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HIP transplants for diabetes

Sana Biotechnology’s ‘hypoimmune pluripotent’ genetic engineering creates insulin-producing cells that dodge immune attacks in monkeys and mice.

Any true cure for type 1 diabetes must successfully replace the insulin-producing pancreatic beta cells that have been destroyed by the body’s own immune system, and then defend those replacement cells from that trigger-happy immune system without immunosuppressive drugs.

Clinical studies, most dramatically the Vertex Pharmaceuticals VX-880 trial, have shown that we now can generate reasonably good replacement cells via pluripotent stem cell science. And this week Vertex received Food & Drug Administration approval for a trial to test its cells in a new encapsulation device without immunosuppression.

To date, however, no such encapsulation scheme has ever worked well in humans.

Given remarkable progress in immunology and gene editing, many labs are working to modify the beta cells themselves to pass muster with the immune system.

Vertex again leads in the clinic, by picking up a collaboration with CRISPR Therapeutics that it acquired with last-year’s purchase of Viacyte. The trial with Viacyte “VCTX210” cells began dosing patients early in 2022 but apparently no results have been reported to date, which might point to limitations. Vertex’s own inhouse quest for “hypoimmune” cell therapies continues under stem cell guru Doug Melton.

This week Sana Biotechnology published encouraging preclinical results in Nature Biology for its “hypoimmune pluripotent” (HIP) cells in rhesus macaques, which often act as the final animal model for drug candidates before first-in-human trials.

Most strikingly, Sana scientists took macaque pancreatic islets (which contain beta cells and various hormone-producing buddies) and created HIP-edited versions of the islet cells. When these cells were transplanted into another macaque, they survived for 40 weeks without immunosuppression. In contrast, transplanted unedited cells quickly died.

The collaborators also generated human HIP pancreatic islet cells that not only survived in humanized diabetic mice for 40 weeks but dramatically dropped blood sugar levels.

So, how do cells get HIP?

Sana researchers, who aim to make cells hypoimmune with as few genetic manipulations as possible, modify three genes for HIP.

Like every other attempt to cloak transplanted cells from the immune system, the Sana strategy starts by turning down the expression of human leukocyte antigen (HLA) proteins that are the cornerstones of attacks from T cells and other players in the adaptive immune system. To do so, the HIP genetic engineering targets the cBM2 and CIITA genes.

Cells also need to be protected from the innate immune system, including natural killer cells and macrophages. Here, HIP builds on years of research by Sonja Schrepfer, a professor of surgery at University of California/San Francisco and a scientific founder at Sana.

As a transplant surgeon, Schrepfer saw the desperate need for better ways to prevent the body’s rejection of transplanted organs. She began pondering why during pregnancy, the fetus is not rejected by the mother’s immune system although half its proteins are from the father. That search led her to the CD47 protein, sometimes called “the don’t eat me, don’t attack me molecule,” she told me in an interview for a 2019 Knowable story. After many many experiments, HIP’s third genetic modification is to overexpress the CD47 gene.

All candidate cell therapies based on pluripotent cells that go into trials probably also will bundle in a genetic suicide switch that can be induced by a drug to destroy the cells if they turn untrustworthy. (In this case, making them terminally HIP, sorry.)

Founded in 2019 and based in Seattle, Sana belongs to the rare lofty set of startup biotechs that gathers enormous amounts of capital long before kicking off any clinical trials. In 2021, the company raised $588 million in its initial public offering. Sana develops two main types of engineered cell treatments—allogeneic (off-the-shelf) cell therapies, like those we’re discussing here, and treatments designed to heal damaged existing cells in place, an even tougher goal.

Sana’s lead HIP program is an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy for certain blood cancers, now in clinical trial. The company expects initial results this year. If successful, the CAR-T trial will be strong encouragement for the HIP approach.

Also in 2023, Sana may get early results from an unusual clinical study for patients with type 1 diabetes. This is an investigator-sponsored trial at an undisclosed European center with HIP-edited cadaveric islet cells. That’s about all we know about this trial, which doesn’t yet appear on European or U.S. clinical trial websites. As far as I know, this is the first clinical study to make such extensive genetic manipulations to cadaveric islets, which are highly difficult to acquire and typically not tremendously robust.

As we’ve been seeing, the mainstream in cell therapies for diabetes instead is cells generated with pluripotent techniques. Sana is developing “SC451” HIP-edited pancreatic islet cells and hopes to file a clinical trial application with the FDA next year.

Top image, mouse pancreatic islet cells, courtesy the James Lo lab at Weill Cornell Medicine. Second image, rhesus macaques by Mark Murchison for Tulane University.

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Climate adaptation education for all

Three Boston programs provide youths of color with thoughtful training for green jobs.

Extreme heat, jaw-dropping storms, devastating floods and other dangers growing in the climate crisis: “If you are 15 to 20 years old, this is normal for you,” says Mark Borrelli of University of Massachusetts/Boston.

That new normal comes alongside an old normal: Young people from disadvantaged communities that are at the greatest environmental risks typically get no say about those risks. And although the U.S. is now starting to generate a wealth of green jobs in the race for climate resilience, youth of color generally are among the last to see employment opportunities.

But three Boston programs are rising to the challenge. Their leaders outlined their efforts for preparing diverse groups of young people for green jobs at an Environmental Business Council of New England/Sustainable Solutions Lab session on April 14.

Starting green in middle school

“The opportunities that exist in Boston always bypass our kids and our communities unless we deliberately build bridges,” said Matt Holzer, principal of Boston Green Academy (BGA). That’s been the mission of the academy since its founding in 2011. Based in Brighton, BGA enrolls more than 500 middle school and high school students. “We represent the mosaic of Boston,” Holzer said, with more than half the students coming from low-income neighborhoods in Roxbury, Dorchester and Mattapan.

Some incoming students have never heard of environmental sustainability. “Our job is to widen their worldview and empower them to take advantage of those opportunities,” he said. “We help them have the language and the skills and the experience to talk about it and to be in the room where it happens.” The goal is not just to deliver a set of skills but to enable students to work with a purpose that makes sense to them.

BGA students quickly get out into the wild at the Blue Hills Reservation, Mattapan’s Boston Nature Center, Thompson Island in Boston Harbor and other places. “We give them mentors, we give them opportunities, we have guest speakers, their classes are focused on ecology and urban ecology–things that are germane to their experience,” said Holzer.

Beginning in ninth grade, about a quarter of BGA students enter an environmental career technology program, “a deep dive with credentials,” Holzer said. As seniors, students do paid internships. “We have to provide stipends, because they work, and we’re competing with McDonald’s,” he said.

