The era of human gene-editing may have begun. Why that is worrying

Humanity’s power to control the four-letter code of life has advanced by leaps and bounds. A new gene-editing technology called crispr-Cas9, which was not discovered until 2012, has been the subject of particular excitement. It allows dnato be edited easily, raising hopes that it could eventually be used to relieve human suffering. This week, however, crispr has caused more unease than optimism, because of claims by a Chinese scientist that he edited the genomes of twin girls when they were embryos, as part of ivf treatment.

He Jiankui, of the Southern University of Science and Technology, in Shenzhen—which was not involved in the work—says he edited a gene, ccr5, that allows hiv to infect human cells (see article). Mr He claims to have created one baby resistant to hiv infection, and a twin who is not. (Another woman is apparently carrying an edited embryo.) If reproductive cells were affected, any such modifications will be passed on to subsequent generations. There is still uncertainty over what Mr He has done. But it is just a matter of time before someone, somewhere, edits human embryos that are grown into babies. Governments and regulators need to pay heed.

Presume that Mr He’s assertions are truthful. One day it may make sense to edit an embryo—to cure genetic diseases, say. That day has not arrived. The technology is so new that the risks to human subjects cannot possibly justify the benefits. Scientists do not fully understand the scope of the unintended damage crispr does to dna elsewhere in the genome or how deactivating ccr5 might leave you vulnerable to other diseases (it may, for instance, make death from flu more likely).

Mr He’s work appears to have had the scantiest oversight and a vice-minister says it violates regulations. Mr He told delegates at a gene-editing conference in Hong Kong this week that he had run the idea for the trial past four people. It seems likely that Mr He himself was largely responsible for deciding whether his human experiment was worth the risks. It is not clear that the babies’ parents gave their informed consent.

Nor did the procedure fulfil any unmet medical need. For the child whose genome was edited to confer resistance, the claimed benefit is protection from a virus that she may never encounter (although her father is hiv-positive, his sperm were washed to prevent infection during fertilisation) and for which there is a good, and improving, standard of care. If the reports are correct, the second child has been exposed to the potential risks of an edited genome but can still be infected by hiv.

The idea that one scientist could make the leap towards editing reproductive cells has been condemned, but it has not been ruled out. Even if Mr He turns out to be a fraud, others have the means, the motive and the opportunity to do similar work. crispr is not a complex technology. That leads to two responses.

The first is practical: better oversight of places such as fertility clinics, where back-room genome-tinkerers may lurk. That applies not just in China, where Mr He has attracted vocal condemnation, but also in America, where ivf clinics could use greater regulatory scrutiny.

The second is proper debate about when gene-editing is warranted. Editing the unhealthy cells of those suffering from genetic diseases such as Duchenne’s muscular dystrophy and cystic fibrosis will alleviate their suffering. It is less clear when it is necessary to edit embryos, but Mr He’s experiment obviously fails the test. Fertility treatments already screen embryos for unwanted genes.

It may even be that editing will one day be used on embryos to enhance genomes (to make people cleverer, say), rather than to cure disease. But that requires regulators, policymakers, scientists and civil society to think through deep ethical questions. Work is already under way to develop principles for editing reproductive cells. Earlier this year the Nuffield Council on Bioethics, a think-tank in Britain, outlined two: that the changes brought about by gene-editing should not increase “disadvantage, discrimination or division in society” and that such changes should not harm the welfare of the future person. Such debate was always going to be needed. Now it is urgent.

 

 

This article was originally published in The Economist. Read the original article.

Editing Babies? We Need to Learn a Lot More First

Sooner or later it was bound to happen: A rogue scientist in China claims to have edited a gene in two human embryos and implanted them in the mother’s womb, resulting in the birth of genetically altered twin girls. We’re no longer in the realm of science fiction. If true, this hacking of their biological operating instructions, which they will pass on to their children and generations to come, is a dangerous breach of medical ethics and responsible research and must be condemned.

This is not to say that medicine won’t someday employ gene-editing technologies in similar ways. But that time has not arrived. There are still too many risks, too many unknowns, about tinkering with our heritable genetic blueprints.

In recent years genome editing has been appropriately heralded as the most important advance of biotechnology of our generation, and most likely the past century. Known as Crispr, this technique, and related DNA editing tools, enable their users to cut and paste discrete letters of the genome. This ability has markedly advanced science, shedding new light on the complex human genome with its billions of A, C, T and G letters that are the architecture of who we are.

Already, many clinical trials using this technology are underway involving patients with rare diseases like hemophilia, thalassemia and sickle cell anemia. The difference between these efforts and what reportedly happened in China is that these genome editing trials involve cells from the patient’s body. The manipulations are not transmissible to the next generation.

These trials are in their early stages, and we don’t yet have results to show whether this type of editing is safe or provides effective treatment. But whatever happens, the consequences are confined to a patient who has consented to the experimental treatment.

While there have been reports of human embryo editing experiments in laboratory petri dishes, until now, so far as we know, none of these embryos have been implanted in humans. In such cases, the hazards become markedly amplified because the editing intervenes in so-called germ line cells that are transmitted from one generation to another. Conceivably every cell in the body, some 37 trillion, could be programmed with the edits.

In the Chinese study, led by He Jiankui, a physicist, not a medical doctor, on the faculty of Southern University of Science and Technology in Shenzhen, the targeted gene was CCR5, which helps enable H.I.V. to enter cells. While preventing this intrusion might sound like an advance in the fight against AIDS, it is completely unnecessary and may even carry the hazard of increasing the subject’s susceptibility to other types of infection, such as influenza and West Nile fever. Previous genome editing studies have shown it is possible to disable the CCR5 gene in adults without working at the embryo level.

So the experiment was needless. It had no scientific basis and must be considered unethical when balanced against the known and unknown risks.

