COVID Variants Are Like “a Thief Changing Clothes” – and Our Camera System Barely Exists
Whether it's "natural selection" as Darwin called it, or it's "mutating" as the X-Men called it, living organisms change over time, developing thumbs or more efficient protein spikes, depending on the organism and the demands of its environment. The coronavirus that causes COVID-19, SARS-CoV-2, is not an exception, and now, after the virus has infected millions of people around the globe for more than a year, scientists are beginning to see those changes.
The notorious variants that have popped up include B.1.1.7, sometimes called the UK variant, as well as P.1 and B.1.351, which seem to have emerged in Brazil and South Africa respectively. As vaccinations are picking up pace, officials are warning that now
is not the time to become complacent or relax restrictions because the variants aren't well understood.
Some appear to be more transmissible, and deadlier, while others can evade the immune system's defenses better than earlier versions of the virus, potentially undermining the effectiveness of vaccines to some degree. Genomic surveillance, the process of sequencing the genetic code of the virus widely to observe changes and patterns, is a critical way that scientists can keep track of its evolution and work to understand how the variants might affect humans.
"It's like a thief changing clothes"
It's important to note that viruses mutate all the time. If there were funding and personnel to sequence the genome of every sample of the virus, scientists would see thousands of mutations. Not every variant deserves our attention. The vast majority of mutations are not important at all, but recognizing those that are is a crucial tool in getting and staying ahead of the virus. The work of sequencing, analyzing, observing patterns, and using public health tools as necessary is complicated and confusing to those without years of specialized training.
Jeremy Kamil, associate professor of microbiology and immunology at LSU Health Shreveport, in Louisiana, says that the variants developing are like a thief changing clothes. The thief goes in your house, steals your stuff, then leaves and puts on a different shirt and a wig, in the hopes you won't recognize them. Genomic surveillance catches the "thief" even in those different clothes.
One of the tricky things about variants is recognizing the point at which they move from interesting, to concerning at a local level, to dangerous in a larger context.
Understanding variants, both the uninteresting ones and the potentially concerning ones, gives public health officials and researchers at different levels a useful set of tools. Locally, knowing which variants are circulating in the community helps leaders know whether mask mandates and similar measures should be implemented or discontinued, or whether businesses and schools can open relatively safely.
There's more to it than observing new variants
Analysis is complex, particularly when it comes to understanding which variants are of concern. "So the question is always if a mutation becomes common, is that a random occurrence?" says Phoebe Lostroh, associate professor of molecular biology at Colorado College. "Or is the variant the result of some kind of selection because the mutation changes some property about the virus that makes it reproduce more quickly than variants of the virus that don't have that mutation? For a virus, [mutations can affect outcomes like] how much it replicates inside a person's body, how much somebody breathes it out, whether the particles that somebody might breathe in get smaller and can lead to greater transmission."
Along with all of those factors, accurate and useful genomic surveillance requires an understanding of where variants are occurring, how they are related, and an examination of why they might be prevalent.
For example, if a potentially worrisome variant appears in a community and begins to spread very quickly, it's not time to raise a public health alarm until several important questions have been answered, such as whether the variant is spreading due to specific events, or if it's happening because the mutation has allowed the virus to infect people more efficiently. Kamil offered a hypothetical scenario to explain: Imagine that a member of a community became infected and the virus mutated. That person went to church and three more people were infected, but one of them went to a karaoke bar and while singing infected 100 other people. Examining the conditions under which the virus has spread is, therefore, an essential part of untangling whether a mutation itself made the virus more transmissible or if an infected person's behaviors contributed to a local outbreak.
One of the tricky things about variants is recognizing the point at which they move from interesting, to concerning at a local level, to dangerous in a larger context. Genomic sequencing can help with that, but only when it's coordinated. When the same mutation occurs frequently, but is localized to one region, it's a concern, but when the same mutation happens in different places at the same time, it's much more likely that the "virus is learning that's a good mutation," explains Kamil.
The process is called convergent evolution, and it was a fascinating topic long before COVID. Just as your heritage can be traced through DNA, so can that of viruses, and when separate lineages develop similar traits it's almost like scientists can see evolution happening in real time. A mutation to SARS-CoV-2 that happens in more than one place at once is a mutation that makes it easier in some way for the virus to survive and that is when it may become alarming. The widespread, documented variants P.1 and B.1.351 are examples of convergence because they share some of the same virulent mutations despite having developed thousands of miles apart.
