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SABG11- Milk Spoilage (Deconstruct & Design)

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SABG11- Milk Spoilage (Deconstruct & Design)

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SABG11 - Deconstruction Template - Milk spoilage

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SABG11 - Deconstruction Template - Milk spoilage

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Article for SHE (Topic Enzyme/ Receptors). Due date for draft: 29 Jan 2018)

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Altmetric: 27

Citations: 4

More detail

Outlook

Advanced tumours may have met their match with new drugs, but why have these treatments proved ineffective at stopping early-stage tumours from coming back?

Kidney cancer has frustrated the best efforts of clinicians. The disease is notoriously resistant to chemotherapy, and is often caught only after it has metastasized. As recently as 2013, survival for people with advanced cancer who were treated in clinical trials was two and a half years on average.

"I've been here taking care of people with kidney cancer for over 25 years," says Robert Motzer, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City. "When I started here in the 1980s, the average survival on chemotherapy was less than a year.

X-ray of a kidney showing a clear-cell renal cell carcinoma (blue) Image: Sovereign/ISM/SPL

Treatment advances were modest over the intervening decades. But in the past year, three new drugs have brought hope. These therapies represent the "first big revolution that is going to change survival and the way we are going to treat our patients", says Bernard Escudier, a kidney-cancer specialist at Gustave Roussy near Paris. The key developments revolve around research on the genetic changes that allow kidney tumours to create their own blood supply and grow. The new drugs target the specific pathways in the process, and hold promise for personalized therapy that is more effective, and has fewer side effects, than previous treatments. "The paradigm has changed with these new drugs all coming in within a year," says Motzer.

But it is a revolution that seems to have passed by early-stage kidney cancer. Targeted therapies do not prevent initial tumours from recurring and can have serious toxic effects. This 'good news, bad news' story, however, is teaching researchers more about how the disease works.
Ambushing cancer pathways
Targeted therapy arose from the discovery that a gene called VHL is inactivated in most people with clear-cell renal cell carcinoma (RCC), which accounts for about 70% of kidney cancers. When it is functioning, VHL suppresses tumours by regulating angiogenesis - the formation of new blood vessels. Tumours need their own blood supply to grow, the loss of VHL allows this angiogenesis.

Researchers have been exploring the promise of drugs that treat cancer by stopping angiogenesis since the process was first proposed in 1971 by the US vascular researcher Judah Folkman. The first antiangiogenesis drug for any type of cancer, bevacizumab, was approved in 2004 for metastatic colon cancer. The drug has since been approved for a variety of cancers, including advanced RCC. The first antiangiogenesis drugs approved specifically for RCC, sorafenib and sunitinib, were approved in 2005 and 2006. "It changed the way we treated this disease, away from chemotherapy and towards these targeted drugs," says Motzer. "It opened up a whole new era of treatment."

Sorafenib and sunitinib opened the floodgates. In the next ten years came pazopanib and axitinib (see 'A new era of treatment'). Each of these drugs targets the tyrosine kinase receptors of an enzyme involved in the growth of blood vessels, vascular endothelial growth factor receptors (VEGFRs). In spring 2016, two more VEGFR inhibitors, cabozantinib and lenvatinib (in combination with everolimus), were approved by the US Food and Drug Administration (FDA) for the treatment of RCC. These newly approved drugs are more effective than their predecessors, increasing the time before the cancer progresses as well as improving survival. This might be because the drugs target other pathways in addition to VEGFR, says Motzer.

Another new class of drug targets a different enzyme linked to angiogenesis, known as mTOR. Temsirolimus and everolimus were approved for advanced RCC by the FDA in 2007 and 2009, respectively.

A third pathway involves a molecule made by many types of cancer cell: the ligand PD-L1 binds to a receptor called PD-1 on immune cells known as T cells and stops these cells from attacking the cancer. Nivolumab was approved for advanced RCC in November 2015. The checkpoint inhibitor blocks PD-1 on T cells, allowing the cells to find and kill the tumour (see page S109).

"Patients have their disease controlled for a certain time period and then generally progress."

Until the past-year's entrants on the scene, this plethora of new drugs had positive, but mixed, results. Motzer has led randomized trials of several of these drugs, and found that survival generally improved. Pazopanib and sunitinib increased average survival time to two and a half years. "Patients have their disease controlled for a certain time period and then generally progress," Motzer says. "We see very few complete remissions."

The outcomes have disappointed Naomi Haas, who specializes in kidney and prostate cancer at the University of Pennsylvania's Abramson Cancer Center in Philadelphia. The initial rush of excitement following the drugs' approvals has faded, she says. "As time went on, we realized the drugs had a lot of side effects and it was a small proportion of people who had complete disappearance of their cancer.

And the drugs do not work for early-stage tumours. If RCC is caught before it has spread beyond the kidney, the survival rate is very high. Unfortunately, because early-stage tumours rarely cause pain or significant bleeding, they are usually found by accident, after diagnostic imaging for other reasons. If tumours are not caught early, they are often not detected until the cancer has metastasized.

For early-stage tumours, the main treatment is surgery. Part or all of the kidney is removed, depending on the extent of the tumour. The nearby adrenal gland and lymph nodes may also be removed. Follow-up involves observing the kidneys for recurrence or spread. Clinical trials of chemotherapy, hormonal therapy and immunotherapy with interleukin-2 or interferon have all shown no difference in recurrence of tumours.

