When athletes or soldiers have a concussion, the most beneficial course of action is to simply get them off the playing field or out of the action so they can recover. Yet much about head injuries remains a mystery, including the reasons why some impacts result in concussion while others don’t.
But new measuring devices are being developed that could help deliver a wealth of information about head impacts. By giving an immediate warning that a person needs to be removed from action or play, they could help protect soldiers and athletes alike from brain damage.
Appreciation of the real risks of head injuries has been a long time coming. “Even 10 years ago, if someone took a big hit they were told to get up and play or keep going,” says Mike Shogren, CEO of Prevent Biometrics. “Now reducing major head impacts and understanding concussion risk is a major focus in sports and the military.”
Prevent is one of several companies developing new sensors to precisely measure and record head impacts, which would help identify possible concussions and provide data for studies of cumulative effects.
Scientists have been trying to measure the forces involved in head trauma for a long time, says Adam Bartsch, the company’s chief science officer. “Decades ago, scientists had to use Rube Goldberg contraptions to study head impact,” he says. “Sometimes these were made from a dental mold with a rigid plate and sensors bigger than dice, with a 10-meter-long cable connecting it to a computer. The wearer would drool and the data wasn’t perfect, but it was the best they had.”
First conceived at the Cleveland Clinic, Prevent’s device, the Impact Monitoring Mouthguard (IMM), fits into the wearer’s mouth, working as both a monitoring tool and a functional mouthguard. It calculates the force, location, direction, and number of impacts and can then transmit data via Bluetooth to other devices for assessment.
Prevent is using the IMM to study parachute landing falls (or PLFs), a landing technique that was developed by the United States Army as part of its paratrooper training program, using over 2,000 paratroopers as subjects. A correctly executed PLF absorbs the shock of hitting the ground as the parachutist lands feet first and falls sideways, successively distributing the landing shock along the calves, thighs, hips, and back. But an error can whip the parachutist’s head backwards and onto the ground. The IMM’s sensors revealed that this occurs far more often than anyone realized.
PREVENT BIOMETRICS
“We found a significant head impact in about 5% of jumps,” says Bartsch. “That’s about 30 times as much as the published incidence of concussion in paratroopers.” A battery of tests confirmed that the events the mouthguard registered as possibly causing concussions had in fact done so. Paratroopers tend to just get up and carry on after a bad landing, so the official figures had previously reflected only the injuries of those who were physically unable to get up on their own.
In sports, similarly, athletes are often encouraged to “get over it” rather than report an injury. Prevent is carrying out a large-scale project with World Rugby, which will monitor players and allow coaches to take injured players off the field and have them assessed. (Several other instrumented mouthguards—the Biocore, the ORB, and HitIQ—are being developed for other sports, including boxing and lacrosse.) In the future, Prevent hopes to be able to evaluate the total effect of lots of smaller shocks to see under what circumstances they cause serious cumulative injury. “Understanding total exposure on top of just major impacts is also critical,” Shogren says. “It’s like in a boxing match. The impact that knocks you out at the end might not have knocked you out on its own in the first round.”
David Hambling is a technology journalist based in South London.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Welcome back to The Checkup. This will be our last issue of 2023, so this week I’ve been reflecting on our biotechnology coverage over the past year. As I scrolled through our archives, I was struck by the vast number of stories we wrote about gene editing.
It really shouldn’t have come as a surprise. Perhaps no technology has more power to transform medicine, and its vast potential is just beginning to be realized. Gene editing can be used to delete, insert, or alter portions of our genetic code. We’ve been able to modify DNA for years, but newer technologies like CRISPR mean that we can do it faster, more accurately, and more efficiently than ever before. In 2023, we saw the first approval of a CRISPR-based gene-editing therapy. And many more are to come. So let’s take a look at the developments that made news this year. What is the promise of gene editing, and what are the current pitfalls?
Lucky breaks and next steps
Casgevy, the first CRISPR therapy, has already been approved in the UK and US to treat sickle-cell disease. And it’s now on the cusp of approval in the European Union. Sickle-cell disease is caused by a mutation in the hemoglobin gene that leads to a characteristic crescent moon shape of the red blood cells. The treatment doesn’t address the underlying cause of the disease; instead, it disables another gene, one that hampers production of a type of hemoglobin that people normally produce only in the womb and as babies. With that gene out of commission, production of this second type of hemoglobin resumes. The therapy works because cells with fetal hemoglobin won’t form sickles. You can read more about the fascinating backstory on the development of Casgevy in this story by my colleague Antonio Regalado.
Why go at it in this roundabout way? Current versions of CRISPR work best as a pair of scissors, creating snips that disable genes. That limits its usefulness. New versions of CRISPR will allow researchers to alter the genetic code or even insert new genes, which will make it possible to address a wide variety of genetic diseases.
Verve Therapeutics, for example, is testing an approach called base editing. Jessica Hamzelou covered this technique in depth in this story in January: “There are four DNA bases: A, T, C, and G. Instead of cutting the DNA, CRISPR 2.0 machinery can convert one base letter into another. Base editing can swap a C for a T, or an A for a G.” According to Kiran Musunuru, cofounder and senior scientific advisor at Verve, “It’s no longer acting like scissors, but more like a pencil and eraser.”
Verve’s therapy, now being tested in a small clinical trial, swaps out a single base in a gene for a protein called PCSK9, which is linked to high cholesterol. (The therapy was one of MIT Technology Review’s 10 Breakthrough Technologies 2023.) That change disables the gene, which means that the body makes less PCSK9 and cholesterol levels fall. In November the company announced interim results: a single injection of the therapy reduced LDL levels in the blood by up to 55% in 10 people with a genetic condition that causes high cholesterol.
CRISPR 3.0, which allows scientists to replace bits of DNA or insert new chunks of genetic code, is still being tested in animals. One company, Prime Medicine, plans to seek FDA approval to launch a human trial of a treatment for chronic granulomatous disease, a genetic immune disorder, in 2024 .
Pitfalls remain, at least for now.
The only approved CRISPR therapy isn’t a simple fix. Patients have to undergo a bone-marrow transplant: after chemotherapy to destroy their faulty cells, stem cells are extracted, edited in the lab, and then reinfused. Jimi Olaghere, one of the few people to have received the therapy, wrote about how arduous this was. The cell collection process left him so weak he needed blood transfusions. And the chemo meant “dealing with nausea, weakness, hair loss, debilitating mouth sores, and the risk of exacerbating the underlying condition.” All told, he spent 17 weeks in the hospital.
Given the complexity of the treatment, you won’t be surprised to learn that it’s expensive—it costs an estimated $2.2 million. That price tag means it’s out of reach for many, especially people in low-income countries.
Vertex is already exploring strategies to make sickle-cell therapies more accessible and affordable. Antonio spoke to the company’s head of research, David Altshuler, about some of the strategies earlier this month. One of the more promising approaches might not involve gene editing at all.
“One question I get a lot is: How are we going to get to the rest of the world?” Altshuler said. “And I think the answer is not by trying to do bone-marrow transplants in the rest of the world. It’s just too resource intensive, and the infrastructure is not there. I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively.”
Safety concerns abound.Gene editing is permanent, and one of the biggest concerns is that these therapies might miss the mark and create “off-target” effects. Regulators were so concerned about this possibility that an FDA advisory committee met in November to assess whether Vertex would need to provide additional data to prove Casgevy’s safety. (They ultimately decided the existing data was sufficient for approval.) The company plans to follow up with patients for 15 years to confirm safety.
