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.

allogeneic label

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 by the immune system.

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 the same immune-evading tricks 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)

 

Nobel art of science

Santiago Ramón y Cajal’s drawings lay out the brain in surprising detail—and beauty.

“An entire universe that has scarcely been explored lies before the scientist… Each cell presents us with the unknown, and each heartbeat inspires profound meditation within us.”

He grew up in poor Spanish hill towns near the French border, bright, impulsive, strong-willed, prone to escapades that have more than a touch of the medieval. He was endlessly curious, experimental, energetic, determined to think things through by himself. By eight years old he was drawing incessantly wherever he could, coloring his drawings with paint flaked from walls, bitterly opposed by his doctor father. He was a famously disobedient student, often beaten by teachers, once locked up by himself for more than a day. His father pulled him out of school and apprenticed him to a shoemaker for a year. He was an enthusiast and expert for drawing, painting, birds, nature walks, wooden cannons he built himself. Years later, he plunged deeply into gymnastics, chess, gymnastics, philosophy, hypnotism and whatever else caught his interest. When he grew excited by photography, he not only taught himself excellent shooting skills but developed emulsions for developing prints that were better than what he could buy. He and his father stole bones from a graveyard to help their anatomy studies. He joined the Spanish army as it fought rebellions at home and in Cuba. He survived malaria and then tuberculosis.

Such was the education of Santiago Ramón y Cajal, who became the world’s greatest neuroscientist.

He won the Nobel Prize in 1906 and is best known for his theory that nerve cells in the brain are not directly wired together but connected by chemicals—a theory not confirmed until the electron microscope debuted, decades later. He possessed an astonishing intuition for guessing at brain function based on structure, backed by an astonishing amount of hard work to reveal that structure. He couldn’t afford a good microscope until he was given one for his help in a cholera epidemic. He taught himself German, the language of biomedical science, to keep in touch with the latest findings. He published his own scientific journal when it was the only way to spread his own discoveries, which were numerous and major.

Perhaps most famously, Ramón y Cajal presented what he saw in the brain in thousands of drawings that elegantly show the brain’s wild menageries under the microscope, artwork that is stunningly created to emphasize structure and concepts. You can now see 80 of these masterpieces in the well-received Beautiful Brain exhibition at the MIT Museum.

Ramón y Cajal lived in a very different time—for instance, his autobiography has nothing but good to say about his wife but never mentions her name. He was not just genius but appealing human being. He was thoughtful, kind, wryly humorous, sociable, patient with others, resourceful, surprisingly tough, endlessly curious.  He wrote superbly on science and his own remarkable life. His aphorisms are still quoted. His lessons still stand.

“Drawing enhances discipline and attention, for it forces us to observe the totality of the phenomenon and see details overlooked in ordinary observation.”

“In our parks are there any trees more elegant and luxurious than the Purkinje cell from the cerebellum?”

“Nature is a harmonious mechanism where all parts, including those appearing to play a secondary role, cooperate in the functional whole.”

Raging hormone

Why is insulin so expensive in this country?GoFundMe insulin

We run on sugar, and sugar needs insulin to get into our cells. It’s no surprise that insulin was the first genetically engineered drug, approved by the FDA in 1982. Synthetic insulin keeps millions of people with type 1 diabetes, and a greater number of people with type 2 diabetes, alive.

Basic research keeps turning up surprises about the hormone—its starring roles in the brain, for instance, and its production by some viruses.

Drug companies mostly focus, though, on fiddling with how quickly the body absorbs it. Insulin variants that work either very quickly or very slowly are very important, but why can’t we have insulin that doesn’t need refrigeration? Or “smart insulin” that responds to blood glucose levels, first proposed when Jimmy Carter was president? Although Sanofi supports interesting projects aimed at smart insulin, as do the other market leaders Novo Nordisk and Lilly, there’s little visible progress toward the clinic.

But the biggest question about insulin is: Why is it so expensive in this country?

A 2016 study published in JAMA, for instance, showed that insulin costs doubled between 2002 and 2013. This trend is only accelerating, because there’s no price competition. Irl Hirsch, an endocrinologist at the University of Washington, summarized the story well in an ADA presentation back in 2016 and his points still apply. Year after year,  extremely profitable drug makers and pharmacy benefit managers point their fingers at each other. But as Hirsch noted, “we can point our fingers at everyone.”

New entries such as Basaglar, the first biosimilar insulin approved by the FDA, delayed by predictable patent battles but now available, don’t seem to change the story.

And the story has plenty of human faces. Among them was Shane Patrick Boyle, who died a year ago, unable to raise the money to buy insulin for his type 1 as he saved up for his mother’s funeral. Look at GoFundMe today to see similar personal pleas for help.

As with every other problem in healthcare cost, there are no simple solutions.

One new approach comes from the Open Insulin Project and similar biohacking groups that are making worthy efforts to create generic insulins. But those are  only early steps in the process, and clinical trials are too expensive to crowdfund.

You can argue that in a more rational world, the federal government would step in. Why not launch a 28th National Institute of Health that develops selected high-value high-need generics and biosimilars, brings them through clinical testing and into the clinics? Or simply control the costs of crucial drugs, lowering prices in the years after generics or biosimilars enter the market, as Australia apparently is now doing? OK, not likely. But what actually would help?