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Gene therapy

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For most of her life, Allison Corona lived in a world dimmed by bad genetic luck. A disease called Leber's congenital amaurosis left her legally blind at age 4. She could not navigate the short distance from her driveway to her front door after dusk.

Three years ago, Corona, now 23, received an experimental medical treatment aimed at fixing the faulty genes in her eyes. Researchers at the Children's Hospital of Philadelphia injected viruses carrying a good copy of her errant gene into her right eye and, nine days later, her left eye.

The world around her, once dark and austere, soon grew brighter. Her vision is still far from perfect, but for the first time, she sees that paper towels have texture. She marvels at the velvet floral wallpaper that covers her bedroom wall. She takes a college class that gets out at 10:30 p.m. and no longer fears getting stranded in the night.

"Things became much more beautiful for me," Corona said.

First tested in patients a quarter-century ago, gene therapy - a risky approach aimed at fixing the malfunctioning genes at the root of some diseases - is finally emerging from its own darkness after weathering high-profile tragedies, including the death of a teenage patient.

As it evolves from experimental to applied medicine, gene therapy might soon find itself steeped in a new controversy: soaring drug prices. No therapy is approved yet in the United States, so discussions about price - as well as crucial questions about how much patients will pay directly - are hypothetical. But industry leaders are already talking about ways to get ahead of potentially massive one-time price tags that could make insurers and patients balk.

A gene therapy approved in Europe in 2012 costs close to $1 million, and prices are expected to follow suit in the United States. The therapies in the pipeline are mostly for rare genetic diseases: sickle cell, hemophilia or immune deficiency. Their likely high prices stem from the expected value; unlike drugs that a person takes regularly, gene therapies are designed to be given once and have lasting effects.

But everyone involved anticipates the potential backlash against a seven-figure price tag, which is leading to radical proposals. Instead of paying for a treatment all at once, insurers and patients could make installment payments as long as the therapy works, similar to a mortgage on a house. Some researchers are adding up the cost of the traditional treatments that a patient will be able to avoid each year to determine a price that, although high, could lead to savings for the health-care system.

To Corona, the gift of vision is something approaching a miracle. But how much is that miracle worth in dollars?

In the 1980s, a daring idea seized the imagination of scientists and physicians. What if they could design a drug that wouldn't just treat the symptoms of a disease caused by a mutant gene, but could instead replace the gene with one that worked normally?

Gene therapy was technically difficult but conceptually simple. Scientists would modify a virus so that when it infected a cell, it would ferry in the correct version of a broken gene.

If the process worked, doctors would have a powerful weapon against rare but devastating maladies such as cystic fibrosis and "bubble boy" disease, which leaves children without immune defenses.

As basic research moved forward, excitement about gene therapy soared. But, as with many new biomedical technologies, that initial exuberance would die down as the powerful idea of replacing broken genes collided with the inherent complexity of human biology. For gene therapy, the blip wouldn't be just a scientific setback fought out on the pages of scientific and medical journals, but an international scandal in which patients were harmed and public faith was shaken.

In 1999, an Arizona teenager named Jesse Gelsinger died after he experienced an unexpected, severe immune reaction while participating in a clinical trial of gene therapy led by researcher James M. Wilson at the University of Pennsylvania.

"Everybody sort of stepped back and said, 'Okay, we really have to consider, now that gene therapy has lost its innocence, what are we doing here? And what are the ways in which, if we're going to do additional experiments, we don't let this happen again?' " Francis Collins, director of the National Institutes of Health, said recently. "It was big; it was very big. I would not be surprised if some young scientists who were thinking of going down this path decided to do something else."

Wilson became the subject of legal action and scathing media coverage. The government restricted his work on human subjects. Lawmakers on Capitol Hill held hearings to probe the lack of oversight and the ethical lapses that had marked some gene-therapy trials. Gelsinger's father, Paul, told one Senate panel in 2000, "The concern should not be on getting to the finish line first but on making sure no unnecessary risks are taken, no lives filled with potential and promise are lost forever, no more fathers lose their sons."

Also in the early 2000s, a few patients in a French gene-therapy trial developed leukemia. Along with the Gelsinger case, it proved a tipping point. Private investment in the field rapidly dried up, and it entered what Cowen & Co. Managing Director Phil Nadeau calls a "nuclear winter." Regulators halted dozens of trials. To many, gene therapy seemed close to dead; a field of science that had been on a fast track appeared to have been relegated to little more than an interesting academic pursuit for a small cadre of researchers.

With less money, less hype, and much more humility and caution, Wilson and other researchers searched for ways to improve the safety of the viruses used to insert genes.

"It was a realization that the technology we had, which was on the shelf when we began the field, was inadequate for this field to move forward in any substantive way," Wilson recalled. "It was really to go back to the drawing board, for me. That was a complete reorganization of what I was doing, how I was doing it, the kind of people who worked for me. It was a complete reboot."

Gene therapy's comeback started with a trickle. In 2008, researchers reported that a small number of patients with an inherited form of blindness gained modest improvements in vision with gene therapy. Not long after, gene therapy restored immune function in eight of 10 children with typically lethal "bubble boy" disease.

Katherine High, a researcher at the Children's Hospital of Philadelphia who worked on one of the early blindness trials, started getting cold calls from investors and from pharmaceutical companies, asking if they could partner with her. Then the team of experts she had assembled in Philadelphia began to get job offers.

"I remember very clearly, around 2011, I began to think to myself, 'If we don't form a company so we can all stay together, I'm going to lose these people,' " High said. She co-founded Spark Therapeutics, which went public this year and is sponsoring the trial in which Corona participated. The company is expected to put its blindness therapy before U.S. regulators, likely next year.

It's one of many companies with treatments in the pipeline. UniQure's drug, Glybera, in 2012 became the first gene therapy approved in Europe, for a rare metabolic disease. Bluebird Bio, a biotechnology company that went public in 2013, is developing a variety of gene therapies, including a treatment for a genetic blood disease. Regenxbio, where Wilson serves as chief scientific adviser, went public in September.

"This is only the beginning of what's going to be a remarkable era in medicine," Wilson said. "But if it's the beginning, that suggests there's significant room for improvement. That means there will be failures and there will be successes."

On the precipice of having a treatment finally make it onto the market, gene therapy faces yet another controversy: price.

Although much of the current outrage has been spurred by companies that take old drugs and jack up their prices, the potential sticker shock from a million-dollar drug - even if it's for a previously incurable disease - is sure to raise some of the same questions from politicians and the public.

Nadeau, of Cowen & Co., said his firm has estimated that Spark Therapeutics' gene therapy will cost $500,000 per eye. A study published last year in the journal Nature Biotechnology examined current health-care spending on hemophilia B and found that a gene therapy could conceivably be priced as a one-time payment of $4 million to $6 million. The authors argued that paying $150,000 a year as long as the drug works could potentially save the health-care system money.