Most experts think base editing, which doesn’t involve snipping, should be safer than the CRISPR scissors. But even there, safety has been front and center in discussions. The positive results in Verve’s trial of base editing to treat high cholesterol were partly overshadowed by the fact that two participants had heart attacks, and one of them died.
The epic patent dispute over CRISPR has long been another potential hiccup for possible therapies. But this month Antonio reported on a partial resolution. Vertex agreed to pay tens of millions of dollars to competitor Editas and the Broad Institute for the right to use Broad’s CRISPR patent, thus avoiding a potential lawsuit. “It’s not yet clear if the license agreement points to an end of the fierce patent fight between Broad and Berkeley. That has been continuing before a US patent court, with Berkeley still trying to overturn its rival’s claims,” he wrote.
Despite the pitfalls, it’s clear that gene-editing therapies, when they work, can be transformational. Olaghere detailed his experience as a trial participant. “I started to experience things I had only dreamed of: boundless energy and the ability to recover by merely sleeping. My physical symptoms—including a yellowish tint in my eyes caused by the rapid breakdown of malfunctioning red blood cells—virtually disappeared overnight,” he wrote. “Most significantly, I gained the confidence that sickle-cell disease won’t take me away from my family, and a sense of control over my own destiny.”
Another thing
Hunter-gatherer societies may still retain many of the microbes that people living in industrialized societies lack. That’s why scientists are racing to catalog their microbiome. But there’s a catch, writes senior reporter Jessica Hamzelou. “We don’t know whether those in hunter-gatherer societies really do have ‘healthier’ microbiomes—and if they do, whether the benefits could be shared with others.” What’s more, members of these communities say some research is being conducted without regard for ethics or equity. “Taking advantage of an Indigenous population and using their microbes to try to reinstate health in somebody from a wealthy, industrialized nation, I think, is a problematic thing to do,” Justin Sonnenburg, a microbiome scientist at Stanford University, told her.
From around the web
A New York Times investigation delves into the increasingly popular practice of snipping “tongue-ties” in babies, an often unnecessary procedure being aggressively pushed by some lactation consultants and dentists. A heartbreaking must-read. (NYT)
Studies call into question the benefit of spinal cord stimulation for pain (Medpage)
Researchers are testing a new non-hormonal male birth control pill in a clinical trial in the UK.. (Stat)
Chemotherapy drug shortages are robbing cancer patients of the therapies they desperately need and highlighting systemic problems in the generic drug market. (NYT) But there are some possible fixes. (NYT)
The high lead levels in some applesauce pouches, which sickened more than 100 children in the US, came from the cinnamon that was added. Regulators are still trying to work out why the cinnamon contained lead. (Washington Post)
What if all you needed to lose weight were some good vibrations? That’s the idea behind a new weight-loss pill that tricks the brain into thinking the stomach is full, by stimulating the nerve endings that sense when the stomach expands.
The capsule, about the size of a large vitamin, houses a tiny motor that starts vibrating when it hits the stomach, stimulating the organ’s stretch receptors.
So far this “electroceutical” has only been tested in a handful of young Yorkshire pigs, but with promising results. According to a new paper in Science Advances, the six pigs that were given the pill ate 40% less than swine that received a placebo over the course of two weeks. That’s roughly what the team expected, but “we were very surprised when it had such a consistent effect,” says Shriya Srinivasan, a biomedical engineer at Harvard and one of the study’s authors. The pigs didn’t lose weight—they were still growing—but the animals that received the vibrating capsule didn’t gain as much weight as the control group.
The capsule, called the Vibratory Ingestible BioElectronic Stimulator (VIBES), mimicked the effects of a full stomach in other ways, too. After the pill started buzzing, insulin levels in the swine rose and levels of the hunger hormone ghrelin fell, just as they do when the stomach expands after a large meal.
Carlos Campos, a neuroscientist at the University of Washington who studies signaling between the gut and the brain, says the technology is impressive. “There’s quite a bit of engineering that went into making this vibrating pill,” he says. Here’s how it works: When the capsule hits stomach acid, the outer gelatinous membrane dissolves, releasing a spring-loaded pogo pin that completes an electrical circuit. That pin activates a battery-powered motor that drives the vibrations, which last for about half an hour. The vibrations trigger the stretch receptors, which give the brain “an illusory satiety effect,” Srinivasan says. And if you feel full, you might eat less.
Even with new, more effective weight-loss medications, Campos says, there is still a need for new therapies to address the obesity epidemic. Wegovy and Zepbound injections are expensive, and studies suggest people will need to take them indefinitely to keep the weight off. “With mechanical stimulation, you can decide when to use it, when not to use it. You have a lot better control of how the stimulus is given,” he says.
But there’s a caveat, Campos says. You can’t dupe the brain forever. If it decides those stretch signals aren’t a reliable cue for how much food was consumed, “then the brain might start to use other signals to decide how much to eat,” he says. “We don’t know how long that trick is going to work.”
The researchers envision that people would take the VIBES pill about 20 or 30 minutes before each meal. In pigs at least, the capsule seemed safe, vibrating at a level that Srinivasan said was gentler than an electric toothbrush. “We didn’t see any nausea, vomiting, bloating—nothing like that,” she says. But the experiment didn’t entirely mimic the way VIBES might be used in humans. Pigs are bad at swallowing pills without biting or chewing, so the researchers placed the pill in the animals’ stomachs through a feeding tube. The capsules were tied to an external battery and activated before the pigs got their twice-daily serving of food pellets.
If this ever makes it to humans, people would be ingesting multiple bioelectric capsules each day. The animals managed to safely clear a single capsule in four days, on average, but “we don’t know what the effect will be in humans,” Srinivasan says. The pills might pass through the body faster.
Srinivasan hopes they might be able to test that in a year or two. The VIBES technology doesn’t use any expensive materials, so the team expects it could be mass-manufactured for a dollar or less per pill. “The fact that it is a pill makes it accessible to the populations of the world that can’t afford these other more invasive or costly options that usually are acquired with implants or surgeries,” she adds. “I think it would be extremely affordable for the masses.”
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Covid shots do an admirable job of boosting our immune response enough to protect against serious illness, but they don’t boost immunity in the one spot we’d like them to: our airways. That’s why researchers have been working on vaccines you breathe into your lungs or spray into your nose. The idea is that these vaccines will elicit an immune response in the mucous membranes of your respiratory tract that might help stave off infection or, if you do become infected, make you less likely to transmit the virus.
These “mucosal” covid vaccines aren’t available in the US or Europe, but they are in other parts of the world. When we last reported on efforts to develop a mucosal vaccine in 2022, two had been approved in China and India. Now five are in use in China, India, Iran, Indonesia, Morocco, and Russia. A couple dozen more candidates are in clinical trials. And many, many more are on the way.
This week I came across a paper from a team in China developing another inhalable vaccine. This vaccine differs from most others in at least one notable way: it is a powder, which means that it’s shelf stable and doesn’t need refrigeration. That would make it easier to transport and deliver, especially to places where refrigeration is difficult.
This candidate won’t be available anytime soon. It’s still in preclinical development, along with more than a hundred other similar vaccines. But now that we’re almost four years out from the start of the pandemic, it seems like a good time to take stock. When will the US get its first mucosal covid vaccine? What will it look like? And will it work as intended?
What is the timeline?