However, even variants that are emerging in different places at the same time don't present the kind of threat SARS-CoV-2 did in 2019. "This is nature," says Kamil. "It just means that this virus will not easily be driven to extinction or complete elimination by vaccines." Although a person who has already had COVID-19 can be reinfected with a variant, "it is almost always much milder disease" than the original infection, Kamil adds. Rather than causing full-fledged disease, variants have the potiental to "penetrate herd immunity, spreading relatively quietly among people who have developed natural immunity or been vaccinated, until the virus finds someone who has no immunity yet, and that person would be at risk of hospitalization-grade severe disease or death."
Surveillance and predictions
According to Lostroh, genomic surveillance can help scientists predict what's going to happen. "With the British strain, for instance, that's more transmissible, you can measure how fast it's doubling in the population and you can sort of tell whether we should take more measures against this mutation. Should we shut things down a little longer because that mutation is present in the population? That could be really useful if you did enough sampling in the population that you knew where it was," says Lostroh. If, for example, the more transmissible strain was present in 50 percent of cases, but in another county or state it was barely present, it would allow for rolling lockdowns instead of sweeping measures.
Variants are also extremely important when it comes to the development, manufacture, and distribution of vaccines. "You're also looking at medical countermeasures, such as whether your vaccine is still effective, or if your antiviral needs to be updated," says Lane Warmbrod, a senior analyst and research associate at Johns Hopkins Center for Health Security.
Properly funded and extensive genomic surveillance could eventually help control endemic diseases, too, like the seasonal flu, or other common respiratory infections. Kamil says he envisions a future in which genomic surveillance allows for prediction of sickness just as the weather is predicted today. "It's a 51 for infection today at the San Francisco Airport. There's been detection of some respiratory viruses," he says, offering an example. He says that if you're a vulnerable person, if you're immune-suppressed for some reason, you may want to wear a mask based on the sickness report.
The U.S. has the ability, but lacks standards
The benefits of widespread genomic surveillance are clear, and the United States certainly has the necessary technology, equipment, and personnel to carry it out. But, it's not happening at the speed and extent it needs to for the country to gain the benefits.
"The numbers are improving," said Kamil. "We're probably still at less than half a percent of all the samples that have been taken have been sequenced since the beginning of the pandemic."
Although there's no consensus on how many sequences is ideal for a robust surveillance program, modeling performed by the company Illumina suggests about 5 percent of positive tests should be sequenced. The reasons the U.S. has lagged in implementing a sequencing program are complex and varied, but solvable.
Perhaps the most important element that is currently missing is leadership. In order to conduct an effective genomic surveillance program, there need to be standards. The Johns Hopkins Center for Health Security recently published a paper with recommendations as to what kinds of elements need to be standardized in order to make the best use of sequencing technology and analysis.
"Along with which bioinformatic pipelines you're going to use to do the analyses, which sequencing strategy protocol are you going to use, what's your sampling strategy going to be, how is the data is going to be reported, what data gets reported," says Warmbrod. Currently, there's no guidance from the CDC on any of those things. So, while scientists can collect and report information, they may be collecting and reporting different information that isn't comparable, making it less useful for public health measures and vaccine updates.
Globally, one of the most important tools in making the information from genomic surveillance useful is GISAID, a platform designed for scientists to share -- and, importantly, to be credited for -- their data regarding genetic sequences of influenza. Originally, it was launched as a database of bird flu sequences, but has evolved to become an essential tool used by the WHO to make flu vaccine virus recommendations each year. Scientists who share their credentials have free access to the database, and anyone who uses information from the database must credit the scientist who uploaded that information.
Safety, logistics, and funding matter
Scientists at university labs and other small organizations have been uploading sequences to GISAID almost from the beginning of the pandemic, but their funding is generally limited, and there are no standards regarding information collection or reporting. Private, for-profit labs haven't had motivation to set up sequencing programs, although many of them have the logistical capabilities and funding to do so. Public health departments are understaffed, underfunded, and overwhelmed.
University labs may also be limited by safety concerns. The SARS-CoV-2 virus is dangerous, and there's a question of how samples should be transported to labs for sequencing.
Larger, for-profit organizations often have the tools and distribution capabilities to safely collect and sequence samples, but there hasn't been a profit motive. Genomic sequencing is less expensive now than ever before, but even at $100 per sample, the cost adds up -- not to mention the cost of employing a scientist with the proper credentials to analyze the sequence.
The path forward
The recently passed COVID-19 relief bill does have some funding to address genomic sequencing. Specifically, the American Rescue Plan Act includes $1.75 billion in funding for the Centers for Disease Control and Prevention's Advanced Molecular Detection (AMD) program. In an interview last month, CDC Director Rochelle Walensky said that the additional funding will be "a dial. And we're going to need to dial it up." AMD has already announced a collaboration called the Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance (SPHERES) Initiative that will bring together scientists from public health, academic, clinical, and non-profit laboratories across the country with the goal of accelerating sequencing.
