Herd on the street

Could previous exposure to other coronaviruses offer some protection against SARS-CoV-2?

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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 the ability to spread 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.

What’s ‘safe enough’ for a Covid-19 vaccine?

Understanding the risks and benefits in the first lines of defense against the pandemic.

NIAID SARS CoV2

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”.*

 

Sending the messengers

If mRNA vaccines for Covid-19 prove themselves, manufacturers may ramp up production surprisingly quickly.

jigsaw2Speculation 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?

* On April 16th, the Biomedical Advanced Research and Development Authority (BARDA) announced funding up to $483 million for Moderna to ramp up. “Plans now call for producing millions of doses in the fall, tens of millions next year.”

Moderna’s vaccine dream machine

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.

Images courtesy Moderna.

Object lessons

What do museums save of our pasts and which of those treasures do they surface in public?

In a giant two-year-old warehouse in South Greenwich, the Prince Phillip Maritime Collection holds… well, almost anything you can imagine that connects to Britain and the sea. Huge rooms filled with racks of paintings. Calfskin charts of the Mediterranean that predate lines of latitude and longitude, 400-year-old astronomical globes of remarkable precision and beauty, a 4,000-year-old Egyptian boat model… altogether, something like two million objects. Last week it was my privilege to take a behind-the-scenes tour of this motherlode, led by friendly staff.

I also wandered the Museum of London, just north of Saint Paul’s Cathedral, and its beautifully designed galleries with artifacts along a timeline from the prehistorical to the present day. This is not at all a small museum but a vastly larger version is well underway, created in part to display more of the  collection of some seven million items. And I gave a wave to HMS Belfast, the largest survivor of the British WW2 navy.

I’m a huge fan of digital humanities efforts, notably the European Time Machine megaproject, that seek to digitally preserve and present a wealth of historical material that otherwise could never appear in public. But we also hunger to see the original beasts—to come (almost) close enough to touch the actual paintings or charts or globes. How do museum curators choose?

HMS Belfast

To be or not to be virtual

In ‘Hamlet 360’, the play is the thing wherein to catch the concept of virtual reality drama.

How well can you present a serious theatrical performance with virtual reality (VR) tech?

That’s the challenge taken on by “Hamlet 360: Thy Father’s Spirit”, an hour-long condensation of the play created by Boston’s beloved Commonwealth Shakespeare Company and Google. “Hamlet 360” can be seen online but is best delivered to small groups of people, each with their own VR headset and swivel chair. We were lucky enough to see it in its short Boston run, presented by Commonwealth founding artistic director Steven Maler.

Given Commonwealth’s professional skills, it was no surprise that the play was beautifully acted and staged. We quickly adjusted to the VR setup. The headsets and earphones were comfortable and easily removed. The visual resolution and color quality were disappointing, like a 360-degree version of old broadcast TV. Some of us particularly liked being held within our own hermetically sealed VR environment, some of us not so much.  I wondered how the experience would strike people in their teens and twenties, who grew up with sophisticated computer games and primitive VR platforms such as Nintendo’s Wii.

We were soon turning in our chairs to follow the action, which might be anywhere around us since we were in the middle of each scene. (Yes, the inverse of theater-in-the round.)  Since that viewpoint is fixed during the scene, the director and performers may need to fundamentally reconsider their stage directions. But the action scenes were convincing, especially the fatal duel between Hamlet and Laertes. And there’s a twist at the end of the play that has nothing to do with tech and that I found moving.

Cartography blanche

Guerrilla Cartography highlights the power of maps to inform, persuade and inspire.

“Everyone believes a map. No other narrative device—not story or song or historical treatise—is so readily accepted as true. We have come to accept the map as fact.”

So writes Darin Jensen in Water: An Atlas, a remarkable collection of maps with many ways to view water that was released in 2017.