Only one mucosal vaccine—FluMist—has ever been approved in the US, and that happened two decades ago. But efforts to develop one for covid are moving quickly. So when might the US see its first mucosal covid vaccine? “Maybe never. But I think there’s increasing likelihood that it may happen before the end of 2024,” speculated Eric Topol, a cardiologist who has been following Covid research closely since 2020, in a recent newsletter.
The federal government is working to speed things along with an injection of cash through Project NextGen, a $5 billion effort to usher new and improved covid vaccines to market. In October, the Department of Health and Human Services announced that nearly $20 million would go to two companies developing mucosal vaccines—Codagenix and CastleVax. That money will help the companies gear up for studies to test how well their vaccines work to prevent symptomatic infections.
Codagenix’s candidate, a nasal vaccine called CoviLiv, is already part of a phase 3 global efficacy trial coordinated by the World Health Organization. And in October, the company reported results from a safety study in adults in the UK who had never been vaccinated for covid before. The nasal mist prompted robust immunity, at least as measured by markers in the blood. But evidence of an immune response in the blood doesn’t necessarily indicate an immune response in the mucosal lining of the airways. Or, as one physician puts it, “just like the ‘far, dark side of the Moon’, which is invisible from the earth, the mucosal response to pathogens is a far, dark side of immunity that is poorly or not visible from the peripheral blood and more complicated to probe than systemic immunity.”
What’s the best way to elicit mucosal immunity?
TBD. Different groups are trying a variety of strategies. The goal is to induce immunity in the airways that is robust, broad, and durable. But which strategy will succeed is a bit of a question mark at the moment. Mucosal vaccines fall into a few categories depending on how they’re administered and the platform they use. Some are sprays that are squirted into the nose (CovLiv, for example). Others are meant to be inhaled into the lungs (such as one developed by CanSinBIO in China).
Sometimes these two routes of administration get lumped together, but they actually are very different, says Mangalakumari Jeyanathan, a researcher at McMaster University and coauthor of an editorial that accompanies the new inhalable-vaccine paper. With a nasal vaccine, the contents go into the nasal cavity. But Jeyanathan thinks inhaled vaccines, which go deep into the lungs, are likely to work better. Her team’s research suggests that nasal vaccines induce immune responses only in the upper respiratory tract, not in the lower respiratory tract. That means, she says, that if the vaccine doesn’t prevent infection, the lungs are still vulnerable, and “we really need the immune responses to prevent any sort of serious damage to the lung.”
The vaccine outlined in the recent Nature paper is meant to be inhaled. It is a subunit vaccine, meaning it contains a portion of the pathogen. In this case, the subunit is actually a piece of cholera toxin that has been engineered to display a portion of SARS-CoV-2. These proteins are placed into microcapsules small enough to travel deep into the lungs.
I’ve been vaccinated, and I had covid. Don’t I already have good mucosal immunity?
Maybe. Studies show that people who have been infected and vaccinated do have better mucosal immunity than people who have been vaccinated but not infected. But Jeyanathan says her group has also seen quite a few people who have been infected and don’t have much mucosal immunity in their lungs. When they wash the lungs with saline to collect samples from the lower respiratory tract, they don’t find detectable T-cell responses. “It’s really sort of very strange,” she says.
But it’s not just about whether you’ve got mucosal immunity. It also matters how broad that immunity is. One of the most problematic things about SARS-CoV-2 is that it’s constantly evolving. Each month seems to bring a new variant. The changes mainly affect the spike protein, the target of all current vaccines. But some groups are working to variant-proof their mucosal vaccines. Jeyanathan’s group is putting in parts of the interior of the covid virus, which aren’t apt to change as quickly as the portion that binds to cells. “So that way, we don’t need to do this variant-chasing approach,” she says.
What will it take to show that a mucosal vaccine works?
Regulators are still trying to work out how to measure success. In some cases, companies can demonstrate vaccine effectiveness through surrogate markers such as antibody levels. That’s how the latest boosters were approved. But with mucosal vaccines, it’s not clear what surrogate marker would be most useful. Antibody levels in the nose or mouth? Or the abundance of certain immune cells?
In an editorial published a year ago, Peter Marks from the FDA and colleagues argued that vaccines that differ substantially from those already approved might need to be tested in large, randomized clinical trials. What we really want to see is that these next-generation vaccines outperform existing vaccines and curb transmission. That data isn’t in yet, and it could take years before we know whether mucosal vaccines actually do what we hope they will: stop the virus from spreading.
Another thing
Vertex, maker of the recently approved CRISPR sickle-cell therapy, has agreed to pay tens of millions of dollars to avoid any patent infringement lawsuits. Antonio Regalado has the story.
Read more from MIT Technology Review’s archive
When the first two mucosal vaccines were approved in 2022, we published an explainer by Jessica Hamelzou.
Wouldn’t it be wonderful if we had a vaccine that worked against all coronaviruses? One team’s mosaic nanoparticle may be the key to success, reports Adam Piore.
From around the web
The first gene therapies for sickle-cell disease have arrived, but patients in the countries with the greatest burden of the disease won’t be able to access them. (NYT)
CAR-T, a cell therapy developed to treat cancer, has seemingly eliminated autoimmune disease in 15 patients (Nature)
The US Supreme Court plans to review a case that could affect access to the abortion medication mifepristone. (Washington Post)
A single hormone seems to be to blame for morning sickness, a discovery that may lead to better treatments. (NYT)
Vertex has been in the headlines for its newly approved sickle-cell therapy, but the company is also closing in on a non-opioid painkiller. Here’s a fascinating deep dive into the backstory. (Stat)
The company that just got approval to sell the first gene-editing treatment in history, for sickle-cell disease, is already looking for an ordinary drug that could take its place.
Vertex Pharmaceuticals has a 50-person team working “to make a pill that doesn’t do gene editing at all,” says David Altshuler, head of research at the Boston drug company.
“We’re trying to out-innovate ourselves,” he says.
Vertex won approval in the US to sell the world’s first treatment using CRISPR, the gene-editing technique, on December 8. It took eight years to develop, and at huge expense. Regulatory documents filed with the government during the approval process exceeded a million pages.
Yet now that medicine’s CRISPR era has begun, some of the technique’s limitations are already visible.
The treatment, called Casgevy, is both tough on patients and hugely expensive. Patients must spend several weeks in a hospital as doctors remove, genetically edit, and then reintroduce their bone-marrow stem cells, which make blood. The treatment will cost $2.2 million, not including hospital costs, according to Vertex.
The company proved the gene fix can be a permanent remedy forpeople who have the most severe sickle-cell symptoms. These individuals, numbering around 16,000 in the U.S., suffer recurring pain crises when misshapen red blood cells block blood vessels in their bodies.
But it’s unclear how many Americans will opt for gene editing. In an opinion column for MIT Technology Review, one patient who got the treatment, Jimi Olaghere, said the bone-marrow replacement an “intense months-long journey” that will create barriers to access.
“It’s simultaneously a miracle and has a drawback that prevents wide use,” says Geoffrey von Maltzahn, a partner at Flagship Pioneering, who leads biotech ventures but was not involved in the sickle-cell treatment. “That is a common duality.”
Such drawbacks are why a pill to alleviate sickle-cell, if developed, could sweep CRISPR from the playing field. A pill version could also resolve a brewing moral dilemma: Vertex so far has no plans to offer its gene-editing treatment in those countries where sickle-cell is most common.
