In an era of science-fiction medicine, why can’t we engineer the hormone to adjust itself?
More than 40 years ago, diabetes researchers began trying to modify insulin so that it would be released in just the right amounts at the right time, to keep blood glucose levels in a good range.
Today, there’s no such smart insulin in the clinic or apparently even in clinical trials.
Designer insulins keep millions of people with type 1 diabetes alive and improve the health of many millions more with advanced type 2 diabetes. But to over-generalize only slightly, these folks always have the wrong amounts of insulin circulating. Too little insulin, and people are prone to nasty long-term complications, including heart and kidney failure. Too much, and they can pass out within minutes from low blood glucose levels.
So, the quest for smart insulins is still underway in labs around the world. Occasionally smart insulin expertise gets purchased by a large pharmaceutical company. Sometimes those initiatives proceed into early clinical trials. Which fail.
Meanwhile, diabetes afflicts more than 400 million people and is ramping up. The annual insulin market is at least around $30 billion. Smart insulins could grab the lion’s share and become some of the best-selling medicines in history.
Perhaps we are waiting on conceptual breakthroughs, because insulin is a famously tricky protein and a keystone of human metabolism. Perhaps only Big Pharma firms have the necessary scientific chops, clinical experience, funds and oh yeah patents to pull it off.
But really, what’s the logjam? How will it be broken?
Designer insulins Humalog, Tresiba and Novolog, courtesy Protein Data Bank.
MIT’s tough-tech accelerator joins the march toward truly individual therapies.
Sometimes, limitations on a given technology that seem set in stone instead will vanish pretty quickly. That might be happening in the field of cell therapies, where treatments that remove, turbocharge and reinfuse your own cells might seem way too difficult and expensive for all but the deadliest diseases.
But maybe not.
That’s what experts keep telling me as I work on a Nature story about regulatory T cell therapies for autoimmune diseases. Maybe the bring-your-own-cells approach will work out for a number of these conditions, and maybe even we’ll see that in clinics this decade.
If so, these living drugs will be built on progress in immunology, cell engineering for chimeric antigen receptor (CAR) T cell treatments for blood cancers, stem cell research, and genome editing tools headlined by CRISPR-Cas9. And the drugmakers will employ industrial tools provided by startup firms.
The Engine has placed very few bets on biomedical firms, but Cellino Biotech and Kytopen are exceptions.
Cellino “has the potential to manufacture personalized cell therapies at-scale for the first time,” as co-founder and CEO Nabiha Saklayen puts it. “Progressing towards scalable stem cell manufacturing is the only way to provide personalized cell therapies to all patients.”
“Kytopen aims to transform the cell and gene therapy industry with its microfluidics and electric-field-based platform that can automate and manufacture the genetic engineering of cells 10,000x times faster than current methods,” the company says.
In autoimmune labs and clinics, hopes are high for individualized cell therapies. “In the right context, these cells can be effective in resetting the immune system,” one prominent immunologist told me. “This can be really transformational.”
Image courtesy Doug Melton’s lab at Harvard, now routinely churning out batches of half a billion human cells that act very much like the pancreatic islet cells that fail in type 1 diabetes.
As Boston plans for resilient waterfronts, there’s still a case for a barrier in the outer harbor.
Along Boston Harbor, the big worries from climate change are sea-level rise and storms—but not in that order, William Golden remarked in a Environmental Business Council (EBC) of New England session on December 10.
Currently in Boston, sea-level rise is “a nuisance issue that can be addressed for another 30 or 40 years with a couple of feet of seawall,” said Golden, an attorney and environmental activist best known for filing the lawsuit that led to the cleanup of Boston Harbor. “The real issue is storm surge.”
That is, when the sea climbs to scary heights—say, the 14-foot-above-high-tide wall of water that swamped lower Manhattan in Superstorm Sandy in 2012.
Much of the Boston waterfront was originally tidal flats and its edges remain highly vulnerable to ocean storms, which are growing more numerous and often more terrifying. In this record-breaking year, 12 named Atlantic storms hit the U.S., one clobbering Louisiana with winds over 150 mph and a storm surge of 17 feet.
Now leading the Boston Harbor Regional Storm Surge Working Group, Golden renewed his call for a harbor barrier stretching from Hull to Deer Island in outer Boston Harbor, guarding against storms for 15 cities and towns with 175 miles of coastline. (Such a barrier wouldn’t do anything about sea-level rise, which instead would be addressed by relatively modest structures onshore.)
