On April 18th, 2015; the journal Protein & Cell published a paper, authored by researchers at Sun Yat-Sen University in Guanghzou, China, that detailed the results of experiments conducted by the researchers on gene editing – modifying the DNA of human embryos. The academic report went viral in the mainstream media, coupled with the ideas of designed people and manufactured DNA. However, it was really just a confirmation of rumours that genomic/genetic engineering is being experimented with in China; a practice strictly banned in a number of countries. It hass added fuel to the ongoing debate about gene editing: the safety, and whether we can really have an idea of the impact of permanently altering a person’s genetic code? And the ethics: if we have the power to design the humans of the next generation, should we? Pioneering geneticist Jennifer Doudna says, a little alarmingly, that “most of the public does not know what is coming.” This could be the most important moment in the field of biomedicine, according to another eminent scientist. But what is gene editing? Can we really rewrite our genome, the one unchangeable part of our identity?
The ability to modify an organism’s DNA has existed since the 1970s in fact; in 1986 Nobel prize winner Mario Capechhi showed that we could suppress certain genes in the cells of mice. However, techniques were primitive and unreliable – we may have been messing with nature’s blueprint, but in an unspecific, unusable way. Other the fact that the genome was not sequenced at the time (we didn’t know which gene caused what effect), the suppression didn’t always work, and in the end it was just suppression. Through the late 1990s and the dawn of the millennium, chemicals were found by which we could edit DNA with both freedom and precision. The new technology, a programmable protein called Zinc-finger nucleases (ZFN), allowed scientists to select specific sequences of DNA and cut them out, like a pair of DNA scissors. Not just that, they were able to delete, replace and add genes to the genomes of animals: true ‘gene editing’. They could create white blood cells that behaved like red blood cells, remove/add unnatural mutations, and even modify the genes of one animal to resemble another. Another huge breakthrough came when, in 2010, Fyodor Urnov and other geneticists applied the gene editing techniques to human cells; the five years since have been a flurry of activity and advance in the field.
Practical applications have emerged almost instantaneously: the DNA of blood cells and other body cells are being modified as a possible cure for cancer, AIDS and thalassemia. If the genome of enough mutated cancerous cells can be edited to resemble the normal genome, it could kill the cancer. The use of the gene editing in the search for the cure for HIV/AIDS has begun to look especially promising after the discovery of a new gene editing technique called CRISPR/Cas9. “It was gift from nature,” says Harvard researcher George Church, describing the technology which emerged from a widespread natural phenomenon seen in bacteria. The new technique was cheaper, easier, quicker and far more efficient: and its emergence in 2013 made the far-off seeming practical usage of gene editing a reality. Any scientist with basic molecular biology skills is will able to use it according to Doudna, one of the scientists responsible for discovering the CRISPR editing technique. In the two years since; hundreds of papers have been published all over the world by scientists studying its various possibilities and applications.
Somatic Cells, and Germ Cells
If gene editing was already such an established field of research, it’s difficult for people outside the science to understand the controversy around the most recent study. The debate is actually about the cells’ whose DNA is being modified: all the research and possibilities described above in gene editing in humans involve modification of the genome in somatic cells. Somatic cells comprise of all the body cells except two: the reproductive sperm and egg cells, which combine to give birth (also known as germ cells). Editing the genes of sperms, eggs or the zygote formed by the fusion is either banned or strictly regulated in most nations, excepting of course China. The reasons are manifold: some of the concerns are biological, and others are ethical. There is not yet a consensus on this, however, many are performing experiments on animal germ cells, and hope to enhance the procedure till it can be used in humans. In March, there were already rumours such research was being conducted in China; while a company, OvaScience was cashing in on gene edited egg cells, and Church’s lab at Harvard was testing the limits of the technology. At this time when germ line research seemed to be finally breaking out, several pioneers and scientists (including Fyodor Urnov) in the field wrote a piece, available on Nature.com that asked explicitly “not to edit the human germ line.” A number of other leading geneticists and biomedical experts, including Jennifer Doudna and George Church, met in January to discuss this very issue; and conclude, according to Doudna (the main organizer) that research in human germ line editing needs to be slowed down, until editing techniques are improved and made safer, and so that the general public can be involved in a debate that has momentous consequences according to her. The attendees of the meeting wrote an editorial in the journal Science on the prudent path forward in the field; which does recommend that the non-scientific general public be informed of the problems and possibilities of the field but is, ironically, available only to Science subscribers and members of the academic community. It can be read here, though. Although the recommendations put forth by the two groups do differ, their concerns are the same. And the alarm at the fact that such research is already taking place unregulated is universal.
The key difference between editing the “germ line” and modifying any other cells is that germ line editing is hereditarily permanent: if you edit the DNA of a person’s reproductive cells, any child that person has will possess the modified genome. The child’s reproductive cells will also be genetically modified, so his kids will be genetically modified, and so on. Aside from the ethical implications, scientists including Doudna are concerned about the use of such a new, experimental technology to affect a permanent change. Some say that much is still unknown about the genome, and development of characters in human beings – scientists would really have no idea what the impact of such genetic tampering could be generations later. Even considering short term implications, Edward Lanphier and colleagues proclaim adamantly that the use of CRISPR and other gene editing tools on embryos is still a field in its infancy – and according to them, we could not really tell the “precise effects of the modification until after birth”, i.e., when the embryo has developed into a human being. So far genomic modification tests in animal germ lines have not yielded good results: possibly contributed to by the fact that the zygote/early embryo is unique cell that is constantly dividing. Guoping Feng, who is applying CRISPR to monkey embryos at MIT, says the desired edit works only 20% of the time: sometimes the subjects die, and sometimes completely unwanted results are obtained. With such a low success rate, Feng believes that experiments on human embryos are “scientifically trivial” and sensationalist; until the technology is improved, they can have no practical use. Not everyone agrees: Church, whose lab at Harvard is engaging in the equally path-breaking research on unextinction with the help of gene editing and modifying animal organs so they can be used in humans, believes that recent (April 2015) advancements in the CRISPR editing technique could bring germ line editing far closer. Feng agrees that in the long run, “improving health” and “correcting diseases” should “definitely be supported”: but that it’s still 10-20 years away.