A wide ribbon of lower-income nations across the middle of Africa, including Nigeria and Ghana, account for 80% of sickle-cell cases but, according to US researchers, lack the hospitals, medical expertise, and money to implement this complex intervention.
“One question I get a lot is: How are we going to get to the rest of the world?” says Altshuler. “And I think the answer is not by trying to do bone-marrow transplants in the rest of the world. It’s just too resource intensive, and the infrastructure is not there. I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively.”
Three strategies
In an interview with MIT Technology Review, Altshuler outlined three ideas Vertex is exploring to improve on its breakthrough CRISPR treatment.
One is to come up with a substitute for the intense chemotherapy that’s used to kill a person’s bone marrow and make space for the edited cells to take over. Vertex and other gene-editing companies, like Beam Therapeutics, say they are looking into gentler methods that could make the procedure easier for patients.
A second strategy Vertex and other companies are exploring is called “in vivo” editing. That’s when gene-editing molecules are dripped directly into a person’s veins, or even injected like a vaccine, no transplant needed.
To achieve in vivo editing for blood diseases, research groups are trying to develop homing systems—viruses or special nanoparticles—that would convey CRISPR directly to a person’s blood-making stem cells. Such “single shot” editing concepts have won substantial support from the Bill & Melinda Gates Foundation, which thinks it could help solve sickle-cell and HIV in Africa. But it remains at an experimental stage, and some question if it will ever be possible.
The final idea is a conventional drug, the kind you swallow. That would be the easiest to distribute where it’s needed. Angela Koehler, a biochemist at MIT, says “broadly accessible” drugs with a “low barrier to access” would have the greatest impact on sickle-cell disease globally.
“This does not diminish my excitement about the CRISPR-based approaches, but it partially explains the motivations of folks trying to develop ‘traditional’ drugs,” says Koehler.
Keep innovating
Sickle-cell is caused by defects in hemoglobin, the oxygen-carrying molecule in red blood cells. The CRISPR treatment stops the worst disease symptoms by making a targeted DNA edit that turns on “fetal hemoglobin,” a second version that we all have but is largely inactive after we’re born.
By early 2019, Altshuler says, he had seen results from the first gene-edited patients who volunteered for the company’s trial. It was clear then that the theory was true: turning up fetal hemoglobin was a cure.
Within weeks of seeing those results, Altshuler says he’d launched a hunt for a conventional drug that could do the same thing, even as the CRISPR program steamed ahead. “The goal is to achieve a similar profile with a pill instead of a gene editing,” he says.
Reaching the whole world with a treatment was part of the motivation, but it wasn’t the only one. Part of what is driving Vertex is a painful lesson it learned following the 2011 launch of its breakthrough drug for hepatitis C, called Incivek. The drug had the fastest increase in sales for any product in history at the time, reaching $1.5 billion in a year.
Yet within three years, Vertex had to stop selling Incivek after a competitor, Gilead Sciences, came up witha more effective alternative with fewer side effects.
The brutal lesson: keep innovating.
“Something I have never understood about biopharma: they discover the first medicine in a disease, and let other people eat their lunch,” Altshuler says. “They stop doing research and wait.”
Pill hunt
The pill hunt remains shrouded in secrecy—Altshuler won’t reveal any of the details, saying the lack of information in the public domain is part of what makes it an attractive project.
But it’s likely that Vertex’s search centers on the same biological “target” that CRISPR changes. That is a gene called BCL11A, which acts like a switch controlling fetal hemoglobin. Gene editing turns that gene down, allowing fetal hemoglobin to rise.
It’s not easy to get an ordinary drug to copy that effect. The tricky part is that the BCL11A gene manufactures a transcription factor, a type of protein that’s floppy and formless and lacks the precise kinks and corners that chemists can aim drugs at. Indeed, such molecules have the reputation of being “undruggable.”
According to Altshuler, no marketed drug currently works by binding to a transcription factor.
Although the hunt for a drug has so far been low key and out of sight, clues have started to spill out, including some from other companies pursuing similar goals. This week, at a major blood-disorders meeting, the pharmaceutical company Novartis said it had screened several thousand molecules and found some that were able to raise fetal hemoglobin.
Separately, a team at Children’s Hospital in Boston said at the same meeting it had made discoveries about how the BCL11A protein folds, highlighting potential ways drugs could act on it.
That lab is led by Stuart Orkin, a scientist whose discoveries about the fetal-hemoglobin switch we recently profiled in MIT Technology Review. “Some people are trying to find new targets, but I don’t think there is anything else worth studying,” says Orkin. “I think it’s the only one that will get us to the other side of the problem.”
Orkin says he’s been looking for a drug, too, but those attempts, some in collaboration with Koehler, have not yet paid off. “I can say we’ve tried a lot of things that don’t work,” he says.
Orkin also still believes gene editing will be a better treatment, if you can get it. “If I had a child and the choice was a cure versus taking pills for life, I would go for the editing. If you can fix it, I would,” he says. “But many patients are not ready for the rigors of transplant, and many are not in a setting where it can be done. There aren’t enough hospitals or physicians.”
And that is the irony of CRISPR’s first treatment. It can cure individuals but can’t yet conquer a disease. In fact, the problem of sickle-cell is only expanding. That is because countries with high rates of this inherited condition also have booming populations. Every year, more people, not fewer, suffer with the disease. CRISPR can’t yet reverse the trend, but a pill might.
“It’s solved from a disease standpoint, but not a burden-of-disease standpoint,” says Orkin. “That is the next chapter. Sickle-cell is a big problem. And it’s growing, not shrinking.”
37 trillion. That is the number or cells that form a human being. How they all work together to sustain life is possibly the biggest unsolved puzzle in biology. A group of up-and-coming technologies for spatially resolved multi omics, here collectively called “spatial omics,” may provide researchers with the solution.
Over the last 20 years, the omics revolution has enabled us to understand cell and tissue biology at ever increasing resolutions. Bulk sequencing techniques that emerged in the mid 2000s allowed the study of mixed populations of cells. A decade later, single-cell omics methods became commercially available, revolutionizing our understanding of cell physiology and pathology. These methods, however, required dissociating cells from their tissue of origin, making it impossible to study their spatial organization in tissue.
Spatial omics refers to the ability to measure the activity of biomolecules (RNA, DNA, proteins, and other omics) in situ—directly from tissue samples. This is important because many biological processes are controlled by highly localized interactions between cells that take place in spatially heterogeneous tissue environments. Spatial omics allows previously unobservable cellular organization and biological events to be viewed in unprecedented detail.
A few years ago, these technologies were just prototypes in a handful of labs around the world. They worked only on frozen tissue and they required impractically large amounts of precious tissue biopsies. But as these challenges have been overcome and the technologies commercialized by life science technology providers, these tools have become available to the wider scientific community. Spatial omics technologies are now improving at a rapid pace, increasing the number of biomolecules that can be profiled from hundreds to tens of thousands, while increasing resolution to single-cell and even subcellular scales.
Complementary advances in data and AI will expand the impact of spatial omics on life sciences and health care—while also raising new questions. How are we going to generate the large datasets that are necessary to make clinically relevant discoveries? What will data scientists see in spatial omics data through the lens of AI?
Several areas of life science are already benefiting from discoveries made possible by spatial omics, with the biggest impacts in cancer and neurodegenerative disease research. However, spatial omics technologies are very new, and experiments are challenging and costly to execute. Most present studies are performed by single institutions and include only a few dozen patients. Complex cell interactions are highly patient-specific, and they cannot be fully understood from these small cohorts. Researchers need the data to enable hypothesis generation and discovery.
