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Red alert over DNA mutation, editing of human embryos

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DNA editing… If defective genes make someone sick, why not just edit out the malfunctioning versions and add in ones that work? That’s the idea behind gene therapy — but it hasn’t lived up to its promise.

DNA editing… If defective genes make someone sick, why not just edit out the malfunctioning versions and add in ones that work? That’s the idea behind gene therapy — but it hasn’t lived up to its promise.

Scientists have in three separate studies raised alarm over possibilities that precision gene-editing techniques have been used to modify the DNA of human embryos, even as they called for a moratorium on the use of the technology in reproductive cells.

They are also apprehensive whether the H7N9 avian influenza that has infected more than 560 people in China and killed 204 might yet evolve to spread easily among people. But the largest-ever genomic survey of the virus in poultry now provides a more detailed picture of its evolution and spread.

Also, geneticists are having trouble deciding between one measure of how fast human DNA mutates and another that is half that rate. The rate is key to calibrating the ‘molecular clock’ that puts DNA-based dates on events in evolutionary history.

In a Comment published on March 12, 2015, in Nature, Edward Lanphier, chairman of the Alliance for Regenerative Medicine in Washington DC, United States, and four co-authors call on scientists to agree not to modify human embryos- even for research.

“Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development,” write Lanphier and his colleagues, who include Fyodor Urnov, a pioneer in gene-editing techniques and scientist at Sangamo BioSciences in Richmond, California.

Many groups, including Urnov’s company, are already using gene-editing tools to develop therapies that correct genetic defects in people (such as by editing white blood cells). They fear that attempts to produce ‘designer babies’ by applying the methods to embryos will create a backlash against all use of the technology.

Known as germline modification, edits to embryos, eggs or sperm are of particular concern because a person created using such cells would have had their genetic make-up changed without consent, and would permanently pass down that change to future generations.

“We need a halt on anything that approaches germline editing in human embryos,” Lanphier, who is also chief executive of Sangamo, told Nature’s news team.

But other scientists disagree with that stance. Although there needs to be a wide discussion of the safety and ethics of editing embryos and reproductive cells, they say, the potential to eliminate inherited diseases means that scientists should pursue research.

Geneticist Xingxu Huang of ShanghaiTech University in China, for example, is currently seeking permission from his institution’s ethics committee to try genetically modifying discarded human embryos. In February 2014, he reported2 using a gene-editing technique to modify embryos that developed into live monkeys. Human embryos would not be allowed to develop to full term in his experiments, but the technique “gives lots of potential for its application in humans,” he says.

Besides Huang’s work, gene-editing techniques are also being used by Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, to eliminate disease-causing mutations from mitochondria, the cell’s energy-processing structures. Belmonte’s work is on unfertilized eggs; human eggs with such modified mitochondria could one day be used in in-vitro fertilization (IVF) procedures to prevent a woman’s offspring from inheriting mitochondrial disease.

There are also suspicions that scientists have already created human embryos with edited genomes. Several researchers who do not want to be named told Nature’s news team that papers describing such work are being considered for publication.

Meanwhile, no one knows whether the H7N9 avian influenza that has infected more than 560 people in China and killed 204 might yet evolve to spread easily among people. But the largest-ever genomic survey of the virus in poultry now provides a more detailed picture of its evolution and spread.

H7N9 was first detected in and around Shanghai at the end of March 2013, and cases soared throughout April that year. The initial outbreak was swiftly brought under control after live-bird markets were identified as the main route of spread to humans, and were temporarily closed.

Hopes that the virus might have fizzled out were dashed, however, when H7N9 returned the following winter, spread south, and caused a large second wave of human infections. Confirming the seasonal pattern, there was a lull in new cases in the summer of 2014, but infections rose again late last year in a third wave that is still going on.

In a paper published on Nature’s website this week, an inter­national team of researchers describes how it tracked the virus from October 2013 to July 2014 by taking swabs from poultry at live-bird markets in 15 cities over 5 provinces in eastern China. The group detected the virus in markets in seven cities and in 3% of samples on average.

The team then sequenced the genomes of 438 viral isolates and found that as the virus spread south, it evolved into three main branches, with multiple sub-branches.

Such diversification is expected, but tracking it can help to identify the main trade routes and markets that fuel a virus’s spread. “The extent of viral transmission among chickens was largely unclear until our paper showed that the virus had diverged into regional lineages,” says Yi Guan, a co-author of the paper and a virologist at the State Key Laboratory of Emerging Infectious Diseases in Shenzhen, China. “Eastern China remains as a reservoir and ‘distribution centre’ for this virus,” he says.

