How Should Genetic Engineering Shape Our Future?
An artist's rendering of genetic codes.
Terror. Error. Success. These are the three outcomes that ethicists evaluating a new technology should fear. The possibility that a breakthrough might be used maliciously. The possibility that newly empowered scientists might make a catastrophic mistake. And the possibility that a technology will be so successful that it will change how we live in ways that we can only guess—and that we may not want.
These tools will allow scientists to practice genetic engineering on a scale that is simultaneously far more precise and far more ambitious than ever before.
It was true for the scientists behind the Manhattan Project, who bequeathed a fear of nuclear terror and nuclear error, even as global security is ultimately defined by these weapons of mass destruction. It was true for the developers of the automobile, whose invention has been weaponized by terrorists and kills 3,400 people by accident each day, even as the more than 1 billion cars on the road today have utterly reshaped where we live and how we move. And it is true for the researchers behind the revolution in gene editing and writing.
Put simply, these tools will allow scientists to practice genetic engineering on a scale that is simultaneously far more precise and far more ambitious than ever before. Editing techniques like CRISPR enable exact genetic repairs through a simple cut and paste of DNA, while synthetic biologists aim to redo entire genomes through the writing and substitution of synthetic genes. The technologies are complementary, and they herald an era when the book of life will be not just readable, but rewritable. Food crops, endangered animals, even the human body itself—all will eventually be programmable.
The benefits are easy to imagine: more sustainable crops; cures for terminal genetic disorders; even an end to infertility. Also easy to picture are the ethical pitfalls as the negative images of those same benefits.
Terror is the most straightforward. States have sought to use biology as a weapon at least since invading armies flung the corpses of plague victims into besieged castles. The 1975 biological weapons convention banned—with general success—the research and production of offensive bioweapons, though a handful of lone terrorists and groups like the Oregon-based Rajneeshee cult have still carried out limited bioweapon attacks. Those incidents ultimately caused little death and damage, in part because medical science is mostly capable of defending us from those pathogens that are most easily weaponized. But gene editing and writing offers the chance to engineer germs that could be far more effective than anything nature could develop. Imagine a virus that combines the lethality of Ebola with the transmissibility of the common cold—and in the new world of biology, if you can imagine something, you will eventually be able to create it.
The benefits are easy to imagine: more sustainable crops; cures for terminal genetic disorders; even an end to infertility. Also easy to picture are the ethical pitfalls.
That's one reason why James Clapper, then the U.S. director of national intelligence, added gene editing to the list of threats posed by "weapons of mass destruction and proliferation" in 2016. But these new tools aren't merely dangerous in the wrong hands—they can also be dangerous in the right hands. The list of labs accidents involving lethal bugs is much longer than you'd want to know, at least if you're the sort of person who likes to sleep at night. The U.S. recently lifted a ban on research that works to make existing pathogens, like the H5N1 avian flu virus, more virulent and transmissible, often using new technologies like gene editing. Such work can help medicine better prepare for what nature might throw at us, but it could also make the consequences of a lab error far more catastrophic. There's also the possibility that the use of gene editing and writing in nature—say, by CRISPRing disease-carrying mosquitoes to make them sterile—could backfire in some unforeseen way. Add in the fact that the techniques behind gene editing and writing are becoming simpler and more automated with every year, and eventually millions of people will be capable—through terror or error—of unleashing something awful on the world.
The good news is that both the government and the researchers driving these technologies are increasingly aware of the risks of bioterror and error. One government program, the Functional Genomic and Computational Assessment of Threats (Fun GCAT), provides funding for scientists to scan genetic data looking for the "accidental or intentional creation of a biological threat." Those in the biotech industry know to keep an eye out for suspicious orders—say, a new customer who orders part of the sequence of the Ebola or smallpox virus. "With every invention there is a good use and a bad use," Emily Leproust, the CEO of the commercial DNA synthesis startup Twist Bioscience, said in a recent interview. "What we try hard to do is put in place as many systems as we can to maximize the good stuff, and minimize any negative impact."
But the greatest ethical challenges in gene editing and writing will arise not from malevolence or mistakes, but from success. Through a new technology called in vitro gametogenesis (IVG), scientists are learning how to turn adult human cells like a piece of skin into lab-made sperm and egg cells. That would be a huge breakthrough for the infertile, or for same-sex couples who want to conceive a child biologically related to both partners. It would also open the door to using gene editing to tinker with those lab-made embryos. At first interventions would address any obvious genetic disorders, but those same tools would likely allow the engineering of a child's intelligence, height and other characteristics. We might be morally repelled today by such an ability, as many scientists and ethicists were repelled by in-vitro fertilization (IVF) when it was introduced four decades ago. Yet more than a million babies in the U.S. have been born through IVF in the years since. Ethics can evolve along with technology.
