Scientists May Soon Be Able to Turn Off Pain with Gene Editing: Should They?
The CRISPR-Cas9 gene editing tool could be used to "turn off" pain directly, raising ethical questions for society.
Scientists have long been aware that some people live with what's known as "congenital insensitivity to pain"—the inability to register the tingles, jolts, and aches that alert most people to injury or illness.
"If you break the chain of transmission somewhere along there, it doesn't matter what the message is—the recipient will not get it."
On the ospposite end of the spectrum, others suffer from hyperalgesia, or extreme pain; for those with erythromelalgia, also known as "Man on Fire Syndrome," warm temperatures can feel like searing heat—even wearing socks and shoes can make walking unbearable.
Strangely enough, the two conditions can be traced to mutations in the same gene, SCN9A. It produces a protein that exists in spinal cells—specifically, in the dorsal root ganglion—which transmits the sensation of pain from the nerves at the peripheral site of an injury into the central nervous system and to the brain. This fact may become the key to pain relief for the roughly 20 percent of Americans who suffer from chronic pain, and countless other patients around the world.
"If you break the chain of transmission somewhere along there, it doesn't matter what the message is—the recipient will not get it," said Dr. Fyodor Urnov, director of the Innovative Genomics Institute and a professor of molecular and cell biology at the University of California, Berkeley. "For scientists and clinicians who study this, [there's] this consistent tracking of: You break this gene, you stop feeling pain; make this gene hyperactive, you feel lots of pain—that really cuts through the correlation versus causation question."
Researchers tried for years, without much success, to find a chemical that would block that protein from working and therefore mute the pain sensation. The CRISPR-Cas9 gene editing tool could completely sidestep that approach and "turn off" pain directly.
Yet as CRISPR makes such targeted therapies increasingly possible, the ethical questions surrounding gene editing have taken on a new and more urgent cast—particularly in light of the work of the disgraced Chinese scientist He Jiankui, who announced in late 2018 that he had created the world's first genetically edited babies. He used CRISPR to edit two embryos, with the goal of disabling a gene that makes people susceptible to HIV infection; but then took the unprecedented step of implanting the edited embryos for pregnancy and birth.
Edits to germline cells, like the ones He undertook, involve alterations to gametes or embryos and carry much higher risk than somatic cell edits, since changes will be passed on to any future generations. There are also concerns that imprecise edits could result in mutations and end up causing more disorders. Recent developments, particularly the "search-and replace" prime-editing technique published last fall, will help minimize those accidental edits, but the fact remains that we have little understanding of the long-term effects of these germline edits—for the future of the patients themselves, or for the broader gene pool.
"We need to have appropriate venues where we deliberate and consider the ethical, legal and social implications of gene editing as a society."
It is much harder to predict the effects, harmful or otherwise, on the larger human population as a result of interactions with the environment or other genetic variations; with somatic cell edits, on the other hand— like the ones that would be made in an individual to turn off pain—only the person receiving the treatment is affected.
Beyond the somatic/germline distinction, there is also a larger ethical question over how much genetic interference society is willing to tolerate, which may be couched as the difference between therapeutic editing—interventions in response to a demonstrated medical need—and "enhancement" editing. The Chinese scientist He was roundly criticized in the scientific community for the fact that there are already much safer and more proven methods of preventing the parent-to-child transmission of HIV through the IVF process, making his genetic edits medically unnecessary. (The edits may also have increased the girls' risk of susceptibility to other viruses, like influenza and the West Nile virus.)
Yet there are even more extreme goals that CRISPR could be used to reach, ones further removed from any sort of medical treatment. The 1997 science fiction movie Gattaca imagined a dystopian future where genetic selection for strength and intelligence is common, creating a society that explicitly and unapologetically endorses eugenics. In the real world, Russian President Vladimir Putin has commented that genetic editing could be used to create "a genius mathematician, a brilliant musician or a soldier, a man who can fight without fear, compassion, regret or pain."
"[Such uses] would be considered using gene editing for 'enhancement,'" said Dr. Zubin Master, an associate professor of biomedical ethics at the Mayo Clinic, who noted that a series of studies have strongly suggested that members of the public, in the U.S. and around the world, are much less amenable to the prospect of gene editing for these purposes than for the treatment of illness and disease.