“We are addressing economic inequality,” he said. “There’s a deliberate commitment to equity everywhere. All we are doing is trying to give our students everything that they would have if they went to high resource places without racism or economic oppression. That’s what we want. And so we’re trying to create those spaces.”

Training the unemployed and underemployed

Often when attending green workforce development meetings, “I’m the only one that looks like me,” said Davo Jefferson. “So we’re trying to expand on that.”

Jefferson is executive director of PowerCorpsBOS, a green jobs program for young adults that the city launched last year. “It’s a six-month program targeted towards opportunity for folks in Boston age 18 to 30, who are generally not on a higher educational career track, typically unemployed or underemployed,” Jefferson said.

Based on a successful Philadelphia program, PowerCorpsBOS graduated its first class of 21 in December. Participants are paid each week and given a monthly T pass. PowerBOS offers two professional tracks, urban forestry and energy-efficient building operations.

Urban forestry might not seem the most obvious job entry point. “For many young folks from the communities that we’re recruiting from, trees are not on your radar,” Jefferson said. He noted that one street in the Dorchester neighborhood where he grew up lacks a single tree.

But the need for trees grows ever more obvious with climate change, and PowerCorpsBOS training supports the expansion of Boston’s urban tree canopy, particularly urban wilds like Buena Vista in Roxbury, above.

The program builds toward certifications in OSHA safety measures, first aid, pesticide application, energy efficient building operations, and other relevant skills. Training takes a village: inhouse experts, project partners from other city agencies, contract trainers and especially potential employers.

“Students receive professional skills training, which consists of things like time management, workplace etiquette, conflict resolution, working independently and on teams,” Jefferson said. They also get help finding and keeping jobs: resume building, job search techniques, networking, interview preparation, keeping the job and moving up in their careers.

Crucially, Jefferson said, PowerCorpsBOS also offers support mechanisms to help trainees navigate life obstacles they may be encountering, including assistance with housing, childcare, legal issues, obtaining vital documents and other stumbling blocks.

Creating climate ambassadors

Last summer a month-long program led by the University of Massachusetts/Boston turned 15 high school students into climate ambassadors, doing field research on extreme heat in Roxbury.

The program is a cooperative effort with the Boston Planning & Development Agency, Boston public schools and Roxbury Community College.

“The intent here was to encourage youth of color to consider public sector careers,” said Alan Wiig, associate professor of urban planning and community development at UMass. “And then through that, to do a project that would reinforce resident-led and city-supported efforts to address extreme heat in lower Roxbury.”

“We wanted a real-world project that would pull us out of the classroom and into the city,” said Wiig, “and would focus on a critical issue that’s confronting the community that these youth live in… Perhaps most importantly, in my opinion, it was a paid work experience that they could put on a resume.”

In addition to classroom studies, the group took weekly field trips at places ranging from Boston Harbor to City Hall. In the field at Roxbury’s Nubian’s Square, they managed to perform 109 interviews in 75 minutes. Residents generally were happy to talk with the teenagers, and agreed that extreme heat is a serious problem in the neighborhood.

A week after those interviews, the students measured air temperature at 26 locations in Roxbury on what turned out to the hottest day of the year around the world. Boston’s official high point, measured at Logan Airport, was 89 degrees. “However, in lower Roxbury, the findings were 10 degrees hotter and in some cases 20 degrees hotter,” Wiig said. “That speaks to the effect of urban heat islands, and how uneven [heat] is across neighborhoods like lower Roxbury that lack shade trees.”

Surprisingly, parks and playgrounds were particularly hot. This summer, the program expects to enroll about 40 students and work with Boston Parks & Recreation to redesign two parks in the neighborhood.

Another surprise was the high student interest in getting jobs as climate ambassadors. “This isn’t something that myself and other professors thought of; this is something that the teenagers thought of themselves,” Wigg said. These young people could conduct outreach to connect residents with the resources to adapt to extreme heat and other climate stressors, and they could act as advocates to City Hall and the State House, he said.

Like other speakers at the session, Wiig emphasized the critical need for programs and people to stay engaged with their students over the long run. “We need to commit to 10 years of mentoring with the same group of youths,” he said.

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Creating the next cell therapies for diabetes

As new encapsulation devices go on trial for type 1 diabetes, Vertex’s Doug Melton polishes strategies for insulin-producing cells that guard themselves against immune attack.

Two cell therapy candidates for treating type 1 diabetes took visible steps forward last week. Vertex Pharmaceuticals received Food & Drug Administration approval for a clinical trial of its VX-264 therapy, while Sernova announced that two patients in an ongoing trial received transplanted pancreatic islet cells in an upgraded version of its Cell Pouch capsule.

Vertex’s ongoing VX-880 clinical study, which combines stem-cell-derived islet cells with immune-suppressing drugs, in 2021 “cured” one patient of type 1 diabetes for at least several months. This drew great attention as the first clinical proof that stem-cell-derived islet cells could do useful work.

The VX-264 therapy now given an FDA green light employs the same cells but packages them in a surgically implanted “channel array” device. A VX-264 trial is already underway in Canada. The company expects to recruit about 17 volunteers globally.

As far as I know, Vertex has not released details on this device but it is based on an approach that began in the startup Cystosolv, which was acquired by Semma Therapeutics, which then was bought by Vertex. (Above, images of the approach in one perhaps-still-relevant patent.)

Sernova’s therapy is implanted in three steps: The Cell Pouch is surgically inserted, followed by two rounds of islet cell implants. The company expects to release interim results for this second cohort of patients by year-end. Its treatment uses cadaveric donor cells; Sernova plans to move future candidates to stem-cell-derived cells.

Also last week, Doug Melton outlined his research towards the next generations of stem-cell-drived cells during an American Diabetes Association webinar.

Melton, who led the development of stem-cell-derived insulin-producing beta cells for more than 20 years at Harvard and is on leave at Vertex, focuses on two main challenges. First, gaining complete mastery over cell composition. Second, eliminating the need for systemic immune suppression.

His group is bringing large-scale genetic screening to the job. “We can knock out one gene at a time in the embryonic stem cell stage, and then look for genes which improve composition or provide immune protection,” Melton said. “We’ve identified pathways that I had never thought about as being important for beta cell formation.”

He believes that optimal cell therapies will include the right mix of various types of hormone-producing pancreatic islet cells, not just the insulin-producing beta cells. Similar amounts of alpha cells, which produce glucagon that counter-acts insulin, also seem good. Additionally, there may be a helpful much smaller role for the delta cells that generate somatostatin, which inhibits the release of insulin, glucagon and other hormones. Other cell types should be weeded out.