Such a collaboration is a step toward following the recommendations in the paper Warmbrod coauthored. Building capacity now, creating a network of labs, and standardizing procedures will mean improved health in the future. "I want to be optimistic," she says. "The good news is there are a lot of passionate, smart, capable people who are continuing to work with government and work with different stakeholders." She cautions, however, that without a national strategy we won't succeed.
"If we maximize the potential and create that framework now, we can also use it for endemic diseases," she says. "It's a very helpful system for more than COVID if we're smart in how we plan it."
What Will Make the Public Trust a COVID-19 Vaccine?
With a brighter future hanging on the hopes of an approved COVID-19 vaccine, is it possible to win over the minds of fearful citizens who challenge the value or safety of vaccination?
Globally, nine COVID-19 vaccines so far are being tested for safety in early phase human clinical trials.
It's a decades-old practice. With a dose injected into the arm of a healthy patient, doctors aim to prevent illness with a vaccine shot designed to trigger a person's immune system to fight serious infection without getting the disease.
This week, in fact, the U.S. frontrunner vaccine candidate, developed by Moderna, safely produced an immune response in the first eight healthy volunteers, the company announced. A large efficacy trial is planned to start in July. But if positive signals for safety and efficacy result from that trial, will that be enough to convince the public to broadly embrace a new vaccine?
"Throughout the history of vaccines there has always been a small vocal minority who don't believe vaccines work or don't trust the science," says sociologist and researcher Jennifer Reich, a professor at the University of Colorado in Denver and author of Calling the Shots: Why Parents Reject Vaccines.
Research indicates that only about 2 percent of the population say vaccines aren't necessary under any circumstance. Remarkably, a quarter to one third of American parents delay or reject the shots, not because they are anti-vaccine, but because they disapprove of the recommended timing or administration, says Reich.
Additionally, addressing distrust about how they come to market is key when talking to parents, workers or anyone targeted for a new vaccine, she says.
"When I talk to parents about why they reject vaccines for their kids, a lot of them say that they don't fully trust the process by which vaccines are regulated and tested," says Reich. "They don't trust that vaccine manufacturers -- which are for-profit companies -- are looking out for public health."
Balancing Act
Globally, nine COVID-19 vaccine candidates so far are being tested for safety in early phase human clinical trials and more than 100 are under development as scientists hustle to curtail the disease. Creating a new vaccine at a record pace requires a delicate balance of benefit and risk, says vaccinology expert Dr. Kathryn Edwards, professor of pediatrics in the division of infectious diseases at Vanderbilt University School of Medicine in Nashville, Tenn.
"We take safety very seriously," says Dr. Edwards. "We don't want something bad to happen, but we also realize that we have a terrible outbreak and we have a lot of people dying. We want to figure out how we can stop this."
In the U.S., all vaccine clinical trials have a data safety board of experts who monitor results for adverse reactions and red flags that should halt a study, notes Dr. Edwards. Any candidate that succeeds through safety and efficacy trials still requires review and approval by the Food and Drug Administration before a public launch.
Community vs. Individual
A major challenge to the deployment of a safe and effective coronavirus vaccine goes beyond the technical realm. A persistent all-out anti-vaccine sentiment has found a home and growing community on social media where conspiracies thrive. Main tenets of the movement are that vaccines are ineffective, unsafe and cause autism, despite abundant scientific evidence to the contrary.
Best-case scenario, more than one successful vaccine ascends with competing methods to achieve the same goal of preventing or lessening the severity of the COVID-19 virus.
In fact, widespread use of vaccines is considered by the U.S. Centers of Disease Control and Prevention to be one of the greatest public health achievements of the 20th Century. The World Health Organization estimates that between two million to three million deaths are avoided each year through immunization campaigns that employ vaccination to control life-threatening infectious diseases.
Most people reluctant to give their children vaccines, however, don't oppose them for everyone, but believe that they are a personal choice, says Reich.
"They think that vaccines are one strategy in personal health optimization, but they shouldn't be mandated for participation in any part of civil society," she says.
Vaccine hesitancy, like the teeter totter of social distancing acceptance, reflects the push and pull of individual versus community values, says Reich.
"A lot of people are saying, 'I take personal responsibility for my own health and I don't want a city or a county or state telling me what I should and shouldn't do,'" says Reich. "Then we also see calls for collective responsibility that says 'It's not your personal choice. This is about helping health systems function. This is about making sure vulnerable people are protected.'"