He Jiankui, a physicist and researcher, says he edited the genes of twins, a claim that has drawn widespread criticism.CreditVCG/VCG, via Getty Images

 

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He Jiankui, a physicist and researcher, says he edited the genes of twins, a claim that has drawn widespread criticism.CreditVCG/VCG, via Getty Images

The predominant risks are the potential impacts of the editing on other letters of the genome, which could induce diseases. We don’t have the assurance yet that Crispr provides laserlike precision in editing — for example, certain important genes for suppressing cancer are particularly susceptible to unintended editing. The way we assess this risk is to sequence the genome before and after editing, to see whether changes were made in genes other than the target gene.

But our ability to discern these changes is still rudimentary, and it is entirely likely that we will miss something. The fact that we may not have seen unintended mutations brought about by editing is by no means proof of their absence.

With six billion letters in the genome that could be affected, the risk of unintended editing is considerable and requires extensive scrutiny to understand and mitigate. That’s partly why the implantation of edited human embryos has been widely banned.

Even beyond the actual editing, this episode appears to have been marked by breaches of scientific conduct. One issue is informed consent. It is unclear whether the parents were told that there were simple ways to protect the embryos from disease that might have been transmitted by the H.I.V.-infected father. If they had known that, why would they consent to this risky procedure?

Moreover, no report by the researchers has been produced for the biomedical community to review. Through a journalist reporting about this, I had the opportunity to see some of the data, and there’s little question that Dr. He at least attempted to edit the genomes of the embryos. But no sequencing data has been presented or independently assessed.

Nor has data been released to show whether the targeted gene was functionally disabled, which would require cell experiments. Science demands such transparency, but all we have is a YouTube video by the researcher, who makes the bold claim that “the gene surgery was safe.”

Dr. He’s university has disavowed knowledge or support of the research and said an inquiry is underway. It said his “conduct in utilizing CRISPR/Cas9 to edit human embryos has seriously violated academic ethics and codes of conduct.”

We don’t know whether the intended human genome editing was achieved in the twins and have no idea whether it will prove to be safe if it was accomplished.

But we can conclude that this was a misguided, reckless use of powerful gene-altering tools to create edited human beings. We should not proceed down this road until we know far more about the consequences of what we are doing.

 

This article was originally published in The New York Times.  Read the original article.

Chinese Scientist Claims to Use Crispr to Make First Genetically Edited Babies

Ever since scientists created the powerful gene editing technique Crispr, they have braced apprehensively for the day when it would be used to create a genetically altered human being. Many nations banned such work, fearing it could be misused to alter everything from eye color to I.Q.

Now, the moment they feared may have come. On Monday, a scientist in China announced that he had created the world’s first genetically edited babies, twin girls who were born this month.

The researcher, He Jiankui, said that he had altered a gene in the embryos, before having them implanted in the mother’s womb, with the goal of making the babies resistant to infection with H.I.V. He has not published the research in any journal and did not share any evidence or data that definitively proved he had done it.

But his previous work is known to many experts in the field, who said — many with alarm — that it was entirely possible he had.

“It’s scary,” said Dr. Alexander Marson, a gene editing expert at the University of California in San Francisco.

While the United States and many other countries have made it illegal to deliberately alter the genes of human embryos, it is not against the law to do so in China, but the practice is opposed by many researchers there. A group of 122 Chinese scientists issued a statement calling Dr. He’s actions “crazy” and his claims “a huge blow to the global reputation and development of Chinese science.”

If human embryos can be routinely edited, many scientists, ethicists and policymakers fear a slippery slope to a future in which babies are genetically engineered for traits — like athletic or intellectual prowess — that have nothing to do with preventing devastating medical conditions.

While those possibilities might seem far in the future, a different concern is urgent and immediate: safety. The methods used for gene editing can inadvertently alter other genes in unpredictable ways. Dr. He said that did not happen in this case, but it is a worry that looms over the field.

Dr. He made his announcement on the eve of the Second International Summit on Human Genome Editing in Hong Kong, saying that he had recruited several couples in which the man had H.I.V. and then used in vitro fertilization to create human embryos that were resistant to the virus that causes AIDS. He said he did it by directing Crispr-Cas9 to deliberately disable a gene, known as CCR₅, that is used to make a protein H.I.V. needs to enter cells.

Dr. He said the experiment worked for a couple whose twin girls were born in November. He said there were no adverse effects on other genes.

In a video that he posted, Dr. He said the father of the twins has a reason to live now that he has children, and that people with H.I.V. face severe discrimination in China.

Dr. He’s announcement was reported earlier by the MIT Technology Review and The Associated Press.

In an interview with the A.P. he indicated that he hoped to set an example to use genetic editing for valid reasons. “I feel a strong responsibility that it’s not just to make a first, but also make it an example,” he told the A.P. He added: “Society will decide what to do next.”

It is highly unusual for a scientist to announce a groundbreaking development without at least providing data that academic peers can review. Dr. He said he had gotten permission to do the work from the ethics board of the hospital Shenzhen Harmonicare, but the hospital, in interviews with Chinese media, denied being involved. Cheng Zhen, the general manager of Shenzhen Harmonicare, has asked the police to investigate what they suspect are “fraudulent ethical review materials,” according to the Beijing News.

The university that Dr. He is attached to, the Southern University of Science and Technology, said Dr. He has been on no-pay leave since February and that the school of biology believed that his project “is a serious violation of academic ethics and academic norms,” according to the state-run Beijing News.

In a statement late on Monday, China’s national health commission said it has asked the health commission in southern Guangdong province to investigate Mr. He’s claims.

Many scientists in the United States were appalled by the developments.

