, shortly after the dawn of the information age in the United States, a popular television show, Star Trek: The Next Generation, introduced my all-time favorite villain to fear: "the Borg". The Borg was a collective that captured and assimilated all useful life forms and technology into its being. Gone was the individual, gone was the creative creature, and gone was the ability to seek your own goals. At around the same time, I was introduced to Donna Haraway's A Cyborg Manifesto ( Haraway, 1991). I began to understand through her work the necessity of viewing the boundary between science fiction and social reality as (in Haraway's words) an "optical illusion" - our construction of experience is as much a fiction as the construction of a science fiction story, but both can be useful for interpretation.

The metaphorical, psychological, sociological, and intellectual battles that ensued upon my re-education as a graduate student seeking a PhD made me feel trapped between the realms of the positivists, the modernists, the postmodernists, the racists, the sexists, the homophobes, the mentally unstable, the power-mongers, the sideliners, the tenured, the untenured, the techies, the technophobes, the friend, the foe, the teacher, and the student. The boundaries of these realms were, for me, at best, fuzzy and blurry - perhaps the educational environment was already Borg-like in attempting to transform people into cyborgs to serve a larger entity.

In retrospect, my survival in that educational setting, where I saw no boundaries and struggled to forge a safe "space", was founded on the psychological deployment of two core concepts: cognitive dissonance and temporal refusal. My early studies majoring in psychology introduced me to Festinger's (1957) theory of cognitive dissonance. Festinger's work was originally based on participant observation of a cult expecting to be rescued from a flood by a flying saucer, and the means in which "believers" reconcile the contradictions among their beliefs, behaviors, and a failed prophecy ( Festinger et al., 1956). Cognitive dissonance came to refer to the social psychological response to the discomfort experienced through exposure to conflicting beliefs and/or experiences. Cognitive dissonance can arguably be a response to those who see a blurring of science fiction and reality.

My first real significant experience with cognitive dissonance in education was in the graduate school environment. I witnessed how some that I perceived as slow-witted were protected, pampered, held with esteem, granted PhDs, and positioned into fourth-tier colleges and universities as if they were of high intellectual capacity, while others with high intellectual capacity were brought to tears, rejected, and pushed out of the academic setting sometimes with a PhD, sometimes without. The mind-trip that was created in experiencing such cognitive dissonance in an educational establishment (an establishment that I had personally reified as an intellectually and ethically sound realm) was resolved through my exploration of feminist critical analysis and discourse and critical race theory, as well as action that is characteristically known as "temporal refusal". Temporal refusal is a term used by Anthony Lemelle (1996) to describe black young men's resistance to aspects of oppressive practice. I was able to use my knowledge of Lemelle's concept as a survival strategy to cope with the coercive nature of power-mongers in the educational setting.

I revisit and expand on these two core concepts - cognitive dissonance and temporal refusal - as I explore the emergent/present relationship between the networked realms of education and technology. Again, I am drawing on personal experience. I have been teaching in the college/university classroom since 1993 and have consistently and increasingly taught online classes for over six years. This past year, for the first time, my entire teaching load was completely online. This transformation from all face-to-face classes, to some online classes, to mostly online classes, to the present at 100% online, mimics for me the transformation from an independent organism, to a cyborg, to a fully fledged machine. I am seeing a battleground between a "collective" that seeks capital, power, and control and an "individual" seeking the sharing of knowledge, peace, and well-being.

This paper is an attempt to take my experience in higher education and reframe it in a way that, to some extent, imitates Haraway's (1991) "rhetorical strategy and political method" as well as employs her understanding of our roles as cyborgs. I hope to revitalize the core concepts of cognitive dissonance and temporal refusal in exploring the present and future relationships of education and technology in the e-learning environment. I shall show that they may have played their own part in our oppression, while continuing to offer a route away from it.

I find the following are useful tools and strategies in this task: irony, exposure of illusion and social delusion, and critical reflexivity. After some observations on my methodological approach, I first examine the ironic connections of cybernetic fictions in the online learning environment in terms of narratives, tropes, metaphors, and myths (drawing from Star Trek's Borg and Doctor Who 's Daleks). Next I seek to reveal the illusion of networked realities in certain educational practices. I show how cognitive dissonance and temporal refusal have themselves been implicated in the manipulation of low-choice preference for online courses/learning, mirroring the assimilation practices of these cybernetic fictions. The resulting shared social delusion - which also has parallels in science fiction - is the creation of assimilated cyborg learning through increasing connections between technologies and education. Finally, I employ critical reflexivity to generate a practical response to the assumptions and actions of such e-learning realms. In this way, a more collaborative, responsive, and ethical learning environment may be both imagined and developed to resist absorption and assimilation in inappropriate online educational environments.

The paper combines several interpretive approaches to bring together personal experience, a cultural context, and a social structure as data in a social environment. If labels are necessary, it might be seen as a manipulated ethnomethodology using fictional characters to construct parallels connecting culture, structure, and the plight of the individual. In this study, the interpretation reveals and demonstrates why resistance does not have to be futile, even in cases where there has been an attempt to ensure that it is. Because such revelations and demonstrations are typically elusive and covert, I regard this method as most appropriate in both constructing empirical data for analysis and in identifying means to construct a "hoped for future" in online educational environments. This method is particularly useful in situations where educators themselves have been subordinated to the will of an organizing elite and resistance must take different forms to be effective.

Cybernetics is commonly understood as the automated, interconnected functioning of computers, machines, and organisms. The organism is typically understood as human-based but with freewill and independence incapacitated. Formally, the term cybernetics is defined as follows:

( Merriam-Webster, 2014)

In this sense, cybernetics (and the cyborg) can be treated as tropes of a grand narrative of computerized control and manipulation where power rests on an elusive integrative entity. This narrative is the foundation of science fiction like Star Trek's Borg on the quest to assimilate organisms and technology, or Doctor Who 's Cybermen set to upgrade the universe by cyber-conversion, or the Daleks set to rule the universe by exterminating all other life forms.

The development and structure of the educational system has evolved, to some extent, like the Borg, with both instructors and students assimilated into cyborgs to do the work of the collective. Ironically, the means to become the critical thinker, the intellect, in the online classroom is absorbed by the technology and tools. At its worst, the result is a cyborg using developed software, and engineered machines to do the job of teaching and learning. The technology forces an assimilation in the structure through the processes of downloading, uploading, and submitting. Yet, while the distinctiveness of teaching, the classroom, the teacher, and the student are all easily subject to absorption and assimilation, particularly in the e-learning environment, there are also many unique experiences in the assimilation process.

In my own past experiences at other institutions of higher learning, I have been contracted to teach online classes in which the courses were fully populated with narratives written in the first person to give the student the sense that the professor has constructed those narratives. In reality, however, the learning objectives, the lessons, the examples, and the assignments along with the introductory narratives were constructed by a group made up of other contract professors and administrators. This group is typically primarily concerned with quality control and student satisfaction, with the goal of learning as secondary. My notion is that when this group - a collective most likely subjected to groupthink and deadline driven - is approving courses to be offered by the institution, then managerial practices override pedagogical strategies. This group is concerned with (and wants to be assured that there is a level of) consistency and quality in which any rank-and-file professor can easily be slotted to teach almost any course. Rank-and-file professors (or the pool of intellectual reserve labor) are those individuals that have undergone the rigor of being granted a master's degree and/or doctorate degree but perhaps lack the opportunity, privilege, rights, and/or economic means of a typical tenured faculty member. Such rank-and-file professors are many times subjected to "training" to use the software package to "deliver" the course without much authority to modify the course on the basis of pedagogy. (Most modification includes adding one's name and contact information, with the agreement to monitor the progress of students.) As such, "teaching and learning" seems to be a manipulated practice.

In these circumstances, teaching and learning in networked environments are also subjected to a number of factors beyond the control of those affected, particularly corruption of files, surveillance of practice, and routinization. Files that are viewable/not viewable, audible/inaudible, and readable/incomprehensible can be responsible for haphazard experiences in the online, e-learning experience. The experiences for both student and teacher or professor are monitored and documented (or recorded) via keystrokes, file size, and time spent online ( Rose and Hibsman, 2014). The move to routinize curriculum, course objectives, and class discussions, as well as the dictates of a common textbook and common assignments, creates a combined imposition of "best practices" and assimilation of intelligence. This move seems to be done in a robotic, cybernetic fashion whereby the expression "best practices" is utilized in an insidious manner, creating an environment where resistance is portrayed as futile.

"Best practices" is a business buzzword meaning to follow the lead of others in an industry. In the case of networked realms, education in some instances is treated as a complex industry competing for the market share of both proprietary funds and government funds. Shareholders in the proprietary education industry as well as administrators seek increasing profits and/or departmental budgets in which salaries and new hires are sometimes dependent. Routinized practices in e-learning environments are easily constructed as "best practices" because others are doing it, constructing documentation or "benchmarks", and seeking to further the project of routinizing the practice. The questions, "Who is doing what and is it working better than what we are currently doing?" and "How can we then move to the next level?" are business models proposed by and shared with business leaders (for example, Bogan and English, 1994). In e-learning environments, the irony of this is that innovative teaching and learning strategies have been reduced to those that could best fit the need for asynchronous delivery of previously synchronous practices.

The pleasure of a shared experience taking into account time, space, and immediacy (such as in an artistic performance) is not captured in the differential experience of one-way (asynchronous) communicative modes that I have experienced. I cannot help but think of Goffman's (1959) dramaturgy, the analogy between life and the theatre. There are interactions that take place on the front stage - performance - as opposed to the backstage interactions where participants put on less of a show, but where things are still being done. In the traditional teaching environment, a performance might be an experience shared by lecturers and students. Online, a lecture downloaded and disseminated to the whole class may not actually be experienced as intended or in a shared manner. Listening to a pre-recorded lecture, while watching your kids play and cooking dinner for the family, is a differential experience from that of someone listening to the lecture at a desk with headphones and taking notes, or someone napping on a bed with the lecture as background. There are as many experiences as there are students. The cyborg is thus cut off from an intellectual collective - that is, there is no-one immediately there to share the experience. "Best practices" have become the route to quality assurance that easily leaves monitoring and evaluations to the rote practices of a right/wrong (credit/no credit) dichotomy rather than coming to an intellectual shared understanding among thought-provoking individuals.

The producer as well has a role in managing the constructed (cybernetic) presentation. This is done in terms of deciding how to produce a presentation in the digital format, such as audio recording or video recording. The constructed length of the produced digitalized presentation breaks down the performer from a human real-life performance to a static performance at the mercy of the one that is watching, manipulating (by either pausing or fast forwarding), or ignoring the performance on some type of digital device.

Furthermore, online environments can easily be manipulated and limited to one of several major educational virtual learning environments that are attempting to embody "best practices", such as Blackboard, E-college, and Moodle. These virtual environments compete in the marketplace and limit that competition by seeking patents. Universities typically adopt a virtual learning environment at the institutional level. Such uniformity has the effect of siphoning resources to industry of educational software, which is typically external to universities. This relationship is quite complex in that some virtual learning environments were initially developed within the university settings and then migrated to the marketplace - some immediately as entrepreneur enterprises, and others as free/libre/open source systems. Most major management systems are now at some level connected to a proprietary industry that offers its services as a commodity to educational institutions. The provision of services (as well as the complexity of the software) limits the creativity and can have the effect of forcing an outside structure on online teaching and learning. This is especially evident in the development of universal, user-friendly interfaces that can easily inhibit and dictate the duties, roles, and performances of the class environment, the teacher, and the student.

The marketing tools additionally lead to the reifying of one's brand. "Branding" is further used in the assimilation process to create a common, non-negotiable experience for users where choices in some settings are many times presented as illusory. As Žižek (2002) has observed: "the reduction of freedom is presented to us as the arrival of new freedoms". Think about some of the apparent choices facing a university and also those within it. The associated battles are presented as strict binary dichotomies even though they are quite complex and dialectical. This "battle" is reminiscent of a dialogue between Doctor Who's Cybermen and the Daleks (see Figure 1).

A similar exchange might happen with a virtual learning environment provider proposing an "upgrading" alliance with a university - or a university engaging in such an alliance facing ultimate threat of extermination or assimilation. Cyborg students and professors require the updating of their own systems through information and communication technology. This in turn may be affected by complex alliances between a university, multiple internal and external stakeholders, and industries.

In the 1980s and 1990s, the "assimilation" characteristic for the civil rights movements of the 1960s and the drug culture of the 1970s seems to have been replaced with the rhetoric of multiculturalism, reassertion of individualism and hedonism, and a strong commitment to the free market. So, it should be no surprise that the emergence of science fiction villains like the Borg, the Borg Queen, Cybermen, or the Daleks has played into a socially constructed fear or social delusion. In other words, perhaps these types of villains indicate the subconscious fear of a culture in the digital age - that the world's citizens will be assimilated into robot-like, establishment-servicing cyborgs.

The development of online e-learning environments was initially treated by most established institutions of learning as suspect. However, nowadays resistance to the online model of education seems futile. How did that happen? Perhaps the acceptance of online education, e-learning, and online networking is an outcome of a psychological response (cognitive dissonance) and a sociological response (temporal refusal). While my recognition of these as conditions and strategies helped me to cope with graduate school, I now see how their deployment can be an aspect of the oppression as well as a potential response to it.

Cognitive dissonance is a concept developed by Leon Festinger and described in his book, A Theory of Cognitive Dissonance (1957). This theory has been summarized as follows:

... pairs of cognitions (elements of knowledge) can be relevant or irrelevant to one another. If two cognitions are relevant to one another, they are either consonant or dissonant. Two cognitions are consonant if one follows from the other, and they are dissonant if the obverse (opposite) of one cognition follows from the other. The existence of dissonance, being psychologically uncomfortable, motivates the person to reduce the dissonance and leads to avoidance of information likely to increase the dissonance. The greater the magnitude of the dissonance, the greater is the pressure to reduce dissonance. ( Harmon-Jones and Mills, 1999)

The concept of cognitive dissonance has had a tremendous impact in the field of social psychology and can arguably be utilized to understand the widespread acceptance of online education in even the most unlikely of educational environments. Along with the mantra of "If you can't beat 'em, join 'em", comes the psychological outcome that once you "join 'em" the only way to reduce the resulting uncomfortable psychological effects is to realign the dissonance by looking at the positive sides of virtual learning environments in teaching and learning. An example of this would be a teacher assigned an online class and then being strongly persuaded (perhaps socially coerced if a precariat member of the faculty - i.e. tenure-track, non-tenured, or seeking promotion) to present to a group of peers, or the like, on the positive aspects of teaching online and the benefits to students. Such "forced compliance" is closely associated with cognitive dissonance in the literature ( Festinger and Carlsmith, 1959).