Spark Therapeutics chief executive Jeffrey Marrazzo is reluctant to talk about a dollar figure, but he does think it's time to consider changes in the way the health-care system pays for treatments.

The options being discussed include a down-payment model, with annual payments. University of Washington economist Anirban Basu has proposed an alternate health currency, HealthCoin, that insurers pay for when buying a cure and then sell to another insurance plan at a depreciated price if a patient switches insurers or becomes eligible for Medicare.

The feasibility of these plans remains uncertain. But gene-therapy executives are arguing that, even at unprecedented prices, their drugs will save the health-care system money - and carry other benefits.

"How do we recognize that there's truly something that's important and valuable to people, not only to have certain aspects of their vision restored, but . . . to have it done once and then have the ability to go on with their lives?" Marrazzo said.

Corona, who excitedly woke up her family in the middle of the night when she read about the possibility of gene therapy years ago, didn't have to pay for her treatment, because she was part of a clinical trial.

But she said her family would have found a way to get her the therapy if it had already been on the market, even if it meant battling an insurance company or taking out a loan. After all, she said, it's not only about seeing better. She now feels like a happier, more confident person. That part feels priceless.

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Gene therapies offer dramatic promise but shocking costs

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For most of her life, Allison Corona lived in a world dimmed by bad genetic luck. A disease called Leber's congenital amaurosis left her legally blind at age 4. She could not navigate the short distance from her driveway to her front door after dusk.

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Pros and Cons of Gene Therapy in Humans (JV)

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Pros and Cons of Gene Therapy in Humans (JV)

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Pros
- Preventing and overcoming diseases
-  Allows parents to choose their baby's trait
-  Having the abilty to enhance medical advancements

Cons
-  Failure can lead to discontinuation of embryos
-  Genetically modified babies could have worse imperfections than normal
- Diminish human individuality

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Genetic engineering in is founded on the idea of manipulating the gene pool in order to make lives better. One way of doing this is to start from the basic, from the egg cell and sperm cell. Another way is to swap "bad" genes in a fully formed human with "good" ones.

There are moral and ethical controversies surrounding genetic engineering or genetic mutation in humans. Personal convictions alone dictate people what to oppose and what to accept. However, it takes an objective inspection of this medical technology for us to draw a more acceptable conclusion and prevent pre-created biases.

List of Pros of Genetic Engineering in Humans

1. Helps Prevent Genetic Disorders
Many of the diseases today are hereditary or genetic. By manipulating the genes in humans, scientists find a way to prevent people from suffering from an otherwise hereditary health condition.

2. Helps Individual Have Better Life
Genetic engineering helps humans have a chance at a healthier, longer life with more desirable physical characteristics. By altering the genes of fetuses, there is a strong likelihood that future generations will be taller, stronger, healthier and better looking.

3. Helps Deepen Understanding of Genes
Promoting genetic engineering is one way of deepening our understanding about human genetics. It helps scientists find ways to cure or prevent hereditary diseases, most especially.

4. Allows Parents to Choose Baby's Traits
Some parents would want their children not to inherit their less desirable traits, if given the chance. By modifying the genes of babies, parents have a chance at "designing" their own babies, according to what they want - gender, color of hair, etc.

5. Probes into Medical Advancements
There are many areas in science, which continue to be a mystery to even the most learned scientists and researchers today. Other advancements in the medical field can spring from genetic engineering.

List of Cons of Genetic Engineering in Humans

1. Test Failure Leads to Termination of Embryos
Since genetic engineering is not a perfect science, and far from being so, there will be failures along the way, and this leads to termination of embryos with "undesirable" gene pool. To some people, this is tantamount to abortion.

2. Who Decides the "Good" and "Bad" Genes
No one has the right to decide or judge what specific traits are good or bad. With genetic engineering, the power likely rests on the scientists, the future parents, or the political leader. However, are these people accountable or responsible when experiments go wrong?

3. Engineered Babies Could Have Worse Imperfections
When the actual results are not the outcome initially intended, society could have grave issues regarding the presence of erroneously engineered humans, specifically if they turn out to be mentally ill, psychotic, abusive, or non-responsive. How does society control these badly designed humans - by murder, by further experimentation or by imprisonment?

4. It Is Very Expensive
Engineering the genes of animals is already intricate and expensive enough, how much more an entire human being? It takes a team of skilled geneticists and researchers, plus a topnotch facility, to perform the experiment. This means that genetic engineering may only be available to the wealthy, furthering the gap in society.

5. Reduces the Individuality among Humans
When there is a consensus as to which traits are good or bad, there is a tendency for future generations to lose their diversity and individuality. There will be no short people because being tall is more desirable. There will be no fat people because being slender is more desirable. Ultimately, the reduction of undesirable traits in humans would lead to a generation of "pure breeds" with very little capability of adapting to changes in the environment as in the case of pure breed animals, which are prone to disease.

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Genetic Engineering in Humans Pros and Cons List

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Genetic engineering in is founded on the idea of manipulating the gene pool in order to make lives better. One way of doing this is to start from the basic, from the egg cell and sperm cell. Another way is to swap "bad" genes in a fully formed human with "good" ones.

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Somatic gene therapy: changes, fixes, and replaces the affected genes in just one person. This is not able to be passed down to the next generations.
Germ line gene therapy: makes changes in the sperm or eggs. The changes made will the continue to pass down to further generations.

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Treatment of genetic disorders by introducing proper genes into cells of the target organ, is called gene therapy. the gene used in gene therapy is often called gene drug. The drug gene may be introduced into somatic cells or germ cells or zygotes.

If genes are introduced into somatic cells, it is called somatic cell gene therapy. If genes are introduced into eggs or zygotes, it is called germline gene therapy. Gene therapy is used to cure asthma, non Hodgkin's lymphoma, melanoma etc.

Technical expertise for somatic cell manipulations in vitro introduction of gene of interest and replanting somatic cells in body to make them functional is developed.

There are still many technical difficulties in introduction of genes into germ cells.

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Difference between Somatic Therapy and Germline Therapy

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Treatment of genetic disorders by introducing proper genes into cells of the target organ, is called gene therapy. the gene used in gene therapy is often called gene drug. The drug gene may be introduced into somatic cells or germ cells or zygotes. If genes are introduced into somatic cells, it is called somatic cell gene therapy.

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Laws and Regulations in Gene Therapy (ER)

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Laws and Regulations in Gene Therapy (ER)

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It states why there is a need for creating laws that will regulate gene therapy; assuming that gene therapy becomes available to consumers. ( Visit Section B on page 11 of link)

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Genetic Therapy is when specific DNA is inserted into the body to fix a mutated gene that is causing a disease.

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Gene therapy is when DNA is introduced into a patient to treat a genetic disease. The new DNA usually contains a functioning gene to correct the effects of a disease-causing mutation.

Gene therapy uses sections of DNA (usually genes) to treat or prevent disease.

The DNA is carefully selected to correct the effect of a mutated gene that is causing disease.