“I think that’s completely insane,” said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Dr. Mitalipov broke new ground last year by using gene editing to successfully remove a dangerous mutation from human embryos in a laboratory dish.

Dr. Mitalipov said that unlike his own work, which focuses on editing out mutations that cause serious diseases that cannot be prevented any other way, Dr. He did not do anything medically necessary. There are other ways to prevent H.I.V. infection in newborns.

Just three months ago, at a conference in late August on genome engineering at Cold Spring Harbor Laboratory in New York, Dr. He presented work on editing the CCR₅ gene in the embryos of nine couples.

At the conference, whose organizers included Jennifer Doudna, one of the inventors of Crispr technology, Dr. He gave a careful talk about something that fellow attendees considered squarely within the realm of ethically approved research. But he did not mention that some of those embryos had been implanted in a woman and could result in genetically engineered babies.

“What we now know is that as he was talking, there was a woman in China carrying twins,” said Fyodor Urnov, deputy director of the Altius Institute for Biomedical Sciences and a visiting researcher at the Innovative Genomics Institute at the University of California. “He had the opportunity to say ‘Oh and by the way, I’m just going to come out and say it, people, there’s a woman carrying twins.’”

“I would never play poker against Dr. He,” Dr. Urnov quipped.

Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology, who co-led an advisory group on human gene editing for the National Academy of Sciences and the National Academy of Medicine, said that group and a similar organization in Britain had determined that if human genes were to be edited, the procedure should only be done to address “serious unmet needs in medical treatment, it had to be well monitored, it had to be well followed up, full consent has to be in place.”

It is not clear why altering genes to make people resistant to H.I.V. is “a serious unmet need.” Men with H.I.V. do not infect embryos. Their semen contains the virus that causes AIDS, which can infect women, but the virus can be washed off their sperm before insemination. Or a doctor can inject a single sperm into an egg. In either case, the woman will not be infected and neither will the babies.

Dr. He got his Ph.D., from Rice University, in physics and his postdoctoral training, at Stanford, was with Stephen Quake, a professor of bioengineering and applied physics who works on sequencing DNA, not editing it.

Experts said that using Crispr would actually be quite easy for someone like Dr. He.

After coming to Shenzhen in 2012, Dr. He, at age 28, established a DNA sequencing company, Direct Genomics, and listed Dr. Quake on its advisory board. But, in a telephone interview on Monday, Dr. Quake said he was never associated with the company.

This article was originally published in The New York Times.  Read the original article.

Taming the Groundcherry: With Crispr, a Fussy Fruit Inches Toward the Supermarket

The groundcherry might look at first like a purely ornamental plant. A member of the genus Physalis, it bears papery, heart-shaped husks that resemble Chinese lanterns. (The plant popularly known as the Chinese lantern is a close cousin.) Within each groundcherry casing is a small, tart, edible fruit, similar in appearance to a cherry tomato, that is sometimes sold at farmer’s markets.

The fruit might be more common in supermarkets were it not so difficult to grow in large quantities. Groundcherry bushes sprawl untidily and can drop their fruits early, and the plants possess other undesirable traits. Diminishing these traits through selective breeding would take years.

On Monday, however, a team of researchers reported that, by removing certain portions of the plant’s DNA using common gene-editing techniques, they’ve produced a groundcherry with a larger fruit and a more ordered bush, greatly speeding the process of domestication. Their work, which appeared in the journal Nature Plants, is part of a scientific initiative called the Physalis Improvement Project.

Groundcherries are related to tomatoes, which have a well-studied genome. Joyce Van Eck, a plant geneticist at Cornell University and the Boyce Thompson Institute and an author of the paper, and her colleagues had already discovered that, using Crispr, a gene-editing technique that can snip out portions of the genome, they could alter a specific tomato gene and produce plants that produced flowers more quickly.

The scientists wondered whether the groundcherry could be similarly altered, to help fast-track the domestication process. They examined the groundcherry genome for analogues of known tomato genes, and found one: an analogue of a gene called “SELF-PRUNING” or SP, that in tomatoes controls the shape of the plant.

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Stages of a groundcherry fruit’s growth at left, with the plant at right.CreditZachary Lippman/Cold Spring Harbor Laboratory/Howard Hughes Medical Institute

Using Crispr, the team removed a small portion of SP from the groundcherry genome. The resulting plants, when they grew, arranged themselves into more compact bushes. The team performed similar experiments with genes that influence flower number and fruit size.

“Sure enough, when we got those fruit off, they were larger than the parent groundcherry,” Dr. Van Eck said. “Close to 25 percent more weight in the fruit.”

Heartened by these successes, the researchers are working to see whether they can control the shape of groundcherry bushes with more precision. They are also keen to find a solution to the problem of fruit dropping off the bush.

“That can really complicate harvesting,” Dr. Van Eck said.

Tomatoes are known to carry a gene that influences the formation of a weak point on the stem of the fruit. Perhaps modulating this gene in the groundcherry will make possible a variety that keeps a firmer grip on its fruits.

It took around two years to complete the experiments. In the future, changes could take less time, or more, depending on how much work is necessary to adjust a given trait.

Still, Dr. Van Eck estimates that with conventional breeding techniques, addressing such traits can often take at least five years. And that’s if the trait breeders want to encourage is already present in some plants. If the trait isn’t readily available, then they face a much more difficult task of trying to track it down, then beginning the breeding process.

Because this application of Crispr involves only the removal of DNA, not the addition of new material, the resulting produce isn’t considered a genetically modified organism in the U.S. or Canada, Dr. Van Eck said.

The researchers suggest that this technique could be helpful in bringing plants that aren’t grown widely into greater circulation. The groundcherry, with its unusual look and enticing taste, could be a good first candidate.

 

This article was originally published in The New York Times.  Read the original article.