The advancements of technology and technological communications allows for the advancement of knowledge using even less sophisticated tools. Take, for example, the excerpt in Figure 2 from a tongue-in-cheek history of cognitive dissonance created using the rules and practices of the widespread modern-day communication tool, Twitter, creating typical "tweets".

I particularly like the last tweet: "After people make difficult decisions, they devalue the thing they didn't choose." This is the crux of cognitive dissonance. In addition, and ironically, a sophisticated theory can cognitively be reduced to unsophisticated tweets drawing one to accept the theory as relevant and sophisticated to reduce any cognitive dissonance. Our preference and what we value is very much a constructed or contrived illusion, a mind game (perhaps a game of the heart) where we come to see networked realities in the e-learning environments as real and just. The science - which tells us ubiquitous online education is just, fair, and awesome - may really be an illusion of networked realities or, in terms of cognitive dissonance, the effect of "ideological" and "technological" propaganda. It seems today that nearly every major educational establishment seeks online presence, creates virtual classrooms, and markets their online environment as less "Borg-like" than the next. Simultaneously, many institutions embrace the cybernetic cloning in e-learning thorough institution-imposed (or possibly soon to be imposed) "best practices". As such forced compliance becomes institutionalized, the illusion is revealed as one reminisces about the learning environment of the face-to-face classroom and the manipulation tactics using dissonance theory to covertly elicit compliance and "buy-in".

Auster (1965) uncovered empirical evidence of how cognitive dissonance theory is connected to mass persuasion. In linking Auster's work with modern-day networked realities of teaching and learning, we may come to see the widespread dissemination of online education as a virus that has already replicated itself, perhaps as a shared social delusion.

When proprietary schools entered the online educational market and found themselves within a certain social niche, an evolution in education resulted. The outcry of those in opposition to online, mass education has been successfully squelched through assigning an online class to "try-out" a form of forced compliance ( Festinger and Carlsmith, 1959). Perhaps through the process of an orchestrated, networked reality there was a systematic exposure to mass cognitive dissonance resulting in a shared social delusion. The educational needs of the student were networked with the needs of being economically sound. In addition, as the 24/7 model of available study time was psychologically introduced and marketed to potential students, an evolution of social relationships outside of the educational environment has suddenly been constructed as a part of the educational environment.

This refers to social delusions as arbitrary constructions of a reality that are shared by the masses. In the process, they become reified as the one and only reality. An excellent example of this is the movie The Matrix. In the movie, the masses were engaged in a shared social delusion, which blinded all from the "truth" that all were born into bondage. In some sense, social structure, social institutions, and social cultures are all a form of bondage in which we are collectively enslaved. The Borg enslaved the human mind and body so that one could not step out of the delusion and resistance was futile.

The practice of credentialing education can be viewed as such a delusion. Having constructed documentation regarding one's educational attainment deludes one into a false sense of being educated. The same occurs in the virtual learning environment that is charged with moving students through a networked labyrinth. Here, students become transformed from human beings to cyborgs with wireless, Bluetooth devices coming out of their ears, pockets, glasses, and hands as well as their living spaces. In understanding how social delusions may be utilized as tools to examine the manipulation of online low-choice preference for online learning, we can resist - resistance is not futile.

A possible strategy may be to create and utilize space for temporal refusal. Temporal refusal is a term used by Lemelle (1996) to refer to everyday interactions that take advantage of opportunities to challenge and oppose the existing structures of domination and oppression. Lemelle (1996) describes temporal refusal in terms of black male deviance as the following: "In the situations in which they are placed [black males], they must, given their experience, select, check, suspend, regroup, and transform the direction of their statements and behaviors" (1996: 37). In other words, perhaps this means that one can participate in the delusion when it is advantageous and disengage when it becomes a disadvantage. Perhaps it is even possible to reconstruct a different social delusion.

Lemelle (1996) is describing temporal refusal to explain and account for black male deviance. However, temporal refusal can also be observed in online educational networks and environments. The most prevalent kinds of temporal refusal practices are those in which students can objectively decide: what school they will attend; what class they will register to take; and what activities in that class they will fully participate in. Teachers or professors also operate using a form of temporal refusal in terms of if and when they will respond to a particular student; when they will accept a paper or not; and when they will produce new ways of educating students using digital technologies. Constructing an illusion of networked realities (between and among teachers and students as well as between and among various technologies) cognitively (and often covertly) affects the ability to think critically about a model of online education, thus resulting in a non-thinking, non-sensing cyborg.

When the structure is dictated and monitored, resistance in the online environments can indeed seem to be futile. However, there are strategies that can serve the purpose of moving beyond a networked cyborg existence as professor or student. One strategy is critical reflexivity.

Cunliffe (2004) describes critical reflexivity as the practice of generating a practical response to thinking more critically about the assumptions and actions whereby a more collaborative, responsive, and ethical learning environment may be both imagined and developed. A "practical response" means action that can be employed by stakeholders, such as online professors, without imposition. Some of the current issues that make a response impractical are related to the micromanaging or centralization of course design by institutions or proprietary entities, software/password security access, or even the impact of uncertain outcome for precariat faculty. Critical reflexivity includes a strategy to try new ideas in the e-learning environment by moving away from the managerial style of learning and focusing on the continued resistance to assimilation. In this process, imagination plays an important role. The practice of imagining, developing, and trying-out new ways of utilizing networking technologies just might be a strategy that both the professor and the student can exert resistance in a system that potentially focuses only on assimilation and absorption.

In virtual learning environments, resistance can be exerted in many different ways. However, lessons in micro-resistance can be learned from many other groups outside of educational establishment. For example, Cooper and McCoy (2009) presented the notion of showdown boxing as a way that African American mothers exerted resistance towards biased ideologies. I can only imagine how showdown boxing could be used in a networked environment to resist assimilation. When professors or students log into online classes and run up the time to show that they are "working", they thwarted time used in managerial realms and engage in a form of shadow boxing. Certainly, this example is only the tip of the iceberg, and it will be interesting to see various strategies that could emerge in utilizing critical reflexivity.

In this paper, I introduced the theory of cognitive dissonance as a strategy to unveil assimilation by recognizing how resolving dissonance walked us into tightly woven networked realities. Temporal refusal may be a strategy to disconnect from the cybernetic devices that are plugged into our ears, strapped to our hips and pockets, and/or connected to an outlet until we are fully charged. Perhaps, these strategies might help us place brakes on the contemporary process of absorbing distinctiveness in the online educational environment.

My own early days as a theorist entrenched in a relationship involving education, technology, and a "hoped for future" was a decade in which resistance was futile. However, I have not given up, as I continue to try and resist being plugged in as a cybernetic being. In this paper, I have shown that understanding the key uses of cognitive dissonance and temporal refusal might be useful for deploying and manipulating networked realms for the greater good. My overall practice is to continually seek a better world for my students. Sometimes it seems that we are free to embrace new technologies for the betterment of learning environments. At other times, we must resist various modes of operation in the online environment in order to be able to inhibit assimilation. Each day, resistance to hyper-controlled and constructed online models of education seems to become more and more futile: traditional universities are less frequently searched for online than the newer technology-governed ones ( Coughlaan, 2014). With so many major educational establishments offering opportunities to earn certificates, associate degrees, bachelor degrees, and graduate degrees, the mass-produced online presence is taking the online classrooms into the cube of the Borg. But there, "resistance is futile" is not the only option. We need to find methods - and this paper modestly outlines some early attempts - through which we can understand and perhaps seek a means to manipulate the e-learning environment and the constructed cybernetic networked relationships for the betterment of everyone.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Žižek, S (2002) A plea for Leninist intolerance. C, ritical Inquiry 28(2): 542-566. Google Scholar Crossref, ISI

Author biography

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Resistance is Futile: Cognitive dissonance, temporal refusal, and the e-learning environment as cyborg

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This study uses interpretive sociological methods to explore parallels between fictional accounts of cyborgs and educational technology-based practices currently present in some e-learning environments. Specifically, the cyborg in fictional accounts ( Star Trek and Doctor Who) and the cyborg in academic accounts (Donna Haraway's A Cyborg Manifesto) are used to frame an analysis of the potential of regarding e-learners as cyborgs.

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3D printing of smart materials: A review on recentprogresses in 4D printing

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3D printing of smart materials: A review on recentprogresses in 4D printing

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Author:  Zhong Xun Khoo
Date: 26 October 2015

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Geoengineering Earth's Climate : Resetting the Thermostat

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Geoengineering Earth's Climate : Resetting the Thermostat

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Jennifer Swanson 2017

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Geoengineering Earth's Climate : Resetting the Thermostat: EBSCOhost

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Yes, space tourism is for the rich. But sending artists to space is good for us all

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Yes, space tourism is for the rich. But sending artists to space is good for us all

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On Monday night, Elon Musk introduced announced billionaire Yusaku Maezawa as the first space tourist slated to take a trip on SpaceX's Blue Falcon rocket to the moon in 2023. Initially, the choice seemed to perpetuate the idea that space is a playground only for rich non-astronauts. But Maezawa upended that assumption by introducing the " Dear Moon " project and declaring his intention to bring between six and eight artists to the moon with him, providing otherworldly inspiration for their work.

It's a beautiful idea that recognizes the role space, the moon and views of Earth have had on art and culture since humans first cast their gazes skyward. By recognizing the importance of art and artists, SpaceX and Maezawa could inspire and stoke the curiosity of the human race, urging us to widen our perspectives. Even more important, they could help make space accessible to all of us, not just to the wealthy.

Space tourism isn't a new idea, and companies offering such trips have often claimed they're "democratizing" space. Charles Walker, an engineer with McDonnell Douglas, was the first private citizen to join a space mission, which he did three times between 1984 and 1985 at a ticket price of $ 40,000 (about $97,000 today). In 2001, California millionaire Dennis Tito paid $20 million (around $28.5 million today) for an eight-day trip on a Russian rocket brokered by Virginia-based company Space Advent ures. Between then and 2009, six other space tourists took the trip for sums ranging from $20 million to $35 million. Space Adventures now advertises " circumlunar " trips that come within 62 miles of the moon, but won't specify how much they might cost.
[What the Air and Space Museum's Kickstarter could mean for the future of space exploration]
SpaceX isn't the first company to conceive of bringing artists to space. In 2015, Lady Gaga thrilled fans by announcing that she would be the first person to perform a song in space aboard a Virgin Galactic shuttle as part of the Zero G Colony music festival, but a fatal explosion during a 2014 test flight of SpaceShipTwo put those plans on hold. (Virgin Galactic has since rebuilt and has successfully tested its new ride, and reports that more than 600 people have plunked down the $250,000 deposit for a trip.)

In the early 1980s, NASA established the Space Flight Participant program to recognize the importance of sending citizens to space. First up was the Teacher in Space program, for which more than 11,000 people applied. New Hampshire teacher Christa McAuliffe made the cut, but she died in the Challenger disaster of 1986. The tragedy led to the cancellation of the program, through which NASA had also intended to bring journalists and artists to space after the successful completion of McAuliffe's flight. In 2003, NASA announced another program to bring journalists to space, but that plan ended with the explosion of the Columbia spacecraft.

Humans, whether artists or astronauts, are the most precious cargo, and of course SpaceX has to be as certain as it can be about the safety and success of the mission. Initially, SpaceX planned to bring two tourists on a lunar flight in 2017, but the additional six years leaves time for testing and preparation - and for SpaceX and Maezawa to carefully consider the impact this mission could have on art and culture, as well as people's perceptions of space.
[Of course the new star of 'Doctor Who' is a woman. Sci-fi has always been about progress.]
In a keynote address at the 2008 National Space Symposium, Neil deGrasse Tyson argued that space exploration is crucial not just for the economy, science or knowledge, but also because it affects culture. Tyson referenced everything from science fiction to car designs to environmentalism as evidence of space's cultural impact. In December 1968, Apollo 8, the first crewed moon mission, generated the first photo of Earth as a whole.

Known as " Earthrise," this image, taken for granted by those of us born since, changed humanity's perception of the planet. Every human ever born hails from our pale blue dot, which is small and fragile in the cosmic perspective. Bill Anders, the astronaut who took the iconic picture, has said that even though they trained for a lunar exploration, the astronauts "discovered Earth."

It's impossible to predict exactly how this mission might affect our culture, but it's safe to say that if it gets off the ground, it certainly will. Maezawa seeks a fashion designer, a musician, a painter and a film director (among possible others) to produce work inspired by the physical, spiritual and artistic discoveries of the trip. Without giving an indication of who he might ask to accompany him, he simply asked the artists he approaches to "please say yes."

Here's hoping he understands how monumental these invitations will be, and how important it is to choose artists of different persuasions from different countries. This mission may not "democratize" space, but it will be the first time humans will have the opportunity to experience art made by non-astronauts who have witnessed something few will ever see firsthand: our entire planet against the backdrop of the infinite cosmos.

It's hard to imagine a more important time for humanity to rediscover earth and what it means to a citizen on our beleaguered planet. Monday's announcement suggests that Maezawa and SpaceX realize that. Now they've got a chance to demonstrate they really mean it.

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Perspective | Yes, space tourism is for the rich. But sending artists to space is good for us all.

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On Monday night, Elon Musk introduced announced billionaire Yusaku Maezawa as the first space tourist slated to take a trip on SpaceX's Blue Falcon rocket to the moon in 2023. Initially, the choice seemed to perpetuate the idea that space is a playground only for rich non-astronauts.