Boston turned down this concept in 2018 after a preliminary feasibility study argued that the sea-gate system would be less cost-effective than onshore measures, take decades to build and pose uncertain technical risks. Golden and his allies, however, remained unconvinced.
Sanjay Seth, Boston’s climate resilience program manager, didn’t comment on the harbor barrier proposal at the EDC meeting but did outline the city’s active program to defend itself onshore.
“There are several areas of Boston that can serve as entry points for significantly damaging floods,” Seth noted. “We do have a real but very narrow window to achieve a unified network of protection in the city. .. Climate change really isn’t waiting.”
The downtown Boston waterfront, with its almost completely private ownership and messy underpinnings, may be the hardest neighborhood to handle. “There’s no silver bullet here,” Seth said. Instead, the plan calls for a mix of four options: raising the main roads closest to the waterfront, reconfiguring parks and other open spaces, beefing up the Harborwalk, and placing structures directly in the sea.
The preferred strategy for the downtown is a line of defense along the outside edge of the waterfront. “It’s not going to be easy, but it’s going to be doable,” said Seth. He acknowledged that success will require “entirely new levels of public/private coordination, as well as new, more robust coordination among private property owners themselves.”
Golden applauded Boston’s resilience planning but pointed out the limitations of any land-based measures. “Flood walls, particularly when they’re meant to address storm surge and sea level rise, can separate the public from the water,” he noted. The walls also can leave marine uses such as cargo shipping and ferry traffic unprotected. Moreover, the structures can act as bathtubs that need pumps to clear themselves after heavy rainstorms.
Harbor barriers can minimize those problems. Truly massive barriers are quietly guarding London, Rotterdam, Saint Petersburg and other cities. Smaller ones have worked well in New Bedford and other New England cities, Golden pointed out.
The leading U.S. contender for a giant gate system is the one proposed for Galveston Bay and Houston, part of a grand scheme for the Texas coast that seems headed to Congress this spring.
William Merrell of Texas A&M in Galveston came up with the concept back in 2008 while he was trapped in an apartment building by high water of Hurricane Ike. Once known as the Ike Dike, now as the Texas coastal spine, the idea is “extremely simple,” Merrell said during the EDC meeting. “Stop the water at the coast.”
The central barrier would cross Bolivar Roads, the main entrance to Galveston Bay and the Houston Ship Channel. It would combine a set of 300-foot-wide vertical-lift gates with massive horizontal swinging gates on the navigation channel, like those in Rotterdam. Left open in normal conditions, these entry points would allow almost-normal tidal flow. In addition to the gates, the project would bundle in defensive local measures for the city of Galveston and other sites inside the Bay, along with 43 miles of beach and dune restoration on barrier islands plus a wealth of ecosystem restoration efforts.
A far more colossal harbor barrier has been proposed for metropolitan New York, where Sandy killed more than 100 people. This humongo structure could close the Ambrose shipping channel with a five-mile barrier stretching from the Rockaways to Sandy Hook. Additionally, a one-mile barrier could close the East River.
This regional system would work together with lower onshore barriers designed to deal with sea level rise and most storms, said Robert Yaro, professor of practice at the University of Pennsylvania School of Design, at the EBC session.
However, New York City chose instead to pursue a number of very large onshore projects, with very little to show to date. “Nothing’s operational after eight years, and none of them are fully funded,” Yaro said.
“Every one of these onshore barriers is a lot more complicated, a lot more expensive and a lot more time-consuming than anybody anticipated at the outset,” he added. Many protective measures depend on deployable flood barriers, an operational nightmare. And it’s still not at all clear that there’s even a working concept to protect Wall Street, whose waterfront is particularly constrained.
“When you add up the cost of the various onshore barrier systems that have been proposed for the New York metropolitan area, they exceed the cost of an offshore barrier system,” Yaro said. He also declared that even projects on this enormous scale can be constructed in a few years if the will is there—for instance, the Army Corps of Engineers rebuilt the New Orleans barrier system in less than five years after Hurricane Katrina.
“We believe that the surge barriers that we’re proposing will give us a hundred years or more to adapt our region to climate change,” Yaro said. “We need to have some time to plan to reinvent our cities and our civilization around the even more destructive changes that may be coming.”