Ethics vs Designer Babies
Of course there are ethical issues. As MIT Technology Review puts it, we can now (or will be able to soon) engineer the human race. We can modify the DNA of our children; choose the attributes they will be born with, and even influence their destinies. As the experiment showed, and as researchers already knew: that’s not here yet – the technical glitches are far from resolved – but it isn’t far away now. So when it comes – the first question is of consent; when the body’s other cells are modified – they affect a single adult and no one else, his/her consent is all that is required. But if we are modifying the genome of unborn baby – its most fundamental aspect – do we have the right: do its parents have the right? It is a bit like the questions raised by Eragon and Elva in the eponymous fantasy novel, especially if the modification goes wrong – it is a great power, but should it be used? Some feel the question will be answered in a similar way as 3 parent babies were legalized in the UK recently. That too involved a kind of genetic selection – of the two mothers, the one with the healthier mitochondrial DNA was selected during in vitrio fertilization – mDNA being the DNA in a different part of the cell, that affects only health and not characteristics. Which brings us to one of the most important words in this debate: “therapeutic”. It means a medicinal technology is used to help defeat or prevent disease, instead of any other use. Modifying the DNA of a still unborn baby to ensure it is never afflicted with thalassemia is one thing, but programming its eye colour based on parental preference is a “non-therapeutic” use. Not just that: with the addition of new genes – not seen in humans – now a possibility; we could realistically engineer babies with superhuman capabilities. Some enthusiastic scientists call genetically engineered or enhanced children the future of the human race; but others fear “a dystopia of superpeople and designer babies for those who can afford it”, in the words of journalist Antonio Regalado, who wrote presciently about this two months ago. It can be argued that non-therapeutic uses are those that will generate large monetary returns, and these maybe prioritized/endorsed in a big way in an unregulated environment. It has also been argued that there are no obvious therapeutic uses of germ line editing, as of now, that couldn’t be satisfied by current methods, likeselection of healthy embryos in IVF. This might not always be true: say, if gene editing provided a cure for hereditary blindness in the near future. The distinction isn’t always clear either: you’d probably call a modification that prevents the baby from ever having Alzheimer’s disease therapeutic. But what about a gene that decreases the likelihood of it catching a cold? Or one that prevents it from becoming fat? It’s “a slippery slope”, in the eyes of some, and clarity is required to prevent researchers from doing something rash.
We’re Already There
In defence of Chinese geneticist Jinjiu Huang and his colleagues, they sidestepped the first few ethical concerns by using “unviable” embryos, i.e., defective embryos which cannot result in a birth, from an IVF clinic. They tried to induce specific mutations in the DNA of the embryos using CRISPR/Cas9: the result was a failure, in their own words. They describe that the successful modifications were very rare, at a lower rate than expected even from the experiments on animal embryos, while the incidence of other undesired mutations being caused was very high. Their paper was rejected by the two biggest journals Nature and Science for both ethical reasons and complaints against thoroughness. The editor of the journal that published the research wrote an impassioned defence explaining that they published it to “provide evidence of the safety concerns” with germ line editing; the paper too declares its conclusion to be that the CRISPR/Cas9 system must be improved before any practical application on human embryos. However, the paper also comes as evidence that the meetings and pleas of scientists a few months back were not scaremongering; far from it – the controversial research they were speaking of is already taking place. It may only be for academic reasons and therapeutic uses, but the fact remains that 4 more Chinese labs are rumoured to be doing similar experiments: without preventive rules and legislation, anyone could take advantage. Not every excited researcher sees the concerns: some liken it to IVF – controversial at first, but universal by the end; the thought of editing out the aging gene, or adding a little bit of super-intelligence has made some dismiss ethical issues.
There was the subtle difference between the Nature essay, and the Science editorial: in that the former postulated that there was not yet a compelling argument for the therapeutic benefits of germ line editing, and research on it in humans should be suspended until one emerges; while the latter advocated research on animal germ line editing and other human gene editing to evaluate whether human germ line editing may have future applications. Both asked that this controversial moral and ethical issue be discussed inside and outside the scientific community. The cover of George Church’s book Regenesis is a painting of god creating the world. Make no mistake, we will soon obtain the power of the gods: the question of whether we should use it is probably one of the hardest we will face? It is not the choice of the scientists – it is a decision for all of humanity. Though that is kind of hard if most people do not know – or do not care.
Do read Antonio Regalado’s prescient article for MIT Technology Review: Engineering the Perfect Baby
The appeals from leading biologists: on Nature and on Science
Photo Credits: PublicDomainPictures/Pixabay
References: MIT Technology Review, Nature.com, The Long Now Foundation, Nature Reviews Genetics, Schering-Plough, io9