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Modern Biotechnology : Defining and Solving Human Problems

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Modern Biotechnology : Defining and Solving Human Problems

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Stephanie Stockwell. 2017

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By Robert Colvile, 2016

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Scientists fear its potential for misuse too

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Scientists fear its potential for misuse too

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2015-AP video news (opposing viewpoints)

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By A. Sydney Gladman
Jan. 2016

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Sep. 12, 2018, No given author

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Custom Electronics, Quality PWM Circuits, and DIY Science Projects - Research Media & Cybernetics

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Recent research into AI is wielding some fascinating discoveries. Researchers have found that adding noise (random signals) to simulated neural networks can produce 'creativity' in a machine. Stephen Thaler, CEO of Imagination Engines, Inc. has patented a program he calls a 'Creativity Machine'. This program uses noise to disrupt signals in a rigid, rule based neural network, causing the creation of new data. Thaler fed his software lots of data about different toothbrush designs and performance levels, which resulted in a brand new toothbrush design, now known as the Oral-B Cross Action toothbrush. This is one of the first consumer products that has been invented by a machine!

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A.I. Research - Cybernetics - RMCybernetics

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Recent research into AI is wielding some fascinating discoveries. Researchers have found that adding noise (random signals) to simulated neural networks can produce 'creativity' in a machine. Stephen Thaler, CEO of Imagination Engines, Inc. has patented a program he calls a 'Creativity Machine'.

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4D Printing – Dawn of an Emerging Technology Cycle

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4D Printing – Dawn of an Emerging Technology Cycle

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By:  Dr Eujin Pei
UK

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Craig Venter creates synthetic life form

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Craig Venter creates synthetic life form

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By: Ian Sample, 2010
this article states the possibilities of synthetic and the positives of the technology. these include bacteria that create biofuels, soak up carbon dioxide from the atmosphere and even manufacture vaccines.

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Craig Venter creates synthetic life form

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Craig Venter and his team have built the genome of a bacterium from scratch and put it into a cell to make a synthetic life form

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Ethics of Synthetic Life:A Jania Perspective 

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Ethics of Synthetic Life:A Jania Perspective 

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Chappie, Christopher Key
2013

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The Future of Artificial Intelligence and Cybernetics

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The Future of Artificial Intelligence and Cybernetics

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By Kevin Warwick. 10 November 2016. The article discusses several ethical and moral questions that would be raised if these technologies rise to prominence, but also discusses the benefits of these advancements to people with disabilities.

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Science fiction has, for many years, looked to a future in which robots are intelligent and cyborgs are commonplace. The Terminator, The Matrix, Blade Runner and I, Robot are all good examples of this vision.

But until the last decade, consideration of what this might actually mean in the future was unnecessary because it was all science fiction, not scientific reality. Now, however, science has not only done some catching up; it's also introduced practicalities that the original story lines didn't appear to include (and, in some cases, still don't include).

What we consider here are several different experiments linking biology and technology together in a cybernetic way-essentially ultimately combining humans and machines in a relatively permanent merger.

When we typically first think of a robot, we regard it simply as a machine. We tend to think that it might be operated remotely by a human, or that it may be controlled by a simple computer program.

But what if the robot has a biological brain made up of brain cells, possibly even human neurons? Neurons grown under laboratory conditions on an array of non-invasive electrodes provide an attractive alternative with which to realize a new form of robot controller. In the near future, we will see thinking robots with brains not very dissimilar to those of humans.

That development will raise many social and ethical questions. For example, if the robot brain has roughly the same number of human neurons as a typical human brain, then could it, or should it, have rights similar to those of a person? Also, if such robots have far more human neurons than in a typical human brain-for example, a million times more neurons-would they, rather than humans, make all future decisions?

Many human brain-computer interfaces are used for therapeutic purposes to overcome medical or neurological problems, with one example being the deep brain stimulation (DBS) electrodes used to relieve the symptoms of Parkinson's disease. However, even here it's possible to consider using such technology in ways that would give people abilities that humans don't normally possess-in other words, human enhancement. In some cases, those who have undergone amputations or suffered spinal injuries due to accidents may be able to regain control of devices via their still-functioning neural signals.

Meanwhile, stroke patients can be given limited control of their surroundings, as indeed can those who have motor neurone disease. With those cases, the situation isn't straightforward, as patients receive abilities that normal humans don't have-for example, the ability to move a cursor on a computer screen using nothing but neural signals.

It's clear that connecting a human brain with a computer network via an implant could, in the long term, open up the distinct advantages of machine intelligence, communication, and sensing abilities to the individual receiving the implant. Currently, obtaining the go-ahead for each implantation requires ethical approval from the local authority governing the hospital where the procedure is performed. But looking ahead, it's quite possible that commercial influences, coupled with societal wishes to communicate more effectively and perceive the world in a richer form, will drive market desire.

For some, brain-computer interfaces are perhaps a step too far just now-particularly if the approach means tampering directly with the brain. As a result, the most studied brain-computer interface to date is that involving electroencephalography (EEG). While EEG experimentation is relatively cheap, portable, and easy to set up, it's still difficult to see its widespread future use. It certainly has a role to play in externally assessing some aspects of brain functioning for medical purposes. However, the idea of people driving around while wearing skullcap of electrodes, with no need for a steering wheel, doesn't seem realistic. Completely autonomous vehicles are much more likely.

Such experimental cases indicate how humans-and animals, for that matter-can merge with technology. That, in turn, generates a plethora of social and ethical considerations as well as technical issues. That's why it's vital to include a sense of reflection so that the additional experimentation we'll now witness will be guided by the informed feedback that results.

This article is excerpted from a lengthier exploration of AI and cybernetics. Read the full article on Kevin Warwick is deputy vice chancellor for research at Coventry University in the United Kingdom. He is former professor of cybernetics at Reading University, also in the U.K. He is the author or co-author of more than 600 research papers. BBVA's OpenMind site.

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The Future of Artificial Intelligence and Cybernetics

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Science fiction has, for many years, looked to a future in which robots are intelligent and cyborgs are commonplace. The Terminator, The Matrix, Blade Runner and I, Robot are all good examples of this vision. But until the last decade, consideration of what this might actually mean in the future was unnecessary because it was all science fiction, not scientific reality.

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Why Space Tourism is going to be utterly disappointing

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Why Space Tourism is going to be utterly disappointing

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By Joseph Stromberg

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People have been dreaming about space tourism for nearly a century. Think of the orbiting space hotels in 2001: A Space Odyssey, or the Martian visits in Total Recall. Years before anyone had ever even been to space, people were thinking of vacationing there.

Now billionaires like Jeff Bezos and Richard Branson have poured tons of money into building vehicles for space tourism - and it seems possible that sometime in the next few years, one of their companies will become the first to carry paying passengers into space.

But there's a catch. Their plans merely involve flights into suborbital space: high enough up to technically cross the 100-kilometer line considered the lower boundary of space and give fliers a few minutes of weightlessness, but not high enough to actually enter Earth's orbit like a satellite or the International Space Station.

The sad reality is that Virgin flights, currently priced at $250,000 for an estimated six minutes of weightlessness, might not provide an experience tremendously different from what's currently available to anyone willing to spend $5,000: a brief zero gravity flight on a plane often called the "vomit comet."

Now, all these companies - along with Elon Musk's SpaceX - have vague plans to eventually bring tourists all the way into Earth's orbit, but experts say it's a long shot. "Fundamentally, it's all very hard to do," says John Logsdon, founder of the Space Policy Institute. "We've been launching people into space for 54 years now, and less than 600 people have made the trip. I think the idea that there's some magic bullet that could open up orbital space to large numbers of people is illusory."

The hard truth is that we're closer to the era of space tourism than ever before - but if you're waiting for vacations in space, you'll probably be disappointed.

The X Prize jump-started the space tourism industry

"The idea of space tourism has been bandied about, at least in science fiction, since the 1920s," Paul Milo, author of Your Flying Car Awaits - a book about 20th-century speculation on future technologies - told me for an article last year. "In the 1960s, there was this perception that by the 21st century, space tourism - whether a stint aboard an orbiting hotel or a trip to the moon - would be as common as a flight from New York to Tokyo."

The main reason that isn't the case is money. After the moon landing and the perception that the US had won the space race, Congress's funding for NASA dried up significantly in the 1970s. For decades, dreams of space tourism went nowhere, as space travel remained far too expensive and risky.

That began to change in the late 1990s, when a pair of entrepreneurs created the X Prize: a standing offer of $10 million to the first private organization that created a reusable spacecraft. In 2004, the prize was won by Burt Rutan, who twice flew his spaceplane, SpaceShipOne, to an altitude of more than 100 kilometers - and in doing so, scraped the bottom edge of space.

Soon after, Richard Branson licensed the technology for use in developing a similar craft (SpaceShipTwo) that could carry paying passengers to the same altitude, allowing them to experience zero gravity and see the curvature of Earth from space. But though his new company Virgin Galactic has generated lots of hype - and got about 700 people to sign up for the waiting list for the $250,000 flights - it has had to repeatedly push back its timetables for commercial flights. Most recently, plans had called for them to begin in the spring of 2015, but a crash that destroyed the sole SpaceShipTwo in existence and killed one of the co-pilots has caused delays.

To date, just seven people have gone into space as tourists - and they were all carried there on existing flights operated by the Russian space agency, paying $20 million to $40 million each for weeklong stays on the International Space Station. Even these flights have been put on hold (mainly because NASA will pay more to reserve those spots for American astronauts), but they're expected to start back up in late 2015.

We might finally be getting close to spaceflight for tourists

After many years of delays, there's some reason to think that at least suborbital tourist flights might be around the corner.

For one, the field has recently become crowded with a number of legitimate, well-funded companies. Apart from Virgin, Jeff Bezos's Blue Origin has quietly been working on its own suborbital rocket. After a few failed test flights, it finally conducted its first successful one earlier this year, sending it to an altitude of 93,000 meters - just below the lower edge of space.

Eventually, the company says, its New Shepard craft will be able to carry three people into suborbital space, for tourism and research purposes.

Meanwhile, the California-based company XCOR Aerospace began developing a series of spaceplanes for the same purpose in 2008. It still hasn't conducted any actual flights, but last month the company raised the price of future flights on its Lynx craft from $100,000 to $150,000, promising that test flights will soon follow.

Virgin has seemingly moved on from its crash and appears to be the farthest along in development. A federal investigation largely blamed Scaled Composites (the company contracted to design and test SpaceShipTwo) for the disaster, and Virgin reportedly plans to begin testing an improved replacement craft later this year.

But there are some good reasons for skepticism

On the other hand, it seems that we've been just a few years away from commercial flights for some time now.

In 2008, for instance, Virgin founder Richard Branson predicted commercial flights would begin sometime in 2009. In 2012, the company's CEO, George Whitesides, said they'd start in 2013. When XCOR debuted its spaceplane design in 2008, it was supposed to fly by 2010; in 2012, it was supposed to fly in 2013.

You get the idea. "It's always the same number, but it never gets any closer," says space expert Howard McCurdy.

Still, he believes that suborbital flights will eventually happen, given the number of companies involved and the large pool of wealthy people willing to pay for the thrill. Virgin and others have some technical problems to solve (most importantly, the aerodynamic difficulties of decelerating a plane from 2,600 miles per hour to landing speed), but they're doable, given enough money.

The Virgin crash, however, was a painful reminder of the inherent risks of space travel: after decades of research, about 5 percent of rocket launches still end in failure. For a purely recreational flight, this number might be too high for many would-be space tourists to swallow.

At the same time, McCurdy points out that even though 1 percent of the people who attempt to climb Mount Everest die, about 1,000 still attempt it each year. "The extreme adventure market carries substantial risk, but that doesn't keep people off Everest," he says. If Virgin or another company can approach this 1 percent figure, many thrill seekers might be willing to fly.

Why the next step in space tourism might never happen

These companies' hope is that once they start flying people into suborbital space, they'll make enough money to fund the development of orbital spaceflight. That would eventually lead to true space tourism à la 2001: space hotels, weeklong zero-gravity vacations, the whole shebang.

But even though suborbital flight and this sort of spaceflight might seem similar, from an engineering perspective they're vastly different. Right now, Virgin and XCOR are trying to fly a plane to a relatively high altitude, then coast back down. But it's essentially impossible to reach orbit this way because you can't reach the high speeds necessary.

"For a suborbital flight, you only have to accelerate to Mach 3 or 4. For an orbital flight, it's Mach 25," says Logsdon. "The energy difference needed to reach that speed is exponential." To date, everyone who's ever gone to orbit has gotten there with a vertically launching rocket.

But rocketry is the rare technology that has seen barely any advancement in the last 50 years. The rockets being used to launch satellites and astronauts today aren't all that different from the one that put Sputnik in space in 1957. Both involve large tubes that burn fuel, expelling huge amounts of gas to push the payload into orbit, and then fall away, breaking into pieces and disintegrating.

The problem with this model is that it makes orbital spaceflight really expensive. Elon Musk has famously likened it to throwing away a brand new 747 after a single flight to London. Because of the one-use model, NASA has to pay Russia more than $80 million for each astronaut it carries up to the International Space Station, after retiring its own space shuttles in 2011. If a company wants to carry out flights primarily for tourists, it'd have to drive down this price significantly.

The most obvious way to do so would be to figure out how to make that rocket reusable, instead of throwing it away after each launch. This is why SpaceX keeps trying to land its rockets vertically: A new Falcon 9 rocket costs $54 million, but the fuel needed to relaunch only costs about $200,000.

SpaceX still hasn't managed to land a rocket, but it's made a bit of progress toward the goal - and though its main business is conducting launches for the government, it could eventually enter the space tourism field. However, even if it managed to reuse a rocket, there'd be another big hurdle before it could be viable for orbital space tourism: It will need really fast turnaround between flights.

At the moment, it'd take a huge number of engineers many months to fully refurbish a Falcon 9 rocket for the next flight. NASA's Space Shuttle - which included a reusable spaceplane launched atop a pair of reusable rocket boosters - was the closest anyone hascome, but it took 19,000 engineers several months to refurbish all the equipment for the next flight. All this labor meant it ended up costing even more than the traditional method of spaceflight: launching a capsule atop a disposable rocket.

Here's what you can actually expect on your spaceflight

Given these difficulties, what can we realistically expect for the future of space tourism? In all likelihood, Virgin, XCOR, Blue Origin, or another company will eventually achieve suborbital flights, offering wealthy flyers the chance to scrape the bottom edge of space for a few hundred thousand dollars.