The maps for this crowd-funded publication were contributed by cartographers and other researchers around the world via Guerrilla Cartography, an open collaboration Jensen founded to “widely promote the cartographic arts.” The group’s first project was Food: An Atlas, a milestone accomplishment in 2012.

Its latest production is Atlas in a Day: Migration, a stunning response to a challenge to research and design an atlas about migration in one day last October. No fewer than 43 maps “interpret the theme of migration in diverse ways, considering the movements of people, animals, climates, physical materials and cultural artifacts over time and space. Some of them represent the culmination of years of research on a critical topic; others are quick sketches inspired by current events and concerns.”

All three atlases can be downloaded free, and Food and Water can be bought as books.

Maps retain plenty of power in print, Jensen points out.

“Guerrilla Cartography is about letting story emerge from data and illustrating the story through the art of cartographic design,” he says. “We give voice to the talents of mapmakers who may have no other platform for a wide and printed distribution of their work and ideas.”

Inflammatory statements

Maybe the culprit in type 1 diabetes isn’t T cells gone bad.

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Follow diabetes research and you start obsessing about beta cells—maybe a gram of cells buried across the pancreas that produce the insulin we need to live. Or stop producing it, in the case of type 1 diabetes.

These cells are heroic microbeasts. “The beta cell is a wonder of nature,” Bart Roep of the City of Hope National Medical Center told me during an interview for a Knowable story. “It’s the hardest-working cell in our body. Every second, each beta cell can make two thousand molecules of insulin; that’s daunting. It also has to be able to release insulin when it’s needed and only when it’s needed.”

In type 1 diabetes, some mix of fairly well understood genetics and not very well understood environmental factors goes wrong. T cells go haywire and begin to wipe out beta cells. So type 1 is described as an autoimmune disease in tens of thousands of research papers.

But maybe things work the other way around: Beta cells stress out and misbehave, and the immune system is just doing its job.

“I actually think that type 1 diabetes is not an immune problem, it is a beta cell problem,” said Roep.

He and his colleagues laid out some evidence in a 2017 Nature Medicine article. “We showed that if beta cells get stressed, which they do very quickly, they produce new antigens like those that expose cancers and infections to the immune system,” he noted.

“I now contend that the immune system is not making a mistake,” Roep said. “It’s the beta cell, and the immune system is actually responding with the best intentions, namely to target stressed tissue… The immune system is not interested in happy tissue.”

Roep is not the only prominent scientist who questions the T-cells-gone-wrong framework for type 1. At the Joslin International Symposium last month in Boston, Olle Korsgren of Uppsala University made another case, skimming through decades of studies on human pancreatic tissue samples analyzed by many researchers.

Among his points, Korsgren cited data suggesting that the T cell attack is surprisingly weak, this attack goes after the whole pancreas rather than just beta cells, and there are frequent signs of beta cell stress such as bleeding. “Could bleeding cells attract the immune system?” he asked.

His hypothesis: Type 1 is not an autoimmune disease that targets beta cells. Rather, it’s an inflammatory disease affecting the entire pancreas. Moreover, the inflammation might be driven by gut microbes invading the pancreas next door.

And Korsgren’s theory just might dovetail very nicely with recent research on the role of the gut microbiome in type 1, now well documented in large epidemiological studies and explored in many labs.

Image: Pamela Itkin-Ansari lab

Turing the world

AI will bring us many new understandings. And confusions, as Joseph Weizenbaum warned.

As we think our electronic world is becoming more human, often it’s becoming less.

In the past few years, Siri and Alexa and their kin have shot past the Turing test, proposed by British mathematician Alan Turing in 1950. We can’t always tell if there’s a human or machine on the other side of conversation. The raw power of the underlying artificial intelligence keeps accelerating, especially for the type of AI known as deep learning, built on connections between layers of neural networks. Deep learning systems already can beat humans at making predictions from, say, medical images. And they can make findings that humans wouldn’t attempt—for instance, tapping ECG data to predict patient sex and age.