How stress echoes down the generations

THE effects of child abuse can last a lifetime. Neglected or abused children have a higher risk of developing all sorts of ailments as adults, including mental illnesses such as depression but also physical ones like cancer and stroke. In fact, the effects may last even longer. Emerging evidence suggests that the consequences of mistreatment in childhood may persist down the generations, affecting a victim’s children or grand-children, even if they have experienced no abuse themselves.

Exactly how this happens is not well understood. Rigorous experiments on human subjects are difficult. Scientists have therefore turned to rats and mice. But now Larry Feig of Tufts University and his colleagues have shown that psychological stress seems to cause similar changes in the sperm of both mice and men. Their study is published this week in Translational Psychiatry.

Biologists know that traits are carried down the generations by genes. Genes encode proteins, and proteins make up organisms. That is still true. But it has recently become clear that it is not the whole story. Organisms regulate the activity of their genes throughout their lives, switching different genes on and off as circumstances require. It is possible that such “epigenetic” phenomena can be passed, along with the genes themselves, to an animal’s descendants. They offer a mechanism by which an animal’s life experiences can have effects on its offspring.

Hunting for signs of this, Dr Feig and his colleagues asked 28 male volunteers to complete a questionnaire assessing the severity of any trauma they had experienced as youngsters. They also asked their volunteers to provide sperm samples. They then looked for evidence for a common epigenetic mechanism involving small molecules called micro-RNAs. Their job is to bind to another molecule called messenger RNA, whose task in turn is to ferry information read from a gene to the cellular factories that create the required protein. Micro-RNA renders messenger RNA inactive, reducing the activity of the gene in question—and it can travel in sperm alongside DNA.

Sure enough, upon screening the men’s sperm, the researchers found that concentrations of two types of micro-RNAs, miR-34 and miR-449, were as much as 100 times lower in samples from abused men.

The team then turned to their mice. A standard way to stress mice is to move them to new cages, with new mice, from time to time until they reach adulthood. When the team did this they found that the stressed males had lower levels of miR-34 and miR-449 in their sperm. They mated these males with unstressed females. The resulting embryos also had low levels of the two micro-RNAs. And so in turn did sperm produced by the male offspring of these unions.

Dr Feig and others have shown that the female offspring of stressed male mice tend to be more anxious and less sociable. Furthermore, the sons of stressed fathers themselves produce stressed daughters. The effects of cage-shuffling, in other words, seem to last for at least three generations. The researchers have not demonstrated conclusively that miR-34 and miR-449 are responsible. But their results are suggestive.

To try to nail their case, the researchers plan to carry out a bigger study. This time, they will give questionnaires to their human subjects’ fathers, to tease out whether any epigenetic changes they observe arise from the childhood experiences of the subject or his father. Sisters and daughters may be included in the study, too. That is an ambitious goal. It is also a worthy one. Unless genetic engineering can one day be perfected, changes in genes are hard-wired. But epigenetic effects might be treatable, by boosting levels of particular micro-RNAs in sperm, for example. That could mean the legacy of abuse is no longer passed to future generations.

 

 

This article was originally published in The Economist. Read the original article.

Why Your DNA Is Still Uncharted Territory

You have a gene called PNMA6F. All people do, but no one knows the purpose of that gene or the protein it makes. And as it turns out, PNMA6F has a lot of company in that regard.

In a study published Tuesday in PLOS Biology, researchers at Northwestern University reported that of our 20,000 protein-coding genes, about 5,400 have never been the subject of a single dedicated paper.

Most of our other genes have been almost as badly neglected, the subjects of minor investigation at best. A tiny fraction — 2,000 of them — have hogged most of the attention, the focus of 90 percent of the scientific studies published in recent years.

A number of factors are largely responsible for this wild imbalance, and they say a lot about how scientists approach science.

Researchers tend to focus on genes that have been studied for decades, for example. To take on an enigma like PNMA6F can put a scientist’s career at risk.

“This is very worrisome,” said Luís A. Nunes Amaral, a data scientist at Northwestern University and a co-author of the new study. “If the field keeps exploring the unknown this slowly, it will take us forever to understand these other genes.”

A gene may come to light because scientists encounter the protein it encodes. At other times, the first clue comes when scientists recognize that a stretch of DNA has some distinctive sequences that are shared by all genes.

But giving a gene a name doesn’t mean you know what it does.

Consider a gene called C1orf106. Scientists found it in 2002 but had no idea of its function. In 2011, researchers found that variants of this gene put people at risk of inflammatory bowel disease. Yet they still had no idea why.

In March, a team of researchers based at the Broad Institute in Cambridge, Mass., solved the mystery. They bred mice that couldn’t make proteins from C1orf106, and found that the animals developed leaky guts.

That protein, the scientists discovered, keeps intestinal cells properly glued together. Now investigators have a new way to look for treatments for inflammatory bowel disease.

Researchers noticed that something was wrong with the study of human genes as early as 2003. Just a small group of them attracted most of the scientific attention.

Genetics has changed dramatically since then. Scientists now have a detailed map of the human genome, showing the location of just about every gene on the human genome, and the technology for sequencing DNA has become staggeringly powerful.

Recently, Dr. Amaral and his colleagues checked to see if researchers had broadened their focus by analyzing millions of scientific papers published up to 2015. Our knowledge about human genes, the team found, remained wildly lopsided.

Not only did Dr. Amaral and his colleagues document the ongoing imbalance, they tested 430 possible explanations for why it exists, ranging from the size of the protein encoded by a gene to the date of its discovery.

It was possible, for example, that scientists were rationally focusing attention only on the genes that matter most. Perhaps they only studied the genes involved in cancer and other diseases.

That was not the case, it turned out. “There are lots of genes that are important for cancer, but only a small subset of them are being studied,” said Dr. Amaral.

