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.”

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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.

Debugging global health

Why don’t governments more directly sponsor novel antibiotics, as they do vaccines?
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The stories we write today about the threats of antibiotic-resistant bacteria read very much like the ones we wrote 15 years ago. Bacteria evolve more threatening forms, drug companies evolve toward more profitable markets, and we still depend on the invisible hand of the market to fix everything as it does so smoothly in the rest of healthcare. But there’s another option: Bringing national governments and international agencies more directly into full supervision and sponsorships of the drugs, as often is done extremely effectively with vaccines. Why not? Check out this early proposal for “a joint, internationally-funded antimicrobial development institute that would fund permanent staff to take on roles previously assigned to pharmaceutical companies.”

Hot water for fisheries management

As climate change deepens, we’ll need to understand entirely new marine ecosystems.

Here’s the good news: Since 1990, the catch of Maine lobsters has quintupled.

Okay, the rest of the news, as in other stories about climate change, is not so good.

The bumper crops of lobsters apparently have been driven by warming in the Gulf of Maine. Sea surface temperatures have climbed about four times as much in recent decades in the Gulf as in the global ocean average, according to Andrew Pershing, chief scientific officer at the Gulf of Maine Research Institute.

Lobster populations have moved northeast from southern New England waters,  Pershing said, speaking at a Metcalf Institute seminar on climate change held in Cambridge last Saturday. The shift has been a boon for Maine but a bust for fisheries south of Cape Cod.

Warmer water in the Gulf also has knocked down populations of other marine life, including some we eat (or once ate) such as northern shrimp and cod.

For hundreds of years, cod in the northwest Atlantic was one of the world’s richest fisheries. Back in the 1970s, my older brother took a trip to Georges Bank as a whale watcher on a giant Russian factory ship. At night, the sea looked like a city, dotted with the lights of dozens of fishing vessels busily sucking up cod and everything else on the seafloor.

Cod never recovered. The U.S. soon took control of our waters out 200 miles and managed the seafood take as well as it could. But most of the cod we eat now comes from China or Iceland.

Today climate change is delivering not just disruptions in ocean temperature and circulation patterns but acidification, extreme storms, loss of mangroves and marshes… As fisheries are disrupted around the world, the familiar difficulties of managing them get worse.

We don’t really know how to model newly emerging marine ecosystems, Tatiana Rynearson of the University of Rhode Island remarked at the Metcalf session. We lack the years of data needed to understand the fluctuations in conditions and populations, as Jorge García Molinos and colleagues pointed out in a 2015 paper.

Our need for long-term ocean monitoring and related research couldn’t be clearer, but climate change research is under heavy attack in the U.S.

Fortunately, compared to most of the waters of the world, we do have good historical information on Gulf of Maine waters and seafood. And while lobsters are a luxury food, they offer a positive example for management.

Unlike the case in some other states, Maine fishers must toss back lobsters that are too big as well as too small. Simulations have shown that saving the big ones has helped the shellfish survive the fishing onslaught in the Gulf, where 90% of legal-size lobsters are caught each year, Pershing said.

The saga of Maine lobsters, of course, rolls on. The catch dropped significantly in the last two years, and the highest landings keep moving north.

Watching the river flow

The Thames Barrier is still prepped for decades defending London against high water.

On Tuesday, the warmest winter day ever recorded in Britain, there was not a cloud in the sky over the Thames Barrier. A tug calmly pulled its barge through one of the channels in the Barrier, which shuts off the Thames when the incoming tide will rise over sixteen feet. This offbeat superdam doesn’t look like anything else: a necklace of giant steampunk silver mussel shells stretched a third of a mile across the river. London began seriously contemplating means of protection after a major dousing in the great North Sea storm of 1953. The Barrier went into operation three decades later. It has decades of usefulness ahead; although climate change was not considered in its design, sea levels along the southern English coast aren’t inching up from geologic causes as fast as originally expected. The Barrier has been shut about 200 times, 50 of them in the 2013/2014 season, when the culprit was not super surges from the ocean but super rain surges that incoming tides would have pumped up further. “It is designed to be bomb-proof and failure-proof,” the Londonist once noted. “When a 3,000-tonne dredger hit the Barrier in 1997, the ship sank. The Barrier lost a ladder.” One of these decades, the enormous wall may be supplemented by a much more enormous dike downstream. In the meantime, “the structure is fundamental to the lives of millions of Londoners,” the London Review of Books commented, “which may be the reason very few of them want to look at it.”