The technique was first developed in 1972 but has, so far, had limited success in treating human diseases.

Gene therapy may be a promising treatment option for some genetic diseases, including muscular dystrophy and cystic fibrosis.

There are two different types of gene therapy depending on which types of cells are treated:

Somatic gene therapy: transfer of a section of DNA to any cell of the body that doesn't produce sperm or eggs. Effects of gene therapy will not be passed onto the patient's children.

Germline gene therapy: transfer of a section of DNA to cells that produce eggs or sperm. Effects of gene therapy will be passed onto the patient's children and subsequent generations.

Gene therapy techniques

There are several techniques for carrying out gene therapy. These include:
Gene augmentation therapy

This is used to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein.

This therapy adds DNA containing a functional version of the lost gene back into the cell.

The new gene produces a functioning product at sufficient levels to replace the protein that was originally missing.

This is only successful if the effects of the disease are reversible or have not resulted in lasting damage to the body.

For example, this can be used to treat loss of function disorders such as cystic fibrosis by introducing a functional copy of the gene to correct the disease (see illustration below).

Gene inhibition therapy

Suitable for the treatment of infectious diseases, cancer and inherited disease caused by inappropriate gene activity.

The aim is to introduce a gene whose product either:

inhibits the expression of another gene

interferes with the activity of the product of another gene.

The basis of this therapy is to eliminate the activity of a gene that encourages the growth of disease-related cells.

For example, cancer is sometimes the result of the over-activation of an oncogene (gene which stimulates cell growth). So, by eliminating the activity of that oncogene through gene inhibition therapy, it is possible to prevent further cell growth and stop the cancer in its tracks.

Killing of specific cells

Suitable for diseases such as cancer that can be treated by destroying certain groups of cells.

The aim is to insert DNA into a diseased cell that causes that cell to die.

This can be achieved in one of two ways:

the inserted DNA contains a "suicide" gene that produces a highly toxic product which kills the diseased cell

the inserted DNA causes expression of a protein that marks the cells so that the diseased cells are attacked by the body's natural immune system.

It is essential with this method that the inserted DNA is targeted appropriately to avoid the death of cells that are functioning normally.

How is DNA transfer done?

A section of DNA/gene containing instructions for making a useful protein is packaged within a vector, usually a virus, bacterium or plasmid.

The vector acts as a vehicle to carry the new DNA into the cells of a patient with a genetic disease.

Once inside the cells of the patient, the DNA/gene is expressed by the cell's normal machinery leading to production of the therapeutic protein and treatment of the patient's disease.

Challenges of gene therapy

Delivering the gene to the right place and switching it on:

it is crucial that the new gene reaches the right cell

delivering a gene into the wrong cell would be inefficient and could also cause health problems for the patient

even once the right cell has been targeted the gene has to be turned on

cells sometimes obstruct this process by shutting down genes that are showing unusual activity.

Avoiding the immune response:

The role of the immune system is to fight off intruders.

Sometimes new genes introduced by gene therapy are considered potentially-harmful intruders.

This can spark an immune response in the patient, that could be harmful to them.

Scientists therefore have the challenge of finding a way to deliver genes without the immune system 'noticing'.

This is usually by using vectors that are less likely to trigger an immune response.

Making sure the new gene doesn't disrupt the function of other genes:

Ideally, a new gene introduced by gene therapy will integrate itself into the genome of the patient and continue working for the rest of their lives.

There is a risk that the new gene will insert itself into the path of another gene, disrupting its activity.

This could have damaging effects, for example, if it interferes with an important gene involved in regulating cell division, it could result in cancer.

The cost of gene therapy:

Many genetic disorders that can be targeted with gene therapy are extremely rare.

Gene therapy therefore often requires an individual, case-by-case approach. This may be effective, but may also be very expensive.

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Gene therapy is when DNA is introduced into a patient to treat a genetic disease. The new DNA usually contains a functioning gene to correct the effects of a disease-causing mutation. Gene therapy uses sections of DNA (usually genes) to treat or prevent disease.

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Human Genetic Engineering: During Pregnancy (JV)

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Human Genetic Engineering: During Pregnancy (JV)

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By editing the DNA within the embryos, and fixing the "unwanted" cells and turning them into more "ideal healthy" cells, this can permanently pass the genetically fixed genes onto the future generations.

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If anyone had devised a way to create a genetically engineered baby, I figured George Church would know about it.

At his labyrinthine laboratory on the Harvard Medical School campus, you can find researchers giving E. Coli a novel genetic code never seen in nature. Around another bend, others are carrying out a plan to use DNA engineering to resurrect the woolly mammoth. His lab, Church likes to say, is the center of a new technological genesis-one in which man rebuilds creation to suit himself.

When I visited the lab last June, Church proposed that I speak to a young postdoctoral scientist named Luhan Yang. A Harvard recruit from Beijing, she'd been a key player in developing a powerful new technology for editing DNA, called CRISPR-Cas9. With Church, Yang had founded a small biotechnology company to engineer the genomes of pigs and cattle, sliding in beneficial genes and editing away bad ones.

As I listened to Yang, I waited for a chance to ask my real questions: Can any of this be done to human beings? Can we improve the human gene pool? The position of much of mainstream science has been that such meddling would be unsafe, irresponsible, and even impossible. But Yang didn't hesitate. Yes, of course, she said. In fact, the Harvard laboratory had a project under way to determine how it could be achieved. She flipped open her laptop to a PowerPoint slide titled "Germline Editing Meeting."

Here it was: a technical proposal to alter human heredity. "Germ line" is biologists' jargon for the egg and sperm, which combine to form an embryo. By editing the DNA of these cells or the embryo itself, it could be possible to correct disease genes and pass those genetic fixes on to future generations. Such a technology could be used to rid families of scourges like cystic fibrosis. It might also be possible to install genes that offer lifelong protection against infection, Alzheimer's, and, Yang told me, maybe the effects of aging. Such history-making medical advances could be as important to this century as vaccines were to the last.

That's the promise. The fear is that germ-line engineering is a path toward a dystopia of superpeople and designer babies for those who can afford it. Want a child with blue eyes and blond hair? Why not design a highly intelligent group of people who could be tomorrow's leaders and scientists?

Just three years after its initial development, CRISPR technology is already widely used by biologists as a kind of search-and-replace tool to alter DNA, even down to the level of a single letter. It's so precise that it's expected to turn into a promising new approach for gene therapy in people with devastating illnesses. The idea is that physicians could directly correct a faulty gene, say, in the blood cells of a patient with sickle-cell anemia (see " Genome Surgery "). But that kind of gene therapy wouldn't affect germ cells, and the changes in the DNA wouldn't get passed to future generations.

In contrast, the genetic changes created by germ-line engineering would be passed on, and that's what has made the idea seem so objectionable. So far, caution and ethical concerns have had the upper hand. A dozen countries, not including the United States, have banned germ-line engineering, and scientific societies have unanimously concluded that it would be too risky to do. The European Union's convention on human rights and biomedicine says tampering with the gene pool would be a crime against "human dignity" and human rights.