These same debates are likely to continue if a vaccine comes to market, she says.
Building Public Confidence
Reich offers solutions to address the conflict between embedded American norms and widespread embrace of an approved COVID-19 vaccine. Long-term goals: Stop blaming people when they get sick, treat illness as a community responsibility, make sick leave common for all workers, and improve public health systems.
"In the shorter run," says Reich, "health authorities and companies that might bring a vaccine to market need to work very hard to explain to the public why they should trust this vaccine and why they should use it."
The rush for a viable vaccine raises questions for consumers. To build public confidence, it's up to FDA reviewers, institutions and pharmaceutical companies to explain "what steps were skipped. What steps moved forward. How rigorous was safety testing. And to make that information clear to the public," says Reich.
Dr. Edwards says clinical trial timelines accelerated to test vaccines in humans make all the safeguards involved in the process that more compelling and important.
"There's no question we need a vaccine," she says. "But we also have to make sure that we don't harm people."
The Road Ahead
Think of manufacturing and distribution as key pitstops to keep the race for a vaccine on the road to the finish line. Both elements require substantial effort and consideration.
The speed of getting a vaccine to those who need it could hinge on the type of technology used to create it. Best-case scenario, more than one successful vaccine ascends with competing methods to achieve the same goal of preventing or lessening the severity of the COVID-19 virus.
Technological platforms fall into two basic camps, those that are proven and licensed for other viruses, and experimental approaches that may hold great promise but lack regulatory approval, says Maria Elena Bottazzi, co-director of Texas Children's Center for Vaccine Development at Baylor College of Medicine in Houston.
Moderna, for instance, employs an experimental technology called messenger RNA (mRNA) that has produced the encouraging early results in human safety trials, although some researchers criticized the company for not making the data public. The mRNA vaccine instructs cells to make copies of the key COVID-19 spike protein, with the goal of then triggering production of immune cells that can recognize and attack the virus if it ever invades the body.
"We were already seeing a lot of dissent around questions of individual freedoms and community responsibilities."
Scientists always look for ways to incorporate new technologies into drug development, says Bottazzi. On the other hand, the more basic and generic the technology, theoretically, the faster production could ramp up if a vaccine proves successful through all phases of clinical trials, she says.
"I don't want to develop a vaccine in my lab, but then I don't have anybody to hand it off to because my process is not suitable" for manufacturing or scalability, says Bottazzi.
Researchers at the Baylor lab hope to repurpose a shelved vaccine developed for the genetically similar SARS virus, with a strategy to leverage what is already known instead of "starting from scratch" to develop a COVID-19 vaccine. A recombinant protein technology similar to that used for an approved Hepatitis B vaccine lets scientists focus on identifying a suitable vaccine target without the added worry of a novel platform, says Bottazzi.
The Finish Line
If and when a COVID-19 vaccine is approved is anyone's guess. Announcing a plan to hasten vaccine development via a program dubbed Operation Warp Speed, President Trump said recently one could be available "hopefully" by the end of the year or early 2021.
Scientists urge caution, noting that safe vaccines can take 10 years or more to develop. If a rushed vaccine turns out to have safety and efficacy issues, that could add ammunition to the anti-vaccine lobby.
Emergence of a successful vaccine requires an "enormous effort" with many complex systems from the lab all the way to manufacturing enough capacity to handle a pandemic, says Bottazzi.
"At the same time, you're developing it, you're really carefully assessing its safety and ability to be effective," she says, so it's important "not to get discouraged" if it takes longer than a year or more.
To gauge if a vaccine works on a broad scale, it would have to be delivered into communities where the virus is active. There are examples in history of life-saving vaccines going first to people who could pay for them and not to those who needed them most, says Reich.
"Agencies are going to have to think about how those distribution decisions are going to be made and who is going to make them and that will go a certain way toward reassuring the public," says Reich.
A Gallup survey last year found that vaccine confidence, in general, remains high, with 86 percent of Americans believing that vaccines are safer than the diseases that they are designed to prevent. Still, recent news organization polls indicate that roughly 20 to 25 percent of Americans say they won't or are unlikely to get a COVID-19 vaccine if one becomes available.
Until the 1980s, every vaccine to hit the market was appreciated; a culture of questioning science didn't exist in the same way as today, notes Reich. Time passed and attitudes changed.
"We were already having robust arguments nationally about what counts as an expert, what's the role of the government in daily life," says Reich. "We were already seeing a lot of dissent around questions of individual freedoms and community responsibilities. COVID-19 did not create those conflicts, but they've definitely become more visible since we've moved into this pandemic."
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."