This requires a shift in mentality toward collaborative projects, which can generate large-scale reference datasets both on healthy organs and human diseases. Initiatives such as The Cancer Genome Atlas (TCGA) have transformed our understanding of cancer. Similar large-scale spatial omics efforts are needed to systematically interrogate the role of spatial organization in healthy and diseased tissues; they will generate large datasets to fuel many discovery programs. In addition, collaborative initiatives steer further improvement of spatial omics technologies, generate data standards and infrastructures for data repositories, and drive the development and adoption of computational tools and algorithms.
At Owkin we are pioneering the generation of such datasets. In June 2023, we launched an initiative to create the world largest spatial omics dataset in cancer, with a vision to include data from 7,000 patients with seven difficult-to-treat cancers. The project, known as MOSAIC (Multi-Omics Spatial Atlas in Cancer), won’t stop at the data generation, but will mine the data to learn disease biology and identify new molecular targets against which to design new drugs.
Owkin is well placed to drive this kind of initiative. We can tap a vast network of collaborating hospitals across the globe: to create the MOSAIC dataset, we are working with five world-class cancer research hospitals. And we have deep experience in AI: In the last five years, we have published 54 research papers generating AI methodological innovation and building predictive models in several disease areas, including many types of cancer.
AI’s transformative role in discovering new biology
Spatial omics was recognized as method of the year 2020 by Nature Methods, and it was named one of the top 10 emerging technologies by the World Economic Forum in 2023—alongside generative AI.
With these two technologies developing in tandem, the opportunities for AI-driven biological discoveries from spatial omics are numerous. Looking at the fast-evolving landscape of spatial omics AI methods, we see two broad categories of new methods breaking through.
In the first category are AI methods that aim to improve the usability of spatial omics and enable richer downstream analyses for researchers. Such methods are specially designed to deal with the high dimensionality and the signal-to-noise ratio that are specific to spatial omics. Some are used to remove technical artifacts and batch effects from the data. Other methods, collectively known as “super-resolution methods,” use AI to increase the resolution of spatial omics assays to near single-cell levels. Another group of approaches looks to integrate dissociated single-cell omics with spatial omics. Collectively, these AI methods are bridging the gap with future spatial omics technologies.
In the second category, AI methods aim at discovering new biology from spatial omics. By exploiting the localization information of spatial omics, they shed light on how groups of cells organize and communicate with unprecedented resolution. Such methods are sharpening our understanding of how cells interact to form complex tissues.
At Owkin, we are developing methods to identify new therapeutic targets and patient subpopulations using spatial omics. We have pioneered methods allowing researchers to understand how cancer patient outcomes are linked to tumor heterogeneity, directly from tumor biopsy images. Building on this expertise and the MOSAIC consortium, we are developing the next generation of AI methods, which will link patient-level outcomes with an understanding of disease heterogeneity at the molecular level.
Looking ahead
Spatial biology has the potential to radically change our understanding of biology. It will change how we see a biomarker, going from the mere presence of a particular molecule in a sample to patterns of cells expressing a certain molecule in a tissue. Promising research on spatial biomarkers has been published for several diseases, including Alzheimer’s disease and ovarian cancer. Spatial omics has already been used in research associated with clinical trials to monitor tumor progression in patients.
Five years from now, spatial technologies will be capable of mapping every human protein, RNA, and metabolite at subcellular resolution. The computing infrastructure to store and analyze spatial omics data will be in place, as will the necessary standards for data and metadata and the analytical algorithms. The tumor microenvironment and cellular composition of difficult-to-treat cancers will be mapped through collaborative efforts such as MOSAIC.
Spatial omics datasets from patient biopsies will quickly become an essential part of pharmaceutical R&D, and through the lens of AI methods, they will be used to inform the design of new, more efficacious drugs and to drive faster and better-designed clinical trials to bring those drugs to patients. In the clinic, spatial omics data will routinely be collected from patients, and doctors will use purpose-built AI models to extract clinically relevant information about a patient’s tumor and what drugs it will best respond to.
Today we are witnessing the convergence of three forces: spatial omics technologies becoming increasingly high-throughput and high-resolution, large-scale datasets from patient biopsies being generated, and AI models becoming ever more sophisticated. Together, they will allow researchers to dissect the complex biology of health and diseases, enabling ever more sophisticated therapeutic interventions.
Davide Mantiero, PhD, Joseph Lehár, PhD, and Darius Meadon also contributed to this piece.
This content was produced by Owkin. It was not written by MIT Technology Review’s editorial staff.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
The human body is a labyrinth of vessels and tubing, full of barriers that are difficult to break through. That poses a serious hurdle for doctors. Illness is often caused by problems that are hard to visualize and difficult to access. But imagine if we could deploy armies of tiny robots into the body to do the job for us. They could break up hard-to-reach clots, deliver drugs to even the most inaccessible tumors, and even help guide embryos toward implantation.
Okay, I know what you’re probably thinking. We’ve been hearing about the use of tiny robots in medicine for years, maybe even decades. And they’re still not here. Where are my medical microbots already?
They’re coming, says Brad Nelson, who works in robotics at ETH Zürich. Soon. And they could be a game changer for a number of serious diseases. In a perspective published in Science today, Nelson and his coauthor Salvador Pané argue that these tiny machines could help deliver drugs exactly where they are needed. That would help minimize toxicity. “So we can use stronger doses and maybe we can rethink the way we treat some of these diseases,” Nelson says.
What makes Nelson optimistic that these technologies are on their way? Some such robots have made their way off the lab bench and into large animals, including pigs. There are at least four startups working on medical microrobots that could travel “untethered” inside the body. One of these, Bionaut, raised $43 million earlier this year to take its therapy into phase 1 trials. It will use the money to develop devices about the size of a pencil tip that are designed to deliver drugs to the site of glioma brain tumors and pierce cysts that block the flow of spinal fluid in the brain, a symptom of a rare childhood disorder called Dandy-Walker syndrome.
“Microrobot” is a catch-all term covering robots that range in size from one micron (about 100th of the width of a human hair) up to a few millimeters in scale. If the robot is really tiny, smaller than a micron, it’s a nanorobot. And while it may be enticing to say “microbot” because it sounds really cool, that’s “more of a Hollywood kind of term,” Nelson says.
Microrobots can be composed of synthetic materials, biological materials (these are called biological robots or biobots), or both (biohybrid robots). Many of them, including the ones that Nelson is developing, move thanks to magnets.
But others can move on their own. Last week a team of researchers from Tufts and Harvard reported that they had turned tracheal cells into biobots. The human trachea has waving cilia on the inside to catch microbes and debris. But these researchers encouraged the tracheal cells to form an organoid with the cilia on the outside. Depending on their shape and cilia coverage, the bots could travel in straight lines, turn circles, or wiggle. And—surprise twist—when the researchers scraped a metal rod across a layer of living neurons growing in a dish, the biobots swarmed the area and triggered new neurons to grow. “It is fascinating and completely unexpected that normal patient tracheal cells, without modifying their DNA, can move on their own and encourage neuron growth across a region of damage,” said Michael Levin, an engineer at Tufts who led the work, in a press release. “We’re now looking at how the healing mechanism works, and asking what else these constructs can do.”