“We’ve got to be more resilient, but we’ve got to be smarter about how we do it,” he summed up.
For Golden, that means a deeper study of the potential for a Boston harbor barrier, leading toward a shovel-ready coastal defense plan that could tap into the federal funding that he sees on the horizon. When and if such big bucks arrive, “we need to know what we’re going to do with that money,” he said.
Living Breakwaters will bring many coastal benefits, but direct flood protection is not among them.
When Superstorm Sandy hit Staten Island at the mouth of New York Harbor, the storm surge rose to 16 feet and 24 people died. Eight years later, the island is inching ahead on raising new seawalls and rebuilding dunes and buying out properties in the zones that can’t be protected.
And launching Living Breakwaters, a pioneering “nature-based” project off the town of Tottenville in the southwestern corner of Staten Island, which is finally out for construction bids.
Living Breakwaters will install a set of eight meticulously designed, partly submerged structures aimed to reduce shoreline erosion and storm waves, help to restock local finfish and shellfish populations, and offer opportunities for community learning about marine ecosystems and social resilience.
The $60 million project originated in the Rebuild by Design competition held by the U.S. Department of Housing and Urban Development after Sandy, said project leader Kate Orff, speaking at a University of Maryland Center for Environmental Science webinar on November 5.
“What’s truly innovative about this project is it aims to be combinatory,” said Orff, founding principal of SCAPE, a landscape architecture and urban design studio in New York. “It combines risk reduction of a physical breakwater with fostering an active shoreline culture, rebuilding the shoreline, and rebuilding the three-dimensional ecological substrate through active oyster restoration.”
What Living Breakwaters won’t do is keep out floodwater.
Instead, they will work in tandem with a dune restoration project, one of whose goals is flood reduction.
“Just stopping flooding is only one of maybe 10 different concepts that we have to think about when we think about purpose,” Orff said. “If one were to build a four-foot linear seawall in this area, with any intense rain event the entire town of Tottenville would get flooded out.”
The breakwaters are configured to bring down the crests of waves coming from the east and southeast, the most common direction in storms. The structures also will minimize shoreline erosion, which is primarily driven by day-to-day waves, and help marine ecosystems recover more quickly after storms.
The design goal is to handle storms with up to 30-inch sea-level rise. “One of the nice things about breakwaters is they don’t stop functioning with sea-level rise,” commented Joseph Marrone, associate vice president and area lead for urban and coastal resiliency at the international engineering firm Arcadis. “They’ll still provide wave reduction and erosion reduction… along with the ecological benefits.”
Built with a mix of hard stone and “bio-enhancing” concrete, the breakwaters will incorporate precast tide pools and other components tailored to provide niche habitats for many marine species. Additionally, “we worked with the Billion Oyster Project and educators on shore to advance the idea of oyster gardening and rebuilding the historic reefs that were once part of this ecosystem,” Orff said.
She sees bringing back such ecosystems as an obligation in resilience projects.
Moreover, it’s critical to test these natural and nature-based measures at scale. “A 20-by-20-foot bed of wetlands won’t have a lot of impact relative to risk reduction, but larger contiguous systems absolutely will,” she said.
“As we are looking more towards natural nature-based features, because we are looking now simultaneously at the climate crisis, sea-level rise, more rainfall, et cetera, we’re also looking at a crisis of biodiversity,” Orff emphasized. “We need to begin to think about all of these things at the same time.”
And to plan more proactively, “because otherwise we’ll get constantly caught in this disaster response framework,” she said.
Resilience roadmaps should stop focusing solely on protecting today’s built shorelines, Orff suggested. Instead, they can reflect how those dynamic coastal environments might benefit from layered solutions “that can keep people safer and can also keep our shorelines living and alive and suitable for marine life,” she said. Among the options, nature-based measures often may be much better suited for the wild complexity of future environments and events.
Orff also calls for a common blue-sky vision in which the almost endless groups of coastal stakeholders all march in the same direction. “When we’re just working at this tiny scale and fighting the small battles, it feels like we’ll never add up to enough to really meet the climate crisis and ecological crisis that we’re facing,” she said.
Biologist Kate Rubins returns to the International Space Station.
On Wednesday, Kate Rubins celebrated her 42nd birthday by blasting off with two Russian colleagues for her second trip to the International Space Station (ISS).