For many people, that raises an obvious question: Is it worth it? It's hard to say, since no tourists have taken this sort of flight yet. But thousands have gone up on Zero-G "vomit comet" plane flights, initially developed by NASA in the 1950s as a means of training astronauts and now offered by a handful of companies.

During each flight, a plane goes in a series of parabolas, diving steeply downward to produce a feeling of weightlessness for several 30-second periods. It's certainly not spaceflight, but it's the closest analogue we have to the "several minutes of weightlessness" Virgin promises for the future - far closer than the weeklong stay at the International Space Station a handful of tourists have had from Russia.

When I spoke with several Zero-G passengers, I found that they generally found it to be a fascinating, unique experience - but perhaps not a life-changing one.

"You're lying down, and then all of a sudden, you begin to feel your limbs lift up on their own," says Maraia Hoffman, who worked as an in-flight coach for the company. "It was just a weird, amazing feeling," says Cynthia Emmons, who took a flight in 2007. "I couldn't help but keep laughing the whole time."

"I wouldn't call the weightlessness life-changing," says Miriam Kramer, a space reporter for Mashable who took the flight for a 2013 article. "It was fun, but it was so quick." Though Zero-G says its flights are short enough to prevent nausea, Kramer also notes that, at least among her passenger group, the plane still lived up to its vomit comet nickname.

Suborbital flight probably won't give you a new perspective of Earth

Of course, there's one big difference between suborbital spaceflight and the vomit comet: The former will offer passengers the chance to look down from about 10 times higher and see the curvature of Earth. Space tourism companies hope that will induce the so-called overview effect. Many astronauts have reported that seeing Earth from above - isolated as a marble floating in space - gave them a profound sense of awe and a dramatically different perspective on life.

But even though suborbital flights might come closer to providing this experience than Zero-G, they won't allow for a full-on overview of Earth. "At 100 miles up, you are just skimming the surface and you don't get a feeling for the Earth as a whole," astronaut Michael Collins said in 1986. On Virgin's SpaceShipTwo, you'll be peering through 17-inch-wide portholes to see out. And these flights won't necessarily even reach 100 miles - the lower boundary of space is just 62 miles up. The space station, by contrast, is 250 miles from Earth.

Still, these passengers and space experts believe there's a market for suborbital flights. "I can totally see the average person being really interested in it and wanting to experience it, as much for the aura of spaceflight as the experience itself," Kramer tells me.

You'll have to be superrich to afford it

At the same time, even if one of these companies succeeds in operating regular flights - and thereby driving down the price - we're still talking about hour-long flights, providing a few minutes of weightlessness, that will costs hundreds of thousands of dollars. And if orbital tourism ever happens, tickets will certainly cost millions. Both options might eventually get cheaper, but there's absolutely no way either will soon be accessible to the average person.

That brings us to what may be the most disappointing aspect of the future of spaceflight: its elitism. More than anything, spaceflight seems poised to become a new status symbol for the superrich.

"The odd thing about the space tourism business is that it's based on the assumption of income inequality, of intense concentrations of wealth," says McCurdy. "There might be a market for it, but it makes you ask: Is that really the kind of society that we really want to live in?"

Correction: This article previously stated that a suborbital craft would have to decelerate from 17,000 miles per hour, rather than 2,600 miles per hour.

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Why space tourism is going to be utterly disappointing

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People have been dreaming about space tourism for nearly a century. Think of the orbiting space hotels in 2001: A Space Odyssey , or the Martian visits in Total Recall . Years before anyone had ever even been to space, people were thinking of vacationing there.

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On the road to synthetic life: the minimal cell and genome-scaleengineering

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On the road to synthetic life: the minimal cell and genome-scaleengineering

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By: Mario Juhas, 2016

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Sign in with your credentials to access the EBSCOhost premium information resources provided by your subscribing institution.

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4D printing of polymeric materials fortissue and organ regeneration

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4D printing of polymeric materials fortissue and organ regeneration

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Author: Shida Miao
Date: July 2017

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Six reasons why Space Tourism is a good thing.

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Six reasons why Space Tourism is a good thing.

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By Richard Hollingham

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Right now, one of the most exciting space facilities in the world is a World War Two hangar in the Mojave Desert in California.

The wooden hangar belongs to Xcor, one of the start-up companies building rocket planes to fly tourists into space. In the hangar next door, you can glimpse Virgin Galactic's spaceplane, slung beneath its carrier aircraft. Further along the runway, Microsoft billionaire Paul Allen's company, Stratolaunch, is developing a new space launch system. Eleven other small space businesses are spread around the site at the Mojave Air and Space Port.

Later this year, Virgin aims to fly its first paying passengers into space. The experience will not come cheap. Virgin Galactic is charging $250,000 for the privilege of experiencing five minutes of weightlessness; Xcor plans to charge $95,000 for a ride in its two-seater rocket ship. The cost alone puts this fledgling space-tourism industry beyond the means of most of us.

So it is easy to dismiss the whole enterprise as private jets in space rather than benefits for all mankind (as BBC Future readers have done on our Facebook page). But having followed the development of the private space industry for the last 20 years, and after a recent visit to the Mojave Air and Space Port for a BBC radio programme, I thought it was worth outlining why I think space tourism matters.

1. It frees space ambitions from traditional burdens
The audacious plan to put men on the Moon was championed by politicians and backed with billions of taxpayer dollars. By the time men had actually stepped onto the lunar surface, Nasa's budget was already being cut. Subsequent US, Russian and European space programmes - from the Shuttle to the International Space Station (ISS) - have suffered from political compromise and lack of ambition.

Private space travel companies using reusable spaceplanes could help boost space exploration (AFP/Getty Images)

Private spaceflight, on the other hand, is unburdened by the favour of taxpayers or whims of politicians. If the company can raise the cash, it can build a spacecraft. Inevitably, this free market favours people who already have a lot of money. But that is not true of all the companies in the private space business.

"We don't have a multi-billionaire funding us," admits the CEO of Xcor, Jeff Greason. For him, building a sub-orbital tourist craft is part of a long-term strategy. "We started examining how a fully-reusable orbital system would look and realised we would need to develop earlier versions of that to learn how to build them," he says. "Those earlier versions also have to make money."

2. Failure is now an option
Nasa is forever burdened with the phrase "failure is not an option". Private companies have no such restrictions until the money runs out.

The entrance to the Mojave Air and Space Port is dominated by a reminder that not all space projects succeed. Resembling a giant white traffic cone, the Rotary Rocket is one of the most peculiar flying machines ever built - probably best described as half-helicopter, half-spacecraft, and if you were being cruel, you might also call the concept half-baked.

It was one of the first spacecraft to be developed at Mojave and, in 1999, made some brief atmospheric test flights. The engineering proved sound but funding problems caused the company to fold. Today it is gathering desert dust in a small memorial garden.

One person who worked on the Rotary is Kevin Mickey, President of Scaled Composites - the company now building Virgin's spaceplane. "I look at this, and I'm proud of it," says Mickey, as we stand beside the white conical spacecraft.

"One of the hurdles in today's society is an intolerance for risk and failure and if you are truly going to innovate, you are going to fail sometimes," he says. The carbon composite materials technology that went into the Rotary is now being adapted for Scaled Composite's aircraft and spaceplanes, so the expertise has not totally gone to waste.

3. It will inspire a new generation of engineers
The spaceport looks more like a college campus than a space centre. Take, for example, 26-year-old Xcor engineer, Jeremy Voigt. He proudly shows me one of the rocket engines he is helping to develop: currently, it's a mass of pipes, wires and valves.

Rockets can only be launched once - and can cost up to $12m a time (AFP/Getty Images)

"It's the engineer's dream job," he says. "Most engineers sit behind a desk all day, I don't. I get to come out here in the shop, turn wrenches and fire rocket engines."

He looks around the crowded hangar, crammed with bits of rocket motor and partially constructed spaceplane. "If I was at Nasa, I would be part of a large team of engineers working on something," he says excitedly. "Here I actually lead the rocket test, I get to push the button."

The way of working at Mojave, in small teams with limited resources, is completely different to the way the space agencies work. Many people compare what is going on at Mojave with the early days of Silicon Valley and it is easy to draw parallels between the garage where Steve Jobs and Steve Wozniak built the first Apple computer, and the Xcor workshop. Maybe the young engineers here will have equally world-changing effects.

4. The cost of reaching space will go down
Right now, if you want to launch a satellite, it will cost upwards of $12m and that is before the compulsory insurance (which can sometimes double the price). Not only can conventional space rockets only be used once, they are extremely expensive to launch - and there is limited competition.

Compare that with the $250,000 cost of a flight on the reusable Virgin spaceplane. Scientific institutions have already signed up to fly experiments on these sub-orbital flights. If the next generation of space planes can reach orbit then that will massively reduce the cost of getting into space.

This means we will be able to launch satellites, spacecraft and space exploration missions for a fraction of the cost. The final frontier could finally become economically viable to a lot more people.

It is certainly something that gets CEO of Virgin Galactic and ex-Nasa employee, George Whitesides excited. "By lowering the cost of space access, we'll be able to do things like sending little nanosats all over the Solar System and do all this incredible science, that is so expensive now," he says. "If we are able to tackle some of these challenges by demonstrating access to space technologies, then I think that will be profound."

5. Hypersonic travel could become a possibility
Remember the idea that you can take off from London, fly into space and touch down in San Francisco an hour or so later? When discussing technologies that are promised but never quite deliver, a close runner-up behind flying cars has to be so-called sub-orbital point-to-point travel. Could the space tourism companies at Mojave finally help make this dream a reality? George Whitesides thinks so: "This is fundamentally transformational for humanity," he tells me.

How much would you be willing to pay for a view like this? (Nasa)

"I really think of our customers as pioneers, opening up the new frontier," he says. "For one thing, everyone would like to get there faster, another reason is that you're not chugging through the atmosphere for 12 hours, so there could be environmental benefits to that."

But few people are going to pay $250,000, or even $95,000, for a flight to San Francisco, however fast. Space tourism companies counter with the argument that as the technology evolves, costs will inevitably come down. The history of aviation suggests this is indeed the case.

"Most technologies at the front end are funded by wealthier folks," says Whitesides. "If you go back to the dawn of commercial aviation, the real adjusted cost of crossing the Atlantic was $10,000 or if you look at the early cellphones they were thousands of dollars, now you can get them for free if you sign up for a contract."

Right now, the space companies are only on their first-generation rocket planes. By the 10th generation, point-to-point travel via space may become a reality.

6. It will provide a new view of our planet
It is widely accepted that one of the greatest achievements of the Apollo Moon programme was the view of the Earth from space. Apollo 8 astronaut Bill Anders summed up the impact of the pictures captured by his mission: "We came all this way to explore the Moon," he said, "and the most important thing is that we discovered the Earth". The images put us in our place, a blue marble against the backdrop of nothingness.

Every astronaut I have interviewed talks about how seeing the Earth from space changed their view of the world. So imagine what would happen if we started sending business and political leaders into space and back? Would that view of the world change them in the way it affected astronauts? And as a result, could it influence the decisions they make on border disputes, pollution or climate change?
If you would like to comment on this, or anything else you have seen on Future, head over to our Facebook or Google+ page, or message us on Twitter.

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Right now, one of the most exciting space facilities in the world is a World War Two hangar in the Mojave Desert in California. The wooden hangar belongs to Xcor, one of the start-up companies building rocket planes to fly tourists into space.

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Space tourism: Is it safe? - OECD Observer

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OECD Observer: Sections » Science & technology . The space age may be entering a new phase, but the issue of safety continues to weigh against ambitious ideas about manned travel in large numbers, particularly tourism.

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Why Climate Change Skeptics Are Backing Geoengineering

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Why Climate Change Skeptics Are Backing Geoengineering

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KATHERINE ELLISON

3/28/18

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Next month, a Silicon Valley engineer plans to head out on a snowmobile from Barrow, on the northern tip of Alaska, to sprinkle reflective sand on a frozen lake to try to stop it from melting.

It's part of a journey that began in 2006, after Leslie Field watched the climate change documentary "An Inconvenient Truth" and felt like she'd been "hit by a big fat truck." Now, she hopes to gather global support to cover more than 19,000 square miles of sea ice-an area about the size of Costa Rica-with a thin coating of tiny floating silica spheres, which she claims will help reduce the world's rising temperatures.

The cost estimate? $1 billion a year.

"I keep thinking, 'If not me, who?'" Field, a former researcher at Chevron Corp. and HP Labs, said as she led a reporter through a wholesale flower shop that shares access with her office.

In the emerging field of geoengineering, which envisions large-scale efforts to fight climate change by directly manipulating the natural environment, Field's privately funded Ice911 project is a small player. Under the Trump administration, these eclectic, messianic and mostly untested projects have been gaining unprecedented momentum.

For decades, scientists have warned that unchecked climate change will lead to catastrophes and have urged policymakers to curb greenhouse gases at their source. But politicians have dragged their heels, and under President Donald Trump, progress has slowed. The Trump administration has challenged the scientific consensus on climate, moved to repeal curbs on power plant emissions, proposed sweeping cutbacks to renewable energy research and pledged to withdraw from global climate talks.

Amid these developments, some close allies of Trump have taken a seemingly paradoxical stance: While denying climate change is a human-caused problem and rejecting proposals to cut greenhouse gases, they're promoting what many experts worry is the risky default solution of geoengineering.

In 2009, John Holdren, President Barack Obama's science adviser, drew backlash after telling an Associated Press reporter that geoengineering has "got to be looked at." But since Trump took office, advocates of geoengineering research say the political climate for such tactics has warmed. In December, Rep. Jerry McNerney, a California Democrat, introduced an unprecedented bill seeking funds for geoengineering research and development. In February, Trump signed a budget that includes first-ever tax breaks, with bipartisan support, for using new technologies to capture carbon dioxide from the atmosphere, a strategy many experts consider to be a kind of geoengineering.

"The future is bright for geoengineering," Republican Rep. Randy Weber of Texas, chairman of the Energy Subcommittee of the House Committee on Science, Space and Technology, said at a hearing in November.