The potential usefulness of these microrobots is vast. “A lot of people are thinking about vascular diseases,” Nelson says. Microrobots could be injected and dissolve blood clots in the brain to treat stroke patients. Or they could shore up weak spots in vessels in the brain to prevent them from bursting. They could deliver drugs to specific locations. And then there are weirder applications. Researchers at the University of Pennsylvania have developed bots that they hope might one day replace your toothbrush.
Other teams are working on bots that mimic—or are made from—sperm. Researchers have developed cow sperm covered in iron nanoparticles, called IRONSperm, that swim with the help of a rotating magnetic field; the hope is that they can be used for targeted drug delivery. One team from Germany is working on microrobots that help with fertilization by delivering weakly swimming sperm to the egg. Their system even releases drugs to break down the egg’s hard coating. That same group also recently described how microrobots might be used in IVF. In a typical IVF procedure, an egg is fertilized outside the body, and the resulting embryo is transferred to the uterus. The procedure often fails. But if microbots could shuttle the embryo back to the fallopian tube or endometrium, the embryo could develop under more natural conditions, which might improve implantation rates. They envision microrobots guided by magnetic fields that could grip or carry an embryo, release it, and then degrade naturally.
Still, there are some substantial hurdles that the companies will have to overcome to use these bots in humans. Some are technical. “These are very tiny systems,” says Victoria Webster-Wood, a mechanical engineer at Carnegie Mellon University who develops biohybrid robots. And because of that, a bodily fluid like blood is actually relatively viscous. “So if the flow is moving really fast, it’s hard for the robot to go the other direction,” she says.
Other hurdles are regulatory. Microrobots qualify as medical devices, but they may also be delivering a drug. “You’ve got what’s called the drug-device combination,” Nelson says. “While the drug might be well known, its concentration is going to be hopefully significantly different than normal.” That might mean regulators will want to see additional studies.
Webster-Wood has been in the field for years, and she is excited that microrobots are finally getting attention. “Even in the last 10 years, it’s just grown so much,” she says. “I think there’s a lot more potential for actually translating.”
Another thing
This week the FDA is expected to approve Casgevy, the world’s first commercial gene-editing treatment, which treats sickle-cell disease. (The treatment was approved in the UK last month.) Antonio Regalado dug deep into the science behind the treatment for this story, which explains why sickle-cell was an ideal target for CRISPR’s big therapeutic debut.
Earlier this year, Antonio Regalado reported on the first babies conceived with robots and the startups working to automate IVF. These weren’t microrobots, and the goal was mainly to achieve scale. “The main goal of automating IVF, say entrepreneurs, is simple: it’s to make a lot more babies.”
Brain implants helped five people with moderate to severe brain injuries perform 15% to 52% better on cognitive tests. If the results hold up in a larger study, brain stimulation may become the first therapy for traumatic brain injury. (NYT)
Last week the FDA announced that the agency was investigating a possible link between CAR-T therapy and cancer. If CAR-T can cause secondary cancers, it would be a rare occurrence, experts say. (STAT $)
Vets are on a quest to pinpoint the cause of a mysterious respiratory illness that has sickened hundreds of dogs in the US. (Wired $)
The surge in respiratory illness among kids in China is likely the result of a lengthy lockdown, not a new pathogen, as some Republican lawmakers have claimed. (NYT)
Our new 2024 list of 10 Breakthrough Technologies won’t come out until January. But I recently gave attendees at EmTech MIT a sneak peek at one item that made the list—weight-loss drugs. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital in Boston, Massachusetts, then joined me on stage to discuss what these new obesity treatments will mean for public health. You can watch that special announcement and our full discussion below.
The world’s first commercial gene-editing treatment is set to start changing the lives of people with sickle-cell disease. It’s called Casgevy, and it was approved last month in the UK. US approval is pending this week.
The treatment, which will be sold in the US by Vertex Pharmaceuticals, employs CRISPR, the Nobel-winning molecular scissors that have had journalists scrambling for metaphors: “Swiss Army knife,” “molecular scalpel,” or DNA copy-and-paste. Indeed, CRISPR is revolutionary because scientists can so easily program it to cut DNA at precise locations they choose.
But where do you aim CRISPR? That’s the lesser-known story of the sickle-cell breakthrough. The disease is caused by faulty hemoglobin, the molecule that carries oxygen in the blood. To cure it, though, Vertex and its partner company, CRISPR Therapeutics, aren’t fixing the genes responsible for the mutation that leaves those molecules misshapen. Instead, the new treatment involves a kind of molecular bank shot—an edit that turns on fetal hemoglobin, a second form of the molecule that we have in the womb but lose as adults.
You can think of how the edit works as a kind of double negative. It adds a misspelling to the turbo-booster of another gene, BCL11A, that is itself what inhibits the production of fetal hemoglobin in adult bodies. Without that booster, there’s less inhibition, and more fetal hemoglobin. Got it?
“When you inhibit the enhancer, you inhibit the inhibitor,” says Daniel Bauer, a professor at Boston Children’s Hospital and Harvard University, who helped work it out. “It is kind of complicated.”
The important thing is a happy ending—and this edit really works. Some patients say they lived in fear of dying, either from an acute attack of sickling (when their red blood cells start blocking vessels) or from slow, insidious organ damage. Now early volunteers say they’re grateful—and, after living with disease their whole lives, even a little shocked—to be cured.
Newborn theory
The idea that fetal hemoglobin can protect against the disease is an old one. Sickle-cell is most common in people with African ancestry. A doctor on Long Island, Janet Watson, had noticed in 1948 that newborns never showed its signs—the main one being misshapen, crescent-shaped red blood cells. That was pretty odd for an inborn condition.
“Sickle-cell disease should occur in infancy as often as later in life,” Watson wrote. But since it didn’t, Watson hypothesized that the fetal form of the molecule, active in the womb, was protecting babies for a few months after birth, until it was replaced by the adult version: “The theory that at once presents itself is that fetal hemoglobin is unable to produce sickling.”
She was right. But it took another six decades to learn how the switch-over worked—and how to flip it back. Many of those discoveries were made in the laboratory of Stuart Orkin, a Harvard researcher who published his first paper in 1967 and who’s lived through several eras of research on blood diseases, starting near the dawn of molecular biology.
“I am one of the last men standing,” Orkin told me with a grin when I met him for a corned-beef sandwich.
Stuart Orkin analyzing DNA from individuals with blood disorders in his lab in 1985.
BOSTON CHILDREN’S HOSPITAL
He’s a clever scientist who a long time ago decided to study how the blood system is regulated. Logistically, it was a great topic; blood cells are easy to get hold of and study.
“I like to solve a problem, and here is a problem that could be solved,” Orkin says. “How does the system work, and then can you do anything about it?”
Special sauce
Bill Lundberg, the former chief scientific officer of CRISPR Therapeutics, the biotech that first started developing the treatment eight years ago (Vertex later joined as a partner), says the company’s sickle-cell project directly made use of Orkin’s findings. “Stu’s role is really underappreciated,” he says. “In the space of a few years, his lab did a series of experiments, each time with a new student—every one of them published in Science or Nature. That was ultimately the special sauce that we ended up using.”
Given the media accolades for CRISPR editing, many people don’t realize it’s really best at ripping scars into genes, not making stylish rewrites (although that is coming). For the early CRISPR startups, this meant finding genes to disable. What could they break in the genome in order to reverse an illness?