But all these declarations were made before it was actually feasible to precisely engineer the germ line. Now, with CRISPR, it is possible.

The experiment Yang described, though not simple, would go like this: The researchers hoped to obtain, from a hospital in New York, the ovaries of a woman undergoing surgery for ovarian cancer caused by a mutation in a gene called BRCA1. Working with another Harvard laboratory, that of antiaging specialist David Sinclair, they would extract immature egg cells that could be coaxed to grow and divide in the laboratory. Yang would use CRISPR in these cells to correct the DNA of the BRCA1 gene. They would try to create a viable egg without the genetic error that caused the woman's cancer.

Yang would later tell me that she dropped out of the project not long after we spoke. Yet it remained difficult to know if the experiment she described was occurring, canceled, or awaiting publication. Sinclair said that a collaboration between the two labs was ongoing, but then, like several other scientists whom I'd asked about germ-line engineering, he stopped replying to my e-mails.

Regardless of the fate of that particular experiment, human germ-line engineering has become a burgeoning research concept. At least three other centers in the United States are working on it, as are scientists in China, in the U.K., and at a biotechnology company called OvaScience, based in Cambridge, Massachusetts, that boasts some of the world's leading fertility doctors on its advisory board.

All this means that germ-line engineering is much further along than anyone imagined.

The objective of these groups is to demonstrate that it's possible to produce children free of specific genes involved in inherited disease. If it's possible to correct the DNA in a woman's egg, or a man's sperm, those cells could be used in an in vitro fertilization (IVF) clinic to produce an embryo and then a child. It might also be possible to directly edit the DNA of an early-stage IVF embryo using CRISPR. Several people interviewed by MIT Technology Review said that such experiments had already been carried out in China and that results describing edited embryos were pending publication. These people, including two high-ranking specialists, didn't wish to comment publicly because the papers are under review.

All this means that germ-line engineering is much further along than anyone imagined. "What you are talking about is a major issue for all humanity," says Merle Berger, one of the founders of Boston IVF, a network of fertility clinics that is among the largest in the world and helps more than a thousand women get pregnant each year. "It would be the biggest thing that ever happened in our field." Berger predicts that repairing genes involved in serious inherited diseases will win wide public acceptance but says the idea of using the technology beyond that would cause a public uproar because "everyone would want the perfect child": people might pick and choose eye color and eventually intelligence. "These are things we talk about all the time," he says. "But we have never had the opportunity to do it."
Editing embryos
How easy would it be to edit a human embryo using CRISPR? Very easy, experts say. "Any scientist with molecular biology skills and knowledge of how to work with [embryos] is going to be able to do this," says Jennifer Doudna, a biologist at the University of California, Berkeley, who in 2012 co-discovered how to use CRISPR to edit genes.

To find out how it could be done, I visited the lab of Guoping Feng, a biologist at MIT's McGovern Institute for Brain Research, where a colony of marmoset monkeys is being established with the aim of using CRISPR to create accurate models of human brain diseases. To create the models, Feng will edit the DNA of embryos and then transfer them into female marmosets to produce live monkeys. One gene Feng hopes to alter in the animals is SHANK3. The gene is involved in how neurons communicate; when it's damaged in children, it is known to cause autism.

Feng said that before CRISPR, it was not possible to introduce precise changes into a primate's DNA. With CRISPR, the technique should be relatively straightforward. The CRISPR system includes a gene-snipping enzyme and a guide molecule that can be programmed to target unique combinations of the DNA letters, A, G, C, and T; get these ingredients into a cell and they will cut and modify the genome at the targeted sites.

But CRISPR is not perfect-and it would be a very haphazard way to edit human embryos, as Feng's efforts to create gene-edited marmosets show. To employ the CRISPR system in the monkeys, his students simply inject the chemicals into a fertilized egg, which is known as a zygote-the stage just before it starts dividing.

Feng said the efficiency with which CRISPR can delete or disable a gene in a zygote is about 40 percent, whereas making specific edits, or swapping DNA letters, works less frequently-more like 20 percent of the time. Like a person, a monkey has two copies of most genes, one from each parent. Sometimes both copies get edited, but sometimes just one does, or neither. Only about half the embryos will lead to live births, and of those that do, many could contain a mixture of cells with edited DNA and without. If you add up the odds, you find you'd need to edit 20 embryos to get a live monkey with the version you want.

That's not an insurmountable problem for Feng, since the MIT breeding colony will give him access to many monkey eggs and he'll be able to generate many embryos. However, it would present obvious problems in humans. Putting the ingredients of CRISPR into a human embryo would be scientifically trivial. But it wouldn't be practical for much just yet. This is one reason that many scientists view such an experiment (whether or not it has really occurred in China) with scorn, seeing it more as a provocative bid to grab attention than as real science. Rudolf Jaenisch, an MIT biologist who works across the street from Feng and who in the 1970s created the first gene-modified mice, calls attempts to edit human embryos "totally premature." He says he hopes these papers will be rejected and not published. "It's just a sensational thing that will stir things up," says Jaenisch. "We know it's possible, but is it of practical use? I kind of doubt it."

For his part, Feng told me he approves of the idea of germ-line engineering. Isn't the goal of medicine to reduce suffering? Considering the state of the technology, however, he thinks actual gene-edited humans are "10 to 20 years away." Among other problems, CRISPR can introduce off-target effects or change bits of the genome far from where scientists had intended. Any human embryo altered with CRISPR today would carry the risk that its genome had been changed in unexpected ways. But, Feng said, such problems may eventually be ironed out, and edited people will be born. "To me, it's possible in the long run to dramatically improve health, lower costs. It's a kind of prevention," he said. "It's hard to predict the future, but correcting disease risks is definitely a possibility and should be supported. I think it will be a reality."
Editing eggs
Elsewhere in the Boston area, scientists are exploring a different approach to engineering the germ line, one that is technically more demanding but probably more powerful. This strategy combines CRISPR with unfolding discoveries related to stem cells. Scientists at several centers, including Church's, think they will soon be able to use stem cells to produce eggs and sperm in the laboratory. Unlike embryos, stem cells can be grown and multiplied. Thus they could offer a vastly improved way to create edited offspring with CRISPR. The recipe goes like this: First, edit the genes of the stem cells. Second, turn them into an egg or sperm. Third, produce an offspring.

Some investors got an early view of the technique on December 17, at the Benjamin Hotel in Manhattan, during commercial presentations by OvaScience. The company, which was founded four years ago, aims to commercialize the scientific work of David Sinclair, who is based at Harvard, and Jonathan Tilly, an expert on egg stem cells and the chairman of the biology department at Northeastern University (see "10 Emerging Technologies: Egg Stem Cells," May/June 2012). It made the presentations as part of a successful effort to raise $132 million in new capital during January.