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Just 15 explanations mostly accounted for how many papers have been published on a particular gene. The reasons have more to do with the working lives of scientists than the genes themselves.

For example, it’s easier to gather proteins that are secreted than ones that stay trapped inside cells. Dr. Amaral and his colleagues found that if a gene creates a secreted protein, that gene is much more likely to be well studied.

It’s also easier to study a human gene by looking at a related version in a mouse or some other lab animal. Scientists have succeeded in creating animal models for some genes but not others.

Genes that are studied in animal models tend to be studied a lot in humans, too, Dr. Amaral and his colleagues found.

A long history helps, too. The genes that are intensively studied now tend to be the ones that were discovered long ago.

Some 16 percent of all human genes were identified by 1991. Those genes were the subjects of about half of all genetic research published in 2015.

One reason is that the longer scientists study a gene, the easier it gets, noted Thomas Stoeger, a post-doctoral researcher at Northwestern and a co-author of the new report.

“People who study these genes have a head start over scientists who have to make tools to study other genes,” he said.

That head start may make all the difference in the scramble to publish research and land a job. Graduate students who investigated the least studied genes were much less likely to become a principal investigators later in their careers, the new study found.

“All the rewards are set up for you to study what has been well-studied,” Dr. Amaral said.

“With the Human Genome Project, we thought everything was going to change,” he added. “And what our analysis shows is pretty much nothing changed.”

If these trends continue as they have for decades, the human genome will remain a terra incognito for a long time. At this rate, it would take a century or longer for scientists to publish at least one paper on every one of our 20,000 genes.

That slow pace of discovery may well stymie advances in medicine, Dr. Amaral said. “We keep looking at the same genes as targets for our drugs. We are ignoring the vast majority of the genome,” he said.

Scientists won’t change their ways without a major shift in how science gets done, he added. “I can’t believe the system can move in that direction by itself,” he said.

Dr. Stoeger argued that the scientific community should recognize that a researcher who studies the least known genes may need extra time to get results.

“People who do something new need some protection,” he said.

Dr. Amaral proposed dedicating some research grants to the truly unknown, rather than safe bets.

“Some of the things we would be funding are going to fail,” he said. “But when they succeed, they’re going to open lots of opportunities.”

 

 

This article was originally published in The New York Times.  Read the original article.

WITH EMBRYO BASE EDITING, CHINA GETS ANOTHER CRISPR FIRST

SCIENTISTS IN THE US may be out in front developing the next generation of Crispr-based genetic tools, but it’s China that’s pushing those techniques toward human therapies the fastest. Chinese researchers were the first to Crispr monkeys, and non-viable embryos, and to stick Crispr’d cells into a real live human. And now, a team of scientists in China have used a cutting-edge Crispr technique, known as base editing, to repair a disease-causing mutation in viable human embryos.

Published last week in the journal Molecular Therapy, and reported first by Stat, the study represents significant progress over previous attempts to remodel the DNA of human embryos. That’s in part because the editing worked so well, and in part because that editing took place in embryos created by a standard in-vitro fertilization technique.

So-called “germline editing,” the contentious technologythat can permanently change the code in every cell in the human body, has been gaining acceptance in the last few years as research has pushed forward, illuminating the possibilities of Crispr. Immediately following those first reports of embryonic gene-editing in China in 2015, an international summit convened by the US National Academy of Sciences concluded that actually trying to produce a human pregnancy from such modified germlines was “irresponsible,” given ongoing safety concerns and lack of societal consensus. Two years later, a report from the NAS and the National Academy of Medicine stated that clinical trials for editing out heritable diseases could be permitted in the future, but only for serious conditions under stringent oversight.

Attitudes may be slowly changing: Last month, the United Kingdom’s Nuffield Council on Bioethics went so far as to say that heritable genome editing could be “ethically acceptable in some circumstances.” A Pew Research Council study released at the end of July found that 72 percent of Americans think changing an unborn baby’s DNA to treat a serious disease would be an appropriate use of gene-editing technology.

In the study published in Molecular Therapy, the Chinese scientists corrected a mutation that causes Marfan syndrome, an incurable connective tissue disorder that affects about 1 in 5,000 people. A single letter mistake in the gene for FBN1, which codes for the fibrillin protein, can cause a ripple effect of problems—from loose joints to weak vision to life-threatening tears in the heart’s walls. Starting with healthy eggs and sperm donated by a Marfan syndrome patient, the team of researchers from Shanghai Tech University and Guangzhou Medical University used an IVF technique to make viable human embryos. Then they injected the embryos with a Crispr construct known as a base editor, which swaps out a single DNA nucleotide for another—in this case, removing a “C” and replacing it with a “T”.1 They kept the embryos alive for another two days in the lab, long enough to run tests to see how well the editing worked.

Sequencing revealed that all 18 embryos had been edited, with 16 of the embryos bearing only the corrected version of the FBN1 gene. In two of the embryos, additional unwanted edits had also taken place. Previously, the most successful demonstration of gene editing in the human germline was the correction of a mutation that causes a hereditary heart condition in 42 out of 58 embryos. That study, which was published last year, used standard Crispr cut-and-paste technology.

“It’s a nice demonstration of the use of base editors to correct a well-known point mutation that causes a human genetic disease in a setting that may become therapeutically relevant,” says David Liu, whose lab at Harvard developed the base editor used to correct the Marfan mutation, though he was not involved in the study.

Rather than breaking the double-stranded DNA molecule and allowing the cell to repair itself with a healthy gene template, these newer versions of Crispr change just a single letter. If Crispr is a pair of molecular scissors, Liu’s base editors are more like a pencil with a squeaky new eraser. While the hope is that such precise gene-writing implements won’t cause the kind of sloppy chaos that Crispr 1.0 is capable of, Liu says it’s too early to make any general statements about their relative risks as a therapeutic. “Despite more than 50 publications using base editors from laboratories around the world, the entire field of base editing is only about two years old, and additional studies are needed to assess as many possible consequences of base editing as can be reasonably detected.”