She’s in low-earth orbit until April, circling the globe about every 90 minutes, running many experiments in biology and other scientific disciplines. And doing crew work on the huge 20-year-old spacecraft, which lost one of its main oxygen systems shortly after she arrived.
I met Rubins in 2007 at Whitehead Institute for Biomedical Research. She joined as a Whitehead Fellow, a rare opportunity for outstanding postdocs to immediately become principal investigators (PIs), given funding without faculty responsibilities for five years.
She was already a scientific superstar for her contributions to the first animal model of smallpox. She was not just brilliant and energetic but emotionally well-grounded and patient with non-scientists—not universal traits among PIs.
At Whitehead, Rubins quickly built a team to investigate vaccinia, the virus base for smallpox vaccines. She also continued collaborations on several extraordinarily dangerous viruses, including Ebola.
Unlike other Whitehead PIs, she also worked in the field. In fact, she studied monkeypox (a close relative of smallpox) in a remote area of the Democratic Republic of Congo, one of the most dangerous locations I could imagine. (See story on page 16 of this Whitehead magazine PDF.) “It’s amazing to discover the inner workings of this cousin of humankind’s deadliest plague, but also to be making some small impact on this remote corner of the globe,” she told me.
Her viral research stayed on a fast track, but in 2009 she decided to go for her childhood dream of becoming an astronaut. Unsurprisingly, NASA approved, and she began years of training.
Rocketing up to the ISS in 2016, Rubins mastered life in microgravity, performing experiments for dozens of research projects, biological and not. Most famously, she became the first human to do genetic sequencing in space. Another highlight was a study of how cardiovascular cells develop there, with preliminary results that are maybe worrisome for human spaceflight.
Additionally, like all ISS crew, she took on endless chores to keep the station running. One job perk: two spacewalks.
Among projects in her current six-month stint, she’ll follow up on the cardiovascular findings, using more advanced cell microscopy. She’ll also examine the ISS itself as a unique home for microorganisms. “The space station has been separate from Earth for 20 years,” as Rubins told CNN’s Ashley Strickland. “How is it different? The space station is its own biome with its own resources, with humans coming and going. We want to see what these closed environments do when they’ve been separate for a long time.”
Additionally, she has made a high-profile exercise of voting for the November election from space. (Actually, this will be far easier for her than for millions of other Texas residents whose votes the Republican governor tries to suppress.)
In this NASA video, Rubins brings out her sheer joy in pursuing science in space: “It’s an amazing lab and it’s incredibly fun.”
NASA photos from 2016, except the Soyuz spacecraft approaching the ISS on October 14, 2020.
Can therapies with defensive T cells fend off autoimmune diseases?
Within months, the FDA probably will approve the first drug to significantly slow the onset of type 1 diabetes among many at high risk of the disease. This success with the monoclonal antibody teplizumab will top three decades of struggles by immunologist Jeffrey Bluestone and partners.
This year, Bluestone launched Sonoma Biotherapeutics to take another giant leap against autoimmune disease—this one via reengineered immune cells.
“Cell therapy is really the next major medicine, but it’s hard and it’s not for the gentle,” Bluestone noted in an intriguing interview with John Carroll of Endpoints posted on September 30.
In Sonoma’s case, the defenders are a special force of T cells—T regulatory (Treg) cells, whose role in life is to prevent the main groups of T cells from shooting the wrong targets. Such rampages gone wrong drive type 1 diabetes, rheumatoid arthritis, lupus and other autoimmune diseases that together afflict more than 50 million in this country.
Rethinking and reconfiguring the Treg cells themselves might bring unique benefits, Bluestone believes.
“Our whole business model is that this is not a chronic treatment,” he told Carroll. “Your immune system is a living thing, so the drug you’re giving has to be a living thing. Otherwise you won’t control these diseases over the long run…. With Tregs, we can create something that might induce tolerance and require only a single therapy.”
Tregs already can act as multitalented natural pharmacies, churning out molecules for repair or regulation or many other cellular jobs, Bluestone pointed out. And since these regulatory cells evolved as brakes for the immune system, they also feature some built-in safety features.
As everywhere else in immunology, many open questions remain on Tregs, Bluestone and co-authors noted in a 2019 Nature Reviews article. Scientists don’t really understand how to distinguish Tregs in lymph nodes from Tregs in tissue, or in which location they’re active, or how to generate the most effective Treg therapeutic cells, or whether Treg cells will survive and keep functioning properly within patients, or….?