While much work remains ahead, “we’re on the path to having complete mastery over the final composition of the stem-cell-derived product,” Melton said. “Now, how do we deal with this annoying immune system?”

Here his goal is genetically modified islet cells that provide some immune evasion, if not complete immune tolerance. Melton acknowledged that immunologists roll their eyes when he mentions immune tolerance, the Holy Grail for such therapies, but insisted that it may be achievable.

Many labs have pursued many ways to modify cells that might aid in dodging immune attacks. The standard method to evaluate these strategies for type 1 is by injecting candidate islet cells into an immuno-compromised mouse that models the disease. (“There’s no way in which it reproduces what happens in a human type one diabetic,” Melton acknowledged. “Nevertheless, it’s a start.”)

“There’s nothing novel about this approach,” he commented. “The novelty comes from figuring out what is the right combination.” In one early but encouraging achievement, published in a January Cell Reports Medicine paper, one combo (below) engineered by his Harvard group greatly improved mouse survival over nine weeks.

In a separate Vertex effort based on its acquisition of Viacyte last year, the giant biotech is already enrolling patients for a clinical trial of VCTX-211, a “hypoimmune” cell therapy Viacyte created with CRISPR Therapeutics.

May all of these efforts point toward a real cure.

“My dream would be that when a young child is diagnosed with type one diabetes, the endocrinologist says, I’m sorry for you and your family, but I have good news for you,” Melton said. “I have here in my freezer some cells which will control your blood sugars, and your body won’t reject them for a long time. I’m going to inject them into your belly. And good luck, get back to kindergarten!”

“That sounds like a dream, and it is sort of a dream,” Melton added. “But I don’t see any reason we shouldn’t aim for that.”

P.S. Decades of experimentation with encapsulated cell therapies have not been encouraging. But Sigilon Therapeutics, another contender, hopes to ask the FDA next year to approve a type 1 trial with its “Shielded Living Therapeutics” 1.5mm alginate spheres. Sigilon argues (below) that its capsules will guard islet cells better than any modification of the cells themselves.

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Cell help for diabetes

Clinical trials designed to cure type 1 diabetes with insulin-producing cells derived from stem cells are slowly ramping up.

Our best hope for curing type 1 diabetes is transplants of insulin-producing pancreatic beta cells created from induced pluripotent stem cells (iPSCs). So how’s that quest going? Some recent highlights:

The lead player is Vertex, whose VX-880 clinical trial has produced encouraging preliminary results. The Boston biotech giant is enrolling a few more patients for this study and seeking FDA approval for another trial that would protect the transplanted cells not with the usual immunosuppression drugs but within a protective device whose design has never been published.

Vertex bought Viacyte, the first major player in cell therapy for diabetes and Vertex’s most likely competitor, in September. Viacyte had partnered with CRISPR Therapeutics on the first-ever trial with beta cells that had been genetically modified to minimize the need for immunosuppression. I haven’t seen any public update on the status of that trial, which had planned to recruit 40 volunteers.

In November, the FDA gave Sernova of London, Ontario a thumbs-up to recruit up to seven more patients for the type 1 trial of its Cell Pouch system. “The Cell Pouch is made of cylindrical chambers of polymers with removable plugs that are implanted against the abdominal muscle and become wrapped with blood vessels,” says the company. Surgeons then remove the plug and transplant islet cells (beta cells and their hormone-producing pancreatic neighbors). These cells will come from human cadavers, the default source until now. The latest trial recruits will be given an updated version of the Pouch. Sernova expects to release early clinical results for that cohort this year.

iPSC-derived pancreatic islet cells manufactured by Evotec in Hamburg, Germany, will replace the donor cells in Sernova’s next clinical trials. The two companies plan to seek regulatory approvals for this round in 2024.

Sernova also is working with the lab of Alice Tomei at the University of Miami on a way to shield transplanted islet cells against immune system attack with a “conformal coating” of hydrogels that encapsulates the cells. This procedure has an encouraging history of results with animal models.

With iPSC-derived cells now commercially available from Evotec and other suppliers, solving this immunosuppression puzzle seems to be the one remaining (huge) barrier to successful cell therapies for type 1 diabetes. It’s particularly tough in this illness because the immune system is already fully geared up to wipe out the patient’s own beta cells.

Startup firm iTolerance is taking another approach to protectively wrapping the transplanted cells, with a technique that performed well in a study of macaque monkeys over six months. The strategy is based on a protein called Fas that is expressed on the surface of T cells; those cells die if a Fas ligand (FasL) protein binds to the Fas protein.

The researchers whipped up a dual-protein combination of FasL and streptavidin, a protein that dampens T cell activation and proliferation. These protein combos were attached to microgel beads, then mixed with islet calls “and then transplanted to a bioengineered pouch formed by the omentum—a fold of fatty tissue that hangs from the stomach and covers the intestines.” (Yes, it’s hard to visualize the omentum; islet transplants traditionally have gone into the liver.)

This work was a joint project among investigators at Georgia Tech, the University of Missouri, Massachusetts General Hospital and other institutions. Camillo Ricordi of the University of Miami, a prominent pioneer in diabetes and cell therapy studies, is chief scientist for the Miami-based iTolerance.

Delivering FasL locally like this should work out better than genetically modifying islet cells to over-express the protein, which doesn’t always work out in immunosuppression experiments, the researchers suggested.

But other approaches to gene therapy for immunosuppression keep marching ahead. One group is targeting the A20 protein, which is “like a thermostat for the immune system; it can turn it down to a simmer, or ramp it up to be more aggressive,” according to Shane Grey at Sydney’s Garvan Institute of Medical Research.

Grey and colleagues have followed this track for many years, with promising early results for diabetes in mice, and in human and pig cells. “The genetically engineered cells seem to re-educate the immune system to accept the transplant as self,” Grey commented in a news release. “The transplant can tweak the whole immune system.” The Royal Adelaide Hospital in Adelaide, South Australia will kick off a trial with A20-enhanced islet cells in mid-2024.

Perhaps more dramatically, this month stem cell maestro Doug Melton and co-workers published research on a Swiss army knife approach to genetically modifying human islet cells to become “immune-tolerizing”. The scientists modified the cells to target human leukocyte antigens (keystones in activating T cells) and the PD-L1 immune checkpoint protein and to secrete three cytokines that help to recruit regulatory T cells to protect the transplanted islets. This seemed to work quite well in humanized versions of the standard mouse model for type 1 diabetes.