During the meeting, Sinclair, a velvet-voiced Australian whom Time last year named one of the "100 Most Influential People in the World," took the podium and provided Wall Street with a peek at what he called "truly world-changing" developments. People would look back at this moment in time and recognize it as a new chapter in "how humans control their bodies," he said, because it would let parents determine "when and how they have children and how healthy those children are actually going to be."

The company has not perfected its stem-cell technology-it has not reported that the eggs it grows in the lab are viable-but Sinclair predicted that functional eggs were "a when, and not an if." Once the technology works, he said, infertile women will be able to produce hundreds of eggs, and maybe hundreds of embryos. Using DNA sequencing to analyze their genes, they could pick among them for the healthiest ones.

Genetically improved children may also be possible. Sinclair told the investors that he was trying to alter the DNA of these egg stem cells using gene editing, work he later told me he was doing with Church's lab. "We think the new technologies with genome editing will allow it to be used on individuals who aren't just interested in using IVF to have children but have healthier children as well, if there is a genetic disease in their family," Sinclair told the investors. He gave the example of Huntington's disease, caused by a gene that will trigger a fatal brain condition even in someone who inherits only one copy. Sinclair said gene editing could be used to remove the lethal gene defect from an egg cell. His goal, and that of OvaScience, is to "correct those mutations before we generate your child," he said. "It's still experimental, but there is no reason to expect it won't be possible in coming years."

Sinclair spoke to me briefly on the phone while he was navigating in a cab across a snowed-in Boston, but later he referred my questions to OvaScience. When I contacted OvaScience, Cara Mayfield, a spokeswoman, said its executives could not comment because of their travel schedules but confirmed that the company was working on treating inherited disorders with gene editing. What was surprising to me was that OvaScience's research in "crossing the germ line," as critics of human engineering sometimes put it, has generated scarcely any notice. In December of 2013, OvaScience even announced it was putting $1.5 million into a joint venture with a synthetic biology company called Intrexon, whose R&D objectives include gene-editing eggs to "prevent the propagation" of human disease "in future generations."

When I reached Tilly at Northeastern, he laughed when I told him what I was calling about. "It's going to be a hot-button issue," he said. Tilly also said his lab was trying to edit egg stem cells with CRISPR "right now" to rid them of an inherited genetic disease that he didn't want to name. Tilly emphasized that there are "two pieces of the puzzle"-one being stem cells and the other gene editing. The ability to create large numbers of egg stem cells is critical, because only with sizable quantities can genetic changes be stably introduced using CRISPR, characterized using DNA sequencing, and carefully studied to check for mistakes before producing an egg.

Tilly predicted that the whole end-to-end technology-cells to stem cells, stem cells to sperm or egg and then to offspring-would end up being worked out first in animals, such as cattle, either by his lab or by companies such as eGenesis, the spinoff from the Church lab working on livestock. But he isn't sure what the next step should be with edited human eggs. You wouldn't want to fertilize one "willy nilly," he said. You'd be making a potential human being. And doing that would raise questions he's not sure he can answer. He told me, "'Can you do it?' is one thing. If you can, then the most important questions come up. 'Would you do it? Why would you want to do it? What is the purpose?' As scientists we want to know if it's feasible, but then we get into the bigger questions, and it's not a science question-it's a society question."
Improving humans
If germ-line engineering becomes part of medical practice, it could lead to transformative changes in human well-being, with consequences to people's life span, identity, and economic output. But it would create ethical dilemmas and social challenges. What if these improvements were available only to the richest societies, or the richest people? An in vitro fertility procedure costs about $20,000 in the United States. Add genetic testing and egg donation or a surrogate mother, and the price soars toward $100,000.

Others believe the idea is dubious because it's not medically necessary. Hank Greely, a lawyer and ethicist at Stanford University, says proponents "can't really say what it is good for." The problem, says Greely, is that it's already possible to test the DNA of IVF embryos and pick healthy ones, a process that adds about $4,000 to the cost of a fertility procedure. A man with Huntington's, for instance, could have his sperm used to fertilize a dozen of his partner's eggs. Half those embryos would not have the Huntington's gene, and those could be used to begin a pregnancy.

Indeed, some people are adamant that germ-line engineering is being pushed ahead with "false arguments." That is the view of Edward Lanphier, CEO of Sangamo Biosciences, a California biotechnology company that is using another gene-editing technique, called zinc fingers nucleases, to try to treat HIV in adults by altering their blood cells. "We've looked at [germ-line engineering] for a disease rationale, and there is none," he says. "You can do it. But there really isn't a medical reason. People say, well, we don't want children born with this, or born with that-but it's a completely false argument and a slippery slope toward much more unacceptable uses."

Critics cite a host of fears. Children would be the subject of experiments. Parents would be influenced by genetic advertising from IVF clinics. Germ-line engineering would encourage the spread of allegedly superior traits. And it would affect people not yet born, without their being able to agree to it. The American Medical Association, for instance, holds that germ-line engineering shouldn't be done "at this time" because it "affects the welfare of future generations" and could cause "unpredictable and irreversible results." But like a lot of official statements that forbid changing the genome, the AMA's, which was last updated in 1996, predates today's technology. "A lot of people just agreed to these statements," says Greely. "It wasn't hard to renounce something that you couldn't do."

The fear? A dystopia of superpeople and designer babies for those who can afford it.

Others predict that hard-to-oppose medical uses will be identified. A couple with several genetic diseases at once might not be able to find a suitable embryo. Treating infertility is another possibility. Some men don't produce any sperm, a condition called azoospermia. One cause is a genetic defect in which a region of about one million to six million DNA letters is missing from the Y chromosome. It might be possible to take a skin cell from such a man, turn it into a stem cell, repair the DNA, and then make sperm, says Werner Neuhausser, a young Austrian doctor who splits his time between the Boston IVF fertility-clinic network and Harvard's Stem Cell Institute. "That will change medicine forever, right? You could cure infertility, that is for sure," he says.

I spoke with Church several times by telephone over the last few months, and he told me what's driving everything is the "incredible specificity" of CRISPR. Although not all the details have been worked out, he thinks the technology could replace DNA letters essentially without side effects. He says this is what makes it "tempting to use." Church says his laboratory is focused mostly on experiments in engineering animals. He added that his lab would not make or edit human embryos, calling such a step "not our style."

What is Church's style is human enhancement. And he's been making a broad case that CRISPR can do more than eliminate disease genes. It can lead to augmentation. At meetings, some involving groups of "transhumanists" interested in next steps for human evolution, Church likes to show a slide on which he lists naturally occurring variants of around 10 genes that, when people are born with them, confer extraordinary qualities or resistance to disease. One makes your bones so hard they'll break a surgical drill. Another drastically cuts the risk of heart attacks. And a variant of the gene for the amyloid precursor protein, or APP, was found by Icelandic researchers to protect against Alzheimer's. People with it never get dementia and remain sharp into old age.