Using prediction tools called nomogram tables, clinicians can assess the risk of recurrence. The table can include criteria such as the tumour's stage at the time of surgery, the patient's status (extent of symptoms or physical-activity level, for example), the tumour's grade (based on the Fuhrman grading system) and the presence of tumour necrosis. Tumours are considered to be high risk if, according to the criteria, the chance of recurrence is 40% or more.

In a study earlier this year, Haas investigated the effectiveness of the antiangiogenesis drugs sunitinib and sorafenib for people with early-stage RCC who are at high risk of recurrence. Because these drugs halted the progression of advanced cancer, the hope was that they would also prevent it from reoccurring. But that was not the case. "I was very surprised to see that in our hazard ratio, the curves were virtually the same as placebo," Haas says.

The study was stopped earlier than planned. The time to recurrence in the people who were treated with the drugs after the initial tumour was surgically removed was not significantly different to the placebo group. The question is why? Haas thinks that the answer will help researchers to better understand how RCC spreads.

The targeted therapy may not have worked for early-stage RCC because, compared with large, highly vascularized metastatic tumours, the 'micrometastases' that establish new tumours when the disease reoccurs may not yet have their own blood supply, Haas explains.

The drugs also caused more-severe side effects in early-stage patients than had been seen in patients with advanced cancer. These were mainly hypertension, hand-foot syndrome (calluses on hands and feet that can become raised and tender), rashes and fatigue. It is not clear why there is a higher rate of serious side effects in people with early-stage cancer, Haas says. Although the people in her study may have been healthier than later-stage patients and so have simply noticed and reported more side effects, Haas thinks that the drugs may cause worse side effects when there are no tumours. "These drugs have no tumour to hit, so they may have more 'off-target' effects," she says. "They're hitting normal organs and making people feel worse."

Robert Motzer, a medical oncologist at the Memorial Sloan Kettering Cancer Center. Image: Memorial Sloan Kettering Cancer Center

Escudier says that trials are underway to investigate other VEGFR inhibitors in early-stage RCC, but he is not hopeful. "It is very likely that all of these trials are going to be negative," he says. These drugs have also failed in other types of cancer such as breast and colorectal cancer, Escudier says. The negative results of Haas' study were "not a surprise", he says.
Shifting standards of care
But there is good news. Antiangiogenesis drugs have changed the standard of care for advanced RCC, increasing lifespan with a reasonable quality of life for patients.

Following a shift, initially from chemotherapy to immunotherapy and then towards antiangiogenics, the recommended protocols for which drugs to use in which sequence also changed, as new drugs moved from lab to bedside. Up to four lines of defence against RCC are needed because, in most cases, tumours eventually develop resistance to drugs that target a particular pathway. The strategy is to switch drugs - and often pathways - until the cancer eludes the therapy.

Protocols can vary, but first-line treatment will involve either an immunotherapy, a VEGFR inhibitor or an mTOR inhibitor. Once resistance develops and cancer progresses, patients are switched to another therapy - either a different VEGFR or mTOR inhibitor or the checkpoint inhibitor nivolumab.

But Motzer has achieved promising results by combining drugs to target three pathways at once. He used lenvatinib, which targets both VEGFRs and fibroblast growth factor receptor (also thought to be involved in angiogenesis in RCC), combined with everolimus, which targets mTOR. The combination led to improved survival - both before the cancer progressed and overall - than everolimus alone. Although Motzer had hoped for an improved result, he was surprised at the magnitude of the improvement: the drug combination prevented cancer from progressing for a median of 14.6 months.

The phase II trial led to FDA approval of lenvatinib with everolimus for advanced RCC. Motzer is now planning a randomized controlled trial that compares lenvatinib in combinations with two other drugs, with sunitinib as a control.

"We do not know for certain why the results were so good."

Motzer, along with Escudier, also found that cabozantinib led to longer survival than everolimus. "We do not know for certain why the results were so good," says Motzer. In addition to inhibiting VEGFRs, cabozantinib inhibits two other tyrosine kinases, MET and AXL, which are found at high levels in people with clear-cell RCC and are associated with a poor prognosis. The interaction with these proteins may account for the results, says Motzer.

The new therapies make the protocols for treatment a moving target. Escudier says that the priority for research now is to determine how to select the best therapy for the patient. "We really need to know how to use the drugs we have." For example, if one drug works for about 30% of patients, how do you identify the 30% that should be given the drug?

Although patients are currently stratified for therapy, according to their risk of recurrence, stage of cancer and previous treatments, the promise of personalized therapy is that treatments can be aimed at a pathway specific to the individual's cancer - selecting the right drug for the right patient.

Instead of bombarding RCC with drugs that target several pathways, in the future, the target will be determined first. "Probably, in the very near future we are going to treat only those patients who have an mTOR aberration in the pathway" with mTOR inhibitors, Escudier says.

But to decide the best therapy, clinicians need something that they can test for to tell them which is the relevant pathway. This can include biomarkers or genomic and next-generation sequencing methods to determine the phenotype of the tumour, Escudier says. Over the next few years, results should be available from studies examining the selection of therapy based on the tumour phenotype. Personalizing therapy would not only be more effective, but would also help to avoid the accumulated adverse effects of taking several drugs at once.

Researchers also need to understand how long drugs need to be given and at what dosage. "We want to give them as much as we need to - not too much - to avoid toxicity and keep the efficacy," says Escudier.

