For decades we have talked about the jeopardy and promise of genetic engineering without much change. The dramatic recent breakthroughs of CRISPR technology mean that we must now confront the politics and ethics of our newfound power, writes John Parrington.
Imagine if living things were as easy to modify as a computer word file. What if the genetic code of organisms could be tweaked a little here, changed a bit there, to give organisms slightly different properties, or even radically different ones? In such a world, microorganisms might be adapted to produce new types of fuel, and farm animals or plants engineered to produce leaner meat or juicier fruit, but also to withstand extremes of temperature or drought to meet the increasing demands of climate change. Medical research too would be transformed if we could easily modify the genomes of different species in order to generate mutant animals to model human disease. If genomes really could be modified like computer text, medicine itself might look very different. Instead of people having to suffer terrible diseases like cystic fibrosis or muscular dystrophy, the gene defects associated with these conditions could be corrected in the affected tissues. If tinkering with genomes were both precise and efficient, such conditions might become a thing of the past, with genetic defects corrected at the embryo stage or even earlier, in the eggs or sperm within the gonads. Of course, this could pose the question of what was considered a defect. For instance, would the availability of personalized genome information and the ability to manipulate this information lead to parents clamouring to have offspring engineered to kick a football like Cristiano Ronaldo, compose music like Mozart, or have Einstein’s scientific genius?
But there are other, more troubling future scenarios that can be imagined if genetic modification were to become as easy as cutting and pasting a word file. For what would stop such technology being used to engineer new lethal types of viruses, or synthetic life forms escaping and taking over the world? And how could we ensure that new types of genetically modified (GM) food – whether animal or plant – were safe to eat? Could such plants pose a risk to the environment? And what about the welfare of the modified animals? This is also potentially an issue if scientists develop new types of mutant animals to model human disease. Will this lead to pain and suffering in a wider range of species, including our biological cousins – monkeys and other primates? And if researchers developed GM primates to study how the human brain works, could this lead to a Planet of the Apes-type scenario?
The prospect of being able to modify life in such a routine manner may either excite or horrify, depending on your viewpoint. Yet although these imagined future scenarios sound like science fiction rather than fact, thanks to a new technology called ‘CRISPR/Cas genome editing’, many soon may not be. Of course, you could be forgiven for thinking genome manipulation is nothing new. After all, isn’t that the scientific basis for all those past debates about GM crops, gene therapy, or designer babies? And indeed, we’ve had the technology to cut and paste gene sequences in a test tube since the 1970s, while in the 1980s it became possible to modify the genome of an organism as complex as a mouse. But the difference between genome editing and past forms of genetic engineering is a bit like comparing letterpress printing with the first word processor, or modern motor cars with horse-drawn carriages, in terms of scope and potential. So, as Jennifer Doudna of the University of California, Berkeley, recently put it: ‘It’s a technology that gives scientists a capability that has not been in our hands in the past. We’re basically now able to have a molecular scalpel for genomes. All the technologies in the past were sort of like sledgehammers.’
"The difference between genome editing and past forms of genetic engineering is a bit like comparing letterpress printing with the first word processor"
Like many tools used in molecular biology, CRISPR/Cas genome editing is based on a naturally occurring cellular process. Analogous to the way our immune systems protect us against viral infections, bacteria – which can also be infected by viruses called bacteriophages – protect themselves by using CRISPR/Cas to target invading bacteriophages. Essentially the bacteria create a strand of RNA (DNA’s chemical cousin) called a ‘guide RNA’ that recognises the virus’s DNA genome and directs an enzyme called Cas to a site on that genome which Cas then destroys by cutting it in half. While studying this process, Jennifer Doudna and a French scientist called Emmanuelle Charpentier who now works at the Max Planck Institute for Infection Biology in Berlin, realised that by tweaking the molecular properties of CRISPR/Cas they could create a tool that could be used not to destroy but precisely edit genes in living cells of practically any species, including humans.
Perhaps most astonishing is the speed at which the new genetic engineering is taking place. Despite genome editing being a recent development, it’s been taken up and applied in various different ways at a pace that has surprised many scientists. In 2015 Science magazine named CRISPR/Cas its Breakthrough of the Year’, instead of the Pluto flyby or the discovery of a new human ancestor. And in October 2020, the Nobel Prize for Chemistry was awarded to Doudna and Charpentier, the first time two women have shared this Nobel Prize.
‘We all kind of marvel at how fast this took off as a technology,’ says Doudna. ‘There’s just a really tremendous feeling of excitement for the potential of CRISPR.’ One way the technology is having a major impact in biomedical science is through a new-found ability to modify genomes from species used for research ranging from simple bacteria through to mammals – not only mice but large animals like pigs and monkeys. At the same time, the capacity of genome editing to genetically modify animals and plants important for agriculture looks set to have a huge impact on food production. Yet amidst the excitement, the new technology is also creating controversy, precisely because of its greatly enhanced accuracy and power compared to past genetic engineering approaches.
