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.

 

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.

Beta living through stem cells

Insulin-producing cells will be tested first in patients lacking a pancreas.

insulin

Diabetes is way complex. “But it’s a simple disease conceptually—your body doesn’t produce enough insulin,” notes Joslin Diabetes Center researcher Gordon Weir.

In type 1 diabetes, an autoimmune attack wipes out insulin-producing beta cells, which are found in clusters of pancreatic cells called islets. In type 2 diabetes, the beta cells are still there but not hauling all the freight. That disease can be treated with many other types of drugs, along with lifestyle changes. But over time, beta cells wear out. In fact, more people with type 2 take insulin than people with type 1.

And there’s no way to make insulin injections pleasant or easily controllable or as good as insulin production by beta cells.

Thus the huge interest in a long-term research project spearheaded by Harvard’s Doug Melton to create working beta cells by manipulating stem cells. An update on the ambitious project from Melton, Weir and other partners drew a crowd at Harvard on Monday.

Making insulin-producing cells good enough for clinical trials “turns out to be rather difficult; it took more than a decade,” Melton said. “We haven’t made it really perfect, but it’s at the goal line.”

Technology from Melton’s lab has been licensed exclusively to the startup Semma Therapeutics, which is joining with Joslin, Brigham & Women’s Hospital and Dana-Farber Cancer Institute to move toward clinical trials. Traveling under the ungainly title of the Boston Autologous Islet Replacement Therapy Program (BAIRT), the collaboration launched in June.

The first BAIRT studies, starting at least three years from now, will not be among people with type 1 diabetes. Instead, they will recruit people who have had their pancreases removed, usually because of uncontrollable pain after the organs are chronically inflamed by years of heavy drinking.

This approach bypasses the biggest problem in cell treatments for type 1 diabetes: the body renews its autoimmune attack and wipes out the newly introduced cells. “We decided to solve one problem at a time,” Melton explained.

Patients who have prostatectomies often now are given islet cells salvaged from their own pancreas, which helps to improve their diabetes control, but those cells may themselves be damaged or in short supply, said Brigham surgeon Sayeed Malek. Transplants of brand-new beta cells, made from the patients’ own blood, should help.

These reengineered cells will be injected in the arm, where they will be easy to monitor  and to remove if necessary, said Semma CEO Robert Millman. Decades of experience transplanting cells from cadavers has shown that “you can put beta cells just about anywhere,” Weir added.

Against autoimmunity. If all goes well, the project will continue into trials for type 1 diabetes with non-personalized beta cells, where the autoimmune attack will be blunted via encapsulating the cells. Seema is spending about half its budget on encapsulation technologies, Millman said.

Encapsulation is the near-term solution to fend off the autoimmune attack. “The long-term solution is to use the power of biology to understand why the immune system has made this mistake,” Melton remarked.

He briefly mentioned two promising research thrusts. One effort is to learn from the rapid advances in knowledge about how cancer cells dodge the immune system.

Another, led by Chad Cowan of Massachusetts General Hospital, aims to create a “universal donor pluripotent stem cell.” Missing all the billboard signs that alert immune enforcers, these cells could play a role like that of O-positive cells in blood transfusions.

Asked about his own take on the causes of type 1, Melton mentioned one theory that the autoimmune attack may be triggered by gut cells that naturally produce insulin or similar substances under certain conditions.

Slow and steady. Bringing beta cell therapies to the clinic will be a marathon march with not only many scientific steps but many regulatory steps. Millman emphasized, however, that “the FDA is working with us very early on the regulatory path.”

Among potential safety risks, all stem cell therapies must be carefully vetted to avoid the growth of teratomas—tumors with a jumbled mix of cells, usually benign. These cellular junk piles would be relatively easy to remove, but much better to avoid altogether, Millman said.

Another concern is that the cells will secrete insulin even when it’s not needed, dropping the recipient’s blood sugar levels to dangerously low levels.

There also is much cause for worry that the cells won’t last long, a major problem in transplants of cadaver beta cells. However, built-from-scratch cells function “for more than a year in mice, which bodes well for people,” Weir commented. And Millman pointed out that the cells resemble juvenile cells, which may help them withstand the high stresses of transplantation better than worn-out adult beta cells do. “We hope these almost pristine cells going into the patients will last a lot longer,” he said.