“Overall, our approach may eliminate the need for encapsulation or immunosuppression, a longstanding goal of the islet transplantation field,” the researchers wrote. Maybe it’s no coincidence that Melton announced plans to take a leave from Harvard to join Vertex last April, just about the time this paper was submitted.

About 8 million people worldwide live with type 1 diabetes, with half a million more diagnosed each year. So says the Type 1 Diabetes Index, which predicts this population will soar to more than 13 million people by 2040. (And maybe 10 times more people with type 2 diabetes will need insulin by then.) Let’s hope that actual cures will be widely available and affordable many years before that.

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The race to rebuild living shorelines

Along the New England coast, recreated ‘nature-based systems’ such as salt marshes will boost resilience to the rising sea—when we figure out how to build them at scale.

The idea behind “living shorelines” engineering is straightforward: Natural defenses such as salt marshes and oyster reefs often can guard vulnerable stretches of coastline better than seawalls and other forms of gray infrastructure, and help to restore endangered coastal ecosystems at the same time.

Case in point: An eroding sandy bluff above Narragansett Bay in East Providence’s Rosa Larisa Park. Concrete walls weren’t stopping the bluff’s erosion, said Leah Feldman of the Rhode Island Coastal Resources Management Council at a December 9 meeting on nature-based adaptation in Boston. In contrast, two living shoreline measures, a salt marsh planted with Spartina cordgrass (above) and a bank stabilized with coir logs and beach grass, are performing well.

However, despite a sprinkling of early success stories like this one, “there’s hardly any practice of living shorelines in New England,” said Alison Bowden of the Nature Conservancy at the meeting, which was sponsored by the Environmental Business Council of New England and the Sustainable Solutions Lab at UMass Boston. “So why is that and what are we going to do about it?”

She pointed to two holdups specific to New England plus two barriers on the federal level.

One nagging problem is the common doubt that nature-based approaches can deal effectively with the rigors of our coastal environment—the short growing system, ice and high tide range. But believing that a salt marsh that has withstood every storm for thousands of years is less resilient than a wall “is kind of nuts,” Bowden remarked. “Does anybody think a seawall will have a 6,000-year design life?”

Another big hurdle is that each New England state ignores the national wetlands permitting process and sets its own rules. The resulting lack of design standards endlessly complicates regulatory reviews. (Bowden and many allies took on this challenge in a regional analysis that drew lessons from 15 projects.)

At the federal level, the Clean Water Act was written in the 1970s primarily to keep developers from fouling up bodies of water. That goal made a great deal of sense at the time, but the lawmakers didn’t imagine today’s needs to restore badly damaged ecosystems and to protect against the ever-more-obvious effects of climate change. “I’ve spent a good part of my 21 years at the Nature Conservancy working on figuring out how to get the regulatory environment to let us do things like dam removal and salt marsh restoration,” said Bowden.

Moreover, federal regulatory reviews focus on protecting what is there today rather than what may be there in a few decades. “We can’t really keep what we have over time,” Bowden emphasized. Instead, we need to think carefully about tradeoffs—like, when does it make sense to work toward an ecosystem that’s healthy but not the original ecosystem?

This question already looms for Belle Isle Marsh, Boston’s last salt marsh (above), which doesn’t have much room at all to migrate inland to accommodate rising sea levels.

Better planning for such environmental puzzles needs better data. And while coastal engineers can tap into many decades of information about seawalls and other gray infrastructure, relatively little is known about the performance over time of living shoreline engineering with our region’s salt marshes, oyster reefs, dunes, beaches or seagrass meadows.

Small pilot projects such as Rosa Larisa Park are starting to fill in the gaps, but truly scaling up will demand information we just don’t have. Gathering that knowledge is the mission of Boston’s Stone Living Lab, now conducting a wide range of experiments with various partners. Perhaps SLL’s most intriguing project is to try defending the eastern shore of Rainsford Island (above) with a combination of rocky reef and cobble berm.

The most spectacular living shorelines initiative on the U.S. Atlantic coast, New York’s $107 million Living Breakwaters project (below), also is producing a flood of data.

Scheduled to wrap up construction by 2024, this project on Staten Island, which was the epicenter of drownings in Superstorm Sandy, is designed not to keep the ocean entirely out but to reduce storm risk, enhance ecosystems and foster social resilience along the coast. The centerpiece is a half mile of near-shore breakwaters that not only will bring down storm waves but capture sediment and build the shoreline back, said Pippa Brashear of SCAPE, the lead designers.

The breakwaters aren’t oyster reefs but are carefully crafted to be similarly hospitable to marine life. “Like any good designer, you ask, What does my client need?” Brashear said. “In this case, we were asking how fish, crabs, lobsters and benthic invertebrates will use this.”

Across the country in San Francisco Bay, the Oro Loma Living Laboratory presents another innovative take on living shoreline studies. Built in 2018, this research platform examines “horizontal levees” that install a broad wedge of wetland between a levee and the bay (below, left to right).

“The idea behind the horizontal levee is that you can provide flood protection through a natural system, while also treating wastewater within that system,” said Heidi Nutters of the San Francisco Estuary Partnership. “The freshwater input can also increase the plant growth and improve success of restoration just by having water at the site. And the brackish marshes can build organic soils and help keep pace with sea level rise.”

The Oro Loma lab has demonstrated that microbial processes at work below ground in the wetland wedge can remove contaminants such as nitrogen from treated wastewater. Investigators now are testing the levee on highly saline water trucked in from a desalination plant.

Down on the Gulf Coast, Bowden and colleagues analyzed Google Earth images to make a striking finding about Hurricane Michael, which hit the Florida panhandle in 2018 as the first category 5 hurricane to make landfall in the U.S. in almost 30 years. “Pretty much no gray infrastructure survived,” she said, but only 2% of the salt marshes in the study area were damaged.

“That’s a pretty impressive performance on the part of nature,” Bowden remarked. “Natural processes know how to stand up to nature, and we need to learn from them… to help us as the climate changes.”

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Costing out a cure

As Vertex buys Viacyte, is that good news for people with type 1 diabetes?

For 20 years I’ve been rooting for Viacyte, the pioneering startup in growing insulin-producing cells for transplant into people with type 1 diabetes.

Founded in 1999 as Novocell, the San Diego company began its research with human embryonic stems cells rather than the not-yet-discovered induced pluripotent stem cells (the cells re-engineered from adult cells that quickly became the most likely source of stem cell therapies).

Viacyte launched its first clinical trial in 2014 and has doggedly moved ahead in many attempts to optimize its cells and the enscapsulation devices designed to hold the cells. Last month, one patient in a trial finally showed clear clinical benefit, although on immunosuppression drugs.