Three companies—Editas, Intellia, and CRISPR Therapeutics—each won big backing from venture capitalists around 2014. For those startups, just contemplating changing people’s genomes seemed radical enough. “What I said was: Let’s not solve the world’s problems. Let’s simplify. Let’s ask where it is that human genetics teaches us that ifwemake the edit, we cure the disease,” Lundberg recalls about his meetings with the company founders. “And that is where 50 years of research on fetal hemoglobin came in.”
Sickle-cell was an attractive target. It’s the most common serious inherited genetic disease in the US. What’s more, the stem cells that make red and white blood cells can be removed from a person’s body and then put back, in what’s known as a bone marrow transplant. That would avoid the need to use complex technologies to deliver the treatment to people’s bodies. It could all be done in a laboratory.
VERTEX
That’s exactly how the Vertex treatment works. Some of a patient’s stem cells are removed from the blood with a filtering machine, and the CRISPR cutting protein is added to them with an electrical jolt so that it can seek out and break into the BCL11A gene, the one that controls production of fetal hemoglobin. Then the edited cells are then dripped back into a blood vessel. They multiply and start making fetal hemoglobin—just like in those newborns Watson noticed weren’t sick.
It’s all doable—but it’s also a strenuous undertaking for patients. A bone marrow transplant involves chemotherapy. Doctors have to destroy your blood system to make room for the edited stem cells. Patients will spend many weeks in the hospital and can become infertile from the treatment. Only people withthe most unbearable symptoms—perhaps one in 10 sickle-cell sufferers—are expected to opt for this cure.
The Vertex treatment is a landmark because we are now in the era of commercial rewriting of human genomes. “It’s a huge milestone in the history of humankind and an important stepping-stone to what will be possible in the future,” says William Pao, a former head of drug development at Pfizer, who has studied the Vertex drug for an upcoming book on what ingredients go into medical breakthroughs.
“Every medicine that ever gets approved has to get to a sweet spot, which is an intersection of scientific, technical, and clinical understanding,” says Pao. Such combinations are also why new drugs tend to arrive in packs. You don’t just get one new antidepressant—suddenly there are five. “Once you have that amazing insight, everyone rushes in,” says Pao. It’s also true for sickle-cell. Two other gene-editing treatments are now in trials that also attempt to increase fetal hemoglobin, one from Editas Medicines and one from Beam Therapeutics. As well, this month the FDA may also approve a gene therapy from BlueBird Bio that actually adds a complete new copy of the hemoglobin gene.
Molecular disease
Pao told me he doesn’t think the stories behind new drugs are getting enough attention. People like to see movies about how Mark Zuckerberg stole the idea for Facebook or learn how Jony Ive designed the iPhone. “But with drugs, the names are hard to pronounce, most people don’t want to be on medicine, and it happens over decades,” he says. “It’s not an app you have in your hand.”
For sickle-cell, the journey from cause to cure started in 1910, when a US doctor first observed, though a microscope, that the red blood cells of a man from the West Indies had a “crescent” or “sickle” shape. The shape is due to mutated hemoglobin, which makes the cells sticky and less able to carry oxygen around the body.
The disease gained more fame (particularly in scientific circles) in 1949, when the chemist Linus Pauling, who would win two Nobels, measured an atomic charge difference between normal and sickled hemoglobin, leading him to dub sickle-cell the “first molecular disease” and the beginning of a new age of “scientific” medicine.
In their search for a cure, researchers kept returning to Watson’s observation about fetal hemoglobin. They would learn that each of us makes a little of the fetal version—about 1% of our total hemoglobin, though the amount can vary from person to person. Such variation let researchers study its effects in adults, almost as if it were a drug they were taking. By the 1990s, doctors had been following sickle-cell patients long enough to observe that the more fetal hemoglobin they happened to have, the longer they lived.
Molecular models showing normal adult hemoglobin (left) and fetal hemoglobin (right.) Both types have two alpha subunits (shown in red), but the fetal form has 2 gamma subunits (pink) where the adult form has 2 beta units (blue).
SCIENCE PHOTO LIBRARY MOTION
The problem was how to turn up production of fetal hemoglobin in adults. It is known that nearly all vertebrate animals express fetal versions of hemoglobin before birth. Scientists assume it’s an evolutionary adaptation, a way to get more oxygen out of the placenta. Yet even though the hemoglobin genes had all been found, and sequenced, by the 1980s (and the full human genome became available around 2003), researchers still had no idea what was causing the fetal-to-adult switch.
Gene scan
Then a new genetics technology came to the rescue. After the Human Genome Project was finished, researchers had started to generate rough genetic maps for thousands of people. This let them correlate small DNA differences between people with measurable differences in their bodies: how tall they were or whether they had certain diseases. The new technique, called a “genome-wide association,” was a statistical method of asking influential gene variants to step forward and be counted.
The association technique hasn’t always paid off—but starting in 2007, the gene searches hit pay dirt for sickle-cell. In one study, for instance, a team in Italy studied DNA from thousands of Sardinians (some of whom had beta-thalassemia, another hemoglobin disorder, which is shockingly common on the island) as well from Americans with sickle-cell. When they compared each person’s DNA with the amount of fetal hemoglobin each had, variations kept popping up in one gene: BCL11A.
This gene was far from the hemoglobin sequences—in fact, on an entirely different chromosome. And until then, it had been mostly known for its connection to some cancers. It was a complete surprise. “No amount of sequence-gazing would have told you what to look for,” Orkin says now. But the blaring signal told them this could be the control mechanism. Orkin likes to illustrate the impact this clue had with a quote from Marcel Proust: “The only real voyage of discovery consists not in seeking new landscapes but having new eyes.”
All eyes were now on BCL11A. And very quickly, Orkin’s students and trainees showed that it could control fetal hemoglobin. In fact, it was a transcription factor—a type of gene that controls other genes. By shutting off BCL11A they were able to rekindle production of fetal hemoglobin in cells growing in their lab—and later, in 2011, they showed that mice could be cured of sickle-cell in the same fashion. “What this meant is if you could do this to a patient, you could cure them,” says Orkin.
However, in humans it wasn’t going to be as simple as turning the gene off altogether. BCL11A turns out to be an important gene, and losing it wasn’t ultimately good for mice. One study found mice lacking it were mostly dead within six months. But then came another lucky break. Those hits from the Sardinia study? They turned out to cluster in a special region of the BCL11A gene, called an “erythroid enhancer,” that was active only during the production of red blood cells.
Think of it as a gas pedal for BCL11A, but one that is exclusively employed when a stem cell is making red blood cells—a big job, by the way, since your body makes a few billion each day. “It’s absolutely cell specific,” says Orkin. And that meant the gas pedal could be messed with: “We’d gone from the whole genome to one [site] that we could exploit therapeutically.”
Drug target
The switch had mostly been a matter of scientific curiosity. But now researchers at Harvard, and at a company they’d teamed with, Sangamo Biosciences, began to define a treatment. They peppered the enhancer with every possible damaging edit they could—“like a bunch of BBs,” says Bauer, who did the work at Harvard. Eventually, they found the perfect one: a single disruptive edit that would lower BCL11A by about 70%, and consequently allow fetal hemoglobin to increase.
The editing target, a short run of a few DNA letters, never appears elsewhere in most people’s genomes. That’s important, because once programmed, CRISPR will cut the matching target sequence every time it encounters it, whether or not you want it to. Creating unintentional extra edits is considered hazardous, but Bauer says he’s found only one such “off target” site, which he estimates will appear in the genomes of about 10% of African-Americans. But its location isn’t in a gene, so accidental edits there aren’t expected to matter. Bauer thinks the risk, whatever it is, is probably a lot lower than the danger posed by having sickle-cell disease.
