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."
On the morning of April 12, 1955, newsrooms across the United States inked headlines onto newsprint: the Salk Polio vaccine was "safe, effective, and potent." This was long-awaited news. Americans had limped through decades of fear, unaware of what caused polio or how to cure it, faced with the disease's terrifying, visible power to paralyze and kill, particularly children.
The announcement of the polio vaccine was celebrated with noisy jubilation: church bells rang, factory whistles sounded, people wept in the streets. Within weeks, mass inoculation began as the nation put its faith in a vaccine that would end polio.
Today, most of us are blissfully ignorant of child polio deaths, making it easier to believe that we have not personally benefited from the development of vaccines. According to Dr. Steven Pinker, cognitive psychologist and author of the bestselling book Enlightenment Now, we've become blasé to the gifts of science. "The default expectation is not that disease is part of life and science is a godsend, but that health is the default, and any disease is some outrage," he says.
The Rise and Fall of Public Trust<p>When the polio vaccine was released in 1955, "we were nearing an all-time high point in public trust," says Matt Baum, Harvard Kennedy School professor and lead author of <a href="http://www.kateto.net/covid19/COVID19%20CONSORTIUM%20REPORT%2013%20TRUST%20SEP%202020.pdf" target="_blank" rel="noopener noreferrer"><u>several</u></a> <a href="https://shorensteincenter.org/wp-content/uploads/2020/09/COVID19-CONSORTIUM-REPORT-14-MISINFO-SEP-2020.pdf" target="_blank" rel="noopener noreferrer"><u>reports</u></a> measuring public trust and vaccine confidence. Baum explains that the U.S. was experiencing a post-war boom following the Allied triumph in WWII, a popular Roosevelt presidency, and the rapid innovation that elevated the country to an international superpower.</p><p> The 1950s witnessed the emergence of nuclear technology, a space program, and unprecedented medical breakthroughs, adds Emily Brunson, Texas State University anthropologist and co-chair of the Working Group on Readying Populations for COVID-19 Vaccine. "Antibiotics were a game changer," she states. While before, people got sick with pneumonia for a month, suddenly they had access to pills that accelerated recovery. </p><p>During this period, science seemed to hold all the answers; people embraced the idea that we could "come to know the world with an absolute truth," Brunson explains. Doctors were portrayed as unquestioned gods, so Americans were primed to trust experts who told them the polio vaccine was safe. </p>
The Shift in How We Consume Information<p>In the 1950s, the media created an informational consensus. The fundamental ideas the public consumed about the state of the world were unified. "People argued about the best solutions, but didn't fundamentally disagree on the factual baseline," says Baum. Indeed, the messaging around the polio vaccine was centralized and consistent, led by President Roosevelt's successful <a href="https://files.eric.ed.gov/fulltext/EJ978264.pdf" target="_blank" rel="noopener noreferrer"><u>March of Dimes crusade</u></a>. People of lower socioeconomic status with limited access to this information were <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1551508/?page=3" target="_blank" rel="noopener noreferrer"><u>less likely to have confidence</u></a> in the vaccine, but most people consumed <a href="https://www.c-span.org/video/?506891-1/a-special-report-polio" target="_blank" rel="noopener noreferrer"><u>media that assured them</u></a> of the vaccine's safety and <a href="https://www.cbsnews.com/news/the-salk-polio-vaccine-greatest-public-health-experiment-in-history/" target="_blank" rel="noopener noreferrer"><u>mobilized them</u></a> to receive it. </p><p>Today, the information we consume is no longer centralized—in fact, just the opposite. "When you take that away, it's hard for people to know what to trust and what not to trust," Baum explains. We've witnessed an increase in polarization and the technology that makes it easier to give people what they want to hear, reinforcing the human tendencies to vilify the other side and reinforce our preexisting ideas. When information is engineered to further an agenda, each choice and risk calculation made while navigating the COVID-19 pandemic <a href="https://www.nytimes.com/2020/12/19/opinion/sunday/coronavirus-science.html?referringSource=articleShare" target="_blank" rel="noopener noreferrer"><u>is deeply politicized</u></a>. </p><p>This polarization maps onto a rise in socioeconomic inequality