This month, though, Viacyte announced it will merge with Vertex Pharmaceuticals, its major rival, in a $320 million cash deal.

Based in Boston’s Seaport (above), Vertex is a very different biotech, selling $7 billion of cystic fibrosis drugs each year. In 2021, Vertex’s net income was 31% of revenues and the company was sitting on $7.5 billion in cash.

Vertex broke into the diabetes field with the $950 million acquisition in 2019 of Semma Therapeutics. Semma was a well-funded startup built on research by Doug Melton, Harvard superstar of stem cell research. Melton, who joined Vertex this spring, told me back then that the problem of churning out functional insulin-producing cells in volume had been solved. Melton also was impressed with a “very clever and effective” encapsulation device that Semma was quietly polishing.

Viacyte holds many patents but its encapsulation devices have never lived up to our hopes, and Vertex already owns the world’s most advanced technologies to churn out insulin-producing cells. So it seems that Viacyte’s highest technology card probably is progress in genetically modifying insulin-producing cells to dodge attacks from the immune system, done in partnership with CRISPR Therapeutics.

In February, the two companies announced that a volunteer in a clinical trial had received such genetically redesigned cells. This was a “historic, first-in-human transplant of gene-edited, stem cell-derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression,” commented James Shapiro of the University of Alberta, an investigator in the trial and world expert on such matters.

Melton has been working on such immune-dodging-cell techniques for years, and Vertex was an early investor in CRISPR Therapeutics. But knowledge gained from the Viacyte/CRISPR trial can only help.

However, my guess is that Vertex mostly bought the smaller firm to take out its leading competitor, and that this move eventually will bring higher pricing for patients.

Case in point, Vertex’s lead cystic fibrosis combo costs almost $300,000 a year.

In 2020 the Institute for Clinical and Economic Review (ICER), a well-respected Boston non-profit that analyzes cost-effectiveness for prescription drugs, took a look at Vertex’s suite of cystic fibrosis products. Among ICER’s findings:

“Despite being transformative therapies, the prices set by the manufacturer – costing many millions of dollars over the lifetime of an average patient – are out of proportion to their substantial benefits. When a manufacturer has a monopoly on treatments and is aware that insurers will be unable to refuse coverage, the lack of usual counterbalancing forces can lead to excessive prices. Patients who receive the treatments will benefit, but unaligned prices will cause significant negative health consequences for many unseen individuals.”

That’s Vertex’s current economic model. That’s my worry.

True, diabetes unlike cystic fibrosis is not a rare disease. Something like 1.9 million people in the U.S. have type 1 diabetes, which makes it more than 50 times as common as cystic fibrosis. And most insulin actually goes to people with type 2 diabetes that can’t be managed well by other medications, who would also be candidates for cell treatment.

So, given this widespread need, would diabetes be different? The sad story of insulin, which people with type 1 need to stay alive, says not.

Insulin has been available around the world for decades and costs maybe $3/vial to manufacture. But about one in four people dependent on insulin in the U.S. go through periods when they can’t afford the surprising high pricetags for the drug, whose lack immediately puts those folks at truly serious risk. A small number of them die.

Lilly, Novo Nordisk and Sanofi see that situation as a minor public relations problem. And despite an ever-expanding public chorus of cries for cheaper insulin, insulin provisions magically disappeared last week from the pending Senate bill on medications.

Moreover, in a problem extending far beyond the realm of diabetes, nobody knows what limits will be set on costs for cell therapies, those shiny super-powered new kids on the block.

Partly the charges for these treatments will be based on actual effectiveness and value, as per ICER analyses. Beyond that, we might expect biotechs to follow the classic pricing strategy here: charge as much as you can while keeping a straight face. In preliminary public discussions of pricing, cell treatments often are lumped together with the gene therapies that generally seem to cost more than a million bucks.

My guess is that Vertex will create successful cell therapies for type 1 diabetes in my lifetime. My hope is that everyone who desperately needs these therapies can afford them. I’m a little less hopeful now.

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Game-changing museums

Playful approaches let visitors engage better with museum content and each other.

As museums struggle to break free of the pandemic, they are unleashing fun and games on the world.

We may picture museums as venerable repositories of static objects that are embedded in glass cases or hanging on white walls, perhaps explored in a guided tour. But institutions big and small are adding dramatically more personalized programs to engage their visitors–some very simple, some very complex, some tightly based in the real world, some not.

Last week’s Museums, Games and Play Summit, a virtual global gathering held by MuseumNext, highlighted dozens of such initiatives. Their goal is not only to broaden and deepen the museum experience but to draw in people who don’t visit–among them, millions of young people who enthusiastically play online games but don’t know how to play a museum.

“It’s a new kind of participatory storytelling,” commented Erica Gangsei of the San Francisco Museum of Modern Art. Offerings such as the Tate Modern’s team card game and the New York Hall of Science’s Connected Worlds have been proving themselves for years, Gangsei said, but we’ve moved beyond the pioneering stage.

Group games can connect visitors not only with museum content but with each other. “Through collective activities we find meaning and happiness,” said Rachel Briscoe of Fast Familiar, a London developer of “audience-centric” theatre. “Collective experience is an excuse for people to talk to each other… Games are the ultimate collective experience.”

Take the Acquisition Panel, “a serious play game where a group of strangers take on the role of an advisory board to a local museum, helping them to decide which objects to acquire and what stories to tell about them,” Briscoe said. “Over 90 minutes, participants hear a range of different perspectives on a single object, which becomes a prism through which to examine the legacies of European colonialism and to ask what role we want museums to play in our society. A group of strangers wrangle together with big complex questions. The last time we did the show, we had someone say, I’d much rather do this than go to a museum, because the experience helped him go deeper, and allowed him to hear the perspectives of other people with different experiences.”

Another Fast Familiar showcase was the Life Course Golf Course, a version of the Life board game focused on health. Participants played minigolf, given quite different golf balls, and those differences affected their healthcare experiences as they moved down the course. Why minigolf? Conversations open up when you’re busy doing something. (“It’s easier to have conversations when walking because it’s difficult to eyeball someone,” Briscoe points out.) Also, players don’t have to worry about how they’re appearing in public. (“You can’t look particularly stupid playing minigolf.”) And if they just want to play the game, that’s perfectly all right.