Church thinks CRISPR could be used to provide people with favorable versions of genes, making DNA edits that would act as vaccines against some of the most common diseases we face today. Although he told me anything "edgy" should be done only to adults who can consent, it's obvious to him that the earlier such interventions occur, the better.

Church tends to dodge questions about genetically modified babies. The idea of improving the human species has always had "enormously bad press," he wrote in the introduction to Regenesis, his 2012 book on synthetic biology, whose cover was a painting by Eustache Le Sueur of a bearded God creating the world. But that's ultimately what he's suggesting: enhancements in the form of protective genes. "An argument will be made that the ultimate prevention is that the earlier you go, the better the prevention," he told an audience at MIT's Media Lab last spring. "I do think it's the ultimate preventive, if we get to the point where it's very inexpensive, extremely safe, and very predictable." Church, who has a less cautious side, proceeded to tell the audience that he thought changing genes "is going to get to the point where it's like you are doing the equivalent of cosmetic surgery."

Some thinkers have concluded that we should not pass up the chance to make improvements to our species. "The human genome is not perfect," says John Harris, a bioethicist at Manchester University, in the U.K. "It's ethically imperative to positively support this technology." By some measures, U.S. public opinion is not particularly negative toward the idea. A Pew Research survey carried out last August found that 46 percent of adults approved of genetic modification of babies to reduce the risk of serious diseases.

The same survey found that 83 percent said genetic modification to make a baby smarter would be "taking medical advances too far." But other observers say higher IQ is exactly what we should be considering. Nick Bostrom, an Oxford philosopher best known for his 2014 book Superintelligence, which raised alarms about the risks of artificial intelligence in computers, has also looked at whether humans could use reproductive technology to improve human intellect. Although the ways in which genes affect intelligence aren't well understood and there are far too many relevant genes to permit easy engineering, such realities don't dim speculation on the possibility of high-tech eugenics.

"The human genome is not perfect. It's ethically imperative to positively support this technology."

What if everyone could be a little bit smarter? Or a few people could be a lot smarter? Even a small number of "super-enhanced" individuals, Bostrom wrote in a 2013 paper, could change the world through their creativity and discoveries, and through innovations that everyone else would use. In his view, genetic enhancement is an important long-range issue like climate change or financial planning by nations, "since human problem-solving ability is a factor in every challenge we face."

To some scientists, the explosive advance of genetics and biotech means germ-line engineering is inevitable. Of course, safety questions would be paramount. Before there's a genetically edited baby saying "Mama," there would have to be tests in rats, rabbits, and probably monkeys, to make sure they are normal. But ultimately, if the benefits seem to outweigh the risks, medicine would take the chance. "It was the same with IVF when it first happened," says Neuhausser. "We never really knew if that baby was going to be healthy at 40 or 50 years. But someone had to take the plunge."
Wine country
In January, on Saturday the 24th, around 20 scientists, ethicists, and legal experts traveled to Napa Valley, California, for a retreat among the vineyards at the Carneros Inn. They had been convened by Doudna, the Berkeley scientist who co-discovered the CRISPR system a little over two years ago. She had become aware that scientists might be thinking of crossing the germ line, and she was concerned. Now she wanted to know: could they be stopped?

"We as scientists have come to appreciate that CRISPR is incredibly powerful. But that swings both ways. We need to make sure that it's applied carefully," Doudna told me. "The issue is especially human germ-line editing and the appreciation that this is now a capability in everyone's hands."

At the meeting, along with ethicists like Greely, was Paul Berg, a Stanford biochemist and Nobel Prize winner known for having organized the Asilomar Conference, a historic 1975 forum at which biologists reached an agreement on how to safely proceed with recombinant DNA, the newly discovered method of splicing DNA into bacteria.

Should there be an Asilomar for germ-line engineering? Doudna thinks so, but the prospects for consensus seem dim. Biotechnology research is now global, involving hundreds of thousands of people. There's no single authority that speaks for science, and no easy way to put the genie back in the bottle. Doudna told me she hoped that if American scientists agreed to a moratorium on human germ-line engineering, it might influence researchers elsewhere in the world to cease their work.

Doudna said she felt that a self-imposed pause should apply not only to making gene-edited babies but also to using CRISPR to alter human embryos, eggs, or sperm-as researchers at Harvard, Northeastern, and OvaScience are doing. "I don't feel that those experiments are appropriate to do right now in human cells that could turn into a person," she told me. "I feel that the research that needs to be done right now is to understand safety, efficacy, and delivery. And I think those experiments can be done in nonhuman systems. I would like to see a lot more work done before it's done for germ-line editing. I would favor a very cautious approach."

Not everyone agrees that germ-line engineering is such a big worry, or that experiments should be padlocked. Greely notes that in the United States, there are piles of regulations to keep lab science from morphing into a genetically modified baby anytime soon. "I would not want to use safety as an excuse for a non-safety-based ban," says Greely, who says he pushed back against talk of a moratorium. But he also says he agreed to sign Doudna's letter, which now reflects the consensus of the group. "Although I don't view this as a crisis moment, I think it's probably about time for us to have this discussion," he says.

(After this article was published online in March, Doudna's editorial appeared in Science (see "Scientists Call for a Summit on Gene-Edited Babies".) Along with Greely, Berg, and 15 others, she called for a global moratorium on any effort to use CRISPR to generate gene-edited children until researchers could determine "what clinical applications, if any, might in the future be deemed permissible." The group, however, endorsed basic research, including applying CRISPR to embryos. The final list of signatories included Church, although he did not attend the Napa meeting.)

As news has spread of germ-line experiments, some biotechnology companies now working on CRISPR have realized that they will have to take a stand. Nessan Bermingham is CEO of Intellia Therapeutics, a Boston startup that raised $15 million last year to develop CRISPR into gene therapy treatments for adults or children. He says germ-line engineering "is not on our commercial radar," and he suggests that his company could use its patents to prevent anyone from commercializing it.

"The technology is in its infancy," he says. "It is not appropriate for people to even be contemplating germ-line applications."

Bermingham told me he never imagined he'd have to be taking a position on genetically modified babies so soon. Modifying human heredity has always been a theoretical possibility. Suddenly it's a real one. But wasn't the point always to understand and control our own biology-to become masters over the processes that created us?

Doudna says she is also thinking about these issues. "It cuts to the core of who we are as people, and it makes you ask if humans should be exercising that kind of power," she told me. "There are moral and ethical issues, but one of the profound questions is just the appreciation that if germ-line editing is conducted in humans, that is changing human evolution." One reason she feels the research should slow down is to give scientists a chance to spend more time explaining what their next steps could be.

"Most of the public," she says, "does not appreciate what is coming."

This story was updated on April 23, 2015

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If anyone had devised a way to create a genetically engineered baby, I figured George Church would know about it. At his labyrinthine laboratory on the Harvard Medical School campus, you can find researchers giving E. Coli a novel genetic code never seen in nature. Around another bend, others are carrying out a plan to...