and economic uncertainty. These factors, associated with a sense of lost control, prime people to embrace misinformation, explains Baum, especially when the situation is difficult to comprehend. "The beauty of conspiratorial thinking is that it provides answers to all these questions," he says. Today's insidious fragmentation of news media accelerates the circulation of mis- and disinformation, reaching more people faster, regardless of veracity or motivation. In the case of vaccines, skepticism around their origin, safety, and motivation is intensified. </p><p>Alongside the rise in polarization, Pinker says "the emotional tone of the news has gone downward since the 1940s, and journalists consider it a professional responsibility to cover the negative." Relentless focus on everything that goes wrong further erodes public trust and paints a picture of the world getting worse. "Life saved is not a news story," says Pinker, but perhaps it should be, he continues. "If people were more aware of how much better life was generally, they might be more receptive to improvements that will continue to make life better. These improvements don't happen by themselves."</p>
The Future Depends on Vaccine Confidence<p>So far, the U.S. has been unable to mitigate the catastrophic effects of the pandemic through social distancing, testing, and contact tracing. President Trump has <a href="https://www.washingtonpost.com/politics/bob-woodward-rage-book-trump/2020/09/09/0368fe3c-efd2-11ea-b4bc-3a2098fc73d4_story.html" target="_blank" rel="noopener noreferrer"><u>downplayed the effects and threat of the virus</u></a>, <a href="https://www.washingtonpost.com/outlook/2020/07/14/cdc-directors-trump-politics/" target="_blank" rel="noopener noreferrer"><u>censored experts and scientists</u></a>, <a href="https://www.theatlantic.com/science/archive/2020/06/america-giving-up-on-pandemic/612796/" target="_blank" rel="noopener noreferrer"><u>given up on containing the spread</u></a>, and <a href="https://www.nytimes.com/2020/09/16/world/covid-coronavirus.html" target="_blank" rel="noopener noreferrer"><u>mobilized his base to protest masks</u></a>. The Trump Administration failed to devise a national plan, so our national plan has defaulted to hoping for the <a href="https://www.politico.com/news/2020/08/26/nation-of-miracles-pence-coronavirus-vaccine-rnc-402949" target="_blank" rel="noopener noreferrer"><u>"miracle" of a vaccine</u></a>. And they are "something of a miracle," Pinker says, describing vaccines as "the most benevolent invention in the history of our species." In record-breaking time, three vaccines have arrived. But their impact will be weakened unless we achieve mass vaccination. As Brunson notes, "The technology isn't the fix; it's people taking the technology."</p><p> Significant challenges remain, including facilitating widespread access and supporting on-the-ground efforts to allay concerns and build trust with <a href="https://www.newyorker.com/news/daily-comment/african-american-resistance-to-the-covid-19-vaccine-reflects-a-broader-problem" target="_blank" rel="noopener noreferrer"><u>specific populations with historic reasons for distrust</u></a>, says Brunson. Baum predicts continuing delays as well as deaths from other causes that will be linked to the vaccine. </p><p> Still, there's every reason for hope. The new administration "has its eyes wide open to these challenges. These are the kind of problems that are amenable to policy solutions if we have the will," Baum says. He forecasts widespread vaccination by late summer and a bounce back from the economic damage, a "Good News Story" that will bolster vaccine acceptance in the future. And Pinker reminds us that science, medicine, and public health have greatly extended our lives in the last few decades, a trend that can only continue if we're willing to roll up our sleeves. </p>
Imagine this scenario: you get an annoying cough and a bit of a fever. When you wake up the next morning you lose your sense of taste and smell. That sounds familiar, so you head to a doctor's office for a Covid test, which comes back positive.
Your next step? An anti-Covid nasal spray of course, a "trickster drug" that will clear the once-dangerous and deadly virus out of the body. The drug works by tricking the coronavirus with decoy receptors that appear to be just like those on the surface of our own cells. The virus latches onto the drug's molecules "thinking" it is breaking into human cells, but instead it flushes out of your system before it can cause any serious damage.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
Biochemist David Baker, pictured in his lab at the University of Washington.