The promising outcomes of targeted therapies are changing the treatment goals for people with advanced RCC. Clinicians used to talk in terms of progression-free survival (how long until the cancer progressed) and overall survival (how long until the patient died). Now, they are daring to talk about the disappearance of the cancer. Escudier thinks that complete remission may be achievable in 20-30% of patients in the next few years, on the basis of the rates of response to the new drugs and the increasing rates of survival that have been reported.

The incremental improvements in patients' survival have been double-edged, says Escudier. "You see your patients more frequently and you become friends with them, yet in the end they die." It is frustrating to be unable to offer a cure, he says. With new treatments and improved prognosis, Escudier is looking forward to giving them better news.

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Targeted therapy: An elusive cancer target

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Altmetric: 27 Citations: 4 More detail Outlook Advanced tumours may have met their match with new drugs, but why have these treatments proved ineffective at stopping early-stage tumours from coming back? Kidney cancer has frustrated the best efforts of clinicians. The disease is notoriously resistant to chemotherapy, and is often caught only after it has metastasized.

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Attached is the article for stem cell research in Japan.

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Scientists in Japan now have permission to treat people who have heart disease with cells produced by a revolutionary reprogramming technique. The study is only the second clinical application of induced pluripotent stem (iPS) cells. Th﻿ese are created by inducing the cells of body tissues such as skin and blood to revert to an embryonic-like state, from which they can develop into other cell types.

On 16 May, Japan's health ministry gave doctors the green light to take wafer-thin sheets of tissue derived from iPS cells and graft them onto diseased human hearts. The team, led by cardiac surgeon Yoshiki Sawa at Osaka University, says that the tissue sheets can help to regenerate the organ's muscle when it becomes damaged, a symptom of heart disease that can be caused by a build-up of plaque or by a heart attack.

"It will excite worldwide attention, as many groups are working in the same direction," says Thomas Eschenhagen, a pharmacologist at the University of Hamburg in Germany and chair of the German Centre for Cardiovascular Research.

The treatment will initially be given to three people over the next year. The team will then seek approval to conduct a clinical trial in around ten patients. If it proves safe, the treatment could then be sold commercially under Japan's fast-track system for regenerative medicine.

The system, introduced in 2014, aims to speed the availability of potentially life-saving procedures. But critics say the system is flawed because it allows treatments to be sold to patients before sufficient data have been collected showing that the procedures work.

Mending broken hearts

In their technique, Sawa and his colleagues use iPS cells to create a sheet of 100 million heart-muscle cells. From studies in pigs, the team has shown that grafting these sheets of cells - each 0.1 millimetres thick and 4 centimetres long - onto a heart can improve the organ's function. Sawa says that the cells do not seem to integrate into the heart tissue. He thinks that instead they release growth factors that help to regenerate the damaged muscle.

Scientists say one advantage of the sheets is that they create their own cellular matrix, and can maintain their structure without the need for scaffolding made from foreign materials, a feature of some other engineered tissues.

"It is a very elegant and clever way to deliver cells," says Philippe Menasché, a cardiac surgeon at the Georges Pompidou European Hospital in Paris, who has also experimented with making tissue sheets.

Pharmacologist Wolfram-Hubertus Zimmermann at the University Medical Centre Göttingen in Germany, who is also developing an iPS treatment for heart disease, says that the latest trial is based on work conducted by Sawa and other colleagues in Japan over the past 15 years.

Once Sawa's team has treated its three patients, it will apply to conduct a clinical trial involving a further seven to ten people. If the treatment proves to be safe, and shows some signs of working, it can be approved for sale under the accelerated system. This allows researchers to bypass expensive large-scale clinical trials aimed at proving efficacy, and instead to use small pilot trials to show that the therapy is safe and demonstrates an indication of efficacy.
Insufficient oversight
But some researchers say the bar for approving therapies for commercial use is too low. Even if the cells are found to be safe, there are risks associated with any surgery, and patients could give up other therapies for a treatment that might not work. Ethicists and regulators say that the benefits of any new therapy must outweigh the risks.

Yoshiki Yui, a cardiologist at Japan's Kyoto University, says that, as well as meeting the requirements for safety, researchers should show that their treatment is effective, which would require testing it in larger numbers of people than are currently required. The evaluation process should also use randomized, controlled clinical trials, the gold standard for demonstrating efficacy in medical research, he says.

The iPS-cell therapy has potential, Yui adds, but under the current approval system, "we won't know if it works or not" because it won't have been tested in a controlled trial. "The biggest problem is there's no adequate system of evaluation in Japan," says Yui.

A spokesperson for the health ministry told Nature that the current approval system is sufficient because researchers must still show that a treatment works even if it has been approved for commercial use.

Sawa agrees that a control group is important for proving efficacy, but notes that he is abiding by Japan's rules, which don't require this before a treatment is made commercially available.

He says the health ministry's approval is an acknowledgement that the therapy "is scientifically and ethically justified" to be tested in patients. "Whether it really works, [we] have to find out now," he adds.
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'Reprogrammed' stem cells approved to mend human hearts for the first time

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Scientists in Japan now have permission to treat people who have heart disease with cells produced by a revolutionary reprogramming technique. The study is only the second clinical application of induced pluripotent stem (iPS) cells. Th﻿ese are created by inducing the cells of body tissues such as skin and blood to revert to an embryonic-like state, from which they can develop into other cell types.

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Discussion in class. (DONE)

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BBC - History - Historic Figures: Watson and Crick (1928- )

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discovered structure of DNA, Nobel prize winners

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The biologists had already suspected that optix played a role in activating the butterfly's brown pigment. But they were surprised that the black pigment was turned on in the absence of optix.