Meanwhile, at an intimate meeting in Leipzig, Germany, on February 25 to 27, a dozen speakers puzzled over why calculations of the rate at which sequence changes pop up in human DNA have been so much lower in recent years than previously. They also pondered why the rate seems to fluctuate over time. The meeting drew not only evolutionary geneticists, but also researchers with an interest in cancer and reproductive biology — fields in which mutations have a central role.

“Mutation is ultimately the source of all heritable diseases and all biological adaptations, so understanding the rate at which mutations evolve is a fundamental question,” says Molly Przeworski, a population geneticist at Columbia University in New York City who attended the Human Mutation Rate Meeting.

Researchers tried to put a number on the human mutation rate even before they knew that genetic information is encoded in DNA. In the 1930s, pioneering geneticist J. B. S. Haldane came up with a good estimate by measuring how the mutations responsible for haemophilia appeared in extended families.

Later estimates of the mutation rate counted the differences between stretches of DNA and protein amino-acid sequences in humans and those in chimpanzees or other apes, and then divided the number of differences by the time that has elapsed since the species’ most recent common ancestor appeared in the fossil record. These estimates were clouded by the patchiness of the fossil record, but researchers eventually settled on a consensus: each DNA letter, on average, mutates once every billion years. That is a “suspiciously round number”, molecular anthropologist Linda Vigilant of the Max Planck Institute for Evolutionary Anthropology in Leipzig told Nature in 2012.

In the past six years, more-direct measurements using ‘next-generation’ DNA sequencing have come up with quite different estimates. A number of studies have compared entire genomes of parents and their children — and calculated a mutation rate that consistently comes to about half that of the last-common-ancestor method.

A slower molecular clock worked well to harmonize genetic and archaeological estimates for dates of key events in human evolution, such as migrations out of Africa and around the rest of the world1. But calculations using the slow clock gave nonsensical results when extended further back in time — positing, for example, that the most recent common ancestor of apes and monkeys could have encountered dinosaurs. Reluctant to abandon the older numbers completely, many researchers have started hedging their bets in papers, presenting multiple dates for evolutionary events depending on whether mutation is assumed to be fast, slow or somewhere in between.

Last year, population geneticist David Reich of Harvard Medical School in Boston, Massachusetts, and his colleagues compared the genome of a 45,000-year-old human from Siberia with genomes of modern humans and came up with the lower mutation rate. Yet just before the Leipzig meeting, which Reich co-organized with Kay Prüfer of the Max Planck Institute for Evolutionary Anthropology, his team published a preprint article that calculated an intermediate mutation rate by looking at differences between paired stretches of chromosomes in modern individuals (which, like two separate individuals’ DNA, must ultimately trace back to a common ancestor). Reich is at a loss to explain the discrepancy. “The fact that the clock is so uncertain is very problematic for us,” he says. “It means that the dates we get out of genetics are really quite embarrassingly bad and uncertain.”

Reich hoped that even if the meeting did not reach a consensus on mutation rate, it would highlight the research that is needed to move forward. He and Prüfer kicked off the meeting by polling attendees on their favoured rate, and found that the lower figure had gained popularity, but there was still a wide spread of opinions.

Meanwhile, scientists who attended a meeting in Napa, California, in January to discuss potential uses of germline gene-editing have written a perspective paper about their concerns for publication in Science. Geneticist Dana Carroll of the University of Utah in Salt Lake City, who was at the Napa meeting, says that it will call for discussions of the safety and ethics of using editing techniques on human embryos.

“Germline genome alterations are permanent and heritable, so very, very careful consideration needs to be taken in advance of such applications,” Carroll says.

Germline gene editing is already banned by law in many countries — a 2014 review by Tetsuya Ishii, a bioethicist at Hokkaido University in Sapporo, Japan, found that of 39 countries, 29 have laws or guidelines that ban the practice. But the development of precise gene-editing techniques in recent years has brought fresh urgency to the issue. These techniques use enzymes called nucleases to snip DNA at specific points and then delete or rewrite the genetic information at those locations. The methods are simple enough to be used in a fertility clinic, raising fears that they might be applied in humans before safety concerns have been addressed.

