Interventions to make heritable changes to the human genome are fraught with uncertainties. There are legitimate concerns about using a still imperfect technology that can rewrite the very blueprint of life. Also, the debate on whether it’s ethical to do so is far from being settled. However, would-be baby tinkerers around the world have failed to get the message
“The scientist does not study nature because it is useful to do so. He studies it because he delights in it, and he delights in it because it is beautiful. If nature were not beautiful it would not be worth knowing, and life would not be worth living.”— Henri Poincaré, French mathematician
Twins Lulu and Nana were born famous. They are the pseudonyms of the world’s first genetically edited babies. And if they become the subjects of the medical as well as the journalistic community then they will remain prisoners of their fame for as long as they live. The twin sisters are outliers who risk the chance of never experiencing the beauty of an anonymous life.
Chinese scientist He Jiankui — a biophysicist at the Southern University of Science and Technology in Shenzhen, China — announced the result of his experiment on November 26, 2018 in an exclusive interview to the Associated Press. The experiment using the simple yet powerful technology CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has, in just a few years, shaken the scientific community with its medical potential and ethicists for fear of its abuse.
“The implications go beyond just these twins,” Kiran Musunuru, professor of cardiovascular medicine and genetics at the University of Pennsylvania Perelman School of Medicine told Time magazine.
“If we talk about the sanctity of human life, and the inherent dignity of human life, not much has been gained here. These babies were treated as subjects in a grand medical experiment, and we have to believe that they will be studied for the rest of their lives; it’s sad actually.”
CRISPR-Cas9 genome-editing systems (also CRISPR in short, and pronounced CRISPER) are molecular machines that can target specific sections of DNA in the genome and cut both strands of the double helix molecule. CRISPRs are specialised stretches of DNA and the protein Cas9 is an enzyme that acts like a pair of molecular scissors.
CRISPR allows genes to be knocked out or, in some cases, added. There are many concerns about the CRISPR technology that need to be dealt with before it can be used widely in treatments for the sick — let alone meddle with healthy embryonic humans.
Jiankui’s edit targeted gene CCR5 that codes for a protein which HIV uses to enter cells. The biophysicist was trying to create a specific mutation in the gene, CCR5-delta32 (CCR5-Δ32), that few people naturally have — that possibly confers innate resistance to HIV.
Many scientists have questioned Jiankui’s choice of gene because of concerns about evidence suggesting that the CCR5-Δ32 mutation makes people more susceptible to the effects of infection by influenza and the West Nile virus.
A study published this year on June 3 in the science journal Nature says that Jiankui might have inadvertently shortened the life expectancy of the twins in an attempt to make them resistant to HIV.
This procedure casts further doubt on the wisdom of disabling the gene to protect against HIV, says Philip Murphy, a molecular immunologist at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.
“If you’re unlikely to make it to your third birthday, and could go beyond it if you simply edited a specific gene, that would be a risk worth taking,” he says. But current treatments for HIV allow many people with the virus to live into old age.
THIS IS PARTICULARLY important in the case of germline editing—introducing heritable changes into human sperm, egg, or embryos to make genetically altered children—because it’s so unlike most conventional therapies.
As the UK Nuffield Council has pointed out, it is incorrect to call it a therapy. If one were undertaking gene therapy in a baby, or even a foetus, to address a life-threatening genetic disease, it would be appropriate to accept a certain amount of risk because the alternative is much worse: living with a life-threatening disease.
But in the case of embryo editing, there is not yet a child that is sick and needs to be healed. Because the genome editing molecules are delivered into the egg at the same time as the sperm, one brings the “patient” into being in the same moment as one undertakes the “therapy”.
So, when the experiment is being contemplated, there is no child to heal.
The mutated gene per se is not necessarily dangerous, the contentious issue is that scientists are not sure that protection from HIV is the only thing the CRISPR edit might do to the twins’ genomes. For instance, it’s not clear that CRISPR is as accurate as researchers would like it to be. It makes mistakes, like off-target effects.