Although some of these models try valiantly to explain their decisions, more often than not it’s a mistake to think we understand what’s going on under the covers. “A full explanation might require looking at thousands or tens of thousands of variables and complex probabilistic relationships that connects things where we don’t see any connections,” says David Weinberger, author of Everyday Chaos. “You have to look at all of that, and in many instances we just can’t.”

It’s also a mistake to believe deep learning and other AI technologies actually understand our world. They don’t see a kitten or a tumor or your favorite Calvin and Hobbes collection. All they see are patterns of swirls in their oceans of data.

When chatting with Siri and Alexa and our other semi-loyal cloud servants, though, we tend to anthropomorphize these beasts. Seeing the world as human-like has been a common human trait for longer than we can track. We imagined supernatural beings based on the worst human patriarchs; now we teach our children that dolphins are happy to be enslaved so that they can entertain us. Back in the 1980s as he introduced a crude personal robot, Nolan Bushnell remarked that the robot’s bugs were what gave it personality. We’re still there, looking for personality as we try to tease Siri.

So it’s good to think carefully about the right roles for the strange computing power lurking so many places. In medicine, better ways to figure the around-the-clock insulin dosing for people with type 1 diabetes would be great. Ditto a tool to predict if someone in the ICU will go into cardiac arrest shortly. But forget any chatbot “therapist” that claims to understands us.

Back in 1966 Joseph Weizenbaum wrote the first chatbot, Eliza, with one variant called Doctor modeled on simple psychotherapy. Weizenbaum was horrified when his secretary didn’t want him to see her conversation with the Doctor and then when other computer scientists suggested building clinical versions.

“What I had not realized is that extremely short exposures to a relatively simple computer program could induce powerful delusional thinking in quite normal people,” he wrote in Computer Power and Human Reason, published in 1976. “Computers and men are not species of the same genus… However much intelligence computers may attain, now or in the future, theirs must always be an intelligence alien to genuine human problems and concerns.”

Joseph Weizenbaum 77

Talking about regeneration

What experts are telling me about the march of pluripotent stem cell therapies.

Yes, it takes years to translate brilliant science into therapies, and the routes to translation aren’t predictable. Case in point, the California Institute for Regenerative Medicine, launched via state referendum 15 years ago among the excitement about pluripotent embryonic stem cells. The Institute has sponsored 56 clinical trials. By a quick count, only five of these trials are looking at pluripotent stem cells, the remainder testing adult stem cells for regeneration or cancer treatments.

The waters are muddied by hundreds of for-profit “stem cell clinics” that offer treatments with little or no clinical evidence. “There is no scientific basis for what these people are doing,” one prominent researcher told me. “It’s very important to draw a distinction between the malpractice and quackery of these unsubstantiated stem cell clinics and the incredibly high-tech serious science that is using all of the new targeted approaches to improve patient outcomes for really terrible diseases.”

Therapies based on induced pluripotent stem cells (iPSCs) are entering early studies. The first iPSC clinical trial for Parkinson’s disease launched last year in Japan, for example. jCyte kicked off a successful first trial to treat a degenerative eye condition in 2017 and should post early results of a follow-up study soon. Studies for cardiac condition are likely to launch in 2020, one based on research shown successful in macaques. Also next year, Sigilon Therapeutics expects to kick off a study for hemophilia A, and Semma Therapeutics is planning trials for insulin-producing pancreatic beta cells for type 1 diabetes. “I’m happy to tell you that Semma has solved the production problem for beta cells,” co-founder Douglas Melton told me.

Labs are gearing up for off-the-shelf cell therapies, by engineering “universal donor cells” that dodge immune reaction and/or retraining T cells and other bodyguards of the immune system. This is a very long road with many complexities and safety concerns. But progress is being made, with one example this year from Melton and colleagues.

