How Leqembi became the biggest news in Alzheimer’s disease in 40 years, and what comes next
Betsy Groves, 73, with her granddaughter. Groves learned in 2021 that she has Alzheimer's disease. She hopes to take Leqembi, a drug approved by the FDA last week.
A few months ago, Betsy Groves traveled less than a mile from her home in Cambridge, Mass. to give a talk to a bunch of scientists. The scientists, who worked for the pharmaceutical companies Biogen and Eisai, wanted to know how she lived her life, how she thought about her future, and what it was like when a doctor’s appointment in 2021 gave her the worst possible news. Groves, 73, has Alzheimer’s disease. She caught it early, through a lumbar puncture that showed evidence of amyloid, an Alzheimer’s hallmark, in her cerebrospinal fluid. As a way of dealing with her diagnosis, she joined the Alzheimer’s Association’s National Early-Stage Advisory Board, which helped her shift into seeing her diagnosis as something she could use to help others.
After her talk, Groves stayed for lunch with the scientists, who were eager to put a face to their work. Biogen and Eisai were about to release the first drug to successfully combat Alzheimer’s in 40 years of experimental disaster. Their drug, which is known by the scientific name lecanemab and the marketing name Leqembi, was granted accelerated approval by the U.S. Food and Drug Administration last Friday, Jan. 6, after a study in 1,800 people showed that it reduced cognitive decline by 27 percent over 18 months.
It is no exaggeration to say that this result is a huge deal. The field of Alzheimer’s drug development has been absolutely littered with failures. Almost everything researchers have tried has tanked in clinical trials. “Most of the things that we've done have proven not to be effective, and it's not because we haven’t been taking a ton of shots at goal,” says Anton Porsteinsson, director of the University of Rochester Alzheimer's Disease Care, Research, and Education Program, who worked on the lecanemab trial. “I think it's fair to say you don't survive in this field unless you're an eternal optimist.”
As far back as 1984, a cure looked like it was within reach: Scientists discovered that the sticky plaques that develop in the brains of those who have Alzheimer’s are made up of a protein fragment called beta-amyloid. Buildup of beta-amyloid seemed to be sufficient to disrupt communication between, and eventually kill, memory cells. If that was true, then the cure should be straightforward: Stop the buildup of beta-amyloid; stop the Alzheimer’s disease.
It wasn’t so simple. Over the next 38 years, hundreds of drugs designed either to interfere with the production of abnormal amyloid or to clear it from the brain flamed out in trials. It got so bad that neuroscience drug divisions at major pharmaceutical companies (AstraZeneca, Pfizer, Bristol-Myers, GSK, Amgen) closed one by one, leaving the field to smaller, scrappier companies, like Cambridge-based Biogen and Tokyo-based Eisai. Some scientists began to dismiss the amyloid hypothesis altogether: If this protein fragment was so important to the disease, why didn’t ridding the brain of it do anything for patients? There was another abnormal protein that showed up in the brains of Alzheimer’s patients, called tau. Some researchers defected to the tau camp, or came to believe the proteins caused damage in combination.
The situation came to a head in 2021, when the FDA granted provisional approval to a drug called aducanumab, marketed as Aduhelm, against the advice of its own advisory council. The approval was based on proof that Aduhelm reduced beta-amyloid in the brain, even though one research trial showed it had no effect on people’s symptoms or daily life. Aduhelm could also cause serious side effects, like brain swelling and amyloid related imaging abnormalities (known as ARIA, these are basically micro-bleeds that appear on MRI scans). Without a clear benefit to memory loss that would make these risks worth it, Medicare refused to pay for Aduhelm among the general population. Two congressional committees launched an investigation into the drug’s approval, citing corporate greed, lapses in protocol, and an unjustifiably high price. (Aduhelm was also produced by the pharmaceutical company Biogen.)
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world.