One concern, for example, is that the nucleases could cause mutations at locations other than those targeted. Guanghui Liu, a stem-cell researcher at the Chinese Academy of Sciences Institute of Biophysics in Beijing, collaborated on a study that showed that modifying one gene in stem cells resulted in minimal mutations elsewhere, but he warns that this is only one case.

Every application to use gene-editing technology for a therapy would have to be validated independently as safe and effective, says Jennifer Doudna, a biochemist at the University of California, Berkeley. “It would be necessary to decide, for each potential application, whether the risks outweigh the possible benefit to a patient. I think this assessment must be made on a case-by-case basis,” she says.

Ishii worries about countries such as the United States: there, germline editing is not banned but requires government approval, but such restrictions have a history of being circumvented, as in the case of unproven stem-cell treatments. He is also concerned about China, which prohibits gene-editing of embryos but does not strictly enforce similar rules, as shown by failed attempts to curb the use of ultrasound for sex selection and to stamp out unauthorized stem-cell clinics. China is also where gene-editing techniques in primates have developed fastest. “There are already a lot of dodgy fertility clinics around the world,” he says.

Meanwhile, as flu viruses evolve and diversify in birds, genetic changes can alter their infectivity, virulence or ability to spread among humans, notes Guan. Human infections also provide viruses with opportunities to better adapt to their hosts.

Genetic surveillance is therefore important in tracking mutations, and in testing whether flu strains show any enhanced capacity to spread between mammals such as ferrets and other animal models. From the outset of the outbreak, H7N9 carried mutations that allow it to spread from birds to humans more easily than avian H5N1 flu, which has infected 784 people in 16 countries and killed 429 of them since it appeared in 2003. Guan’s team reported no further acquisition by H7N9 of significant known mutations, however.

The wave of H7N9 infections that is currently under way probably has patterns of spread different from those of the second wave, which the team tracked. But before the latest study’s update, just 8 genome sequences from birds collected in 2014 had been deposited in the GenBank repository, and just 258 sequences from those collected in 2013. That is not enough for geographical mapping of the virus over time, says Marius Gilbert, an avian-flu epidemiologist and ecologist at the French-speaking Free University of Brussels.

The Nature news team has analysed the number of sequenced genomes from all subtypes of avian influenza submitted to GenBank over the past 15 years (before the latest paper’s sequences were added). The results show that overall genetic surveillance worldwide remains patchy and less than prompt. Most viruses are sequenced months or years after they were collected.

Guan agrees that timely monitoring is important. But surveillance and viral sequencing are costly and time-consuming — and isolating and sequencing viruses are all the more so, he points out. This means that surveillance of flu viruses in animal populations is rarely routine, usually done only in response to outbreaks. For H7N9, sequencing the virus also requires access to a biosafety-level-3 lab. Given the complications, Guan thinks that the number of recent H7N9 sequences deposited in GenBank is not grossly low.

Adding to the time lag, public authorities and researchers who sequence flu strains sometimes make the data public only when, or if, they publish — so sequences can languish. The authors of the latest study have sent sequences to GenBank and had already shared the data with the World Health Organization (WHO) and other bodies.

The threat from H7N9 is unlikely to go away any time soon. The virus is now endemic and entrenched in poultry populations across swathes of China, making it likely that people will continue to be infected sporadically. The researchers warn that it seems only “a matter of time before poultry movement spreads this virus beyond China by cross-border trade, as happened previously with H5N1 and H9N2 influenza viruses.

Guan and his co-authors say that given that H7N9 can infect humans, it “should be considered as a major candidate to emerge as a pandemic strain”. But predicting pandemic potential is an embryonic science. Last year, a prominent international group of researchers argued that there is little evidence that flu viruses that cause sporadic human infections are a greater pandemic threat than viruses that have not yet infected humans (C. A. Russell et al. eLife 3, e03883; 2014). But Guan says that given the vast number of flu viruses, it is necessary to prioritize targets for control and vaccine development — and that H7N9 should be high on that list.

There is no shortage of potential threats. The WHO last month warned that the current diversity and geographical range of novel animal influenza viruses is “unprecedented” — with an alphabet soup of new strains, including H10N8, H5N2, H5N3, H5N6 and H5N8, popping up in various parts of the world.

It is unclear to what extent this is a real increase or the result of improved surveillance. But the WHO says there is also evidence that different subtypes are currently swapping genes more easily and rapidly to form novel strains. It is “practically impossible” to assess whether this increased diversity represents a heightened threat of a pandemic virus emerging, says Guan.



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