When and if these devils in the details are mastered, there’s a chance to build a unique treatment platform for many autoimmune diseases, he said. Maybe the method also will aid selected non-immune diseases such as brain degenerative illnesses.
Sonoma has gathered $70 million in early funding, during a year in which six other Treg companies also debuted. Bluestone applauds the competition: “It’s a great thing for the field.”
Biologists patiently unravel the mysteries of insulin-producing cells.
While we stay tuned to Covid-19, biomedical researchers keep reporting major progress on other fronts. Here are three recent papers on key questions about the insulin-producing pancreatic beta cells that are wiped out in type 1 diabetes.
1. Why are beta cells so prone to autoimmune attack? “There is mounting evidence that type 1 diabetes is a disease not only of autoimmunity, but also of the target beta cell itself,” say Roberto Mallone of the University of Paris and Decio Eizirik of the Free University of Brussels.
First, cranking out insulin and other proteins in high volume “is a stressful job,” so the cells are likely to show signs of inflammation and compensate in various ways that are not healthy in the long run, thus worrying the immune system. Second, the pancreatic islets where beta cells live are closely embraced by blood vessels, “which favours face-to-face encounters between immune cells and beta cells.” Third, insulin and related proteins flow directly into the networks of blood vessels and can raise alarms at a distance.
“Agents aimed at limiting the autoimmune vulnerability of beta cells should find their place in the search for disease-modifying treatments, either alone or in combination with immunotherapies,” the authors suggest.
2. Can we create islet organoids with not only beta cells but their islet buddies? Beta cells probably live most happily in pancreatic islet neighborhoods with their homies—other endocrine cells. So, ideally, we would replace the beta cells destroyed in type 1 diabetes with complete islets. Good news, we now can create organoids, 3D tissues with multiple cell types derived from stem cells.
In a Nature paper, Ron Evans of the Salk Institute and colleagues report human islet-like organoids (HILOs) that indeed act very much like islets in controlling blood glucose levels when transplanted into mouse models of type 1 diabetes.
More dramatically, HILOs can do this even in mice with working immune systems, by expressing a cell-surface protein called PD-L1. (An enormous amount of cancer research has laid out how proteins such as PD-L1 can ward off immune-system cells.)
3. Are there better methods to transplant beta cells and other islet cells? For decades, researchers have struggled to find practical ways to embed these cells into people with type 1 diabetes. The most successful route has been the “Edmonton protocol” developed more than 20 years ago at the University of Alberta. Here, islet cells from cadavers are infused into a vein going into the livers of people with particularly difficult-to-control disease. These recipients then are put on immunosuppressive drugs. The treatment is often initially successful but the cells typically die within a few years. And donor islets will always be in extremely short supply.
Fortunately, with stem cell technologies engineered by Doug Melton’s Harvard lab and other groups, we now can grow remarkably beta-like cells in high volumes. These cells release hormones directly into the bloodstream, so they could in theory work well enough in many locations around the body. The transplants would be tiny.
But keeping the implanted cells well and active raises many tough challenges—especially in guarding them from the immune system while they stay fully connected to blood vessels.
Many labs have grappled with this paradox for many years. Startup companies are building clever encapsulation devices but none of these capsules has proven itself in clinical trials. (One intriguing candidate made by Semma Therapeutics, which Melton cofounded, vanished from public view after biotech giant Vertex Therapeutics paid almost $1 billion for the startup.)
Last week in a Nature Metabolism paper, Ali Naji and coworkers at the University of Pennsylvania gave details on an unusual approach with no device at all. Instead, islets were harbored within a mixture mostly made up of collagen (connective protein). This “islet viability matrix” (IVM) then was injected under the skin—a very handy site for transplants, if workable.
IVM proved highly promising in experiments with mouse, pig and human islet cells in various animal models of diabetes, including some animals with working immune systems. One part of the recipe is that the matrix seems to activate a molecular pathway with multiple mechanisms that protect beta cells. IVM “represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes,” the UPenn team claims.
In an accompanying commentary, Thierry Berney and Ekaterine Berishvili of the University of Geneva School of Medicine note that the IVM strategy could include beta cell protective measures that might range from novel biomaterials to amniotic cells that act as shields. “This method is technically simple, minimally invasive in easily accessible sites and acceptable from a regulatory standpoint,” they conclude. “The door is now wide open for the initiation of a pilot clinical trial.”