Some of those studies are being conducted at Beam Therapeutics, the startup that Liu co-founded earlier this year with fellow Crispr pioneer Feng Zhang. Beam’s first license agreement with Harvard covers Liu’s C base editor, which makes programmable G-to-A or C-to-T edits, like the one used to correct the Marfan mutation. The second is the A base editor, which can do T-to-C as well as A-to-G edits. But don’t expect Beam to be erasing genetic diseases from the germline any time soon. The company is focused on using base editing to treat serious diseases in children and adults only, not on embryo editing, says CEO John Evans. “More consideration would be needed before society is ready to consider embryo editing, and we look forward to participating in the discussion.”

In the meantime, Beam will be just one of many US companies looking at an increasingly streamlined path for genetic medicines. In July, FDA Commissioner Scott Gottlieb announced a new regulatory framework for gene therapies to treat rare diseases. The agency issued a suite of six guidance documents updating the approval process. And on August 17, the FDA along with the National Institutes of Health proposed changes in the way the agencies together assess the safety of gene-therapy human trials.

Specifically, the proposals will eliminate review by the NIH’s Recombinant DNA Advisory Committee, which was established in 1974 to advise on emerging genetic technologies. In New England Journal of Medicineeditorial describing the changes, Gottlieb and NIH Director Francis Collins wrote it was their view that “there is no longer sufficient evidence to claim that the risks of gene therapy are entirely unique and unpredictable—or that the field still requires special oversight that falls outside our existing framework for ensuring safety.” A more streamlined approval process may help the US move faster in the long-run, though probably not enough to catch China’s head start. But when it comes to gene editing’s most controversial applications, there’s nothing wrong with being slow.

 

 

This article was originally published in Wired. Read the original article.

Clues to Your Health Are Hidden at 6.6 Million Spots in Your DNA

Scientists have created a powerful new tool to calculate a person’s inherited risks for heart disease, breast cancer and three other serious conditions.

By surveying changes in DNA at 6.6 million places in the human genome, investigators at the Broad Institute and Harvard University were able to identify many more people at risk than do the usual genetic tests, which take into account very few genes.

Of 100 heart attack patients, for example, the standard methods will identify two who have a single genetic mutation that place them at increased risk. But the new tool will find 20 of them, the scientists reported on Monday in the journal Nature Genetics.

The researchers are now building a website that will allow anyone to upload genetic data from a company like 23andMe or Ancestry.com. Users will receive risk scores for heart disease, breast cancer, Type 2 diabetes, chronic inflammatory bowel disease and atrial fibrillation.

People will not be charged for their scores.

A risk score, including obtaining the genetic data, should cost less than $100, said Dr. Daniel Rader, a professor of molecular medicine at the University of Pennsylvania.

Dr. Rader, who was not involved with the study, said the university will soon be offering such a test to patients to assess their risk for heart disease. For now, the university will not charge for it.

Dr. Sekar Kathiresan, senior author of the new paper and director of the Center for Genomic Medicine at Massachusetts General Hospital, said his team had validated the heart risk calculation in multiple populations.

But DNA is not destiny, Dr. Kathiresan stressed. A healthy lifestyle and cholesterol-lowering medications can substantially reduce risk of heart attack, even in those who have inherited a genetic predisposition.

The new tool also can find people at the low end of the risk range for the five diseases. This should prove useful to certain patients: for example, a woman who is trying to decide when she should start having regular mammograms, or a 40-year-old man with a slightly high cholesterol level who wants to know if he should take a statin.

Still, there are concerns about how the genetic test will be used. “It carries great hope, but also comes with a lot of questions,” said Dr. David J. Maron, director of preventive cardiology at Stanford University.

“Who should get tested? How should the results be provided? Physicians are not generally well trained to provide genetic test results.”

And, he wondered, will the results actually lead people to make decisions that improve their health?

People may need genetic counseling before and after getting these sorts of risk scores, noted Eric Schadt, dean of precision medicine at the Icahn School of Medicine at Mount Sinai.

Patients may not appreciate the consequences of learning they have a high likelihood of having a heart attack or breast cancer or one of the other diseases the test assesses.

“Do people really understand that once you learn something you cannot unlearn it?” said Dr. Schadt, who is also chief executive of Sema4, a diagnostics company.

But medical experts said this sort of risk assessment is the wave of the future. “I’m not sure we can stop it,” said Dr. John Mandrola, a cardiac electrophysiologist at Baptist Health in Louisville, Ky.

The study began because there was general agreement among researchers that many common diseases are linked not to one mutation, but rather to thousands or millions of mutations, said the first author of the new paper, Dr. Amit V. Khera, a cardiologist at Massachusetts General Hospital and a researcher at the Broad Institute.

In recent years, scientists have cataloged more than 6 million tiny changes in DNA that slightly affect the chances that people will get various diseases.

Each of those genetic alterations has such a small effect — a 1 percent or so increase or decrease in a person’s odds of getting a disease — that it would not be helpful to test for each one in isolation.

But it should be possible, scientists felt, to combine data on all the small DNA changes to construct an individual risk score. To do that, the researchers needed a new algorithm that would weigh the significance of the variations in the genes.

Then they had to test the risk scores they obtained. Dr. Khera and his colleagues turned to the U.K. Biobank, which holds genetic and disease information on half a million people.

The investigators found that their algorithm did predict the odds of being diagnosed with one of the five diseases. But the U.K. Biobank consists mostly of white Europeans.

So the investigators also tested and validated their method in populations of East Asians, South Asians, African Americans and Hispanics.