These new technologies offer control over the code of life, but only we as a society can seize control over where these tools will take us.
Fertility is just one human institution that stands to be changed utterly by gene editing and writing, and it's a change we can at least imagine. As the new biology grows more ambitious, it will alter society in ways we can't begin to picture. Harvard's George Church and New York University's Jef Boeke are leading an effort called HGP-Write to create a completely synthetic human genome. While gene editing allows scientists to make small changes to the genome, the gene synthesis that Church and his collaborators are developing allows for total genetic rewrites. "It's a difference between editing a book and writing one," Church said in an interview earlier this year.
Church is already working on synthesizing organs that would be resistant to viruses, while other researchers like Harris Wang at Columbia University are experimenting with bioengineering mammalian cells to produce nutrients like amino acids that we currently need to get from food. The horizon is endless—and so are the ethical concerns of success. What if parents feel pressure to engineer their children just so they don't fall behind their IVG peers? What if only the rich are able to access synthetic biology technologies that could make them stronger, smarter and longer lived? Could inequality become encoded in the genome?
These are questions that are different from the terror and errors fears around biosecurity, because they ask us to think hard about what kind of future we want. To their credit, Church and his collaborators have engaged bioethicists from the start of their work, as have the pioneers behind CRISPR. But the challenges coming from successful gene editing and writing are too large to be outsourced to professional ethicists. These new technologies offer control over the code of life, but only we as a society can seize control over where these tools will take us.
Catching colds may help protect kids from Covid
A new study shows that the immune system's response to colds can help prepare it to defend against COVID-19 - but only in the very young.
A common cold virus causes the immune system to produce T cells that also provide protection against SARS-CoV-2, according to new research. The study, published last month in PNAS, shows that this effect is most pronounced in young children. The finding may help explain why most young people who have been exposed to the cold-causing coronavirus have not developed serious cases of COVID-19.
One curiosity stood out in the early days of the COVID-19 pandemic – why were so few kids getting sick. Generally young children and the elderly are the most vulnerable to disease outbreaks, particularly viral infections, either because their immune systems are not fully developed or they are starting to fail.
But solid information on the new infection was so scarce that many public health officials acted on the precautionary principle, assumed a worst-case scenario, and applied the broadest, most restrictive policies to all people to try to contain the coronavirus SARS-CoV-2.
One early thought was that lockdowns worked and kids (ages 6 months to 17 years) simply were not being exposed to the virus. So it was a shock when data started to come in showing that well over half of them carried antibodies to the virus, indicating exposure without getting sick. That trend grew over time and the latest tracking data from the CDC shows that 96.3 percent of kids in the U.S. now carry those antibodies.
Antibodies are relatively quick and easy to measure, but some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
But that couldn't be the whole story because antibody protection fades, sometimes as early as a month after exposure and usually within a year. Additionally, SARS-CoV-2 has been spewing out waves of different variants that were more resistant to antibodies generated by their predecessors. The resistance was so significant that over time the FDA withdrew its emergency use authorization for a handful of monoclonal antibodies with earlier approval to treat the infection because they no longer worked.
Antibodies got most of the attention early on because they are part of the first line response of the immune system. Antibodies can bind to viruses and neutralize them, preventing infection. They are relatively quick and easy to measure and even manufacture, but as SARS-CoV-2 showed us, often viruses can quickly evolve to become more resistant to them. Some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
Kids, colds and T cells
T cells are part of the immune system that deals with cells once they have become infected. But working with T cells is much more difficult, takes longer, and is more expensive than working with antibodies. So studies often lags behind on this part of the immune system.
A group of researchers led by Annika Karlsson at the Karolinska Institute in Sweden focuses on T cells targeting virus-infected cells and, unsurprisingly, saw that they can play a role in SARS-CoV-2 infection. Other labs have shown that vaccination and natural exposure to the virus generates different patterns of T cell responses.
The Swedes also looked at another member of the coronavirus family, OC43, which circulates widely and is one of several causes of the common cold. The molecular structure of OC43 is similar to its more deadly cousin SARS-CoV-2. Sometimes a T cell response to one virus can produce a cross-reactive response to a similar protein structure in another virus, meaning that T cells will identify and respond to the two viruses in much the same way. Karlsson looked to see if T cells for OC43 from a wide age range of patients were cross-reactive to SARS-CoV-2.