Stuart Orkin in the lab at Boston Children’s Hospital.
BOSTON CHILDREN’S HOSPITAL
There are signs Orkin’s lab may have found a perfect edit—one that can’t be easily improved on. His institution, Boston Children’s Hospital, patented the discoveries, and later CRISPR Therapeutics and Vertex agreed to pay it for rights to use the edit. They’ll likely contribute royalties, too, once the treatment goes on sale. Orkin told me he thinks the companies tried to develop an alternative—a different, nearby edit—but hadn’t been successful. “They tried to find a better [one] but they couldn’t,” says Orkin. “We have the whole thing.”
Translating that lucky break into a real-world gene-editing treatment was the bigger, more complex job. And it was not cheap. According to Solt DB, a company that analyzes biotech finances, financial reports from CRISPR Therapeutics indicate that manufacturing the treatment, recruiting hospitals, trying it on about 90 people in a trial, has taken more than $1 billion so far.
It’s a very large investment into a product. For comparison, it is more than twice what Tesla spent before fielding its first electric car, the Roadster. But the return could also be high. After the FDA approves the treatment, sometime this week, Vertex will announce a price. Already, there is speculation the treatment could cost $3 million, not even including the hospital stays.
Orkin is ready to credit the companies for their swift development of the cure. It took them only about eight years. But he thinks it helped that they had the perfect edit. “To me, all the discovery was done by 2015. We defined how to do it, and then it was a question of execution,” he says. “But the companies executed flawlessly, and they don’t all do that.”
On a picturesque fall day a few years ago, I opened the mailbox and took out an envelope as thick as a Bible that would change my life. The package was from Vertex Pharmaceuticals, and it contained a consent form to participate in a clinical trial for a new gene-editing drug to treat sickle cell disease.
A week prior, my wife and I had talked on the phone with Haydar Frangoul, an oncologist and hematologist in Nashville, Tennessee, and the lead researcher of the trial. He gave us an overview of what the trial entailed and how the early participants were faring. Before we knew it, my wife and I were flying to the study site in Nashville to enroll me and begin treatment. At the time, she was pregnant with our first child.
I’d lived with sickle cell my whole life—experiencing chronic pain, organ damage, and hopelessness. To me, this opportunity meant finally taking control of my life and having the opportunity to be a present father.
The drug I received, called exa-cel, could soon become the first CRISPR-based treatment to win approval from the US Food and Drug Administration, following the UK’s approval in mid-November. I’m one of only a few dozen patients who have ever taken it. In late October, I testified in favor of approval to the FDA’s advisory group as it met to evaluate the evidence. The agency will make its decision about exa-cel no later than December 8.
I’m very aware of how privileged I am to have been an early recipient and to reap the benefits of this groundbreaking new treatment. People with sickle cell disease don’t produce healthy hemoglobin, a protein that red blood cells use to transport oxygen in the body. As a result, they develop misshapen red blood cells that can block blood vessels, causing intense bouts of pain and sometimes organ failure. They often die decades younger than those without the disease.
After I received exa-cel, I started to experience things I had only dreamt of: boundless energy and the ability to recover by merely sleeping. My physical symptoms—including a yellowish tint in my eyes caused by the rapid breakdown of malfunctioning red blood cells—virtually disappeared overnight. Most significantly, I gained the confidence that sickle cell disease won’t take me away from my family, and a sense of control over my own destiny.
Today, several other gene therapies to treat sickle cell disease are in the pipeline from biotech startups such as Bluebird Bio, Editas Medicine, and Beam Therapeutics as well as big pharma companies including Pfizer and Novartis—all to treat the worst-suffering among an estimated US patient population of about 100,000, most of whom are Black Americans.
But many people who need these treatments may never receive them. Even though I benefited greatly from gene editing, I worry that not enough others will have that opportunity. And though I’m grateful for my treatment, I see real barriers to making these life-changing medicines available to more people.
A grueling process
I feel very fortunate to have received exa-cel, but undergoing the treatment itself was an intense, monthslong journey. Doctors extracted stem cells from my own bone marrow and used CRISPR to edit them so that they would produce healthy hemoglobin. Then they injected those edited stem cells back into me.
It was an arduous process, from collecting the stem cells, to conditioning my body to receive the edited cells, to the eventual transplant. The collection process alone can take up to eight hours. For each collection, I sat next to an apheresis machine that vigorously separated my red blood cells from my stem cells, leaving me weakened. In my case, I needed blood transfusions after every collection—and I needed four collections to finally amass enough stem cells for the medical team to edit.
The conditioning regimen that prepared my body to receive the edited cells was a whole different challenge. I underwent weeks of chemotherapy to clear out old, faulty stem cells from my body and make room for the newly edited ones. That meant dealing with nausea, weakness, hair loss, debilitating mouth sores, and the risk of exacerbating the underlying condition.
MATT ODOM
My transplant day was in September 2020. In a matter of minutes, a doctor transferred the edited stem cells into me using three small syringes filled with clear fluid. Of course, the care team did a lot to try and make it a special day, but for me that moment was honestly deflating.
However, the days and months since have been enriching. I’ve escaped from the clutch of fear that comes from thinking every occasion could be my last. Noise and laughter from my 2-year-old twin daughters and 4-year-old son echo through my home, and I’ve gained immense confidence from achieving my goal of being a father.
It’s clear to me from my experience that this treatment is not made for everyone, though. To receive exa-cel, I spent a total of 17 weeks in the hospital. Not everyone will want to subject themselves to such a grueling process or be able to take time away from family obligations or work. And my treatment was free as part of the trial—if approved, exa-cel could cost millions of dollars per patient.
Another potential barrier is that some people become enmeshed with their chronic disease. In many ways, your disease becomes part of your identity and way of life. The community of people with sickle cell disease—we call ourselves warriors—is a source of strength and support for many. Even the promise of a better life from a novel technology may not be strong enough to break that bond.
From few, to many
Other challenges are society-wide. In advancing new treatments, the US medical industrial complex has too often left a trail of systemic racism and unethical medical practices in its wake. As a result, many Black Americans mistrust the medical system, which could further suppress turnout for new gene therapies.
Global accessibility has also not been a priority for most of the companies developing these new treatments, which I feel is a mistake. Some have cited the lack of health-care infrastructure in sub-Saharan Africa, which houses about 80% of all sickle cell disease cases globally. But that just sounds to me like a convenient excuse.
The options for treating sickle cell disease are very limited. Denying access to such a powerful and transformative treatment based on someone’s ability to pay, or where they happen to live, strikes me as unethical. I believe patients and health-care providers everywhere deserve to know that the treatment will be available to those who need it.
Conducting gene therapy research and clinical trials in African populations could allow for a more comprehensive understanding of the genetic diversity of sickle cell disease. This knowledge may even contribute to the development of more effective and tailored therapies—not only for Africans, but also for people of African descent living in other regions.
Even as a direct beneficiary of gene therapy, I often struggle with not knowing the full consequences of my actions. I fundamentally, at a cellular level, changed who I am. Where do we draw the line at playing God? And how do we make the benefits of a God-like technology such as this more widely available?
Jimi Olaghere is a patient advocate and tech entrepreneur.