The researchers also tried their algorithm on 20,000 patients who were seen at Brigham and Women’s Hospital and Massachusetts General Hospital.

They found that those who had a high risk score for a heart attack were indeed four times more likely to have had a heart attack than other patients.

“Unless I do this genetic testing, there is no way I could pick those people out,” Dr. Khera said.

Just as important is finding people at very low risk, he and other researchers said.

At the University of Pennsylvania, doctors will incorporate risk scores on heart attacks into advice to patients on preventive care.

Dr. Rader said he often sees healthy patients in their 30s and 40s with a family history of heart disease. They have borderline levels of LDL cholesterol, the dangerous kind. But many do not want to start taking a statin.

For now, he said, he does his best to assess their risk, then tells some of them “it’s kind of up to you” whether to take a statin. But that advice “is not very satisfying,” he said.

A sophisticated genetic risk score might decide the matter. “If you have a really high score, here’s your prescription,” he said. “If your score is pretty low, you can hold off.”

This sort of sophisticated genetic analysis is still very new, Dr. Mandrola noted. But, he said, in five or 10 years doctors “may look back on the way they predict risk today and ask, ‘What were we thinking?’”

 

This article was originally published in The New York Times.  Read the original article.

Swift Gene-Editing Method May Revolutionize Treatments for Cancer and Infectious Diseases

For the first time, scientists have found a way to efficiently and precisely remove genes from white blood cells of the immune system and to insert beneficial replacements, all in far less time than it normally takes to edit genes.

If the technique can be replicated in other labs, experts said, it may open up profound new possibilities for treating an array of diseases, including cancer, infections like H.I.V. and autoimmune conditions like lupus and rheumatoid arthritis.

The new work, published on Wednesday in the journal Nature, “is a major advance,” said Dr. John Wherry, director of the Institute of Immunology at the University of Pennsylvania, who was not involved in the study.

But because the technique is so new, no patients have yet been treated with white blood cells engineered with it.

“The proof will be when this technology is used to develop a new therapeutic product,” cautioned Dr. Marcela Maus, director of cellular immunotherapy at Massachusetts General Hospital.

That test may not be far away. The researchers have already used the method in the laboratory to alter the abnormal immune cells of children with a rare genetic condition. They plan to return the altered cells to the children in an effort to cure them.

Currently, scientists attempting to edit the genome often must rely on modified viruses to slice open DNA in a cell and to deliver new genes into the cell. The method is time-consuming and difficult, limiting its use.

Despite the drawbacks, the virus method has had some success. Patients with a few rare blood cancers can be treated with engineered white blood cells — the immune system’s T-cells — that go directly to the tumors and kill them.

This type of treatment with engineered white cells, called immunotherapy, has been limited because of the difficulty of making viruses to carry the genetic material and the time needed to create them.

But researchers now say they have a found a way to use electrical fields, not viruses, to deliver both gene-editing tools and new genetic material into the cell. By speeding the process, in theory a treatment could be available to patients with almost any type of cancer.

“What takes months or even a year may now take a couple weeks using this new technology,” said Fred Ramsdell, vice president of research at the Parker Institute for Cancer Immunotherapy in San Francisco. “If you are a cancer patient, weeks versus months could make a huge difference.”

“I think it’s going to be a huge breakthrough,” he added.

The Parker Institute already is working with the authors of the new paper, led by Dr. Alexander Marson, scientific director of biomedicine at the Innovative Genomics Institute — a partnership between University of California, San Francisco and the University of California, Berkeley — to make engineered cells to treat a variety of cancers.

In the new study, Dr. Marson and his colleagues engineered T-cells to recognize human melanoma cells. In mice carrying the human cancer cells, the modified T-cells went right to the cancer, attacking it.

The researchers also corrected — in the lab — the T-cells of three children with a rare mutation that caused autoimmune diseases. The plan now is to return these corrected cells to the children, where they should function normally and suppress the defective immune cells, curing the children.

The technique may also hold great promise for treating H.I.V., Dr. Wherry said.

The H.I.V. virus infects T-cells. If they can be engineered so that the virus cannot enter the T-cells, a person infected with H.I.V. should not progress to AIDS. Those T-cells already infected would die, and the engineered cells would replace them.

Previous research has shown it might be possible to treat H.I.V. in this way. “But now there is a really efficient strategy to do this,” Dr. Wherry said.

The idea of engineering T-cells without using a virus is not new, but the immune cells are fragile and hard to keep alive in the lab, and it has always been difficult to get genes into them.

Scientists usually introduced replacement genes into T-cells with a type of virus that was disarmed so that it would not cause disease and that can insert new genes into cells. But when these viruses insert the genes into a cell’s DNA, they do so haphazardly, sometimes destroying other genes.

“We needed something targeted, something fast and something efficient,” Dr. Marson said. “What if we could just paste in a piece of DNA and avoid the viruses altogether?”

The idea would be to slip a type of molecular scissors, known as Crispr, into cells that would slice open DNA wherever scientists wanted a new gene to go. That would avoid the problem of using a virus that inserts genes pretty much at random.

And along with the scissors, they would add a piece of DNA containing the new gene to be added to the cells.

One way to do that would be to use an electrical field to make the cells permeable. It required a herculean effort by a graduate student, Theo Roth, to finally figure out the right molecular mixture of genes, gene-editing tools and electrical fields to modify T-cells without a virus.

“He tested thousands of conditions,” Dr. Marson said.

Already the scientists are talking to the Food and Drug Administration about using the new method to precisely attack solid tumors, as well as blood cancers.

“Our intent is to try to apply this as quickly as possible,” Dr. Ramsdell said.

So when they knew they had a system that worked, did they break out the champagne? Have a party?