A further surprise came when they turned off the optix gene in a second species, the buckeye. The butterfly's usual browns and yellows disappeared, replaced by scales of a blazing iridescent blue. "That knocked our socks off," Dr. Reed said.

A second group, led by Anyi Mazo-Vargas of Cornell University and Arnaud Martin of George Washington University, has explored the role of a gene called WntA, which plays a powerful role in the patterning of butterflies' wings.

The standard pattern of nymphalid butterflies, a 90-million-year-old family of some 6,000 different species, consists of four bands, parallel to the body, that run between it and the edge of the wings. The second band, called the central symmetry system, contains the pattern in the middle of the wings, and the third band holds the eye spots.

Dr. Martin's team found that when they delete the WntA gene with the Crispr technique, the central symmetry system band disappears entirely from the wings of the speckled wood and buckeye butterflies.

But in other species, the loss of WntA has very different effects, suggesting that the gene has been adapted many times to play different patterning roles as new butterfly species evolved.

In the monarch butterfly, for instance, loss of WntA affects an almost invisible white line that edges the distinctive black lines that delineate the wing's veins. In the absence of WntA, the white lines expand into the areas between the veins, replacing the distinctive orange pigment.

The WntA gene becomes active in the caterpillar stage, impressing its patterning information on the embryonic wing structures. Dr. Martin sees the WntA gene as a sketching tool that defines the outline of the wing design, and the optix gene studied by Dr. Reed's group as a "paintbrush" gene that fills in the color.

Dr. Reed hopes in time to understand the patterning mechanism so well that he will be able to recreate the pattern of one butterfly's wings on those of a second species. But understanding butterfly wing patterning is just a step toward addressing larger questions in evolutionary biology.

One is the knotty question of how the string of information in a DNA molecule specifies the 3-D structures of the body. The butterfly wing presents this problem more tractably, in just two dimensions.

Another is that of how species evolve different forms. The work of these two groups shows that genes like WntA and optix - master genes that control the activity of other genes - can evolve very different roles in different species.

The nymphalid butterflies use WntA one way, the monarch for a quite another. The optix gene controls specialized wing scales in moths, but when butterflies evolved it somehow recruited a quite different set of servant genes, ones involved in generating pigment, not scale type.

"A big question in evolutionary biology is how do you rewire these gene networks," Dr. Reed said.

Both Dr. Reed and Dr. Martin are enthralled by the ease and power of the Crispr gene-editing tool, invented in 2012. Before, they could infer what a gene might do but couldn't prove it.

With Crispr, they can manipulate any gene of choice inside an egg and see exactly what it does.

"These are experiments we could only have dreamed of years ago," Dr. Reed said. "The most challenging task in my career has become an undergraduate project overnight."

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proceedings of the national academy of sciences

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Genes Color a Butterfly's Wings. Now Scientists Want to Do It Themselves.

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The biologists had already suspected that optix played a role in activating the butterfly's brown pigment. But they were surprised that the black pigment was turned on in the absence of optix. A further surprise came when they turned off the optix gene in a second species, the buckeye.

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A recent article by Nicholas Wade in the New York Times highlights the importance of epigenetic influences on gene expression and the increasing role understanding the epigenome will play in designing medical interventions of the future. Rett Syndrome provides a dramatic example of the remarkable power and control of an epigenetic gene, demonstrated by the restoration of normal function in mouse models of the disorder.

February 24, 2009

From One Genome, Many Types of Cells. But How?

By NICHOLAS WADE

Secrets of the Cell
One of the enduring mysteries of biology is that a variety of specialized cells collaborate in building a body, yet all have an identical genome. Somehow each of the 200 different kinds of cells in the human body - in the brain, liver, bone, heart and many other structures - must be reading off a different set of the hereditary instructions written into the DNA.

The system is something like a play in which all the actors have the same script but are assigned different parts and blocked from even seeing anyone else's lines. The fertilized egg possesses the first copy of the script; as it divides repeatedly into the 10 trillion cells of the human body, the cells assign themselves to the different roles they will play throughout an individual's lifetime.

How does this assignment process work? The answer, researchers are finding, is that a second layer of information is embedded in the special proteins that package the DNA of the genome. This second layer, known as the epigenome, controls access to the genes, allowing each cell type to activate its own special genes but blocking off most of the rest. A person has one genome but many epigenomes. And the epigenome is involved not just in defining what genes are accessible in each type of cell, but also in controlling when the accessible genes may be activated.
In the wake of the decoding of the human genome in 2003, understanding the epigenome has become a major frontier of research.
Since the settings on the epigenome control which genes are on or off, any derangement of its behavior is likely to have severe effects on the cell.

There is much evidence that changes in the epigenome contribute to cancer and other diseases. The epigenome alters with age - identical twins often look and behave a little differently as they grow older because of accumulated changes to their epigenomes. Understanding such changes could help address or retard some of the symptoms of aging. And the epigenome may hold the key to the dream of regenerative medicine, that of deriving safe and efficient replacement tissues from a patient's own cells.

Because the epigenome is the gateway to understanding so many other aspects of the cell's regulation, some researchers have criticized the "piecemeal basis" on which it is being explored and called for a large epigenome project similar to the $3 billion program in which the human genome was decoded. At present the National Institutes of Health has a small, $190 million initiative, called the Epigenome Roadmap, with the money going to individual researchers.

As is often the case, academic researchers oppose a large, centralized project if the money seems likely to come out of their grants. But it is also true that such projects often fail unless carefully timed and thought out.