In the past, Weber has grilled scientists on "global cooling" and rejected a carbon pollution tax as " blasphemy." Yet at the hearing, he claimed that specific, yet-untested proposals such as "placement of mirrors in space" and "brightening the clouds overhead ... could have a cooling effect on our lower atmosphere."

'Hacking the planet'

Trump himself has not publicly addressed geoengineering, his budget proposals make no mention of it, and none of his cabinet members has publicly endorsed it. Neither Environmental Protection Agency Administrator Scott Pruitt nor Paul Dabbar, the Energy Department's undersecretary for science, responded to requests for comment.

Nevertheless, said Harvard University physics professor David Keith, "there's much more broad support for this than there was just two years ago."

Keith, who wrote a 2013 book, "A Case for Climate Engineering," leads one of the world's most advanced and closely watched geoengineering research projects. Later this year, his team plans to conduct its first outdoor trial, launching a slow-moving balloon over Tucson, Arizona, to disperse substances such as calcium carbonate dust or sulfur dioxide to reflect the sun's rays back into space. The scientists believe this approach, known as solar radiation management, could mimic the climate-cooling effect of a volcano such as the Philippines' Mount Pinatubo, whose eruption in 1991 caused a temporary global drop in temperatures of about 1 degree Fahrenheit. Keith estimates full-scale deployment would cost about $1 billion a year.

The increasing interest in geoengineering, including from climate change skeptics, owes partly to growing pessimism about humanity's capacity-and political will-to ward off the worst effects of climate change without some major technological breakthrough. Microsoft Corp. founder Bill Gates has invested both in Keith's research and in a for-profit company Keith founded to try to capture carbon from the atmosphere. In 2015, two major US environmental groups, the Environmental Defense Fund and the Natural Resources Defense Council, supported small-scale research into projects that one writer has dubbed " hacking the planet."

Several Trump allies are considerably more gung-ho, with some explicitly portraying geoengineering as a cheap alternative to radically transforming a US economy that is still about 80 percent dependent on fossil fuels.

"Instead of forcing unworkable and costly government mandates on the American people, we should look to technology and innovation to lead the way to address climate change," Rep. Lamar Smith chairman of the House Science, Space and Technology Committee, said at last fall's hearing.

Smith, a Texas Republican and Trump stalwart heavily backed by the fossil fuel industry, has been one of the most aggressive climate science skeptics in Congress. Yet at the hearing, he called for more research into geoengineering, saying, "Some scientists believe it could achieve substantial environmental benefits at a cheaper cost than regulations."

Likewise, former GOP House Speaker Newt Gingrich, a devoted ally of Trump's who has portrayed climate change as the left wing's " newest excuse to take control of lives," has also praised geoengineering for its "promise of addressing global warming concerns for just a few billion dollars a year."

Attorney David Schnare, a Trump transition appointee at the EPA who has since left the administration, has challenged mainstream climate science and filed lawsuits seeking access to climate scientists' emails, while championing geoengineering as "a means to put off the most catastrophic potential effects" of global warming.

For several years, conservative think tanks, including the American Enterprise Institute, the Hoover Institution and The Heartland Institute, have taken a similarly paradoxical position, challenging established climate science while promoting geoengineering. Scholars working for the American Enterprise Institute's Geoengineering Project have touted the strategy as "a revolutionary approach to climate change."

'Howlingly barking mad'

Over the past several years, scientists and entrepreneurs throughout the world have proposed more than a dozen different kinds of geoengineering projects. One would send 16 trillion tiny robots into space to deflect the sun's rays from the Earth. Another would build millions of wind-powered pumps in Arctic waters to push freezing water over the ice to thicken it. The " cloud-brightening " scheme praised by Weber last fall envisions shooting salt water into marine clouds to improve their reflective power.

These aren't even the most radical ideas. Back in 1993, an Indian physicist considered whether the Earth could be cooled by somehow increasing the radius of the planet's orbit around the sun. And in a widely condemned operation in 2012, a rogue California businessman conducted the world's largest geoengineering project to date by dumping 100 tons of iron dust into the Pacific Ocean. His goal was to fertilize plankton to absorb carbon dioxide and then sell "credits" to fossil fuel firms.

Solar radiation management proposals, such as the cloud-brightening strategy and the Harvard aerosol-spraying plan, have attracted the most interest from US politicians, even as they've caused alarm among leading climate scientists.

"The idea of 'fixing' the climate by hacking the Earth's reflection of sunlight is wildly, utterly, howlingly barking mad," Oxford University physics professor Raymond Pierrehumbert wrote in a 2015 Slate article. He was a lead author of the Nobel Prize-winning Third Assessment Report from the UN Intergovernmental Panel on Climate Change.

In an interview, Pierrehumbert compared such strategies with "jumping off the Washington Monument and hoping somebody invents anti-gravity before you hit the ground."

He and other scientists say large-scale spraying of sulfur dioxide into the atmosphere, as envisioned by Harvard's Keith, could deplete the ozone layer, harm some plants and animals, and benefit some countries while causing droughts in others, stirring global conflict akin to nuclear rivalries. Furthermore, barring radical cuts in greenhouse gas emissions, such projects, once begun, might have to be continued indefinitely to prevent worse warming than before, a phenomenon known as the termination effect.

An additional danger, which Keith himself has cited, stems from geoengineering's potential "moral hazard," an insurance industry term that refers to how people behave more recklessly when they know they have a fallback. In other words, the promise of geoengineering might convince politicians that they need not worry about reforming our energy economy.

"If we don't cut emissions, we're sunk, and it would be criminal if people use this as an excuse to avoid that," Keith said in an interview with Reveal from The Center for Investigative Reporting.

This is precisely what worries Janos Pasztor, former UN assistant secretary-general for climate change, who has been leading a new global effort to improve public discussion and governance of geoengineering proposals. He said the House hearing last fall "sent the wrong signal to the world," noting that it took place just as world leaders were meeting at the UN's annual climate change conference to discuss ways to lower greenhouse gases.

"At the very same time, US politicians were talking about stopping all these activities that could make a difference and talking about geoengineering, as if it's some sort of a plan B," Pasztor said. "It's not a plan B. Maybe it could give us some time, but it's not a solution."

Boots on the ice

Field, the Ice911 founder, says she's also concerned that the promise of a geoengineering fix might sap political will to cut emissions. Yet that hasn't deterred her from joining other scientists and entrepreneurs rushing into the leadership vacuum.

"I don't want Ice911 to be an excuse for building another coal mine," she said. "But we have to do something. Our backs are up against the wall."

Field, an inventor with 53 patents, began her research with buckets of cold water on the front deck of her home in Portola Valley, California, where she tested a variety of materials, including hay and daisies, to see how well they could prevent the sun's rays from raising water temperatures. After settling on silica, she scaled up her experiments with trials on ice in California's Sierra Nevada and on Canada's Miquelon Lake.

Along the way, she raised funds from private donors, the largest contribution being a three-year, $1.3 million grant from a family foundation she heard about from a wealthy friend with whom she volunteered at her sons' school. The money has helped pay for land-use permits and logistical support from Ukpeaġvik Iñupiat Corp., an indigenous-run organization in Barrow, Alaska. In May, Field and a small group of volunteers used an agricultural spreader, dragged by a snowmobile, to cover an area of ice the size of three football fields on an inland lake in Alaska.

Next week, Field plans to dispatch a buoy into the Arctic Ocean to monitor sea ice, and then return next month to try dispersing more sand on lake ice. She has not yet secured permits to perform tests on sea ice.

"Ice911 is the boots on the ground solution acting now to ease climate change by restoring Arctic ice," reads Field's fundraising pamphlet, what she conceded in an interview was an overstatement. Ice911 has yet to have any impact on climate change. Before that can happen, she said, she needs to build credibility for her approach, which has yet to win respect from the so-called geo-clique -a small group of North American scientists who advise politicians and large funders.

Among Field's harshest critics is Ken Caldeira, an atmospheric scientist at the Carnegie Institution for Science's Department of Global Ecology at Stanford University, who has collaborated with Keith and worked with Bill Gates. Caldeira dismissed Ice911 as unrealistic.

"This isn't anything anyone is going to do," Caldeira said. "It's hard to do, not that effective, and you'd have to do it over millions of acres."

Field disputes this. She said she recently hired climate modelers who she said assured her that Ice911 could lower Arctic temperatures by placing her sand in limited, strategic locations, such as the Fram Strait between Greenland and Svalbard.

"We're working to simply restore an ecosystem that has a profound effect on the planet's weather patterns," she said. "That's a lot better than putting a known pollutant into our one and only atmosphere."

Harvard's Keith, whom Time magazine honored in 2009 as a " hero of the environment," gives voice, often simultaneously, to the world's fears and hopes for geoengineering. In the span of a single conversation with comedian and TV host Stephen Colbert in 2013, he called geoengineering "ugly" and "horrifying" but also said, "It might actually save people and be useful."

Many scientists warn that the longer politicians ignore other strategies, the more likely society eventually will need to make the hard choice to try geoengineering. Still, Keith said he is unnerved by climate change skeptics' recent embrace of geoengineering.

"In some ways," Keith said at a conference last fall, "the thing we fear the most is a tweet from Trump, saying, 'Solar geoengineering solves everything! It's great! We don't need to bother to cut emissions.'"

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Why Climate Change Skeptics Are Backing Geoengineering

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Next month, a Silicon Valley engineer plans to head out on a snowmobile from Barrow, on the northern tip of Alaska, to sprinkle reflective sand on a frozen lake to try to stop it from melting.

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Skepticism surfaces over CRISPR human embryo editing claims

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Skepticism surfaces over CRISPR human embryo editing claims

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By Kelly Servick, 08/31/17

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When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents' genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise. Instead of replacing the gene defect with strands of DNA that the researchers inserted, the embryos appeared to use the mother's healthy gene as a template for repairing the cut made by CRISPR's enzyme.

But such a feat has not been observed in previous CRISPR experiments, and some scientists are now questioning whether the repairs really happened that way. In a paper published online this week on the preprint server bioRxiv, a group of six geneticists, developmental biologists, and stem cell researchers offers alternative explanations for the results. And uncertainty about exactly how the embryos' DNA changed after editing leaves many questions about the technique's safety, they argue. (The authors declined to discuss the paper while it's being reviewed for publication.)

Embryologist Shoukhrat Mitalipov of Oregon Health and Science University in Portland, who led the now-disputed experiments, released a statement saying that his team stands by its explanation. "We based our finding and conclusions on careful experimental design involving hundreds of human embryos," it says.

In the 2 August Nature paper, Mitalipov and his collaborators showed they could bump up the efficiency of human embryo editing by inserting the CRISPR machinery earlier in development than previous experiments. When they combined healthy eggs with sperm bearing a disease-causing mutation and immediately added CRISPR, they found that 72% of the resulting embryos were free of the mutation-rather than the expected 50% that would have avoided inheriting the harmful gene anyway.

Although the researchers inserted short strands of DNA as templates for repair, the cells didn't seem to take them up; those specific sequences were absent from the embryos. The cells must have relied instead on the nonmutated sequence in the egg donor's DNA when making the repairs, the team concluded.

The bioRxiv response, led by developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center in New York City and Columbia University stem cell biologist Dieter Egli, challenges that interpretation. The authors, which also include well-known CRISPR researcher and Harvard University geneticist George Church, say that the Nature paper goes against conventional wisdom about how embryos are organized early in development. Right after an egg is fertilized, the DNA from the sperm and the egg aren't believed to be in close enough proximity to interact or share genes, they explain.

Stem cell researcher Junjiu Huang of Sun Yat-Sen University in Guangzhou, China, who led the first published study of CRISPR editing of a human embryo, isn't on the bioRxiv paper, but shares that concern. It's not unexpected for a cell to use its own sequences to guide repair, he notes. In his group's study, which used nonviable embryos, a gene related to the CRISPR-targeted gene seemed to function as a template. But that gene was on the same chromosome as CRISPR's edits. Here, the sperm and egg nuclei are seemingly too far apart to cooperate in the repairs, he says.

The preprint authors lay out two other scenarios for what Mitalipov's team saw. It's possible that some of the embryos didn't take up paternal DNA at all, and thus never inherited the mutation to begin with. In some in vitro fertilization procedures, embryos can occasionally start to develop from maternal DNA alone, and the study didn't rule out this phenomenon for every embryo, they say.

They also suggest that mutated paternal gene could have been snipped out of young embryos but never actually replaced with a healthy version. CRISPR's cuts can sometimes cause chunks of DNA to be removed from the strand before the two cut ends are rejoined, they note. That would mean no detectable mutation-but it could also mean missing sections of DNA that could have unknown consequences for the embryo.

This possibility of "allele dropout" has been the subject of discussion in the field ever since the Nature paper was published, says developmental biologist Robin Lovell-Badge of the Francis Crick Institute in London. Many scientists are now waiting for a response from Mitalipov, he says.

In his statement, Mitalipov promised to "respond to [the] critiques point by point in the form of a formal peer-reviewed response in a matter of weeks." He also urged follow-up to resolve the matter. "We encourage other scientists to reproduce our findings by conducting their own experiments on human embryos and publishing their results."
*Update, 1 September, 1:30 p.m.: The new version of this story has additional comments from several researchers and clarifies the authorship of the preprint.

doi:10.1126/science.aap8382

Kelly is a staff writer at Science.

More from News

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Skepticism surfaces over CRISPR human embryo editing claims

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When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents' genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise.

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By Vincent Kiernan, 2007
The article explains that the cybernetics have many useful benefits to our modern world such as driving subway trains and even interpreting and generating human languages which is useful for military technology. On the other hand, society as a whole have many speculations when it comes to these robots being able to mimic human personality traits including memory, emotion, and consciousness.

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Rajat M. Gupta and Kiran Musurunu October 1, 2014

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Abstract

The past decade has been one of rapid innovation in genome-editing technology. The opportunity now exists for investigators to manipulate virtually any gene in a diverse range of cell types and organisms with targeted nucleases designed with sequence-specific DNA-binding domains. The rapid development of the field has allowed for highly efficient, precise, and now cost-effective means by which to generate human and animal models of disease using these technologies. This review will outline the recent development of genome-editing technology, culminating with the use of CRISPR-Cas9 to generate novel mammalian models of disease. While the road to using this same technology for treatment of human disease is long, the pace of innovation over the past five years and early successes in model systems build anticipation for this prospect.