Canaries in a coal-mined world

Environmental writers tell great stories about life across our fast-changing globe.

We’re seeing a remarkable series of stories about climate change and other manmade or partly manmade threats—some even complete with hints of solutions. Here’s a fairly random baker’s dozen from this striking crop (hmm, only two of these pieces come from for-profit publications).

Crossing the Ts in diabetes

Advances in cancer immunotherapy may help autoimmune therapies defend themselves.

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Is human immunology basically too crazy complex for the human mind? Evidence to date suggests yes, at least for my mind.

In almost every story I write about cancer immunology or autoimmune disease, I learn about previously unknown (to me) functions within the three-ring circus of immune cells. Or I find out about yet more types of these cells, like double-negative T cells, which can defend against graft disease and maybe type 1 diabetes. Who knew?

Well, yeah, thousands of immunologists.

All of us who follow cancer research, though, do know a (simplified) version of one genuine breakthrough in immunology, checkpoint blockade inhibitors, which garnered Nobel Prizes last October.

These drugs take on one of deepest questions in cancer biology: why the immune system doesn’t snuff out cancer cells, which by definition are genetically abnormal, often wildly abnormal.

Checkpoint blockades can hold off the T cells on patrol for just such outsiders. It turns out that a protein on the surface of tumor cells called PD-L1 can grab onto a surface protein on the T cell called PD-1 and so disarm the T cell. (Nothing to look at here, officer! Ignore my multiple heads and antitank guns!)

Other headlines in cancer immunotherapy come from chimeric antigen receptor T (CAR-T) cell drugs, treating patients with certain blood cancers in which B cells go bad. The two such drugs with FDA approval work by taking T cells from the patients, reengineering the T cells to attack those cancerous B cells, and reinserting the T cells.

This method is often effective when nothing else works, but is always worryingly slow and extremely costly.

So there’s plenty of work in labs, and a few clinics, to take a logical but intimidating next step: Engineering off-the shelf T cells to do the job, hiding them from each patient’s immune system with tricks learned from checkpoint blockade research and similar  immunology findings.

Still with me?

Okay, if those cell-shielding techniques eventually work, can a similar attack be made in autoimmune diseases such as type 1 diabetes?

In type 1 diabetes, effective ways to stop the autoimmune attacks from trigger-happy T cells exist only in lab mice. And that’s a problem not just in slowing or stopping disease progression but in trying to treat it. The most promising current approach is to encapsulate insulin-producing beta cells. This has been pursued for many decades, with many barriers. Perhaps the highest (if least surprising) barrier is that the capsules always get clogged up.

The latest capsule approaches, starting with beta cells made by reprogramming cells, try sophisticated material-science strategies to blunt this attack and may do much better.

But as long as we’re already playing genetic games with those engineered beta cells, why not also try  immune-evading tricks similar to those being studied in CAR-T experiments?

That’s the basic idea behind efforts by Altheascience, a Viacyte/CRISPR Therapeutics collaboration, and others. Which just maybe will produce capsules that, replaced every year or so as necessary, are working cures for type 1 diabetes. Which we would all fully understand.

High water marks

What does the Venice Architecture Biennale say about resilience to climate change? Not so much yet.

Now is the start of acqua alta season in Venice, when high tides occasionally flood low-lying areas like Saint Mark’s Square and sometimes sweep across neighborhoods around the city.* As we jumped on a vaporetto waterbus one warm sunny day, platforms of temporary pedestrian walkways were stacked nearby.