Other researchers seek to apply what we’re learning about cell plasticity to form  desired cells directly within the body. Kristen Johnson of Scripps Research’s Calibr institute, for instance, leads a trial of a small molecule designed to make healthy new knee cells. At an earlier stage, diabetes researchers aim to develop insulin-producing cells by altering pancreatic alpha cells or a recently found population of pancreatic progenitor cells. Startups OxStem and Sana Biotechnology have wildly ambitious programs in this space.

We’ll see what actually translates but the scientists I talk with believe that stem cell research will change medicine dramatically and it won’t take 15 more  years.

Images courtesy Harvard Stem Cell Institute. On left, mouse induced muscle progenitor cells at various stages of differentiation, from Konrad Hochedlinger’s lab. Top right, human green kidney cells and red blood vessels, from work led by Jennifer Lewis and Ryuji Morizane. Bottom right, from the Melton lab, two clusters of human insulin-producing cells (pink), the cluster on the right demonstrating enrichment of these cells.

 

Surge protectors

Will the Boston Harbor ocean barrier rise again?

Built on four centuries of filled land, Boston is wildly vulnerable to the next major hurricanes or winter northeasters. These risks only accelerate as storms get worse and sea levels rise. To their credit, the city and state understood this exposure years ago and have been steadily working away on climate resilience initiatives. One project was to consider a grand Boston Harbor barrier that would close off much or all of the harbor against big ocean storms. A study led by the University of Massachusetts found, however, that such a barrier would be thoroughly impractical.

But maybe not. William Golden, famous here for kicking off the legal struggles that triggered the harbor cleanup a few decades ago, today launched an open meeting of a Boston Harbor storm surge working group. The group’s premise is straightforward: the best defense against the sea is a layered defense that combines a re-thought harbor barrier (to fend off the storms) and relatively modest local measures such as berms (to handle sea level rise).

Among points by Golden and his allies:

  1. There are many alternative barrier routes and designs, some sketched out above by Duncan Mellor of Tighe & Bond. These might mostly follow shallow water, use dual gates for the shipping channels rather than the never-built-anywhere single gate structure examined by UMass researchers, and be considerably less massive. That might make them dramatically less expensive than the $7-12 billion pricetag UMass experts suggested.
  2. Depending on your assumptions about how long construction takes and what you pay for money (discount rates), costs again might drop significantly. And unlike smaller projects, federal funding just might be available.
  3. A barrier that guards the entire harbor, not just Boston, could provide benefits that no one has counted yet. Most dramatically, the savings in regional flood insurance payments might be many times the investment.
  4. The default alternative of building high local berms/seawalls everywhere brings up seriously worrying questions. For one, what about the places that can’t afford them? For another, how will all these patchwork walls connect? And do we really know how to efficiently build a watertight 20-foot seawall all along, say, the North End waterfront, with its crazy web of buried infrastructure and weak geological underpinnings?

Our safeguards against the sea will have domino effects far beyond Boston. “This is going to affect the economy of the whole region,” Golden said. “It’s an existential threat.”

Pre-filled Boston, courtesy Leventhal Map & Education Center, Boston Public Library

Capsule cures get beta

We’ve learned how to churn out zillions of insulin-producing cells and maybe even guard them from the immune system for a year or two.

The commercial “stem cell clinics” that have popped up across the U.S. like mosquitoes after rain, offering treatments with little clinic evidence, typically begin with the patient’s own cells. But the stem-cell-based therapies that will soon fundamentally change regenerative medicine will come off the shelf. Case in point, the insulin-producing treatments for type 1 diabetes that I’ve just covered in The Scientist, which are headed for the clinic in the next year or two. Scientists are mastering ways to make reasonably functional beta cells in high volume. ViaCyte is readying a new version of its capsule that doesn’t require immunosuppression and expects to resume clinical trials soon. Semma Therapeutics and Sigilon Therapeutics are reporting progress in pre-clinical studies. Fingers crossed here, but definite progress.

Images courtesy Sigilon Therapeutics.