The emergence of genome-editing technology

The classical method for gene modification is homologous recombination. This approach has been widely used in mouse embryonic stem cells to generate germline knockout or knockin mice ( 1, 2). A disadvantage is that it typically takes more than a year to generate a genetically modified mouse using the standard approach. Furthermore, similar attempts at using homologous recombination in human cells have proven to be far more challenging, and alternative approaches to knock down gene expression, such as antisense oligonucleotides and short interfering RNAs, have instead become standard. However, these approaches only transiently reduce gene expression, and the effect is usually incomplete and can often affect off-target genes ( 3, 4). These shortcomings have fueled the demand for more effective methods of gene modification.

A new wave of technology that is variously termed "gene editing," "genome editing," or "genome engineering" has emerged to address this demand by giving investigators the ability to precisely and efficiently introduce a variety of genetic alterations into mammalian cells, ranging from knockin of single nucleotide variants to insertion of genes to deletion of chromosomal regions. We describe the key advantages and disadvantages of the three most popular genome-editing tools. This description is not meant to be a comprehensive review of the work leading to the development of the tools, but rather to give readers a working knowledge of the tools and the ability to select among the tools for desired tasks.

Zinc finger nucleases

Zinc finger nucleases (ZFNs) are increasingly being used in academia and industrial research for a variety of purposes ranging from the generation of animal models to human therapies ( 5). ZFNs are fusion proteins comprising an array of site-specific DNA-binding domains - adapted from zinc finger-containing transcription factors - attached to the endonuclease domain of the bacterial FokI restriction enzyme. Each zinc finger domain recognizes a 3- to 4-bp DNA sequence, and tandem domains can potentially bind to an extended nucleotide sequence (typically with a length that is a multiple of 3, usually 9 bp to 18 bp) that is unique within a cell's genome.

To cleave a specific site in the genome, ZFNs are designed as a pair that recognizes two sequences flanking the site, one on the forward strand and the other on the reverse strand. Upon binding of the ZFNs on either side of the site, the pair of FokI domains dimerize and cleave the DNA at the site, generating a double-strand break (DSB) with 5′ overhangs ( 5). Cells repair DSBs using either (a) nonhomologous end joining (NHEJ), which can occur during any phase of the cell cycle, but occasionally results in erroneous repair, or (b) homology-directed repair (HDR), which typically occurs during late S phase or G ₂ phase when a sister chromatid is available to serve as a repair template (Figure ).

The error-prone nature of NHEJ can be exploited to introduce frameshifts into the coding sequence of a gene, potentially knocking out the gene by a combination of two mechanisms: premature truncation of the protein and nonsense-mediated decay of the mRNA transcript, the latter of which is not always particularly efficient (Figure ). Alternatively, HDR can be utilized to insert a specific mutation, with the introduction of a repair template containing the desired mutation flanked by homology arms (Figure ). In response to a DSB in DNA, HDR utilizes another closely matching DNA sequence to repair the break. Mechanistically, HDR can proceed in the same fashion as traditional homologous recombination, using an exogenous double-stranded DNA vector as a repair template ( 6). It can also use an exogenous single-stranded DNA oligonucleotide (ssODN) as a repair template. For ssODNs, homology arms of as little as 20 bp can enable introduction of mutations into the genome ( 7- 9). In either case, the efficiency can be sufficiently high such that antibiotic selection to identify correctly targeted clones is unnecessary ( 8, 10). If antibiotic selection is not used, then extra steps to remove the antibiotic resistance cassette from the genome using systems such as Cre- lox and Flp- FRT are unnecessary, in contrast to traditional homologous recombination.

Despite the advantages of genome editing with ZFNs, there are several potential disadvantages. It has not proven to be straightforward to assemble zinc finger domains to bind an extended stretch of nucleotides with high affinity ( 11). This has made it difficult for nonspecialists to routinely engineer ZFNs. To surmount this difficulty, an academic consortium has developed an open-source library of zinc finger components and protocols to perform screens to identify ZFNs that bind with high affinity to a desired sequence ( 12, 13); nonetheless, it can still take months for nonspecialists to obtain optimized ZFNs. Another potential disadvantage is that target site selection is limited - the open-source ZFN components can only be used to target binding sites every 200 bps in random DNA sequence (of note, commercial sources of ZFNs offer higher design densities, with the ability to target binding sites every 50 bps in random DNA sequences). While this may be a nonissue if an investigator seeks to knock out a gene, since a frameshift introduced anywhere in the early coding sequence of the gene can produce the desired result, it may present challenges if a particular site is required, e.g., to knock in a specific mutation. Since the introduction of the open-source platform, alternative platforms to engineer optimized ZFNs have emerged, each with varying degrees of speed, flexibility in site selection, and success rates ( 14- 18).

Finally, a significant concern about the use of proteins designed to introduce DSBs into the genome is that they will do so not only at the desired site but also at off-target sites. In one study in which ZFNs were used for genome editing in human pluripotent stem cells, the investigators identified ten possible off-target genomic sites based on high-sequence similarity to the on-target site and found a single off-target mutation in the 184 clones assessed ( 19). Two subsequent studies of ZFNs seeking to identify potential off-target sites for several ZFN pairs revealed off-target events at numerous loci in a cultured human tumor cell line ( 20, 21). Thus, investigators should be cognizant of the possibility that ZFNs designed for a particular purpose may incur undesired off-target events at a low rate. One strategy to reduce off-target events is to use a pair of ZFNs that have distinct FokI domains that are obligate heterodimers ( 22- 24). This prevents a single ZFN from binding to two adjacent off-target sites and generating a DSB; rather, the only way an off-target event could occur is if both ZFNs in a pair bind adjacently and thus allow the FokI dimer to form. Another strategy that has been demonstrated to reduce off-target events is the introduction of purified ZFN proteins into cells ( 17).

Transcription activator-like effector nucleases

The recent discovery of a class of proteins called transcription activator-like effectors (TALEs), exclusive to a group of plant pathogens, has led to the characterization of a novel DNA-binding domain, termed TALE repeats. The naturally occurring TALE repeats comprise tandem arrays with 10 to 30 repeats that bind and recognize extended DNA sequences ( 25). Each repeat is 33 to 35 amino acids in length, with two adjacent amino acids (termed the repeat-variable di-residue [RVD]) conferring specificity for one of the four DNA base pairs ( 26- 30). Thus, there is a one-to-one correspondence between the repeats and the base pairs in the target DNA sequences. Elucidation of the RVD code has made it possible to create a new type of engineered site-specific nuclease that fuses a domain of TALE repeats to the FokI endonuclease domain, termed TAL effector nucleases (TALENs) (refs. 31- 33 and Figure ). TALENs are similar to ZFNs in that they can generate DSBs at a desired target site in the genome and so can be used to knock out genes or knock in mutations in the same way (Figure ).

In comparison with ZFNs, TALENs have turned out to be much easier to design. The RVD code has been employed to engineer many TALE repeat arrays that bind with high affinity to desired genomic DNA sequences; it appears that de novo-engineered TALE repeat arrays will bind to desired DNA sequences with high affinity at rates as high as 96% ( 32, 34, 35). TALENs can be designed and constructed in as short a time as two days and in as large a number as hundreds at a time ( 35, 36); indeed, a library with TALENs targeting all of the genes in the genome has been constructed ( 37).

One potential advantage over ZFNs is that the TALE repeat array can be easily extended to whatever length is desired. Whereas engineered ZFNs typically bind 9- to 18-bp sequences, TALENs are often built to bind 18-bp sequences or even longer, though recent evidence suggests that the use of larger TALENs may result in less specificity ( 38). Another advantage of TALENs over ZFNs is that there appear to be fewer constraints on site selection; in theory, there are multiple possible TALEN pairs available for each bp of a random DNA sequence ( 35).

As with ZFNs, off-target effects are a significant concern with TALENs. A study in which TALENs were used for genome editing in human pluripotent stem cells found low but measurable rates of mutagenesis at some of 19 possible off-target sites based on sequence similarity to the on-target sites ( 34). Although comparative data are scarce, one study found that for TALENs and ZFNs targeting the same site in the CCR5 gene, the TALENs produced fewer off-target mutations than the ZFNs at a highly similar site in the CCR2 gene ( 39). Furthermore, the ZFNs produced greater cell toxicity (i.e., inhibited their growth) when introduced into cells compared with the TALENs (however, it should be noted that ZFN versus TALEN protein concentrations were not normalized, and the ZFNs used in this study were of a design that was several years old, rather than being state-of-the-art ZFNs). As with ZFNs, TALENs with obligate heterodimer FokI domains are routinely used to minimize the possibility of off-target events. Recently, whole-genome sequencing studies of human pluripotent stem cell clones edited with TALENs showed that the overall off-target event rate is very low ( 40, 41).

A clear disadvantage of TALENs is their significantly larger size compared with ZFNs. The typical size for a cDNA encoding a TALEN is approximately 3 kb, whereas a cDNA encoding a ZFN is only approximately 1 kb. In principle, this makes it harder to deliver and express a pair of TALENs into cells compared with ZFNs, and the size of the TALENs makes them less attractive for therapeutic applications in which they must be delivered in viral vectors with limited cargo size (such as adenoassociated virus [AAV], with less than 5 kb) or as RNA molecules. Furthermore, the highly repetitive nature of the TALENs may impair their ability to be packaged and delivered by some viral vectors ( 42), though this can apparently be overcome by diversifying the coding sequences of the TALE repeats ( 43).

CRISPR-Cas9

The recent discovery of bacterial adaptive immune systems known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) systems has led to the newest set of genome-editing tools. CRISPR-Cas systems use a combination of proteins and short RNAs to target specific DNA sequences for cleavage. The bacteria collect "protospacers" from foreign DNA sequences (e.g., from bacteriophages), incorporate them into their genomes, and use them to express short guide RNAs, which can then be used by a CRISPR-Cas system to destroy any DNA sequences matching the protospacers.

In early 2013, four groups demonstrated that heterologous expression of a CRISPR-Cas system from Streptococcus pyogenes, comprising the Cas9 protein along with guide RNA(s) (either two separate RNAs, as found in bacteria, or a single chimeric RNA), in mammalian cells results in DSBs at target sites with (a) a 20-bp sequence matching the protospacer of the guide RNA and (b) an adjacent downstream NGG nucleotide sequence (termed the protospacer-adjacent motif [PAM]) ( 44- 47). This occurs via the formation of a ternary complex in which Cas9 binds to the PAM in the DNA, then binds the nonprotospacer portion of the guide RNA, upon which the protospacer of the guide RNA hybridizes with one strand of the genomic DNA. Cas9 then catalyzes the DSB in the DNA at a position 3 bp upstream of the PAM (ref. 46 and Figure A).

In contrast to ZFNs and TALENs, which require recoding of proteins using large DNA segments (500-1500 bp) for each new target site, CRISPR-Cas9 can be easily adapted to target any genomic sequence by changing the 20-bp protospacer of the guide RNA, which can be accomplished by subcloning this nucleotide sequence into the guide RNA plasmid backbone. The Cas9 protein component remains unchanged. This ease of use for CRISPR-Cas9 is a significant advantage over ZFNs and TALENs, especially in generating a large set of vectors to target numerous sites ( 45) or even genome-wide libraries ( 48- 51). Another potential advantage of CRISPR-Cas9 is the ability to multiplex, i.e., to use multiple guide RNAs in parallel to target multiple sites simultaneously in the same cell ( 44, 45). This makes it straightforward to mutate multiple genes at once or to engineer precise deletions in a genomic region, although it should be noted that simultaneous use of multiple ZFN or TALEN pairs can achieve the same outcomes ( 52).

With respect to site selection, CRISPR-Cas9 compares favorably with ZFNs and TALENs. With the most flexible version of the S. pyogenes CRISPR-Cas system, site selection is limited to 23-bp sequences on either strand that end in an NGG motif (the PAM for S. pyogenes Cas9), which occurs on average once every 8 bps ( 44). (Most CRISPR-Cas9 systems express the guide RNA from a plasmid using a RNA polymerase III promoter such as the U6 promoter, which requires a G in the first position, or the T7 promoter, which requires Gs in the first two positions; however, the G or Gs can simply be added to the 5′ end of the 20-nucleotide protospacer in the guide RNA as needed and thus do not affect site selection in the genome.) CRISPR-Cas systems from other species are starting to be employed in mammalian cells ( 44, 53, 54), and their versions of Cas9 have different PAM requirements, which allows for targeting of sites in the genome for which the S. pyogenes system is not optimal. For example, the canonical Neisseria meningitidis Cas9 PAM has been reported to be NNNNGATT, although it appears to be more tolerant of PAM variation than the S. pyogenes Cas9 ( 53, 54).

One disadvantage of CRISPR-Cas9 is the size of the Cas9 protein. The cDNA encoding S. pyogenes Cas9 is approximately 4.2 kb in size, making it somewhat larger than a TALEN monomer and much larger than a ZFN monomer (though both TALENs and ZFNs require dimerization, making their effective sizes larger). This size makes Cas9 challenging to deliver via viral vectors (which would additionally require a promoter and a polyadenylation sequence) or as an RNA molecule. The chimeric version of the guide RNA is only approximately 100 nucleotides in size, but it needs to be delivered in parallel with Cas9, either as a separate RNA molecule or via a DNA cassette with a separate promoter (typically the U6 promoter) with a size of approximately 500 bp. A lentivirus can just accommodate the S. pyogenes CRISPR-Cas9 system; AAV, with its cargo size limited to less than 5 kb, cannot accommodate it. Here again, the emerging availability of CRISPR-Cas systems from other species may prove helpful. For example, the cDNA encoding N. meningitidis Cas9 is approximately 3.2 kb in size and so should allow for delivery via AAV, which may be important for therapeutic applications.