None of this will come cheap. Asked about pricing for cell therapies, way down the road when and if they hit the market, Millman was understandably wary. Initial costs for these treatments will be very high, accompanied by very close regulatory scrutiny. Semma has raised about $50 million, but “we need philanthropy and we need institutions to support this,” he said.

Melton suggested, though, that successful cell-based therapies will make complete  economic sense, given the soaring numbers of people with diabetes and the huge costs of diabetes care. Each year the world spends about $30 billion on insulin alone. “Diabetes is not an orphan disease,” he said. “The cost will come down very quickly.”

Man petabytes dog

husky

One of the earliest stories I wrote about genomics past the gee-whiz aspects of the Human Genome Project covered the first whole-genome sequencing of a dog. Kerstin Lindblad-Toh of the Broad Institute patiently explained the project to me, and scientists who used dog models to study inherited blindness told me why they were more than excited about the prospects.

More than a decade later as I’m putting together a special report on big data for Nature, the genomic revolution has marched ahead, well, much as predicted.

The cost of genomic sequencing has dropped arguably faster than any other technology in human history. Research initiatives that most of us haven’t heard about are gathering genomic data on hundreds of thousands of people. This flood of data is multiplied with data from proteomics and other omics now scaling up to the genomic scale. We talk casually about petabytes (millions of gigabytes). Data scientists, many of them coming in from fields outside biology, are integrating these data and making some astonishingly good predictions about what drugs might work for a given condition, without needing any new wet-lab work. We’ve seen wonderful progress in stem cells and cellular models and genetic engineering tools. And this revolution is on television, also websites, social media and an entirely sufficient plenitude of TED talks.

Not so much in the clinic, though.

Of course omic research on many diseases is starting to pay off for actual patients—for example, The Cancer Genome Atlas has spun off clues for real advances in many cancers—and its grand march points straight ahead through enormous but movable objects.

But clinical steps are slow. Part of the reason is the sheer complexity of disease, for instance the ways cancers duck and weave to dodge treatments. And, of course, clinical trials can’t be rushed.

Last week I asked one neuroscientist why we still lack drugs that treat the causes of neurodegenerative diseases, as opposed to their symptoms. She responded, reasonably enough, that it takes years to build better lab models of the disease and push findings from those models into the long tunnel of pre-clinical work toward trials. She expected that some of the compounds coming from her work will help. She didn’t predict home runs.

But we haven’t lost the gee-whiz discoveries and our faith that they’ll end up in the clinic in our lifetimes. My favorite: Scientists can take a human skin cell, bombard it with select small molecules until it morphs into a reasonable facsimile of an insulin–producing cell (a notoriously fickle beast) and produce such cells in the millions. Maybe those cells will arrive in the next decade, bringing actual cures. And although I don’t follow discoveries in dog proteomics, I see that University of California/Berkeley researchers have restored vision to blind dogs via genetic therapy. Progress, yes. Dogged research!

 

Capping off

sphere_scarringAn MIT alginate microcapsule holding islet cells (in green) and being covered by immune cells (in blue and magenta). Image credit: Omid Veiseh, Joshua Doloff, Minglin Ma and Arturo Vegas.

There’s a worldwide deficit in insulin-producing beta cells, for people with either type 1 or type 2 diabetes, Harvard’s Doug Melton told a session at the ADA annual scientific conference on Friday.

“It’s a completely non-trivial thing that you can now make billions of human beta cells,” he said. “We spent more than a decade trying to march these cells through this procedure.”

Currently, it takes his lab about 40 days to produce the cells at a cost of about $6,000 per flask, but Melton is confident that these numbers can be chopped down.

The achievement required not only brilliant scientific detective legwork, especially on the last steps of differentiation, but lab drudgework on a dramatic scale.

Picking apart the steps that drive cells into beta shape, “we had to sort out three or four factors at a time,” he noted. The lab ran screens of small molecules to find what combinations were effective. Testing eight small molecules, in three concentrations, for different periods, in triplicate meant about 65,000 combinations to examine per screen.