"Definitely this is a genome-sized thing, and I believe it will have benefits beyond what are foreseen at present," says Richard A. Young, a biologist at the Whitehead Institute in Cambridge. But Steven Henikoff of the Fred Hutchinson Cancer Research Center in Seattle says the present methods for studying the epigenome are not yet ready to be scaled up. "It's too early to mount a technology development that would be large scale," he says.

The epigenome consists of many million chemical modifications, or marks as they are called, that are made along the length of the chromatin, the material of the chromosomes. The chromatin includes the double-stranded ribbon of DNA and the protein spools around which it is wound. Some of the marks that constitute the epigenome are made directly on the DNA, but most are attached to the short tails that stick out from the protein spools. Marks of a certain kind generally extend through a large region or domain of the DNA that covers one or more genes. They are recognized by chromatin regulator proteins that perform the tasks indicated by each kind of mark.

In some marked domains, the regulators cause the DNA to be wound up so tightly that the genes are permanently inaccessible. The center and tips of the chromosomes are sites of such repressive domains. So is one of the two X chromosomes in every woman's cells, a step that ensures both male and female cells have the same level of activity of the X-based genes.

In other domains, the marks are more permissive, allowing the gene regulators called transcription factors to find their target sites on the DNA. The transcription factors then recruit other members of the complex transcription machinery that begins the process of copying the genes and making the proteins the cell needs. A third kind of domain must be established ahead of the transcription machinery to let it roll along the DNA and transcribe the message in the underlying gene.

Only a handful of domains are known so far, so it is something of a puzzle that more than 100 kinds of marks have been found in the epigenome, along with specialist protein machines that attach or remove each mark. Some biologists think so many marks are needed to specify a few kinds of domain because the system is full of backups.

The epigenome's role in marking up the genome seems to have been built on top of a more ancient packaging role. The packaging would have been needed by one-celled organisms like yeast that keep their genome in a special compartment, the nucleus. For multi-celled organisms to evolve, the chromatin's packaging system presumably adapted during the course of evolution to index the genome for the needs of different types of cell.

The DNA packaging system alone is an extraordinary technical feat. If the nucleus of a human cell were a hollow sphere the size of a tennis ball, the DNA of the genome would be a thin thread some 24 miles long. The thread must be packed into the sphere with no breakages, and in such a way that any region of it can be found immediately.

The heart of the packaging system is a set of special purpose proteins known as histones. Eight histones lock together to form a miniature spool known as a nucleosome. The DNA twists almost twice round each nucleosome, with short spaces in between. Some 30 million nucleosomes are required to package all the DNA of ordinary cells.

For years, biologists assumed that the histones in their nucleosome spools provided a passive framework for the DNA. But, over the last decade, it has become increasingly clear that this is not the case. The histone tails that jut out from the nucleosomes provide a way of marking up the genetic script. Although one kind of mark is attached directly to the bases in the DNA, more than a hundred others are fixed onto specific sites on the histones' tails. When the DNA has to replicate, for cell division, the direct marks pass only to the two parent strands and all the nucleosomes are disassembled, yet the cell has ingenious methods for reconstituting the same marks on the two daughter genomes. The marks are called epigenetic, and the whole system the epigenome, because they are inherited across cell division despite not being encoded in the DNA.

How is the structure of the epigenome determined? The basic blueprint for the epigenomes needed by each cell type seems to be inherent in the genome, but the epigenome is then altered by other signals that reach the cell. The epigenome is thus the site where the genome meets the environment.

The organization of the epigenomes seems to be computed from information inherent in the genome. "Most of the epigenetic landscape is determined by the DNA sequence," says Bradley Bernstein, a chromatin expert at Massachusetts General Hospital. The human genome contains many regulatory genes whose protein products, known as transcription factors, control the activity of other genes. It also has a subset of master regulatory genes that control the lower-level regulators. The master transcription factors act on each other's genes in a way that sets up a circuitry. The output of this circuitry shapes the initial cascade of epigenomes that are spun off from the fertilized egg.

The other shapers of the epigenome are the chromatin regulators, protein machines that read the marks on the histone tails. Some extend marks of a given kind throughout a domain. Some bundle the nucleosomes together so as to silence their genes. Others loosen the DNA from the nucleosome spools so as to ease the path of the transcription machinery along a gene.

Biologists had long assumed that once the chromatin regulators had shaped an epigenome, their work could not be undone because a cell's fate is essentially irreversible. But a remarkable experiment by the Japanese biologist Shinya Yamanaka in June 2007 underlined the surprising power of the master transcription factors.

By inserting just four of the master regulator genes into skin cells, he showed the transcription factors made by the genes could reprogram the skin cell's epigenome back into that of the embryonic cell from which it had been derived. The skin cell then behaved just like an embryonic cell, not a skin cell. Until then, biologists had no idea that the epigenome with its millions of marks could be recast so simply or that transcription factors could apparently call the shots so decisively.

But subsequent research has shown the chromatin regulators are not pushovers. Only one in a million of the skin cells treated with the four transcription factors reverts fully to the embryonic state. Most get stuck in transitional states, as if the chromatin regulators are resisting a possibly cancerous change in the cell's status. "The take-home story is that yes, the transcription factors are really critical players in determining cellular state, but epigenetics is important, too," Dr. Bernstein said.

The ideal of regenerative medicine is to convert a patient's normal body cells first back into the embryonic state, and then into the specific cells lost to disease. But to prepare such cells safely and effectively, researchers will probably need to learn how to control and manipulate the chromatin of the epigenome as well as the transcription factors that shape cell identity.