Perhaps the biggest concern regarding CRISPR-Cas9 is the issue of off-target effects. It has recently been demonstrated that, although each nucleotide within the 20 nucleotide protospacer contributes to overall S. pyogenes Cas9 binding and specificity, single mismatches are often well tolerated, and multiple mismatches can sometimes be tolerated depending on their locations in the protospacer ( 55- 58). Systematic analysis of the effect of alterations in the protospacer reveals an increasing tolerance for mismatches with increasing distance from the PAM. A number of studies in mammalian cells have documented off-target mutations occurring at significant rates at sites with sequence similarity to the on-target sites, occasionally rivaling or even surpassing mutagenesis at the on-target sites ( 55- 60). These off-target effects, however, are guide RNA specific, and many guide RNAs have been reported for which no off-target activity is detectable ( 55- 60). It has been posited that alternative CRISPR-Cas systems such as that from N. meningitidis may offer better targeting specificity by virtue of their longer protospacers (24 nucleotides for N. meningitidis) and longer PAMs. Experimental confirmation of improved specificity in mammalian cells remains to be shown. Early results with the N. meningitidis CRISPR-Cas9 system suggest that it may be less tolerant of mismatches in the protospacer compared with the S. pyogenes system ( 53).

Efforts to improve the specificity of CRISPR-Cas9 in mammalian cells are in progress. One strategy has been to use a mutant version of Cas9 that can only introduce a single-strand nick into the target DNA, rather than a DSB. Use of a pair of "nickase" CRISPR-Cas9 complexes with binding sites on opposite strands flanking the target site can produce the equivalent of a DSB with 5′ overhangs (Figure B), which is then repaired by NHEJ or HDR and can result in an on-target alteration. At an off-target site, a single-strand nick would be fixed by a different mechanism (base excision repair pathway) that is much less likely to result in a mutation. Because the likelihood of two nickases binding near each other elsewhere in the genome is very low, the off-target mutation rate should be dramatically reduced. Indeed, testing of this strategy in mammalian cells has demonstrated a reduction in off-target activity by up to three orders of magnitude with at most a modest reduction in on-target efficacy ( 57, 60, 61). Another strategy to reduce off-target effects is to reduce the length of the protospacer portion of the guide RNA, which makes it less tolerant of mismatches and thus can preserve the on-target efficacy while reducing off-target mutagenesis ( 62). A third successful strategy is to use a pair of proteins, each comprising a nuclease-dead Cas9 (that cannot cut DNA) fused to a FokI domain (Figure C); each Cas9 is targeted to either of two flanking sequences by a guide RNA, positioning the FokI domains to be able to dimerize and generate a DSB ( 63, 64). Although very large, these fusion proteins combine the most desirable properties of CRISPR-Cas9 and ZFNs/TALENs.

Genome editing in mammalian models

Although the creation of mouse lines with genetic alterations such as gene knockouts or conditional alleles has long been feasible with traditional homologous recombination employed in mouse embryonic stem cells, the last few years have seen the application of novel genome-editing tools for the generation of genetically modified mice with unprecedented ease and efficiency. Furthermore, these tools have made it possible to genetically modify animals for which embryonic stem cell lines are not widely available.

Initial studies of the efficacy of genome-editing tools in the mutagenesis of mammalian embryos were performed with rats. Inspired by studies in which injection of RNAs encoding ZFNs directly into the embryos of fruit flies and zebrafish yielded stable, heritable genomic alterations, injection of ZFN-encoding RNAs into one-cell rat embryos successfully generated monoallelic and biallelic frameshift mutations, resulting in gene knockout ( 65, 66). Numerous knockout rats have since been generated using this ZFN strategy. Subsequently, both TALENs and CRISPR-Cas9 have been used in similar fashion to generate knockout rats ( 67- 69).

A particular advantage is that it is possible to obtain knockout animals in the first generation (assuming the targeted gene is not embryonic lethal), dramatically speeding up the time needed to do genetic studies in animals. Another advantage of this approach is that embryos from any of a variety of animal strains can be used; in the case of mice, there is no longer a restriction to a limited number of embryonic stem cell lines that necessitate backcrossing to an inbred strain of choice. Embryos from that inbred strain can be used to directly generate the knockout mice. Similarly, embryos from a strain that already carries genetic alterations can be used, relieving the need for many generations of interbreeding to obtain mice with multiple genetic alterations. The ability to perform multiplex gene targeting with CRISPR-Cas9 is also helpful in this regard.

All three engineered nucleases outlined above have proven effective at producing targeted mutations in mouse embryos ( 70- 78). The efficiencies vary widely depending on the nuclease, target site in the genome, and amount of RNA injected. The most striking demonstration of efficiency has been with CRISPR-Cas9, with simultaneous targeting of both alleles of two genes in 80% of mice ( 76). CRISPR-Cas9 has also been used along with ssODNs or double-stranded DNA donor vectors in mouse embryos to knock in tags and fluorescent markers into endogenous gene loci and, most impressively, to generate conditional knockout mice in one step by simultaneously knocking in two loxP sites flanking an exon of a gene ( 77).

Finally, the high efficiencies of the genome-editing tools, particularly CRISPR-Cas9, have made it possible to generate targeted mutations in animals far beyond the reach of the traditional homologous recombination/embryonic stem cell approach. CRISPR-Cas9 technology has successfully generated modified organisms across the biologic spectrum, from sweet oranges to tilapia ( 79, 80). Both TALENs and CRISPR-Cas9 have now been used to generate genetically modified monkeys ( 81, 82), in each case targeting genes involved in human diseases. This is a remarkable accomplishment that suggests that there is no technical barrier to using genome-editing tools to modify human embryos, notwithstanding the profound social and ethical repercussions that would result if such attempts were to be made. On more secure ground will be attempts to use CRISPR-Cas9 for in vivo genome editing in adults to treat diseases. In an early proof of principle, a CRISPR-Cas9 plasmid and an ssODN were delivered into mouse liver via hydrodynamic injection, resulting in the correction of a patient-specific mutation in the Fah gene in a small proportion of hepatocytes ( 83). This resulted in the survival of mice that otherwise would have succumbed to liver failure from a disease analogous to type I tyrosinemia in humans.

Genome editing in human cells

To date, there have been a number of reports demonstrating the feasibility of performing genome editing in human pluripotent stem cells with ZFNs, TALENs, and CRISPRs ( 19, 34, 45, 61, 84- 88). Genetically altered pluripotent stem cells offer the possibility of differentiating WT and mutant cell lines into whatever somatic cell type is desired, potentially giving new insights into disease pathophysiology. In one such study, the investigators generated induced pluripotent stem cells (iPSCs) from patients with Parkinson disease caused by the G2019S mutation of the LRRK2 gene as well as from control individuals ( 88). Upon differentiation into midbrain dopaminergic neurons, the cell lines displayed striking differences in whole-genome gene expression patterns, with clustering analysis showing that in some cases a patient line and a control line were more closely matched than lines generated from two different patients. Indeed, even iPSC lines generated from the same patient failed to cluster together, demonstrating the high degree of heterogeneity among iPSC lines. As an alternative approach, the investigators used ZFNs to correct the G2019S mutation in three of the patient-derived iPSC lines and to insert the mutation into a control iPSC line. They found that the matched sets of WT/mutant cell lines clustered together very closely, confirming the superiority of the genome-editing strategy for disease-modeling studies. The investigators consistently found that mutant neurons displayed less neurite outgrowth and more apoptosis in response to oxidative stress than matched WT neurons.

Other human cell types have proven to be quite amenable to genome editing. A therapeutic application that is currently in clinical trials is the use of ZFNs to disrupt the CCR5 gene in human T cells, thus rendering them impervious to HIV entry ( 89, 90). A similar intervention has been performed in human CD34⁺ hematopoietic stem/progenitor cells and may also be evaluated in clinical trials ( 91). In separate work, ZFNs have been used to insert a normal IL2RG gene into CD34⁺ hematopoietic stem/progenitor cells from a subject with X-linked severe combined immunodeficiency ( 92).

In another study, the investigators isolated intestinal stem cells from cystic fibrosis patients homozygous for the common Δ508 mutation in the CFTR gene ( 93). They used CRISPR-Cas9 targeting the site of the mutation, along with a double-stranded DNA donor vector, to correct one mutant allele (sufficient to "cure" the disease in this recessive disorder). They then used the mutant and corrected stem cells to create intestinal organoids in culture. Whereas the mutant organoids failed to respond to forskolin treatment by swelling, consistent with a lack of functional CFTR protein, the corrected organoids did respond by swelling, demonstrating a functional rescue.

The remarkable efficiency and ease of use of CRISPR-Cas9, where only 20 nucleotides in the guide RNA need be changed to retarget the nuclease, have led to the development of genome-wide CRISPR knockout libraries with the potential to knock out each of the genes in the genome. Several groups have performed proof-of-principle, genome-wide knockout screens in both human cells ( 48, 49, 51) and mouse cells ( 50). The results of the screens compared favorably with traditional genome-wide RNA interference screens, establishing a powerful new complementary approach to RNA interference to probe gene function in an unbiased fashion. Furthermore, CRISPR knockout libraries can potentially be used to target regions of interest in the noncoding genome (e.g., promoters, enhancers), enabling screens not possible with RNA interference.

Conclusion

The rapid development and improvement of genome-editing tools provide investigators with three well-characterized options for experiments as diverse as forward genetic screens to correction of pathogenic mutations in iPSC-derived human cells. ZFNs, TALENs, and CRISPRs can all generate site-specific DSBs with varying degrees of specificity and efficiency. The early uses of these systems have demonstrated remarkable new possibilities and allowed for the creation of model systems in a wide variety of organisms. With each iteration, the technology has improved, and the prospects for the study and treatment of human disease with genome editing have never been better.

Acknowledgments

This work was supported in part by a LaDue Fellowship in Cardiology (to R.M. Gupta) and a Sarnoff Scholar Award (to R.M. Gupta). Given the explosive nature of the genome-editing field in recent years, especially in the past year, we regret that due to space limitations we were unable to cite and describe many worthy studies, and we apologize for their omission.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2014;124(10):4154-4161. doi:10.1172/JCI72992.

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Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9

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The past decade has been one of rapid innovation in genome-editing technology. The opportunity now exists for investigators to manipulate virtually any gene in a diverse range of cell types and organisms with targeted nucleases designed with sequence-specific DNA-binding domains.

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https://climate.nasa.gov/evidence/
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James Temple April 18, 2017

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Tatsuro Kiuchi

David Mitchell pulls into the parking lot of the Desert Research Institute, an environmental science outpost of the University of Nevada, perched in the dry red hills above Reno. The campus stares over the tops of the downtown casinos into the snow-buried Pine Nut Mountains. On this morning, wispy cirrus clouds draw long lines above the range.

Mitchell, a lanky, soft-spoken atmospheric physicist, believes these frigid clouds in the upper troposphere may offer one of our best fallback plans for combating climate change. The tiny ice crystals in cirrus clouds cast thermal radiation back against the surface of the earth, trapping heat like a blanket-or, more to the point, like carbon dioxide. But Mitchell, an associate research professor at the institute, thinks there might be a way to counteract the effects of these clouds.

It would work like this: Fleets of large drones would crisscross the upper latitudes of the globe during winter months, sprinkling the skies with tons of extremely fine dust-like materials every year. If Mitchell is right, this would produce larger ice crystals than normal, creating thinner cirrus clouds that dissipate faster. "That would allow more radiation into space, cooling the earth," Mitchell says. Done on a large enough scale, this "cloud seeding" could ease global temperatures by as much as 1.4 °C, more than the planet has warmed since the Industrial Revolution, according to a separate Yale study .

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Big questions remain about whether it would really work, what damaging side effects might arise, and whether the world should risk deploying a tool that could alter the entire climate. Indeed, the suggestion that we should entrust the global thermostat to an armada of flying robots will strike many as preposterous. But the real question is: preposterous compared to what?

Without some kind of drastic action, climate change could be killing an estimated half-million people annually by the middle of this century, through famine, flooding, heat stress, and human conflict. Preventing temperatures from rising 2 °C above preindustrial levels, long considered the danger zone that should be avoided at all cost, now looks nearly impossible. It would mean cutting greenhouse-gas emissions by as much as 70 percent by 2050, and it may well require developing technologies that could suck megatons of carbon dioxide out of the atmosphere, according to the U.N.'s Intergovernmental Panel on Climate Change. But a growing body of research suggests that we probably will not have the time or technology to pull this off. Notably, even if every nation sticks to the commitments it's made under the politically ambitious Paris climate accords, global temperatures could still soar more than 5 °C by 2100.

"Everyone is looking at two degrees, but to me it's a pipe dream," says Daniel Schrag, director of the Harvard University Center for the Environment, who was one of President Obama's top advisors on climate change. "I fear we'll be lucky to escape four, and I want to make sure nobody ever sees six."

The difference between two and four degrees is another quarter-billion people without reliable access to water, more than a hundred million more exposed to flooding, and massive declines in worldwide crop yields, according to a study by the Committee on Climate Change, a London-based scientific group established to advise the U.K. government (see below).

Without some kind of drastic action, climate change could be killing an estimated half-million people annually by the middle of this century.

The idea that we could counteract these dangers by reëengineering the climate itself, techniques collectively known as geoengineering, began to emerge from the scientific fringes about a decade ago (see "The Geoengineering Gambit"). Now momentum behind the idea is building: increasingly grim climate projections have convinced a growing number of scientists it's time to start conducting experiments to find out what might work. In addition, an impressive list of institutions including Harvard University, the Carnegie Council, and the University of California, Los Angeles, have recently established research initiatives.

Few serious scientists would argue that we should begin deploying geoengineering anytime soon. But with time running out, it's imperative to explore any option that could pull the world back from the brink of catastrophe, says Jane Long, a former associate director at Lawrence Livermore National Laboratory. "I don't really know what the answer is," she says. "But I do believe we need to keep saying what the truth is, and the truth is, we might need it."
Dreams of dust
Mitchell works in a small, square office on the top floor of the Desert Research Institute. Stacks of scientific papers crowd his desk; journals and binders pack his bookshelf. Close-up images of delicate ice crystals hang from thumbtacks on the bulletin board above his computer monitor.

In the spring of 2005, during a sabbatical at the National Center for Atmospheric Research in Boulder, Colorado, Mitchell began exploring how the size of ice crystals affects cirrus clouds and the climate system. He and his colleagues that bigger crystals, the type that tend to form in the presence of dust particles, produced fewer and thinner cirrus clouds.