And that is what they found, as reported in the PNAS study last month; there was cross-reactive activity, but it depended on a person’s age. A subset of a certain type of T cells, called mCD4+,, that recognized various protein parts of the cold-causing virus, OC43, expressed on the surface of an infected cell – also recognized those same protein parts from SARS-CoV-2. The T cell response was lower than that generated by natural exposure to SARS-CoV-2, but it was functional and thus could help limit the severity of COVID-19.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco.
“The cross-reactivity peaked at age six when more than half the people tested have a cross-reactive immune response,” says Karlsson, though their sample is too small to say if this finding applies more broadly across the population. The vast majority of children as young as two years had OC43-specific mCD4+ T cell responses. In adulthood, the functionality of both the OC43-specific and the cross-reactive T cells wane significantly, especially with advanced age.
“Considering that the mortality rate in children is the lowest from ages five to nine, and higher in younger children, our results imply that cross-reactive mCD4+ T cells may have a role in the control of SARS-CoV-2 infection in children,” the authors wrote in their paper.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco and author of the book, Endemic: A Post-Pandemic Playbook, to be released by the Mayo Clinic Press this summer. The immune response of kids to SARS-CoV-2 stood our expectations on their head. “We just haven't seen this before, so knowing the mechanism of protection is really important.”
Why the T cell immune response can fade with age is largely unknown. With some viruses such as measles, a single vaccination or infection generates life-long protection. But respiratory tract infections, like SARS-CoV-2, cause a localized infection - specific to certain organs - and that response tends to be shorter lived than systemic infections that affect the entire body. Karlsson suspects the elderly might be exposed to these localized types of viruses less often. Also, frequent continued exposure to a virus that results in reactivation of the memory T cell pool might eventually result in “a kind of immunosenescence or immune exhaustion that is associated with aging,” Karlsson says. https://leaps.org/scientists-just-started-testing-a-new-class-of-drugs-to-slow-and-even-reverse-aging/particle-3 This fading protection is why older people need to be repeatedly vaccinated against SARS-CoV-2.
Policy implications
Following the numbers on COVID-19 infections and severity over the last three years have shown us that healthy young people without risk factors are not likely to develop serious disease. This latest study points to a mechanism that helps explain why. But the inertia of existing policies remains. How should we adjust policy recommendations based on what we know today?
The World Health Organization (WHO) updated their COVID-19 vaccination guidance on March 28. It calls for a focus on vaccinating and boosting those at risk for developing serious disease. The guidance basically shrugged its shoulders when it came to healthy children and young adults receiving vaccinations and boosters against COVID-19. It said the priority should be to administer the “traditional essential vaccines for children,” such as those that protect against measles, rubella, and mumps.
“As an immunologist and a mother, I think that catching a cold or two when you are a kid and otherwise healthy is not that bad for you. Children have a much lower risk of becoming severely ill with SARS-CoV-2,” says Karlsson. She has followed public health guidance in Sweden, which means that her young children have not been vaccinated, but being older, she has received the vaccine and boosters. Gandhi and her children have been vaccinated, but they do not plan on additional boosters.
The WHO got it right in “concentrating on what matters,” which is getting traditional childhood immunizations back on track after their dramatic decline over the last three years, says Gandhi. Nor is there a need for masking in schools, according to a study from the Catalonia region of Spain. It found “no difference in masking and spread in schools,” particularly since tracking data indicate that nearly all young people have been exposed to SARS-CoV-2.
Both researchers lament that public discussion has overemphasized the quickly fading antibody part of the immune response to SARS-CoV-2 compared with the more durable T cell component. They say developing an efficient measure of T cell response for doctors to use in the clinic would help to monitor immunity in people at risk for severe cases of COVID-19 compared with the current method of toting up potential risk factors.
In this week's Friday Five: The eyes are the windows to the soul - and biological aging?
Plus, what bean genes mean for health and the planet, a breathing practice that could lower levels of tau proteins in the brain, AI beats humans at assessing heart health, and the benefits of "nature prescriptions"
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on new scientific theories and progress to give you a therapeutic dose of inspiration headed into the weekend.
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Here are the stories covered this week:
- The eyes are the windows to the soul - and biological aging?
- What bean genes mean for health and the planet
- This breathing practice could lower levels of tau proteins
- AI beats humans at assessing heart health
- Should you get a nature prescription?