The treatment of many diseases may also lie in drugs that manipulate the epigenome. Rett syndrome, a form of autism that affects girls, is caused by a mutation in the gene for an enzyme that recognizes the chromatin marks placed directly on the DNA. At least in mice, the neurons resume normal function when the mutation is corrected. In several forms of cancer, tumor-suppressor genes turn out to have been inactivated not by mutation, the usual known cause, but by the incorrect placement of marks that invite chromatin regulators to silence the genes.

Drugs developed by Peter A. Jones of the University of Southern California reverse the chromatin silencing of these antitumor genes. Two have recently been approved by the Food and Drug Administration for a blood malignancy, myelodysplastic syndrome.

Besides governing access to the genome, the epigenome also receives a host of signals from the environment. A family of enzymes called sirtuins monitors the nutritional state of the cell, and one of them removes a specific mark from the chromatin, providing a possible route for the genome to respond to famine conditions. Accumulating errors in the epigenome's regulation could allow the wrong genes to be expressed, a possible cause of aging.

A principal new technique for studying the marks on an epigenome is to break the chromosomes into fragments, which are then treated with antibodies that bind to a specific mark. The DNA fragments so designated are decoded and matched to sites on the human genome sequence. This provides a genome-wide map of how a particular mark is distributed in a particular epigenomic state. The CHiP-seq maps, as they are called, have been very useful but are far from capturing the full detail of the epigenome, a dynamic structure that can change in minutes.
Individual researchers have made considerable progress but may not be able to assemble the comprehensive set of epigenomic marks and states that would be most useful to those developing new approaches to disease and aging. "I think the effort needs to be organized," Dr. Young said. "It would benefit from being larger than it is."

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epigenetics | Rett Syndrome Research Trust Blog

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A recent article by Nicholas Wade in the New York Times highlights the importance of epigenetic influences on gene expression and the increasing role understanding the epigenome will play in designing medical interventions of the future.

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Epigenetic Influences and Disease | Learn Science at Scitable

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The external environment's effects upon genes can influence disease, and some of these effects can be inherited in humans. Studies investigating how environmental factors impact the genetics of an individual's offspring are difficult to design. However, in certain parts of the world in which social systems are highly centralized, environmental information that might have influenced families can be obtained.

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Credit: Mopic/Shutterstock

The gene-editing tool known as CRISPR is fast becoming known for its potential to treat disease by snipping genetic mutations from DNA.

But genomic tools like CRISPR also have other possible capabilities, such as the ability to screen people for the presence of viruses, like dengue and Zika, as well as debilitating diseases like Parkinson's.

"I think the public perception of CRISPR is very focused on the idea of using gene editing clinically to cure disease. This is no doubt an exciting possibility, but this is only one small piece," said Neville Sanjana, of the New York Genome Center and an assistant professor of biology, neuroscience and physiology at New York University. [ 10 Amazing Things Scientists Just Did with CRISPR]

"With CRISPR, I think you'll see many applications in synthetic biology," like sensors for pathogens, Sanjana told Live Science.

At its core, CRISPR is a natural defense system that evolved in single-celled microorganisms to fight against invading viruses. The fight is an all-out war. Scientist estimate that for every cell on Earth, there are about 10 viruses, all launching relentless missions to replicate themselves by inserting their DNA into the machinery in cells.

Bacteria use an arsenal to fight back, including CRISPR, which is an array of short, repeated sequences of DNA that are separated by spacers that have unique sequences.Bacteria use it when they are infected with a virus. As the virus's genetic bits replicate inside the bacteria, CRISPR steps in, guiding the bacterial defenses toward the foreign material.

The protein in CRISPR cuts up the intruder, but also collects a short DNA sequence from the invader, which the protein inserts it into the bacteria's CRISPR as a spacer. Each time a virus invades and is destroyed, a new spacer gets added to the CRISPR.

In a sense, the spacers in CRISPR are an account of the bacteria's battlefield wins, like kill marks in the stock of a rifle barrel. But the spacers provide another function.

When a virus that was previously defeated tries to invade, the bacteria recognizes it and sets about chopping the invader up into tiny bits. And when the bacteria itself multiplies, it passes it's defense system on to its daughter cells.

"It turns out you can actually leverage these properties to potentially develop a very sensitive diagnostic device" that could detect small amounts of molecules from viruses in human blood, such as Zika virus, said biochemist and CRISPR expert Sam Sternberg, the group leader of Technology Development at Berkeley, California-based Caribou Biosciences Inc., which is advancing new applications for CRISPR-based technologies. [ 5 Amazing Technologies That Are Revolutionizing Biotech]

One of the most recent CRISPR advances in this area is a tool called SHERLOCK (which stands for Specific High Sensitivity Enzymatic Reporter UnLOCKing). In April 2017, a team of researchers led by bioengineer James Collins and CRISPR pioneer Feng Zhang of the Broad Institute of MIT and Harvard reported in Science that they had programmed a CRISPR molecule to seek out strains of Zika and dengue viruses in blood serum, urine and saliva and cut them up.

The researchers programmed the CRISPR molecules to release a fluorescent signal when they were chopping away at the viruses, so that the presence of the virus could be detected. SHERLOCK was so sensitive, it was able to distinguish the American strain of Zika from the African strain and differentiate one strain of dengue from another one.

Collins and his team were able to see the presence of the viruses even in extremely low concentrations, as low as two molecules in a quintillion.