"A scientist at Southern University of Science and Technology in Shenzhen, China, shocked the world when he revealed that he had edited the genomes of two human embryos that were later born as twin baby girls. The twins have been engineered to be resistant to HIV."
Controversially, genome editing has been used to modify the genome of human embryos for the first time in history. In the hands of some scientists, such an approach is being used to study the genes involved in human embryo development, which could help in the diagnosis and treatment of miscarriage and birth disorders, and there was never any intention to implant the edited embryos into women. However, in December 2018, Jankui He, a scientist at Southern University of Science and Technology in Shenzhen, China, shocked the world when he revealed that he had edited the genomes of two human embryos that were later born as twin baby girls. The twins have been engineered to be resistant to HIV. The twins’ father had HIV and Jankui He posed this as a way to allow him to have children. In fact, the father was misinformed; the sperm of a man with HIV can be cleaned so that they do not pass on the disease to the next generation. There were all sorts of other problems with Jankui He’s scientific approach and he broke the law by not having obtained the appropriate ethical approval; as a consequence, he was recently jailed for three years. Yet his actions have effectively breached what was thought to be a ‘no-go area’ in medical ethics.
The range of potential applications of genome editing is such that Dustin Rubinstein, who’s applying this technology at the University of Wisconsin-Madison, believes ‘it’s really going to just empower us to have more creativity . . . to get into the sandbox and have more control over what you build. You’re only limited by your imagination.’ Yet, as Jennifer Doudna has pointed out, ‘Great things can be done with the power of technology, and there are things you would not want done. Most of the public does not appreciate what is coming.’
The potential exciting advances made possible by genome editing also pose serious ethical issues that shouldn’t be ducked. For instance, in agriculture, how can we ensure that genome editing is used to benefit the majority of the world’s population and not just increase the profits of giant companies? In biomedicine, such technology might revolutionize the understanding and treatment of disease, but what are the risks? This question is particularly controversial when we consider the possibility of using genome editing to genetically modify a human embryo. Leaving aside Jankui He’s botched and unethical approach to this issue, more generally the arguments for wanting to modify human embryos for clinical purposes, for instance, to correct a genetic disorder, have not been very convincing. In fact, it’s already possible to analyse human embryos that may have a genetic disorder and distinguish ones that lack the genetic defect underlying the disorder. This involves taking a single cell from an IVF embryo when it’s only a ball of cells and carrying out DNA analysis on the cell. If an embryo is identified as not possessing the defect, then it can be implanted into the mother. This approach is now used to select embryos without defects in the CFTR gene which causes cystic fibrosis; the huntingtin gene that leads to Huntington’s disease, an early-onset dementia; and the BRCA genes, associated with susceptibility to breast and ovarian cancer.
A major concern for some people is that using such genome editing for therapeutic purposes could lead ultimately to ‘designer babies’ – human individuals engineered at birth to have beautiful looks, high intelligence, or exceptional ability at sport or music. Such fears run deep among scientists. So Eric Lander, a geneticist at Harvard University, recently warned that ‘it has been only about a decade since we first read the human genome. We should exercise great caution before we begin to rewrite it.’ And at an international conference that took place in Washington in November 2015 to discuss the science and ethics of genome editing, over 150 biologists submitted a statement calling for a worldwide ban on the genetic editing of embryos, claiming the practice would ‘irrevocably alter the human species’. One particular concern was that such technology would only be available to rich people, leading to a world where inequality and discrimination were ‘inscribed onto the human genome’.
But before we get too carried away with the idea that genome editing could be used to create such enhanced individuals, it’s worth considering the complexity of the interaction between environment and genetics, and between genes themselves, that combines to shape a human being. For if there’s one central message emerging from studies of the link between the human genome and susceptibility to common disorders, it’s that this link is far more complex than had been supposed. And this is also true of other human characteristics. Whether we are talking about intelligence, looks, sporting ability, or musical prowess, all the indications are that such characteristics are the product of a complex interaction between many different genetic variants and also heavily dependent on the environment. So trying to use genome editing to create an enhanced individual, at least with our current knowledge about the link between genetics and the human condition, is far from likely to succeed.
Yet who knows what the situation might be in decades’ time if genome editing becomes increasingly fail-safe and our ability to interpret the genome more refined. Could genome editing one day allow human beings to acquire completely novel characteristics, borrowed from the rest of the animal kingdom? For instance, could a human gain the ability to detect sensitive odours like a dog, the night vision of a cat, or a capacity to remain underwater for long periods of time like a dolphin? In fact, it’s by no means clear that such characteristics could be engineered into a person in a functional manner, without having detrimental effects on the rest of the human body, but that might not prevent some scientist of the future deciding to experiment and explore what is possible. At the same time, will genetic modification of our nearest primate relatives begin to blur the boundaries between what is human and what is not? These are as much socio-political questions as scientific ones, and as such, they should be the subject of a far-reaching, scientifically informed public debate.