Beta cells image courtesy the lab of Douglas Melton at Harvard.
Hopes are high for the Covid-19 molecular antibodies heading into clinical trials.
Before, or maybe after, we get vaccinated against Covid-19, millions of us eventually may get another biologic drug for the coronavirus, made of synthesized proteins known as monoclonal antibodies (mAbs). Clinical trials are underway for many mAbs created to treat the disease, and many of these studies could yield results quicker than vaccine trials because the mAbs are given right to people who have the virus.
We don’t yet have direct public evidence that any Covid-19 vaccine candidate works in humans. We do have evidence that the vaccines produce significant amounts of “neutralizing antibodies”—proteins churned out by immune system B cells that can slow or stop an infectious disease. In this case, the proteins bind to the SARS-CoV-2 virus’s spike protein, the molecular crowbar by which the virus enters cells.
People who survive the disease carry these neutralizing antibodies in their blood, at least for a while. That’s the mechanism behind “convalescent plasma” transplants, using blood from these recovering patients.
Convalescent plasma transplants have been widely used for more than a century for diseases that lack drugs and these transplants are generally considered safe if not necessarily effective. So in addition to the turbocharged global march toward Covid-19 vaccines for prevention, dozens of clinical studies are looking at convalescent plasma.
The jury is still out on how well this approach will work. And as with any blood transplant, the logistics are tough, the supplies are limited and each transplant will work a little differently.
But mAbs that act as neutralizing antibodies may offer a better route.
Dozens of mAb drugs have been approved, mostly for cancers. And we have an astonishing toolkit for precisely designing and testing these biological beasts, and churning them out in volume. So labs in academia and pharma have been rapidly developing Covid-19 mAbs: plucking out B cells from survivors’ blood, analyzing the antibodies these cells produce and how well they work to shut down SARS-CoV-2 infection, testing huge volumes of mAb variants, optimizing their neutralizing characteristics and coming up with the best candidates for clinical trials.
Last week in a webinar hosted by The Scientist, James Crowe of the Vanderbilt Vaccine Center and Joseph Jardine of the Scripps Institute and the International AIDS Vaccine Initiative (IAVI) outlined two round-the-clock initiatives that led to mAb candidates, described in Nature and Science.
The main goal is treating patients with Covid-19. But both groups also hope the drugs will guard other groups at high risk, such as the elderly.
Aside from maybe arriving months earlier, how will mAbs compare to vaccines in preventing Covid-19?
As with vaccines, the biggest question may be how long mAbs remain effective.
In Covid-19 patients, levels of neutralizing antibodies drop off fairly quickly. “That’s concerning; it’s not what you’d like,” says Jardine. The hope for survivors (and people who receive vaccines) is that B cells will remember the threat and ramp up production of neutralizing antibodies again if needed, which seems likely but apparently isn’t proven.
In contrast, mAbs simply don’t last indefinitely. Jardine commented that if they are suitably tuned up, these drugs might deliver protection for three to six months or so.
Crowe suggested, however, that mAbs might actually work longer than vaccines, noting that two of his group’s mAb candidates hung on surprisingly well when tested in rhesus macaques. These drugs probably also will perform well among the elderly, whose immune systems often struggle to produce suitable flows of antibodies.
Moreover, mAbs may come with fewer safety concerns. “Vaccines are pretty complicated, and they have complex safety profiles,” Crowe said. “Antibodies generally have a very high safety profile.”
Both researchers predicted that the newfound ability to quickly whip up targeted mAb drugs and test them in the clinic also may prove invaluable for other infectious illnesses.
“Antibodies increasingly will be a major part in the future of preventing and treating infectious diseases,” Crowe declared.
Jardine emphasized IAVI’s goal to bring mAb technology into lower and middle-income countries (LMICs) as well. “If we can make this viable for LMICs with Covid-19, we should be able to use it for other things like HIV,” he said.
Could previous exposure to other coronaviruses offer some protection against SARS-CoV-2?
Talking with vaccine experts for a Knowable story, I keep hearing about the huge gaps in what we know about SARS-CoV-2. It differs from most better-known coronaviruses in many ways, among them its ugly trick of spreading from people showing no symptoms. Scientists are struggling to understand how SARS-CoV-2 immunity works, including the roles of the antibodies targeting the virus that are created by our innate immune system and of the protective cells such as T cells that are activated by the adaptive immune system.