That point stuck in Mitchell's brain. One morning shortly after returning to Nevada, he had a dream in which that insight morphed into a climate engineering scheme. He awoke wondering if deliberately adding dust in the areas where these clouds form would spawn these larger ice crystals, reducing cirrus coverage and releasing more heat into space.

280 million

120 million

12 million

24%

decline in global maize productivity

more people subjected to coastal flooding

more people exposed to major river floods

more people without access to adequate water

Though he had serious reservations about geoengineering, he decided to explore the idea. In 2009, he and a colleague published a paper suggesting that seeding cirrus clouds with tiny particles of bismuth tri-iodide, an inorganic compound that may break down into the necessary sub-micrometer size, might substantially offset climate change. More recently, Mitchell estimated that it would take around 160 tons of the material annually to seed clouds in the areas he has in mind, at a cost of about $6 million.

8%

34%

21%

of mammal species lose their habitat

of plant species lose half their suitable habitat

drop in spring wheat yields

Not everyone agrees the proposal would work. A 2013 paper in , led by MIT atmospheric scientist , concluded that the formation of ice crystals around dust, known as heterogeneous ice nucleation, is already the dominant mechanism creating cirrus clouds. That might mean adding more dust would, on balance, create thicker clouds that trap more heat. The larger problem with the idea, Cziczo argues, is that clouds are the least understood part of the climate system. We do not have nearly enough knowledge about cloud microphysics, or accurate enough measurements, to precisely manipulate climate in this way, he says.

But Mitchell's most recent research, relying on observations of ice crystal concentrations from NASA's Calipso satellite, has further convinced him that cloud seeding could work, as long as it's done in regions where cirrus clouds form primarily without dust particles. On the monitor in his office, Mitchell pulls up a page of maps from a paper he presented at the National Center for Atmospheric Research in late February. Navy- and light-blue dots, representing Cziczo's heterogeneous clouds, dominate the mid-latitudes, covering much of South America and Africa. But the higher latitudes are covered in red, yellow, orange, and green dots that indicate the sorts of clouds Mitchell has in mind.

The satellite images suggest that in very cold and humid conditions, toward the poles and particularly during winter, tiny ice crystals can form on their own, spontaneously, without dust. That suggests that cloud seeding could work, if it's targeted to those areas during those months. Mitchell even thinks he's come up with a way to get nature to carry out a field experiment to test his theory. During spring and winter, strong winds regularly stir up major dust storms in the deserts of Mongolia and the western edge of China. The fine particles blow across the Pacific and run into an atmospheric wave that rolls over the Rocky Mountains.

If Mitchell is correct, the dust should promote thinner cirrus clouds in an area where the thicker type otherwise tends to dominate. There was no way to properly observe this phenomenon-until late last year, when the National Oceanic and Atmospheric Administration launched a satellite equipped with some of the most powerful imaging technology ever launched into space, as well as sensors that can measure the temperatures of clouds. The satellite should be able to capture exactly what happens as the dust rides over the Rockies, detecting the subtle shifts under way in cloud microphysics.

Mitchell submitted a research proposal to NOAA last year, asking the agency to use the satellite to make such observations. He knows it's a long shot, particularly in light of the Trump administration's efforts to slash funding for climate science. But if NOAA agrees, the test could lend weight to his theory-or, of course, contradict it.

Another outdoor geoengineering experiment should occur even sooner.

By this time next year, Harvard professors David Keith and Frank Keutsch hope to launch a high-altitude balloon from a site in Tucson, Arizona. This will mark the beginning of a research project to explore the feasibility and risks of an approach known as solar radiation management. The basic idea is that spraying materials into the stratosphere could help reflect more heat back into space, mimicking a natural cooling phenomenon that occurs after volcanoes blast tens of millions of tons of sulfur dioxide into the sky (see " A Cheap and Easy Plan to Stop Global Warming ").

Scientists generally believe the technique would ease temperatures, but a lingering question is: what else will it do? Notably, volcanic eruptions have also significantly altered rainfall patterns in certain areas, and sulfur dioxide is known to deplete the protective ozone layer.

"The most likely scenarios for climate over longer time scales are devastating to future generations, absolutely devastating."

Keith has done extensive climate modeling to explore whether other materials, including alumina, diamond dust, and calcium carbonate, might have a neutral or even positive impact on ozone. During a conversation in his office at Harvard, he stressed that the experiments wouldn't constitute a test of geoengineering itself. But they would allow his group to subject its models to real-world data, revealing more about the relevant stratospheric physics and chemistry. "Theory alone doesn't tell you what will happen in the atmosphere," Keith says. "You can fool yourself if you don't go out and make direct measurements."

Keith has already begun design work with the balloon company World View Enterprises, as well as discussions about the appropriate transparency and oversight for such outdoor experiments. The early flights would test the basic workings of the balloon, which would be tethered to a gondola equipped with propellers, sprayers, and sensors. But eventually the experiment would involve releasing a fine plume of materials, probably calcium carbonate, into the stratosphere. The balloon would then track that trail in reverse, allowing the sensors to measure how well the particles scatter sunlight, whether they coalesce or disperse, and how they interact with precursors to ozone.
Unknown unknowns
Full-scale geoengineering would inevitably involve some level of risk. We are likely to face a terrible choice between accepting the clear dangers of climate change and risking the unknowns of geoengineering. Alan Robock, a professor of environmental sciences at Rutgers, has published a list of 27 risks and concerns raised by the technology, including its potential to deplete the ozone layer and to decrease rainfall in Africa and Asia.

Ultimately, Robock worries that geoengineering may simply be too risky to ever try. "We don't know what we don't know," he says. "Should we trust the only planet known to have intelligent life to this complicated technical system?" MIT's Cziczo is blunter. "We know the problem is greenhouse gas, so the solution is you take the greenhouse gas out," he says. "You don't try to do something that we completely don't understand."

The reservations surrounding geoengineering research were on full display in late March as dozens of notable climate and social scientists gathered at the Carnegie Endowment for International Peace in Washington, D.C., for the Forum on U.S. Solar Geoengineering Research. Speakers highlighted a long list of unanswered, and perhaps unanswerable, questions about international governance: Who gets to decide when to pull the trigger? How do we determine "correct" average temperatures when the same ones will affect different nations in markedly different ways? Can one nation be held responsible for the negative effects of its geoengineering scheme on another country's weather? Could these tools be used to deliberately attack a neighboring nation? And could conflicts over these questions tip into war?

"I have yet to hear any description of a future solar-geoengineered world that sounds to me anything other than dystopian or highly unrealistic," said Rose Cairns, a research fellow at the University of Sussex, who joined the morning discussion from England by Skype.

But Harvard's Schrag argued the opposite: that the scariest version of the future may be one where geoengineering is never developed or deployed. "I don't think people understand just what we're up against with climate," he said. "The most likely scenarios for climate over longer time scales are devastating to future generations, absolutely devastating."

As he flashed slides highlighting the dramatic loss of sea ice in the Arctic and Antarctic in recent months, Schrag stressed that climate change is already causing visible impacts faster than anyone expected. He added that it's difficult to foresee any scenario where we can cut greenhouse-gas levels fast enough to avoid far worse dangers: the amount we've already released is likely to lock in another degree of warming even if we halt emissions tomorrow, he said.

To his mind, these hard realities mean we need to try to answer the difficult questions geoengineering poses. "It is still, in every case that I've seen, better than the alternative of just letting the climate warm," he said. "Given the trajectory of the world, and the difficulty of reducing emissions, this is something we really need to understand."
The power of fear
Mitchell was opposed to geoengineering for most of his career. The idea that humankind should tinker with the finely tuned climate system struck him as impossibly arrogant. But like other researchers who spent decades staring at increasingly frightening projections while the world ignored the loudest warnings scientists knew how to sound, he reluctantly changed his view.

It could take decades to learn which geoengineering methods might work, whether environmental side effects can be minimized, and whether it's ultimately too dangerous to try. The longer we wait to begin serious research, the greater the risk we'll deploy an unsafe tool in the face of sudden climate shocks, or not have one in hand when we need it. And no one really knows when that might be.

Says Mitchell, "The need for climate engineering could be coming faster than we realize."

Credit

Data sources: Committee on Climate Change; U.N. Intergovernmental Panel on Climate Change

James Temple Senior Editor, Energy

I am the senior editor for energy at ... and columnist at the MIT Technology Review. I'm focused on renewable energy and the use of technology to combat climate change. Previously, I was a senior director at the Verge, deputy managing editor at Recode, More San Francisco Chronicle. When I'm not writing about energy and climate change, I'm often hiking with my dog or shooting video of California landscapes.

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As climate dangers grow, it might be time to begin limited geoengineering experiments

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Tatsuro Kiuchi David Mitchell pulls into the parking lot of the Desert Research Institute, an environmental science outpost of the University of Nevada, perched in the dry red hills above Reno. The campus stares over the tops of the downtown casinos into the snow-buried Pine Nut Mountains.

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Space Tourism Needs a Reality Check (Op-Ed)

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Space Tourism Needs a Reality Check (Op-Ed)

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By Piers Bizony

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(Image: © Swiss Space Systems)

Piers Bizony has written about science and the history of technology for a wide variety of publishers in the U.K. and the United States. His latest book, just released, is "New Space Frontiers: Venturing into Earth Orbit and Beyond" (Zenith Press, 2014). He contributed this article to Space.com's Expert Voices: Op-Ed & Insights.

In October 2004, Burt Rutan's SpaceShipOne rocket plane won the $10 million X Prize by becoming the first privately funded human-carrying craft to reach the edge of space. Within days of this historic event, Richard Branson announced that his new company, Virgin Galactic, would arrange financing for a successor vehicle, SpaceShipTwo, to carry civilian passengers into suborbital space. Ten years later, SpaceShipTwo is a wreck . One of its pilots, Michael Alsbury, was killed in a test flight on October 31. So far, no civilian customers have left the ground.

Is suborbital-space tourism an impossible dream? It's hard to tell. Despite the recent crash of SpaceShipTwo, Virgin Galactic is still a front-runner. Ignore all of those premature media speculations about difficulties with SpaceShipTwo's hybrid rocket engine. In fact, recent reports suggest part of the machinery was likely not at fault. Rather, something went wrong in the cockpit, triggering a premature command to unlock the rotating wing sections (the "feathering" system). Sure, the crash looks bad, and Alsbury's loss was desperately grim. Nevertheless, we shouldn't overreact. The underlying problem sounds fixable.

(Image credit: Sierra Nevada Corporation/NASA/Griffin Communications)

Failure and the nature of spaceflight
Failures are a necessary part of the aerospace learning curve. If only we could benefit from these lessons without having to mourn so many casualties. Remember the De Havilland Comet jet airliner from the 1950s? It was beautiful and sleek, and for a couple of glorious years, it put my little ol' country, Britain, at the forefront of a revolution in air travel. In quick succession, several Comet jets disintegrated in flight. Passengers and crews died because of a hitherto undiscovered phenomenon: metal fatigue. Although the De Havilland company was doomed, the aviation industry as a whole took note of the problems, and acted accordingly. Today's airliners are incredibly safe; intercontinental flight is far less risky than an automobile trip to the local mall.

Can we reach a similar safety plateau in the space tourism business? I'm not sure. Modern airplane prototypes undergo an extensive regimen of test flights before any civilian versions are launched onto the market. Airliners benefit from a wide range of safety systems, from fire suppressants and escape hatches to life rafts and cockpit data recorders. All of those technologies were refined on the basis of lessons learned.

However, no one has flown a civilian spaceship often enough to figure out what might be termed its "airworthiness." It might sound heartless, but we will probably need to tolerate more spacecraft crashes before we can really understand how to make future variants sufficiently safe for civilian passengers. [ The Future of Private Spaceflight (Gallery)]

(Image credit: NASA, Zenith Press)

Sufficiently safe
This brings me to my central question: What would be "sufficiently safe"? The Virgin Galactic crash surely tells the nascent space tourism industry that it may need to think again about letting untrained, inexperienced passengers into its vehicles. The Federal Aviation Administration (FAA) allows the imposition of insurance waivers for space tourists. In plain terms, as long as a spaceship company is not downright careless in the design and operation of flight hardware, passengers could sign a form indicating their acceptance of risk in an untested new commercial and technological adventure.

That semirelaxed attitude may have to be revised. Recent developments suggest that rocket vehicles are still unusually hazardous, because we simply haven't flown them often enough to know what we're up against.

(Image credit: SPACE.com)

So what do we do? An obvious first step is for space tourism companies to reduce their expectations about passenger numbers, and to charge a substantially greater fee to those few clients who still wish to be accommodated.

Let's have no more talk of movie actors and pop stars popping into space for a quick thrill. Instead, let's focus on serious investors for whom space flight is not just a potential joyride, but a lifelong dedication. We need more pioneers like Dennis Tito and Anousheh Ansari. We need each participant in the space adventure to be substantially prepared for the realities of space flight before they board their vehicle, and to do something meaningful when they finally get up there - something, to be blunt, for which they might be prepared to risk their lives.

I don't think a 15-minute hop above the atmosphere counts as something for which civilians should be asked to risk their necks. The fact that even a few Virgin Galactic customers have canceled their reservations at the first sign of trouble suggests that they, too, have reached similar conclusions. [ Safety Is Key to Private Spaceflight's Rise & Success ]

Private spaceflight is here to stay, and it's going to achieve fantastic things. The future will be even brighter if everyone remembers physicist Richard Feynman's warning to the space community in the wake of shuttle Challenger's loss: "For a successful technology, reality must take precedence over public relations, for nature cannot be fooled."
Follow all of the Expert Voices issues and debates - and become part of the discussion - on Facebook, Twitter and Google+. The views expressed are those of the author and do not necessarily reflect the views of the publisher. This version of the article was originally published on Space.com.

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(Image: © Swiss Space Systems) Piers Bizony has written about science and the history of technology for a wide variety of publishers in the U.K. and the United States. His latest book, just released, is "New Space Frontiers: Venturing into Earth Orbit and Beyond" (Zenith Press, 2014).

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