So far, Leqembi is like Aduhelm in that it has been given accelerated approval only for its ability to remove amyloid from the brain. Both are monoclonal antibodies that direct the immune system to attack and clear dysfunctional beta-amyloid. The difference is that, while that’s all Aduhelm was ever shown to do, Leqembi’s makers have already asked the FDA to give it full approval – a decision that would increase the likelihood that Medicare will cover it – based on data that show it also improves Alzheimer’s sufferer’s lives. Leqembi targets a different type of amyloid, a soluble version called “protofibrils,” and that appears to change the effect. “It can give individuals and their families three, six months longer to be participating in daily life and living independently,” says Claire Sexton, PhD, senior director of scientific programs & outreach for the Alzheimer's Association. “These types of changes matter for individuals and for their families.”
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. It does not halt or reverse the disease, and people do not get better. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world. It has “a rather small effect,” wrote NIH Alzheimer’s researcher Madhav Thambisetty, MD, PhD, in an email to Leaps.org. “It is unclear how meaningful this difference will be to patients, and it is unlikely that this level of difference will be obvious to a patient (or their caregivers).” Another issue is cost: Leqembi will become available to patients later this month, but Eisai is setting the price at $26,500 per year, meaning that very few patients will be able to afford it unless Medicare chooses to reimburse them for it.
The same side effects that plagued Aduhelm are common in Leqembi treatment as well. In many patients, amyloid doesn’t just accumulate around neurons, it also forms deposits in the walls of blood vessels. Blood vessels that are shot through with amyloid are more brittle. If you infuse a drug that targets amyloid, brittle blood vessels in the brain can develop leakage that results in swelling or bleeds. Most of these come with no symptoms, and are only seen during testing, which is why they are called “imaging abnormalities.” But in situations where patients have multiple diseases or are prescribed incompatible drugs, they can be serious enough to cause death. The three deaths reported from Leqembi treatment (so far) are enough to make Thambisetty wonder “how well the drug may be tolerated in real world clinical practice where patients are likely to be sicker and have multiple other medical conditions in contrast to carefully selected patients in clinical trials.”
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval.
Still, there are reasons to be excited. A successful Alzheimer’s drug can pave the way for combination studies, in which patients try a known effective drug alongside newer, more experimental ones; or preventative studies, which take place years before symptoms occur. It also represents enormous strides in researchers’ understanding of the disease. For example, drug dosages have increased massively—in some cases quadrupling—from the early days of Alzheimer’s research. And patient selection for studies has changed drastically as well. Doctors now know that you’ve got to catch the disease early, through PET-scans or CSF tests for amyloid, if you want any chance of changing its course.
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval. His lab already uses blood tests for different types of amyloid, for different types of tau, and for measures of neuroinflammation, neural damage, and synaptic health, but commercially available versions from companies like C2N, Quest, and Fuji Rebio are likely to hit the market in the next couple of years. “[They are] going to transform the diagnosis of Alzheimer's disease,” Porsteinsson says. “If someone is experiencing memory problems, their physicians will be able to order a blood test that will tell us if this is the result of changes in your brain due to Alzheimer's disease. It will ultimately make it much easier to identify people at a very early stage of the disease, where they are most likely to benefit from treatment.”
Learn more about new blood tests to detect Alzheimer's
Early detection can help patients for more philosophical reasons as well. Betsy Groves credits finding her Alzheimer’s early with giving her the space to understand and process the changes that were happening to her before they got so bad that she couldn’t. She has been able to update her legal documents and, through her role on the Advisory Group, help the Alzheimer’s Association with developing its programs and support services for people in the early stages of the disease. She still drives, and because she and her husband love to travel, they are hoping to get out of grey, rainy Cambridge and off to Texas or Arizona this spring.
Because her Alzheimer’s disease involves amyloid deposits (a “substantial portion” do not, says Claire Sexton, which is an additional complication for research), and has not yet reached an advanced stage, Groves may be a good candidate to try Leqembi. She says she’d welcome the opportunity to take it. If she can get access, Groves hopes the drug will give her more days to be fully functioning with her husband, daughters, and three grandchildren. Mostly, she avoids thinking about what the latter stages of Alzheimer’s might be like, but she knows the time will come when it will be her reality. “So whatever lecanemab can do to extend my more productive ways of engaging with relationships in the world,” she says. “I'll take that in a minute.”
What Will Make the Public Trust a COVID-19 Vaccine?
A successful deployment of an eventual vaccine will mean grappling with ongoing cultural tensions.
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."
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."