Well, no, Mr. Roth said in an interview. He just took the data to Dr. Marson.

“We certainly had an exuberant walk to Alex’s office,” he recalled.

 

This article was originally published in The New York Times.  Read the original article.

A Crispr Conundrum: How Cells Fend Off Gene Editing

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Human cells resist gene editing by turning on defenses against cancer, ceasing reproduction and sometimes dying, two teams of scientists have found.

The findings, reported in the journal Nature Medicine, at first appeared to cast doubt on the viability of the most widely used form of gene editing, known as Crispr-Cas9 or simply Crispr, sending the stocks of some biotech companies into decline on Monday.

Crispr Therapeutics fell by 13 percent shortly after the scientists’ announcement. Intellia Therapeutics dipped, too, as did Editas Medicine. All three are developing medical treatments based on Crispr.

But the scientists who published the research say that Crispr remains a promising technology, if a bit more difficult than had been known.

“The reactions have been exaggerated,” said Jussi Taipale, a biochemist at the University of Cambridge and an author of one of two papers published Monday. The findings underscore the need for more research into the safety of Crispr, he said, but they don’t spell its doom.

“This is not something that should stop research on Crispr therapies,” he said. “I think it’s almost the other way — we should put more effort into such things.”

Crispr has stirred strong feelings ever since it came to light as a gene-editing technology five years ago. Already, it’s a mainstay in the scientific tool kit.

The possibilities have led to speculations about altering the human race and bringing extinct species back to life. Crispr’s pioneers have already won a slew of prizes, and titanic battles over patent rights to the technology have begun.

To edit genes with Crispr, scientists craft molecules that enter the nucleus of a cell. They zero in on a particular stretch of DNA and slice it out.

The cell then repairs the two loose ends. If scientists add another piece of DNA, the cell may stitch it into the place where the excised gene once sat.

Recently, Dr. Taipale and his colleagues set out to study cancer. They used Crispr to cut out genes from cancer cells to see which were essential to cancer’s aggressive growth.

For comparison, they also tried to remove genes from ordinary cells — in this case, a line of cells that originally came from a human retina. But while it was easy to cut genes from the cancer cells, the scientists did not succeed with the retinal cells.

Such failure isn’t unusual in the world of gene editing. But Dr. Taipale and his colleagues decided to spend some time to figure out why exactly they were failing.

They soon discovered that one gene, p53, was largely responsible for preventing Crispr from working.

p53 normally protects against cancer by preventing mutations from accumulating in cellular DNA. Mutations may arise when a cell tries to fix a break in its DNA strand. The process isn’t perfect, and the repair may be faulty, resulting in a mutation.

When cells sense that the strand has broken, the p53 gene may swing into action. It can stop a cell from making a new copy of its genes. Then the cell may simply stop multiplying, or it may die. This helps protect the body against cancer.

If a cell gets a mutation in the p53 gene itself, however, the cell loses the ability to police itself for faulty DNA. It’s no coincidence that many cancer cells carry disabled p53 genes.

Dr. Taipale and his colleagues engineered retinal cells to stop using p53 genes. Just as they had predicted, Crispr now worked much more effectively in these cells.

A team of scientists at the Novartis Institutes for Biomedical Research in Cambridge, Mass., got similar results with a different kind of cells, detailed in a paper also published Monday.

They set out to develop new versions of Crispr to edit the DNA in stem cells. They planned to turn the stem cells into neurons, enabling them to study brain diseases in Petri dishes.

Someday, they hope, it may become possible to use Crispr to create cell lines that can be implanted in the body to treat diseases.

When the Novartis team turned Crispr on stem cells, however, most of them died. The scientists found signs that Crispr had caused p53 to switch on, so they shut down the p53 gene in the stem cells.

Now many of the stem cells survived having their DNA edited.

The authors of both studies say their results raise some concerns about using Crispr to treat human disease.

For one thing, the anticancer defenses in human cells could make Crispr less efficient than researchers may have hoped.

One way to overcome this hurdle might be to put a temporary brake on p53. But then extra mutations may sneak into our DNA, perhaps leading to cancer.

Another concern: Sometimes cells spontaneously acquire a mutation that disables the p53 gene. If scientists use Crispr on a mix of cells, the ones with disabled p53 cells are more likely to be successfully edited.

But without p53, these edited cells would also be more prone to gaining dangerous mutations.

One way to eliminate this risk might be to screen engineered cells for mutant p53 genes. But Steven A. McCarroll, a geneticist at Harvard University, warned that Crispr might select for other risky mutations.

“These are important papers, since they remind everyone that genome editing isn’t magic,” said Jacob E. Corn, scientific director of the Innovative Genomics Institute in Berkeley, Calif.

Crispr doesn’t simply rewrite DNA like a word processing program, Dr. Corn said. Instead, it breaks DNA and coaxes cells to put it back together. And some cells may not tolerate such changes.

While Dr. Corn said that rigorous tests for safety were essential, he doubted that the new studies pointed to a cancer risk from Crispr.

The particular kinds of cells that were studied in the two new papers may be unusually sensitive to gene editing. Dr. Corn said he and his colleagues have not found similar problems in their own research on bone marrow cells.

“We have all been looking for the possibility of cancer,” he said. “I don’t think that this is a warning for therapies.”

“We should definitely be cautious,” said George Church, a geneticist at Harvard and a founding scientific adviser at Editas.

He suspected that p53’s behavior would not translate into any real risk of cancer, but “it’s a valid concern.”

And those concerns may be moot in a few years. The problem with Crispr is that it breaks DNA strands. But Dr. Church and other researchers are now investigating ways of editing DNA without breaking it.

“We’re going to have a whole new generation of molecules that have nothing to do with Crispr,” he said. “The stock market isn’t a reflection of the future.”