Putin's comments were made in 2017, before news of He's experiment broke; since then no country has moved to continue experiments on germline editing (although one Russian IVF specialist, Denis Rebrikov, appears ready to do so, if given approval). Master noted that the World Health Organization has an 18-person committee currently dedicated to considering these questions. The Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing first convened in March 2019; that July, it issued a recommendation to regulatory and ethics authorities in all countries to refrain from approving clinical application requests for work on human germline genome editing—the kind of alterations to genetic cells used by He. The committee's report and a fleshed-out set of guidelines is expected after its final meeting, in Geneva this September (unless the COVID-19 pandemic disrupts the timeline).
Regardless of the WHO's report, in the U.S., all regulations of new medical procedures are overseen at the federal level, subjected to extensive regulatory review by the FDA; the chance of any doctor or company going rogue is minimal to none. Likewise, the challenges we face are more on the regulatory end of the spectrum than the Gattaca end. Dr. Stephanie Malia Fullerton, a bioethics professor at the University of Washington, pointed out that eugenics not only typically involves state-sponsored control of reproduction, but requires a much more clearly delineated genetic basis of common complex traits—indeed, SCN9A is one way to get to pain, but is not the only source—and suggested that current concerns about over-prescribing opioids are a more pressing question for society to address.
In fact, Navega Therapeutics, based in San Diego, hopes to find out whether the intersection of this research into SCN9A and CRISPR would be an effective way to address the U.S. opioid crisis. Currently in a preclinical funding stage, Navega's approach focuses on editing epigenetic molecules attached to the basic DNA strand—the idea is that the gene's expression can be activated or suppressed rather than removed entirely, reducing the risk of unwanted side effects from permanently altering the genetic code.
As these studies focused on the sensation of pain go forward, what we are likely to see simultaneously is the use of CRISPR to target diseases that are the root causes of that pain. Last summer, Victoria Gray, a Mississippi woman with sickle cell disease was the second-ever person to be treated with CRISPR therapy in the U.S. The disease is caused by a genetic mutation that creates malformed blood cells, which can't carry oxygen as normal and get stuck inside blood vessels, causing debilitating pain. For the study, conducted in concert with CRISPR Therapeutics, of Cambridge, Mass., cells were removed from Gray's bone marrow, modified using CRISPR, and infused back into her body, a technique called ex vivo editing.
In early February this year, researchers at the University of Pennsylvania published a study on a first-in-human phase 1 clinical trial, in which three patients with advanced cancer received an infusion of ex vivo engineered T cells in an effort to improve antitumor immunity. The modified cells persisted for up to nine months, and the patients experienced no serious adverse side effects, suggesting that this sort of therapeutic gene editing can be performed safely and could potentially allow patients to avoid the excruciating process of chemotherapy.
Then, just this spring, researchers made another advance: The first attempt at in vivo CRISPR editing—where the edits happen inside the patient's body—is currently underway, as doctors attempt to treat a patient blinded by Leber congenital amaurosis, a rare genetic disorder. In an Oregon study sponsored by Editas Medicine and Allergan, the patient, a volunteer, was injected with a harmless virus carrying CRISPR gene-editing machinery; the hope is that the tool will be able to edit out the genetic defect and restore production of a crucial protein. Based on preliminary safety reports, the study has been cleared to continue, and data on higher doses may be available by the end of 2020. Editas Medicine and CRISPR Therapeutics are joined in this sphere by Intellia Therapeutics, which is seeking approval for a trial later this year on amyloidosis, a rare liver condition.
For any such treatment targeting SCN9A to make its way to human subjects, it would first need to undergo years' worth of testing—on mice, on primates, and then on volunteer patients after an extended informed-consent process. If everything went perfectly, Urnov estimates it could take at least three to four years end to end and cost between $5 and 10 million—but that "if" is huge.
"The idea of a regular human being, genetically pure of pain?"
And as that happens, "we need to have appropriate venues where we deliberate and consider the ethical, legal and social implications of gene editing as a society," Master said. CRISPR itself is open-source, but its application is subject to the approval of governments, institutions, and societies, which will need to figure out where to draw the line between miracle treatments and playing God. Something as unpleasant and ubiquitous as pain may in fact be the most appropriate place to start.
"The pain circuit is very old," Urnov said. "We have evolved with the senses that we have, and have become the species that we are, as a result of who we are, physiologically. Yes, I take Advil—but when I get a headache! The idea of a regular human being, genetically pure of pain?... The permanent disabling or turning down of the pain sensation, for anything other than a medical reason? … That seems to be challenging Mother Nature in the wrong ways."
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?