One puzzle is why cases dropped off so quickly in some of the worst-hit areas such as Spain, since studies that measure antibodies to the virus seem to indicate that, even today, relatively low numbers of people have been infected there. That may well be because in some of those infected the antibodies never hit expected levels and/or don’t last long, worrisome scenarios that get a great deal of attention. Another potential factor, which I first saw courtesy Mayo Clinic’s Vincent Rajkumar, is that exposure to other coronaviruses such as colds might help to defend some of us. This hypothesis is backed up by evidence in Cell, Science Immunology and elsewhere that T cells are already geared up to react specifically to SARS-CoV-2 in some probably small fraction of people who haven’t been exposed to the virus. Even if this hypothesis turns out to hold some truth it should change nothing in our defenses against the pandemic. But let’s hope for a glimmer of light here.
Understanding the risks and benefits in the first lines of defense against the pandemic.
Covid-19 vaccines are being developed by the dozen. In the best of all possible worlds, these would all be highly effective, with minimal side effects, since we need to treat people by the billions.
In the real world, in the Moderna Therapeutics phase 1 clinical trial, we know that a healthy 29-year-old fainted after receiving a second dose. He was given the highest dosage of the mRNA vaccine candidate, which has been dropped from the phase 2 trial now launching.
Infectious disease experts remain cautiously optimistic about the vaccine in lower dosages. They wish, however, that Moderna would be more transparent about its early clinical results—avoiding the mere brief upbeat press release.
“What we would have preferred to do, quite frankly, is to wait until we had the data from the entire Phase 1 — which I hear is quite similar to the data that they showed — and publish it in a reputable journal and show all the data,” National Institute of Allergy and Infectious Diseases head Anthony Fauci told STAT’s Helen Branswell.
Given that Moderna has been awarded almost half a billion dollars of federal funding for the effort, such public reporting doesn’t seem too much to ask.
As the biotech and dozens of its peers ramp up to test their various vaccines among tens of thousands of volunteers, we also want to boost the public discussion about what to expect from whichever treatments eventually are approved.
A vaccine’s effectiveness will only be reliably known once a sufficiently large number of people in the trials eventually become exposed to the virus. But my non-expert guess is that the tricky part of vaccine approvals will not be about effectiveness, given the bluntness of our other medical defenses.
Instead, the biggest issue may be safety: What’s good enough to give the billions of the rest of us?
There’s limited safety evidence from other coronaviruses; there are no approved vaccines for SARS (severe acute respiratory syndrome) or MERS (Middle East Respiratory Syndrome). Moderna has worked on a MERS vaccine but not pushed it along into the clinic.
The company, and some of its rivals, have taken mRNA vaccine candidates for other types of viruses into phase 1 trials. Among them, a Moderna study of a Zika vaccine is underway. Additionally, the company has reported positive results for earlier studies of vaccines against pandemic avian H10N8 and H7N9 flu viruses. None of the trials, Moderna says, saw any vaccine-related serious adverse events.
But what does that tell us about covid-19 vaccines?
Maybe annual flu vaccines will give the best guidance on how we balance risks and benefits. Glancing over papers that review each flu season’s results, I was struck by how the authors focus almost exclusively on vaccine effectiveness (yes, a huge problem!) rather than safety.
Of course, that’s not because safety issues are irrelevant in flu vaccines. Instead, these issues have become well understood over the decades—and addressed by intense focus at every step of design, manufacture and delivery. The results are very low rates of risk among vaccine recipients—for example, about 1.6 cases in a million suffer anaphylactic shock.
Given months rather than decades of experience with covid-19, vaccine risks are under a particularly intense global spotlight. Moderna’s planned phase 3 trial will “very carefully look at safety, even more so than is done in a regular trial,” Fauci told STAT.
In this imperfect world, particularly with anti-vaxxers so loud, we will need an informed consensus about what will be “safe enough”.*
If mRNA vaccines for Covid-19 prove themselves, manufacturers may ramp up production surprisingly quickly.
Speculation time: Let’s imagine that Moderna’s messenger RNA vaccine for Covid-19, already in clinical trials, is effective enough for approval. And/or the mRNA candidate from BioNTech, which might begin trials this month. And/or one of the candidates from CureVac or Translate Bio or many other groups feverishly working on mRNA vaccines.
True, no mRNA vaccine candidate has ever been generated in large numbers. So how could we scale up to the billions of doses that the world needs yesterday?