In some cases, CRISPR may make unintended changes in arbitrary parts of the genome, like an autocorrect feature of a word processor that erroneously corrects “typos” to produce a different word. In other cases, CRISPR may not make the edits as unfailingly as needed, so some cells may be edited while others are not, and some cells may even be partially edited, leaving a patchwork result that scientists call mosaicism.
This is where the problem lies as nothing can be said prospectively. We will have to wait and watch in the case of Lulu and Nana. In cases like this the difficulty is that a) you do not know beforehand where the map will go wrong; and b) the mistakes can lead to severe consequences.
You can draw a comparison with potentially helpful medicines that carry random but very severe side effects. Jiankui promised to follow up with the girls until they are 18, but it is unlikely that the Chinese health ministry will allow him to be involved in the evaluations.
It is not known what, if any, special measures are being taken to monitor the girls’ health or to track the third pregnancy that is on its way also due to Jiankui’s experiments.
SCIENTISTS AND BIOETHICISTS are divided on whether there should be a moratorium on germline editing. There is much less ethical resistance for intervention in somatic cells — any cell of a living organism other than the reproductive cells—which would not affect future generations.
The young Chinese American biochemist Feng Zhang, one of the inventors of CRISPR, called for a global moratorium on germline gene editing, a day after Jiankui announced the result of his experiment.
“Given the current state of the technology, I am in favour of a moratorium on implantation of edited embryos,” Zhang, a member of the Broad Institute of MIT and Harvard, said.
Where does one draw the ethical line or a logical and acceptable boundary? The most compelling argument about the ethics of germline gene editing or more precisely about the Chinese twins has been made by J Benjamin Hurlbut, Associate Professor of Life Sciences, Arizona State University and Jason Scott Robert, Director of the Lincoln Center for Applied Ethics, Arizona State University.
Jiankui surely broke many rules. The paperwork doesn’t seem to be as rigorous as the nature of the experiment required. Nothing has been published in any peer review journal and questions are being raised about an informed consent process.
These issues are important as compliance with established standards of practice is vital for public trust in science. But public debate about the experiment should not make the mistake of equating ethical oversight with ethical acceptability. Research that follows the rules is not necessarily good by definition.
“One risk of locating ethics primarily in research oversight is that in cases like this, the focus tends to be on whether the research was ethically compliant — that is, whether it followed the rules — not on whether it was ethically responsible. In a profoundly novel case like this, it’s worth questioning not only whether the rules were followed, but what they are, and are not, designed to protect against.
HE’S (JIANKUI’S) WORK should cause people to ask hard questions about this technology, its implications for human identity and for the integrity of foundational social relationships: parent to child, medicine to patient, state to citizen and society to its members.
Under what circumstances if any might it be appropriate to tinker in the genomes of our children-to-be?”
We also need to consider iatrogenics when it comes to germline gene editing. Iatrogenics is when a treatment causes more harm than benefit. As iatros means healer in Greek, the word means “caused by the healer”.
Distinguished Professor of Risk Engineering at the New York University Tandon School of Engineering and writer Nassim Nicholas Taleb calls these people interventionistas. Often these people come armed with solutions to solve the first order consequences of a decision but create worse second and subsequent order consequences. Luckily, for them at least, they’re never around to see the train wreck they created.
Perhaps the most original and contrarian scholar of the past decade or so, whose 2007 masterpiece The Black Swan established his credentials and inverted conventional wisdom on its head to show how inapplicable it is to our modern, complex and increasingly recursive environment, Taleb makes another hard to ignore observation in his book Antifragile.
Pharmaceutical companies are under financial pressure to find diseases and satisfy the security analysts. They have been scraping the bottom of the barrel, looking for diseases among healthy people, lobbying for reclassifications of conditions, and fine-tuning sales tricks to get doctors to overprescribe. Indeed, pharma plays on the interventionism of doctors.
Another way to view it: the iatrogenics is in the patient, not in the treatment. If the patient is close to death, all speculative treatments should be encouraged — no holds barred. Conversely, if the patient is near healthy, then Mother Nature should be the doctor.