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Athletes are now injecting artificial genes and it is becoming a big problem in modern day sports.

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It is sport's doomsday scenario: a new generation of bioengineered performance-enhancing agents that can transform also-rans into gold medalists. Imagine athletes injecting artificial genes right into their muscles-a virtually undetectable act that would give them the sinewy muscles of a cougar, or endurance like that of an antelope.

But this is not the science fiction of Hollywood, the movie "Gattaca" or a long-lost chapter of H.G. Well's 1904 pharmacological fantasy "The Food of the Gods," about a superhuman race of young giants grown on drugs. This is the coming reality in sports, and it is calling into question cherished beliefs about what is "natural" and "unnatural," fair and unfair, in the world of elite athletics.

"Genetic engineering is accelerating and it's damaging sports," former Norwegian speed skating champion Johann Olav Koss has warned. He's now an assistant coach of Norway's speed skating team, and once served as an athletes' representative to the International Olympic Committee's World Anti-Doping Agency (WADA).

"We can't be naive. We have to be realistic. This is not only an issue for sport, it's a broad ethical issue for human beings." Koss, who is also a physician, has been deeply involved in various athletic performance summits addressing ways to ensure the sport does not cross invisible lines of ethics and safety.

Former WADA president Dick Pound, a staunch advocate of drug testing for athletes, has warned that genetic doping could "end sport as we know it." "We will look back on Ben Johnson with his Stanoloxol [steroid scandal in 1988 for which he was stripped of the 100-meter gold medal], and say that's like an ancient rock painting in a cave compared to what we face now with genetic engineering."

Genetic doping worries sport officials because they see it as further undermining sports' bedrock ethical principle, fairness-and doing so in a way that's infinitely harder to regulate than traditional performance-enhancing drugs. That concern is legitimate, but it runs up against three difficult realities.

First, in the elite world of performance sports like track and field, cycling, power lifting and perhaps swimming, the use of performance-enhancing drugs is already so widespread as to make a mockery of the ideal of the pure, untainted athlete.

Second, in the coming age of the cyber-athlete, detection of genetic enhancement is all but impossible.

And third, the advent of genetic interventions raises ethical dilemmas for which there are no easy solutions. There is no double yellow line separating genetic therapy, which conference participants by and large said was acceptable, from genetic enhancement, which is universally condemned.
Sports gene enhancement on the horizon?
Is it ethical, for example, for an athlete who has injured herself after super-aggressive training to use genetic therapy to repair her body-and gain an advantage over a competitor who was more judicious in her training program? What about athletes who use genetic editing to avoid a debilitating disease - and also realize a side benefit of improved performance? Should they be banned from competition? Or only some kinds of competition?

And beyond victory and defeat, of course, looms the larger issue of an athlete's health. The use of genetic enhancement may pose health hazards, many of them still unknown and some of which may never be known.

To be sure, some concerns about genetic enhancement in sports are overblown and, despite dramatic innovations such as CRISPR gene editing, still futuristic. So-called designer babies, for example, are science fiction, although recent developments suggest the future may be closer than we think. Although some start-up companies have tinkered with the idea, it may be a decade or more before scientists can remove embryonic fluid or swab your genes and generate a readout of the predicted sporting accomplishments of our prodigies in waiting.

Less distant are gene therapies and gene editing, already proven on animals, that if transferable to humans might be able to regulate energy metabolism, alter blood flow to the tissues, modify pain perception, or even postpone sexual development to keep preadolescent females-perhaps gymnasts and figure skaters of the future - in their performance prime. There are hundreds of active studies involving human clinical trials, with numerous therapies seeking federal approval. Scientists and athlete guinea pigs are also busy trying out gene enhancements to regenerate the body after cartilage damage, tears and fractures.

Synthetic drugs to boost endurance or increase strength and speed are already widely available. Confined to international cycling and weightlifting only a few years ago, gene doping invaded winter sports, track and field, the NFL and even World Cup soccer. And despite new screening measures that has curtailed the practice, many people suspect that problems remain. World sporting organizations, the Olympic movement and world cycling in particular, have proved hapless over the years in screening for dopers.

The genetic revolution presents even more difficult challenges. Unlike classic drugs such as steroids, bioengineered substances or body tweaks are chemically identical to the body's natural hormones, making detection difficult at best. The problems will increase exponentially in the next wave of genetic enhancement, the direct injection of viruses or other delivery agents that carry DNA that can turn genes into energy factories or activate dormant muscles.

"If direct injection is used, the DNA will only be present in that specific muscle," noted Peter Schjerling of the Copenhagen University Institute for Sports Medicine. "A positive test would require coring out actual muscle tissue. Not many athletes would allow that. And the sample would have to be at the exact spot of the injection." Certainly genetic engineering is becoming an ever more attractive option for those inclined to cheat.

"Why would anyone use stimulants and steroids when they can use genetically engineered drugs or therapies, which are virtually undetectable?" said Charles Yesalis, a Penn State University sports scientist and world expert on performance enhancing drugs. "If things spin out of control, it could be a freak show in athletics."

Genetic engineering is an issue, whether in stem cell research or GMOs, that stirs an immediate and powerful gut reaction. In recent years, biomedical researchers have made small but measurable strides in developing bio-engineered drugs. Many look forward, perhaps unrealistically, to an age when many diseases will have been wiped out and hospitals will be obsolete except to treat trauma. But such a revolution, if it should occur, invariably would result in collateral damage.
Challenging human limits
The genetics revolution has certainly changed how we view sports and the desire to challenge human performance limits. Since the dawn of the original Olympics in ancient Greece, it had been assumed that training and discipline were the heroic qualities most critical to athletic success. But recent research into population genetics and physiology has battered the myth that sports is a level playing field where athletes who work the hardest go on to glory.

The fact is that humans are not equally endowed. The new axiom in sports, especially performance sports like track where skill and technique are comparatively less important than in ones like tennis, is that choosing one's parents is far more important than choosing a coach. The belief in the power of the environment has been superseded by the reality that much of human nature, and certainly a great deal of the performance potential of elite athletes, is hard-wired and measurable.

For scientists who struggle to measure the real-world relationship of genetics to human behavior, sports offers the refreshing possibility of quantifying differences. Genes matter, and performance sports offer a great way to figure out just how much.

Consider the mystery that still surrounds the cross-country skiing exploits of Eero Mdentyranta. For decades after the Finn won two gold medals in the 1964 Winter Games at Innsbruck, and seven medals over three Olympics, he was dogged by rumors of deceit. Mdentyranta was not noted for his dedicated training habits, which prompted many of his competitors to accuse him of blood doping-adding red blood cells before the race to increase his oxygen and stamina, a not-uncommon practice of cheats of his era. He was tested and shown to have 15 percent more blood cells than normal. But with no evidence of doping, the controversy morphed into one of sports' most intriguing long-running mysteries.