We were off to the Venice Architecture Biennale, the remarkable collection of exhibits from many countries. I was particularly curious about how the huge show would reflect the call for resilience to rising sea levels, scarier storms, droughts, heat waves and the other deadly baggage now arriving courtesy climate change.

Venice has been sinking into its lagoon by about a millimeter a year for hundreds of years. Three decades ago Italy launched the MOSE megaproject, building gates to close three entries to the lagoon against high tides. When and how well the gates will operate still seems uncertain. Perhaps it was unsurprising that Venice’s own pavilion said little about climate change, although it did emphasize advances in predicting tides.

Among the national pavilions, mentions of climate change were rare. This didn’t reflect any lack of brilliant conceptions and designs. Strikingly, many of the most intriguing pavilions didn’t focus on new construction. The French exhibit presents 10 abandoned buildings adopted for cultural use or aiding the homeless, for example. The Egyptian pavilion dives into how street vendors capitalize on public spaces in Cairo.  Other exhibits, such as the Argentinian, do highlight natural landscapes and what’s left of them.

You could profitably spend hours in many of these intriguing spaces. I didn’t, and I probably missed a lot of serious thinking about climate resilience. I definitely although accidentally skipped the Antigua and Barbuda pavilion, which was not at the main Biennale sites but in a monastery near the center of Venice. Last year, Hurricane Irma hit Barbuda with winds over 150 miles per hour and destroyed most of the island’s buildings. All 1,800 residents were evacuated. Unsurprisingly, the pavilion’s theme centers on climate change: Environmental Justice as a Civil Right.

Giant dikes and other grand engineering projects will help us deal with climate change, but most of the heavy lifting will come from rethinking local architecture and design. The Biennale was awash in young architects from around the world, our hope for resilience.

*  Two days after I wrote this, Venice was hit by a storm bringing the worst acqua alta event in years, flooding most of the city.

In good weather, Venice is all about eye candy, not just in architecture and art.

Germ warfare

Do we need a National Institute of Anti-Infective Drugs?

MRSA meets antibiotic

Occasionally I write about the ever-encroaching threat of infections that don’t respond to our embattled arsenal of antibiotics and antivirals. The threat came closer two years ago when my son was hospitalized for days with an infection that wasn’t responding to IV antibiotics. I found myself in his hospital room talking with a surgeon about what would happen if they had to cut out the infection. (Fortunately, not.)

And the threat took another step earlier this month when Novartis joined the ranks of drug companies walking away from anti-infection research, explaining that its science was good but the business was not.

With corporations backing off, do we need a National Institute of Anti-Infective Drugs?

Jennifer Leeds, head of the Novartis anti-bacterial infection group that is being shut down, graciously responded to my question on LinkedIn with an enlightening answer:

“Maybe. The challenge isn’t only in the discovery and development space. The real challenge is in the commercial model. These are low volume, high dose, sterile drugs (therefore often high cost of goods) that sometimes have to be made in dedicated manufacturing facilities (all B-lactams do, and you can’t even mix different B-lactams classes in a single facility), for which the tolerance for pricing is extremely low given the historical low cost for antibiotics, and in many circumstances they are not reimbursed. So, show me another market where low volume, high cost, and low margin is sustainable. Oh, there isn’t one. So, yes, something needs to change.

“The problem I see with trying to ‘institutionalize’ this is that there’s a poor economy of scale in this business because of the different manufacturing needs. Unlike biologics, there really isn’t a ‘platform’ model for manufacturing. So, a National Institute would have to still invest in diverse manufacturing needs. But, it’s time for a change nonetheless. To what? I don’t know.”

Just maybe, it’s worth considering bringing the federal government into the business of making crucial but unprofitable drugs, not just antibiotics but certain pain medications and anesthetics and other “medically necessary” drugs now in short supply. That’s not impossible even in these times, when even this Congress wants to give the NIH more money.

(Above: MRSA meets antibiotic, courtesy RSCB Protein Data Base)