Nature likes to overinsure itself. Layers of redundancy are the central risk management property of natural systems. Human beings have extra spare parts and extra capacity in many things (say, kidneys, lungs, neural system, arterial apparatus), while human design tends to be spare and inversely redundant, so to speak — we have a historical track record of engaging in debt, which is the opposite of a layer of redundancy. Redundancy is ambiguous because it seems like a waste if nothing unusual happens. Except that something unusual happens, usually.
LET’S ENTER THE CRISPR financials with the best advice that “Deep Throat”—the source of the Watergate scandal—supposedly whispered to journalist Bob Woodward of the Washington Post: “Follow the money”. Once a technology, dangerous or otherwise, that carries the prospect of being lucrative can be seen on a distant horizon, there is usually no shortage of adventurous gold diggers.
Despite global condemnation of the Chinese experiment, a Russian scientist on June 15 this year announced his ambition to repeat the Chinese scientist’s gene-editing experiment on human embryos.
Just about three months before Jiankui made his claims, CRISPR co-inventor Jennifer Doudna had said that the field is probably five to 10 years away from having an approved therapy for patients. She said then that major questions remain about the safety and effectiveness of experimental therapies that aim to disrupt or repair defective genes but was optimistic about their prospects.
In mid-June 2019 the optimism about the technology that has taken Wall Street by a storm resulted in a partnership. Bloomberg reported that University of California scientists led by Doudna would join GlaxoSmithKline in a five-year partnership aimed at cancer, the immune system and neuroscience.
The UK pharma company said that it will contribute as much as $67 million to set up a new lab in San Francisco that will bring researchers from big pharma and academia together under one roof. (see ‘CRISPR ownership fight’)
A great deal hinges on the accuracy of CRISPR. Since its discovery in 2012 it has become popular for tinkering with genomes of all kinds. Companies such as CRISPR Therapeutics, Intellia Therapeutics and Editas Medicine have been built on the idea that it could be used to develop treatments for human diseases.
This is good news, as perfection of CRISPR can lead to cures for diseases that are currently only manageable. Verve Therapeutics, a biotech firm in Cambridge, Massachusetts, recently said that it wanted to use genetic editing to protect patients from coronary heart disease.
CRISPR Therapeutics, based in Zug, Switzerland, wants to edit beta cells, which produce insulin, so that they can be transplanted into diabetics without rejection.
In all these therapies, regulators will have to assess the risks and benefits. That will be easier when small risks of mistakes are set against the benefits of curing a fatal disease.
The flipside is that the rush to CRISPR is due to the possibility of potential millions in the business. It is exemplified by the topical advent of CRISPR start-up firms, initial public offerings and venture capital funding rounds that are rising at astounding rates.
Global CRISPR market is estimated to grow at a compound annual growth rate of 33.26 per cent to reach a total market size of $3,086.69 million by 2023 from $551.24 million in 2017.
The Sage of Omaha Warren Buffett, admired for the wisdom he shares with young people around the world, has an apt quote for the gene editing boom: “Be greedy when others are fearful and be fearful when others are greedy.” The rush for CRISPR is a classic case to be fearful.
CRISPR solutions are transforming four significant markets: therapeutic development, agricultural biotechnology, industrial biotechnology, basic and applied biological research and all of them are getting enormous investments from renowned firms.
Large biotech companies and pharmaceuticals like Novartis, Vertex and Bayer AG have skin in the game exploring novel techniques to evolve their drug discovery and development processes, and establishing strategic alliances with crucial CRISPR technology companies to construct gene-based therapies for various genetic diseases.
Evolution of CRISPR technology has transformed gene editing playing field. Not limited to its use as a therapeutic tool, the pharmaceutical industry has found a silver bullet for drug discovery.
CRISPR provides the opportunity to study and alter all types of cell in the human body at a commercially viable pace and cost.
At this momentous time of change, CRISPR technology firms and pharmaceutical giants could do well to have some faith in the Bible.
Matthew, Chapter 6, Verse 24: “No one is able to serve two masters, for either he will hate the one and he will love the other, or he will be devoted to the one and he will despise the other. You cannot serve both God and Mammon.”
CRISPR ownership fightScientists Feng Zhang and Jennifer Doudna are the faces behind the fierce patent battle
(This article was first published in Down To Earth's print edition dated August 1-15, 2019)
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