In a separate test, SHERLOCK was able to detect two different strains of the antibiotic-resistant superbug Klebsiella pneumoniae. [ 6 Superbugs to Watch Out For]

Then, in June 2017, a team at the University of Central Florida reported in the journal Scientific Reports that they had used a CRISPR system to detect the presence of Parkinson's disease. This disorder of the central nervous system causes malfunction and death of nerve cells in the brain, and gets worse over time, causing tremors and problems with movement. The disease affects about 1 million people in the United States, according to the Parkinson's Disease Foundation.

Although the cause is unknown, the amount of a protein called alpha-synuclein, normally found in the brain, rises in people who develop the disease. The researchers used CRISPR to edit the gene that makes the alpha-synuclein protein so that the protein would fluoresce. The larger the amount of the protein, the stronger the fluorescent signal.

The scientists said they think they could use this technique to test out new drugs to treat Parkinson's disease.

"If we take one of these modified cells and treat it with a particular drug, if it doesn't produce light anymore, then this means the drug is a potential treatment for this disease," study co-author Sambuddha Basu, a postdoctoral researcher at Central Florida, said in a statement.

It's still the very early days for these and other CRISPR-related biological tools, and because of the diversity of the immune systems in bacteria, it's quite possible that other tools remain to be discovered, Sternberg said.

"I think it's a really nice example of yet another basic science discovery that has led to a potential breakthrough technology," he said.

Originally published on Live Science.

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The gene-editing tool known as CRISPR is fast becoming known for its potential to treat disease by snipping genetic mutations from DNA. But genomic tools like CRISPR also have other possible capabilities, such as the ability to screen people for the presence of viruses, like dengue and Zika, as well as debilitating diseases like Parkinson's.

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(NaturalNews) U.S. scientists recently announced the birth of a baby containing DNA from three different people in an article in New Scientist. They will present the details of the new procedure they used at the October meeting of the American Society for Reproductive Medicine.

The procedure, which is illegal in the United States, was performed in Mexico.

It is not the first time that scientists have used biotechnology to produce a child with DNA from three separate people, but the researchers claim that their new technique is significantly more precise, and has major implications for the prevention of genetic disease.

Preventing genetic disease

The fertility procedure was performed on a couple in which the woman was a carrier for a fatal genetic disorder known as Leigh Syndrome. The syndrome is a progressive neurological disorder that produces loss of movement and mental function, ending with death by early childhood.

Because the woman carried the mutation in her mitochondria - the structures inside cells that provide them with energy - any child she bore would contract and die from the disease. The couple had already experienced four miscarriages and had two children die from Leigh Syndrome, one at eight months and one at six years.

Mitochondria carry their own DNA, which is separate from the DNA found in the nucleus of the cell. This DNA is inherited only from the mother. Thus, a mitochondrial mutation will be passed down to all of a woman's children.

Leigh Syndrome can be inherited via either mitochondrial or nuclear DNA.

In order to bypass the genetic death sentence, researchers used a new method in which an egg cell was emptied of its mitochondria and its genetic material. That egg was then implanted with nuclear DNA from the mother's egg, and healthy mitochondria from a donor egg. This new, hybrid egg was then implanted with the father's sperm.

The researchers created five eggs by this new technique, but only one was viable. That one was implanted and led to a viable pregnancy and live birth. An estimated 0.1 percent of the child's DNA comes from the donor, and controls only the functioning of the mitochondria. All other DNA comes from the two parents.

What does the technology really mean?

The announcement drew praise from proponents of the technology, but also concern from critics.

Many objections were the same as those cited by the FDA in 2002, when it banned a three-person DNA technique known as cytoplasmic transfer. That technique was successfully used to produce as many as 50 children before the FDA prohibited it, citing unaddressed concerns over side effects and ethical implications.

Some of the children produced using cytoplasmic transfer were born lacking an X chromosome, and at least one showed signs of cognitive impairment.

Animal studies on newer mitochondrial replacement techniques suggest that they may carry some of the same risks. Researchers have seen cognitive impairment in mice and changes in male fertility and ageing in insects.

"It is outrageous that they simply ignored the cautious approach of US regulators and went to Mexico, because they think they know better," said David King of the pro-choice group Human Genetics Alert.

Another concern raised with such techniques is that they consist of germline modification - that is, they make genetic changes that can be passed on to other generations. In a very real sense, the safety implications of such techniques are unknowable until several generations have passed.

Bioethics experts also warn that any germline modification can lead down the slippery slope to "designer babies" and other ethically murky areas.

"Germ line therapy ... is something defined by the EU Charter of Fundamental Rights as effectively constituting eugenics," says British MP Fiona Bruce, chair of the UK's All Party Parliamentary Pro-Life Group.

The United Kingdom recently passed a law making it the only country on earth to explicitly permit three-person fertilization techniques.
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# data[].attributes.attachment_link.title
Genetically modified children: Baby born with DNA from three different people

# data[].attributes.attachment_link.description
(NaturalNews) U.S. scientists recently announced the birth of a baby containing DNA from three different people in an article in New Scientist. They will present the details of the new procedure they used at the October meeting of the American Society for Reproductive Medicine.