CureVac says it can manufacture millions of doses by this summer. Moderna has built an enormous, fully digital, fully operational, very impressive plant in Norwood, Massachusetts.* The other players are making suitably serious plans.
But beyond that, let’s remember that mRNA medical technology is radically different and one key difference is that it lends itself to extremely fast and flexible manufacturing. It’s built around synthesizing DNA and RNA rather than growing the infinitely idiosyncratic cells in traditional biotech factories. The bioreactor that generates the actual antiviral response is the patient’s body, so the amounts of active ingredient in an mRNA vaccine are almost unimaginably tiny.
And unlike traditional biotech factories, mRNA facilities are designed to rapidly switch between multiple products.
So: When and if one of these mRNA vaccines proves itself, is there any technical reason that all of these companies could not switch their production lines to churn out that one? **
How a messenger RNA drug became the first novel candidate to take on the COVID-19 pandemic.
In the world of vaccines, this was crazy fast.
The SARS-CoV2 coronavirus was sequenced on January 7. Scientists at Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) selected a vaccine target on January 13. By February 7, Moderna had a vaccine candidate. After some safety testing, on February 23 the company shipped this “mRNA-1273” vaccine to the NIAID, which is now recruiting for a first clinical trial.*
Moderna is a pioneer of messenger RNA (mRNA) drugs, designed to generate exquisitely tailored therapeutic proteins within each patient’s body.
As you recall, the central dogma of molecular biology is that DNA makes RNA that makes protein. The mRNA drug candidates created by Moderna and a few other biotechs tap into those natural steps.
Once researchers design the desired therapeutic proteins, manufacturing for an mRNA drug starts with a DNA template for those proteins. The DNA is treated with a suite of biological players to generate mRNA. Next, the mRNA is purified and put inside a lipid nanoparticle built to slip inside cells. After quality controls, you get an injectable drug. Once it’s injected, the patient’s own cells churn out proteins that attack the disease—in the case of Covid-19, by mimicking the deadly disease to alert the immune system.
No mRNA drugs have been approved, but there’s a real chance they will become that rare beast, a genuine revolution in medicine. That’s what Juan Andres, chief technical operations and quality officer, told me last summer when I visited the company’s giant facility in Norwood, Massachusetts for a Nature story on flu vaccines.
Traditional biotech drugs go after extracellular proteins, because the drugs can’t enter cells. But mRNA drugs open the possibility of producing proteins inside the cell. Moreover, unlike gene therapies, “we are not touching the DNA,” Andres said. “We are not touching the hardware of the body.”
mRNA drug manufacture and delivery are also stunningly efficient, at least in theory. You’re not using cells at all, so you don’t need the giant bioreactor vats in traditional biotech factories. In fact, the main bioreactor in the Norwood plant was roughly the size of my home’s hot-water heater.
Unusually for a biotech startup, even one as well-heeled as Moderna, the company invested heavily to achieve fully integrated production, starting with raw materials, at Norwood. “We produce the active product ingredient, which is basically mRNA itself,” Andres said. “We formulate it, we fill into vials, we finish it, we do the quality control and we ship it into clinical sites.”
So one of Moderna’s potential manufacturing advantages is speed—especially crucial for vaccines for seasonal flu or for epidemics, where the clock is always ticking (or rather, alarms are ringing loudly). The technology also may offer other major benefits, eventually, in product quality, scalability and cost.
And mRNA drugs just may end up addressing a broad spectrum of medical need. Moderna is examining many opportunities for treatment, among them personalized cancer vaccines and localized regenerative medicine.
But the company’s most advanced programs are in preventive vaccines. So far it has chalked up positive results in phase 1 clinical trials for six vaccines, among them a cytomegalovirus vaccine combining no fewer than six mRNAs that has moved into a phase II trial.
Good safety signals from these early vaccine studies encouraged NIAID to launch the mRNA-1273 trial even before the vaccine was tested in animal studies.
It will be many months before trials can prove safety and efficacy for mRNA-1273, if indeed they do.
The desperate global need drove both quick funding for the novel vaccine from the Coalition for Epidemic Preparedness Innovations (yes, not the CDC) and the supercharged development. “There was a huge amount of motivation,” Andres commented at a Moderna online forum last week. “I have not seen this kind of energy anywhere before.”
* Volunteers received first injections on March 16.