Tabletop role playing, basically games based on printed material with a set of well-known rules, provides another flavor of group experience. Take Carved in Stone, “a project showcasing the rich and complicated landscape of 7th century Scotland… allowing you to truly play as Picts.” The crowdfunded book is a collaboration among experts from Dungeons on a Dime and Dig It! (“a hub for Scottish archaeology”), writers, artists and other talented folks. “In reality, the Picts were a diverse range of farmers, hunters and gatherers, bards and poets, creators and carvers, and all sorts of professions that in a story like Dungeons and Dragons would be background detail,” said Jeff Sanders of the Society of Antiquaries of Scotland. “The way that we’re trying to get people to explore the past is through being these regular people and going on exciting adventures as regular people.”

Location-based augmented reality (AR) technology can offer new experiences. Most of us first heard about such AR apps in 2016 with the Pokemon Go game; your phone lets you interact with objects in front of you. “It’s not just the reality that you see, but it’s an overlay of reality,” said Sarah Burslem of Niantic, which built Pokemon Go.

Niantic now offers the Lightship software platform, designed to make it dramatically easier for organizations to deliver AR apps. Britain’s Historic Royal Palaces and Science Museum both plan to roll out Lightship-based AR offerings this year. The AR environment is a nice match for outdoor settings or for other spaces such as historic rooms that would have been mostly populated with people rather than objects in glass cases, noted Cathy Spalding of the Royal Palaces. An AR experience will enhance this summer’s Superbloom, which will celebrate the Queen’s platinum anniversary by filling the Tower of London moat with flowers.

EPIC, the Irish Immigration Museum in Dublin, was born completely digital. “We are actually a museum of digital stories,” said EPIC’s Shannon Wilson.

Especially stories entered as games. In our media-saturated societies, “humans are now preconditioned towards gamification media since birth,” she remarked. “Gaming, when used with thought and consideration, can directly and positively augment the impact of the experience to make it more meaningful, closing the gap between the past and the present.”

“There’s still a gap between representing the past and understanding it, between learning about history and experiencing it, and between sharing people’s stories, and empathizing with them,” Wilson said. “And this is something that I believe gamification can tackle, due to its immersive nature, by positioning visitors as active players in history they experience rather than just playing witness to it.”

One EPIC story is a life-size electronic version of an 1890s board game based on the 72-day round-the-world adventure of Nellie Bly, the trailblazing investigative journalist.

“More complex information can be communicated and understood more easily by different age groups through gamification,” Wilson claimed. “This is because there are no explicit barriers to engagement, as there might be in more traditional museum exhibits, which rely on a certain level of reading ability.”

“Gamification by its very nature is a social enterprise that encourages teamwork and competition, as players either work together or compete in order to complete a task,” she said. “Encouraging visitors to work together, they bond. And they create shared and lived memories and experiences, in effect, changing the association of museums from solitary and academic to social, vibrant and immersive spaces.”

EPIC has won the World Travel Award for Europe’s Leading Tourist Attraction three years running. Who doesn’t want to visit?

But Summit speakers emphasized that it’s also critical for museums to remember that children in particular play and learn wherever they are with whatever they find around them.

“We don’t have to create a specific area for children to play,” said Claire Hargreaves of the British National Museum of the Royal Navy in Portsmouth. “Believe it or not, children will play anywhere.” Quick exercises like silly selfies can make a museum visit more fun for children and their families, at little or no cost to the museum.

Moreover, there’s a powerful and almost subversive message here for museums, schools and everywhere else: “It doesn’t matter if it leads to learning, play in itself is enough,” Hargreaves said.

“Play is the genius pleasure mechanism that drives children to assimilate everything that they see, hear, think or feel, to understand their minds and their bodies, to discover who they are, and what their special talents and passions are,” said Penny Wilson of Assemble Play. “Almost all of us can trace back to our childhood play a legacy that’s still alive and kicking in our adult life.”

“But over the last decades, play has been adulterated, colonized by adults,” she declared. “We ignore the fact that children experience infinite possibilities when they are left to play. Accepting instead the fallacy that at all times an adult should be in charge, using play to teach or train or control or reward, all on grown up terms reducing its potential, free play is being slowly annihilated.”

Wilson and her allies create pop-up playgrounds “supported with light touch by experienced play workers, and furnished with carefully curated loose parts to offer the richest possible play environment,” she said. “Parents stay, taking the time to relax and enjoy the great privilege of watching their children playing, finding out about their brand new world. We like to work in unusual spots in the public realm, creating a spectacle that adults coming across this powerful, beautiful and rare phenomenon realize that they haven’t seen for years.”

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Type 1 diabetes goes on trial

2022 will offer many clinical clues on cell therapies for insulin-dependent disease.

This year might be make or break for several ambitious cell therapies designed to treat type 1 diabetes, a thoroughly puzzling and dangerous disease. Some clinical projects to watch:

Viacyte and CRISPR Therapeutics are launching a Canadian trial that will be the first in humans with insulin-producing beta cells that are genetically re-engineered to dodge the immune system with little or no immunosuppression drugs.*

Viacyte has been plugging away valiantly on therapies with beta cells derived from stem cells for more than 20 years. Results have been mixed. Most recently, two papers published in December showed partial success with partially differentiated pluripotent cells embedded in Viacyte’s latest capsule (above left), which is open to blood vessels and requires immunosuppression.

“It is the first reported evidence that differentiated stem cells implanted in patients can generate meal-regulated insulin secretion, offering real hope for the incredible potential of this treatment,” said James Shapiro of the University of Alberta, lead author on a Cell Reports Medicine paper. But only six of the 17 subjects in the study showed signs of significant insulin production and no clinical benefit was demonstrated, although that goal apparently was achieved for one subject enrolled later in the trial.

CRISPR Therapeutics will bring its genetic editing wizardry to create allogeneic (off-the-shelf rather than individually tailored) beta cells for the Canadian trial. The company first deployed this strategy in CAR-T cells, treating patients with B-cell blood cancers with allogeneic T cells. First results for the CAR-T trial appeared in October in a news release rather than a peer-reviewed paper. My non-expert guess is that the allogeneic engineering tricks worked fairly well, with the obvious caveats that blood cancers are very different from diabetes, these are very early days, and the type 1 autoimmune attack takes no prisoners.

This first generation of off-the-shelf-we-hope CAR-T cells combines tweaks to T-cell-specific proteins with removal of one class of major histocompatibility complex (MHC) proteins, which help T cells distinguish your own cells from outside threats. CRISPR Therapeutics may make additional immune-dodging engineering changes to its beta cells, among them immune checkpoint proteins (which reassure T cells that the cell is a good citizen) and/or suicide genes that can wipe out the cells if they go wrong and an otherwise non-toxic drug is administered.

Vertex Pharmaceuticals continues its early trial of stem-cell-derived beta cells with immunosuppressive drugs, which did restore one patient with type 1 to relative normality, which was mislabeled as a cure by the NY Times.