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DNA Structure and Function (Reading Note I)

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DNA Structure and Function (Reading Note I)

# data[].attributes.body
Hi & assalamualaikum girls!

I will attach few reading notes related to DNA, it maybe useful for your SHE report. I need all of you to list out the four key concepts of SHE here! Enjoy reading

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August 10, 2017

View gallery - 2 images
The field of xenotransplantation - implanting organs from one species into another - has accelerated dramatically since the discovery of the CRISPR gene editing tool a few years ago. Hurdles that previously seemed insurmountable are now not so daunting. The latest landmark development in the field comes from a team of scientists who successfully created genetically modified piglets free of 25 retroviruses that are generally present in pigs but thought to cause harm to humans.

There are several obvious problems scientists must overcome before successfully being able to transplant pig organs into humans. Despite pig organs posing as prime candidates for human transplantation considering their similar size and function, they generally, and unsurprisingly, trigger significant immune rejection responses in humans.

This first problem is being tackled by several scientists including pioneer transplant researchers Joseph Tector and David Cooper, both currently based at the University of Alabama at Birmingham. Both scientists have made major breakthroughs in identifying key genes in pigs that trigger human immune rejections. Using CRISPR they created pigs with those key genes suppressed and believe human trials using these implanted pig organs could begin soon.

The other major problem scientists face in implanting pig organs into humans is the widespread presence of certain retroviruses in the animals. Called Porcine Endogenous Retrovirus (PERV), these viruses are remnants of ancient viral infections and are harmless in pigs but many believe they could pose a threat when transferred to human systems, particularly when considering the immunosuppressed status of a transplant patient.

This latest breakthrough made by researchers from Harvard and Massachusetts-based company eGenesis involves successfully deploying CRISPR to engineer healthy piglets that are entirely free of PERVs. The research identified and deactivated 25 genomic triggers known to activate PERVs, allowing surrogate sows to then be successfully implanted with PERV-free embryos and giving birth to piglets free of the endogenous viruses.

It's undeniable that CRISPR is accelerating the pace of research in the realm of xenotransplantation. On top of research from earlier this year displaying success in creating a human-pig chimera, it is becoming increasingly clear that we may very well soon crack the challenge of human-animal organ transplantation.

The new PERV-free pig research was published in the journal .

Source: eGenesis

View gallery - 2 images

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Genetically engineered pigs could soon become organ donors for humans

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The latest landmark development in the field of animal to human organ transplantation comes from a team of scientists who successfully created genetically modified piglets free of 25 retroviruses that are generally present in pigs but thought to cause harm to humans.​

# data[].attributes.headline
DNA Structure and Function (Reading Note II)

# data[].attributes.subject
DNA Structure and Function (Reading Note II)

# data[].attributes.body
Hi again!
I will attach few reading notes related to DNA, it maybe useful for your SHE report. I need all of you to list out the four key concepts of SHE here! Enjoy reading

# data[].attributes.attachment_link.readable_text
August 21, 2017

DNA security and privacy is a looming problem that scientists and researchers are only just starting to grapple with. A team at Stanford has now developed a technique that can "cloak" irrelevant genomic information, allowing scientists to access key disease-related mutations without revealing an individual's broader genome sequence.

In a world where everything from dating profiles to medical diagnoses are drawing on DNA data, we're currently just forced to hope that each company with access to our DNA is acting responsibly with out genetic fingerprints. But for many, hope is not enough, and nor should it be. With genomic information becoming increasingly of value, a demand has arisen for a way to secure that data while still being able to enjoy the benefits of DNA analysis.

"Often people who have diseases, or those who know that a particular genetic disease runs in their family, are the most reluctant to share their genomic information because they know it could potentially be used against them in some way," says Gill Bejerano, associate professor of developmental biology, of pediatrics and of computer science. "They are missing out on helping themselves and others by allowing researchers and clinicians to learn from their DNA sequences."

To address such concerns, the Stanford team developed a technique based on a classic cryptographic protocol, known as garbled circuit or Yao's protocol. The individual encrypts their own genome using an algorithm on their smartphone or computer, which translates specific gene variants into a linear set of values that are securely uploaded into the cloud. On the other end of the transaction, the researcher (or any second-party) accesses only the data that is pertinent to their investigation.

"In this way, no person or computer, other than the individuals themselves, has access to the complete set of genetic information," says Bejerano.

The team demonstrated the process by executing several practical demonstrations, including identifying specific gene mutations in patients with rare diseases and comparing a baby's DNA with his parents to target the likely cause of a genetic disease. In all tested instances, at least 97 percent of each subject's unique DNA information was completely hidden from the researchers.

As well as protecting a person's privacy when having their DNA processed for medical reasons, this technique could theoretically be applied to more commercial contexts, such as ancestry genome studies or even the rising field of nutrigenomics.

"There is a general conception that we can only find meaningful differences by surveying the entire genome," says Bejerano. "But these meaningful differences make up only a very tiny proportion of our DNA. There are now amazing tools in computer science and cryptography that allow researchers to pinpoint only these differences while keeping the remainder of the genome completely private."

Just recently it was demonstrated that synthetic DNA could be created containing malware that allows a malicious party to gain control of the computer that sequences it. As we learn more and more about what our genetic fingerprint means, the value of that fingerprint will only increase. In the future, the DNA marketplace will be big business and security protocols such as this new Stanford technique are going to be important.

The team's research was published in the journal .

Source: Stanford Medicine

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Genome cryptography is the new way to secure your DNA data

# data[].attributes.attachment_link.description
DNA security is a looming problem that scientists and researchers are only just starting to grapple with. A team at Stanford has now developed a way to "cloak" irrelevant genomic information, allowing scientists to access key data without revealing an individual's broader genome sequence.

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Here, you may read on how an enzyme inhibitors enables scientist to develop solutions to health & environmental factors.