Although Mdentyranta never failed a drug test, the rumors that he had an advantage turned out to be true. Whether the advantage was unfair depends on what you think of the gifts of fate. By 1993, Finnish researchers were able to conclude that Mdentyranta and his family carry a rare genetic mutation that produced the EPO hormone and loaded his blood cells with 50 percent more red cells than the average man's.

Certainly many elite athletes, especially those in the performance sports, are freaks of nature, but Mdentyranta's genetic advantage was huge and unique. His body was a natural energy factory. Unlike most people, he had no shutdown valve, so his red blood cell count continuously soared and his endurance never flagged. The extra cells bathed his laboring muscles in energy-producing oxygen, providing the boost to glide past competitors.

Mdentyranta's case may seem extreme, but only by degree: Many superstar athletes in highly competitive sports are outliers on the distribution of human possibility, the product of accumulating genetic mutations as rare as those that produce a 150-IQ chess champion or a violin-playing toddler.

"Very many in sports physiology would like to believe that it is training, the environment, what you eat that plays the most important role," Bengt Saltin, former director of the Copenhagen Research Center and a pioneer in the study of the relationship between genes and muscles, told me before he passed away last year. "But we argue based on the data that it is 'in your genes' whether or not you are talented or whether you will become talented. The extent of the environment can always be discussed but it's less than 20, 25 percent."

"You can't change human nature" may be one of the wisest of adages, but today, even a merely good athlete can be turned into a superstar by engineering "genetic defects"-creating future Eero Mdentyrantas. We are confronted with the reality that we can harness random acts of nature. Athletes often are willing guinea pigs, eager to gamble their health and maybe even their lives for the glory and riches of victory-and the genetic revolution will doubtless prove irresistible. And why not? From aging offensive linemen to Kenyan-chasing distance runners, athletes will know that their prospects might be brighter with an injection from the right DNA-filled test tube.
Future of sports and gene manipulation
Should athletes be allowed to use genetic techniques to improve performance? Most physiologists, ethicists and sport authorities say no. According to Saltin, messing around with genes is playing God-and only God should play God. "Biological variation is fundamental to sport," Saltin asserted. "You could say it's what gives a person their talent. This can now be radically affected with bioengineering, and this must be wrong."

Some scientists and ethicists look to a precarious future-perhaps before next year's Brazil games, in which an ambitious sprinter tired of running in Usain Bolt's tailwind turns to a renegade geneticist for help. This scientist would be familiar with new research that has pinpointed genes that can activate dormant human muscle fibers-fibers that resemble muscle from breathtakingly fast animals like cheetahs, and that fire far more quickly than human fast-twitch muscles. Humans only lack a genetic trigger to activate them-and those genes can be turned on.

Just a few injections of the right DNA into the quadriceps, hamstring and gluteus, and the muscle fibers could start cranking out Velociphin, activating the fast myosin gene. Within weeks, the muscles would bulge and burst with energy.

The tale deepens. This desperate athlete faces his long-awaited race into Olympic immortality. BANG! The genetically doped athlete dashes into the lead, extending it with every stride. Then at 65 meters, far out in front of the field, a sudden twinge tickles his thigh.

Bengt Saltin mused to me about what could happen next:

"At 80 meters," he said, "the twinge explodes into an overwhelming pain as he pulls his hamstring. A tenth of a second later the patella tendon gives in - because it is no match for the massive forces generated by his quadriceps muscle. The tendon pulls out part of the tibia bone, which then snaps, and the entire quadriceps shoots up along the femur bone. The athlete crumples to the ground, his running career over."

I gulp as he concluded his tale. "This is not the scenario that generally comes to mind in connection with the words 'genetically engineered super athlete,'" he aded, "but it is very much a part of the reality."

Without question, there is a high potential cost to playing god, even if genetic spigots can be developed to turn on and off at a whim, and therapies perfected. The issue is homeostasis. While many of us naively view the human body as an invincible machine, it is an integrated combination of tendons, cartilage, bones, nerves, muscle and fat. All living creatures are in delicate balance. One small change can have extraordinary and unanticipated consequences.

Olympic authorities have traditionally taken a hard line: Genetic engineering to improve performance is wrong. As former U.S. Olympic scientist Tim Conrad said a decade ago, "Anything you did not get from God is illegal."

"We're not trying to see what country has the best engineers." According to former IOC president Jacques Rogge, who is also a physician and retains close ties to the Olympic movement as a sports administrator in Belgium. "Genetic manipulation is there to treat people who have ailments, not to treat a healthy person. I am very clear on this."

While the issue of genetic performance enhancement is troubling, both because of health concerns and because allowing its use would unfairly benefit the privileged, the issue is not nearly so black and white. First, there's the question of what is "natural" and "normal"-and why those who benefited at birth by a lucky throw of the genetic dice should not have to face equal genetic competition.

Many newly developed drugs and therapies are identical to natural chemicals made by the body. What should be considered "normal" levels of such naturally occurring hormones? Because many great athletes are in effect an accumulation of favorable (for that sport) genetic mutations, at what point do we disallow certain athletes as being too far from the "genetic mainstream"? Should we deny the sons of daughters of Eero Mdentyranta to pursue their dreams of becoming Olympic cross-country skiing champions because they have a huge advantage that is "natural" but no less decisive than an athlete who takes a synthesized version of natural EPO?

The most powerful argument for allowing genetic interventions, however, is that there is a hazy and debatable line between "health restoration" and "performance enhancement." Genetic enhancement offers promising health benefits-as do any number of treatments that are the result of medical breakthroughs. Imagine an athlete using gene modification to overcome congenital asthma or another genetic abnormality. What about aiding someone who is destined to be short, say below 5 feet? Should they be disallowed from playing competitive sports if genetic manipulation will allow them to lead richer lives by making them 5 feet 10 inches? How about 6 feet 10 inches? Should people be punished because the roulette wheel of genetics did not land on their number?

Former world and Olympic champion sprinter Maurice Greene believes that the anti-genetic engineering orthodoxy is fueled by hysteria, and raises an intriguing point about personal responsibility.

"What if you're born with something having been done to you?" he asks. Should manipulation of an embryo be considered cheating? Is it fair to disqualify an athlete if the genetic changes were made before she was even born, perhaps even to save her life?

Finally, there is the pragmatic point. It seems overwhelmingly likely that, whether we like it or not, many world-class athletes in the future will have "had their genes done" the way they now get their knees scoped-and no one will know. What can or should we do about that?

There are no easy answers to these questions. The debate over genetic engineering is just beginning. The Pandora's box is open. There are cyborg athletes among us.
is the author of the best selling book Taboo: Why Black Athletes Dominate Sports and Why We Are Afraid to Talk About It. Follow @JonEntine on Twitter.

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Will genetic cyber-athletes come to dominate sports?

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The era of the über-athlete may be nearer than most people think, and it will spark fierce ethical debates. The most powerful argument for allowing genetic interventions is that there is a hazy and debatable line between "health restoration" and "performance enhancement."