This year the large biotech hopes to launch a followup study that would package these cells in a capsule to bypass or minimize the need for immunosuppression drugs. The capsule builds on implantable device research acquired along with cell technology based on discoveries in Doug Melton’s Harvard lab when it bought Semma Therapeutics in 2019. “Semma has developed a very clever and effective encapsulation device,” Melton told me then. Details on the device or its performance aren’t public although there may be hints in Vertex patents (see one image from a patent application below).

Last week Sernova announced early results of a trial with its “Cell Pouch” (above right). Two participants achieved insulin independence, one of them for more than 21 months. “We believe Sernova is the first company to report that its first two transplanted T1D cell therapy study patients achieved sustained insulin independence,” said chief executive Philip Toleikis. The trial used immunosuppressive drugs and islet cells (clusters of cells in the pancreas that include beta cells and other hormone-producing cells) from cadavers (rather than the stem-cell-derived cells that are becoming available in vastly greater quantities).

“The Cell Pouch,” Sernova says, “is designed as a scaffold made of non-degradable polymers, formed into small cylindrical chambers which, when implanted in the abdominal wall, becomes incorporated with tissue and microvessels to the circumference of removable plugs within as early as two weeks as demonstrated in preclinical studies. After the tissue incorporation, the plugs are removed, leaving fully formed tissue chambers with central void spaces for the transplantation of therapeutic cells.”

2021 was not a good year for another corporate contender in encapsulated cell therapies, Sigilon Therapeutics. The FDA stopped the clinical trial for its lead candidate for hemophilia and then Sigilon found that in one trial participant its cell-holding microcapsules were becoming covered with fibers. Last fall, the company put hemophilia on hold and laid off more than a third of its employees. Sigilon is still partnering with Lilly on type 1 diabetes but there’s still no FDA approval for a clinical study.

Over in academia, scientists at the University of Miami are continuing a trial in which pancreatic islet cells are transplanted into the eyes of people with type 1 who are legally blind in at least one eye. The transplant will go in between the cornea and the iris, a location that seemed promising in animal tests. Recipients will get immunosuppression drugs, but “we believe the eye can confer some benefits that favor long term islet survival and, if we can demonstrate this concretely and over time, we may be able to reduce the anti-rejection drugs,” the researchers say. There’s been some question as to whether this location offers enough space for a sufficiently large transplant for diabetes; one experiment in a monkey suggested that it may.

And one more contender: James Shapiro of the University of Alberta, quoted above re the Viacyte trial, pioneered the Edmonton islet-transplantation protocol that proved cell therapies could work for type 1 diabetes. He is a major figure in the field, involved in a surprisingly broad spectrum of lab and clinical work. I was happy to interview him last year for a Nature story about ramping up cell therapies based on stem cells.

Shapiro and his colleagues are enlisting five participants for a small clinical trial somewhat along the lines of Sernova’s pouch, except without the pouch. That is, the transplant site is prepared in a separate procedure before the transplant. PubMed tells me that Shapiro was leading research in mice for both this concept and the Sernova approach a few years back.

The Shapiro lab’s device-less transplant method “was designed to harness an innate foreign body response in a favorable and controlled manner, to induce growth of new blood vessels to allow the survival of the insulin producing cells without the natural body response to foreign body. Briefly, this site transforms the inhospitable under-the-skin site into a viable location through the temporary implantation of a small tube called an angiocatheter.”

Will such a seemingly simple method work in humans? Let’s hope so. And let’s hope for the best with all the other attempts.

* The first patient in this Viactye/CRISPR Therapeutics trial now has been dosed.

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Winding up the gigawatts

Offshore wind is blowing past the barriers for renewable energy–the technical barriers, anyway.

The U.S. aims to gather 30 gigawatts of power from offshore wind fields by 2030, one enormously ambitious goal. On the technology side, the biggest challenge is bringing the power ashore and integrating it into our not terribly robust existing power grids, while our demands for electricity soar.

But for the wind turbine technology itself, the U.S. can tap into the rapid advances in largescale wind farms globally. That’s what we heard from Danielle Merfeld, chief technology officer for GE Renewable Energy, at a forum on offshore wind sponsored by the National Academy of Engineering’s Gulf Research Program.

Largescale, yes. In fact, today’s turbines are “the largest moving machines humanity has ever built,” Merfeld remarked. “A 15-megawatt offshore wind turbine is on the scale of the Eiffel Tower.”

Manufacturing these monsters is obviously more than tricky. GE’s latest turbines have 107-meter blades, as long as a football field with endzones. “We have to think in a completely different way to be able to efficiently manufacture these blades,” she said. The nacelles, which draw energy off those spinning blades, are correspondingly huge (top right).

Installing the gargantuan machines at sea will be no easy task. There are very few of the required jackup boats (below left) and none under the U.S. flag. Offshore field developers will need many jackups to get anywhere close to the 30GW goal. “And by the end of the decade, some of those vessels will be obsolete because we’ll move to even bigger systems,” Merfeld commented.

Additionally, offshore wind fields more than 30 miles from shore shore will want to run DC power cables. That calls for an AC-to-DC conversion platforms, perhaps as tall as a 15-story building and as wide as a football field, built onshore and towed out to sea. “These are, again, big engineering challenges,” Merfeld said.

Turbines also typically require five or more maintenance visits a year, she said. GE’s new Jules Verne (below right) is a high-tech “service operation vehicle” designed to hang out on a wind farm for days to handle everything from lubricating moving parts to replacing blades.

These giant structures bring significant environmental worries above and below the sea. Early experience with the five GE turbines installed off Block Island suggest that turbines do act as artificial reefs. “There was a tremendous amount of increase in sea life activity, so the fishermen were happier than they thought they were going to be,” Merfeld claimed.

The humongous blades remain big threats to migrating birds, but operators are learning ways to reduce the killing. “Some of it is in the siting,” she said. “You don’t put a wind farm in the middle of a migratory lane for birds, or you turn [the turbines] off during certain migratory periods where you need a week, or even days or hours of the night or day when you expect [birds] to go through.” New mitigation approaches may help. A study last year found that painting one blade black can reduce bird strikes by more than 70%, she added.

All these engineering and environmental demands will be topped by offshore wind’s tough economic, regulatory and political barriers. But in the U.S., as Barbara Kates-Garnick of Tufts University remarked at the forum, “offshore wind is critical to a successful energy transition.”

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Storm season

What we’re learning about hurricanes. And how societies handle them.

I’ve lived through impressive tropical storms, twice on sailboats safe in harbor, but I can’t really imagine a hurricane with 150 mph winds like Ida. That’s the business of coastal scientists, engineers and other experts. Here’s what they’re telling me:

  • It might not always seem this way, but in the past few years the National Hurricane Center has notably upped its game for predicting storm tracks.
  • Structural engineers can now simulate hurricane risks for each individual building in a region, by combining advanced storm simulations with machine learning tricks to predict each building’s shape and strength. Coastal Louisiana, appropriately enough, is one testbed for this NSF-funded open collaboration.
  • The lamentable history of New Orleans before and after Hurricane Katrina is beautifully described in Andy Horowitz’s Katrina. Once again Hurricane Ida is highlighting society’s lack of interest in guarding the vulnerable, while maintaining systemic foulups like police focused on protecting property rather than people.
  • The rebuilt New Orleans levee system “is less ambitious than the one Louisianans lobbied for after Katrina, and the protection it offers grows weaker every day, as the wetlands that buffer the city from the Gulf of Mexico get wetter,” as Horowitz wrote in the New York Times. “But it kept the Gulf of Mexico out of the city, which was its job.”
  • That was a straightforward goal for the Army Corps of Engineer’s $15-billion New Orleans levee project. Achievable goals may be far less clear for megaprojects under consideration for other U.S. cities. Case in point, Miami just turned thumbs down on a Corps plan built on a massive seawall.
  • Miami is among the urban areas hoping to adopt “nature-based systems” (oyster reefs, salt marshes, sea grass meadows, mangroves… ) as part of their resiliency efforts. NBS is a big theme in the Texas coastal spine proposal, centered not just on enormous sea gates but on miles of sand dunes. As with traditional gray engineering, NBS measures have strengths and weaknesses; salt marshes retain no magic if they’re buried under a surge of seawater.
  • There remains the little problem of paying for coastal adaptation measures–ideally, before disasters hit. Boston, which is doing a commendable job of planning for climate change, is among the cities puzzling to find the vastly greater sums needed for actual construction.
  • Traditional benefit/cost analyses for such projects that consider only financial factors “might lead a government to protect only the parts of a city that contain high-value properties while dismissing parts of a community where less advantaged people live,” notes a National Academies report on localized climate action.
  • There’s much talk about “managed retreat” from endangered coastal sites but so far this radical step is taken only when there is no choice at all. “There are reasons people live where they live,” as one prominent engineer pointed out to me.
  • Hurricanes can rip away the accoutrements of civilization over surprisingly huge areas–for instance, Ida killed more people in the Big Apple than the Big Easy. But with the huge exception of rainfall, the worst structural damage is usually highly localized. Properly designed and constructed buildings often survive hurricanes surprisingly well, and the big problem for their occupants becomes waiting for restored power, water, roads and other lifelines.

See also What survives the storm

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Celling up

Some stem-cell-based regenerative therapies will draw on cells from individual patients. Some won’t. How will those alternatives shake out?

Regenerative treatments based on induced pluripotent stem cells (iPSCs) fall into two camps, with the cells drawn either from each patient (autologous) or built off-the-shelf from donor cells (allogeneic). Writing for Nature about manufacturing iPSC-based medicines, I’m struck by the large bets being placed on allogeneic approaches, which haven’t yet been proven clinically.

There’s a lot of progress, in the lab, in solving the obvious big problem with these outside cells: reconfiguring them to slide under the radar of your immune system. Experiments aim to copy the molecular mechanisms by which tumors and fetal cells dodge immune bullets, or to remove the major histocompatibility complex (MHC) molecules by which your T cells recognize your own cells, and/or to pull off many other ingenious genetic tricks.

The potential benefits for off-the-shelf treatments are obvious, beginning with better control, availability and cost than painstakingly created individual treatments.

No surprise, cell therapies will not come cheap. Chimeric antigen receptor (CAR) T cell treatments for blood cancers (the remarkable predecessors for today’s cell therapy candidates) cost around a million bucks per patient. That’s too much for large numbers of cancer patients and waaay too much for the chronic conditions suffered by millions such as Parkinson’s disease, diabetes and heart disease.

And as tricky as it is to make autologous CAR-T cells, even years after those treatments have been commercialized, stem-cell-based therapies are even more laborious.

CAR-T cells are genetically modified to create a receptor protein that goes after bad B cells. OK, not easy. But stem-cell-based therapies require vastly greater modifications, in two huge steps. First, the cells must be pulled back to a pluripotent state. Second, these pluripotent cells must be differentiated into neurons or pancreatic islet cells or heart cells. This differentiation process recapitulates normal cell development and requires weeks or months. Each cell line behaves a little differently during this process. The safety and effectiveness of the results are not givens.

So, nice to need to perform all this magic only once!

Among studies of early allogeneic candidates, BlueRock Therapeutics has launched a trial of dopamine-producing cells that might help with Parkinson’s disease. (Curiously, the cells are derived from embryonic stem cells, not iPSCs; understandably, the company isn’t emphasizing that point.) The first of 10 patients received a transplant in June in surgery at Memorial Sloan Kettering.

Notably, the subjects in the BlueRock study will be given drugs to partly suppress the immune reaction.

This downside is one reason Ole Isacson of McLean Hospital, a pioneer in stem-cell-based treatments for Parkinson’s disease who published a key 2015 paper on research in primates, remains in the autologous camp.

“With allogeneic cells in general, there’s still recognition by the immune system, even in the brain, of these foreign cells,” Isacson noted during an Endpoints seminar last month.

Moreover, autologous cells integrate better within the primate brain and deliver better recoveries, said Isacson. He pointed to a March paper by University of Wisconsin researchers showing that autologous dopamine-producing cells functionally outperformed allogeneic cells in rhesus monkeys that model Parkinson’s.

Isacson also suggested that creating individualized stem cells and then redifferentiated therapeutic cells will be done efficiently and affordably in the foreseeable future with closed-loop automated systems such as those being developed by Cellino Biotech.

Talking with researchers in various forms of cell therapies during the past year, I found that many expect walk-before-you-run progress: When and if autologous treatments work, there will be redoubled work on allogeneic alternatives.

“The immune system is an amazing force of nature that can detect the tiniest little differences,” Jeffrey Bluestone of Sonoma Biotherapeutics told me in an interview for a Nature story on regulatory T cells. “Engineering an invisible cell without the immune system ever seeing it will be a challenge… Having said all that, though, I think the field is moving really well in that space.”

Image of iPSC-derived neurons by Matheus Victor of MIT’s Li-Huei Tsai lab.

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Lacking the smarts for smart insulins

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.

Why not?

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.