The lab of MIT bioengineer Dan Anderson, collaborating with Melton to build microcapsules for the beta cells, took high-volume testing to a much higher level for various capsule designs.

Over the decades, many groups have tried to encapsulate beta cells in tiny spheres of alginate. Historically, “all these capsules end up covered in scar tissue,” Anderson told the ADA session.

But after endlessly tweaking the properties of these spheres, “we have a growing list of materials we could use,” he said.

One capsule material seems to work well in mice with strong immune systems—and in very early testing in macaques. Details on the material aren’t yet public, but the secret isn’t in the material’s permeability but in how the immune system reacts to it, Anderson said.

His group’s exhaustive testing also gave clues to how capsule size affects immune scarring. Last month, he and colleagues reported in Nature Materials that 1.5-mm-diameter capsules do better than 0.5-mm structures. Was that a surprise? “It was for us,” Anderson replied. “We thought smaller would be better.”

Beta than the real thing?

Melton_ beta_cellsHuman stem cells implanted successfully in a mouse. Image courtesy Doug Melton.

We know a true cure for type 1 diabetes will require both a new supply of insulin-producing beta cells and a new way to stop the autoimmune attack that wipes out the original cells. We’ve seen great progress in the past decade on the first challenge, as researchers have learned to morph embryonic stem cells and then normal skin cells into beta cells that now might be very much like the real thing. But despite all we’ve learned about the autoimmune attack and all the clever ideas that have emerged to stop it, so far there’s no clear way to do so.

Today the best bet for autoimmune defense is to embed engineered beta cells in intricately designed porous capsules. While most attempts use spherical capsules on a millimeter scale, last fall Viacyte launched a clinical trial for a device the size of a credit card. We’re all rooting for this trial’s success. But even if it works well, the encapsulated cells won’t function quite normally or last forever.

“I want a forever solution,” says Harvard’s Doug Melton, who has led much of the stem cell engineering work.

At a JDRF session in Boston back in March, Melton suggested two approaches to further modify those engineered cells to dodge the autoimmune bullets. “These are two of my favorite ideas, but I’ll remind you that most of my ideas turn out to be wrong,” he said wryly.

One idea follows the playbook of the hot new class of cancer immunotherapies known as “checkpoint blockaders” —or rather turns it on its head.

As cancer researchers began to discover two decades ago, T cells that charge in to wipe out tumor cells are stopped in their tracks if the tumor cells express certain proteins on their surfaces. Well, how about engineering beta cells to defend themselves by expressing these proteins on their surfaces? (Work in mice by other labs indeed has demonstrated protective effects.)

Melton prefers a second concept, which taps into one of the large questions of immunology: Why doesn’t a mother’s immune system attack the fetus she carries?

Cells called trophoblasts that initially wrap the embryo help to provide the immune shield, he notes. So why not express key trophoblast surface proteins in beta cells, so that the beta cells look like fetal cells to the immune system?

While autoimmune researchers have been kicking around both of these ideas for years, it’s still very early days for bringing beta cells with self-protective surfaces toward the clinic.

But some year, Melton told the JDRF crowd, “my dream is to tell you, not only can we make billions of beta cells but we can transplant them into any person and they won’t be rejected.”

I’m looking forward to hearing about more and better betas from him and from other leading researchers this Friday afternoon, at a session during the American Diabetes Association’s annual scientific conference in Boston.

Smarter insulin?

insulinInsulin was the first hormone to be genetically engineered for human use, and synthetic insulins now control blood glucose levels for almost everyone with type 1 diabetes and millions of those with type 2 diabetes. Many variants of the molecule have been designed to act quickly or slowly or in between, but the Holy Grail is smart insulin—which would not only work over many hours but automatically adjust its own release to keep blood glucose levels in a good range.

Many labs have taken a stab at smart insulin since the first attempt in 1979. New approaches keep cropping up, and a few show particular promise in animal tests. A “nanoparticle network” reported in 2013 is one of the more interesting. These nanoparticles combine insulin, dextran (a complex sugar often employed to slow down glucose effects) and enzymes that target glucose. Given opposite electrical charges, the nanoparticles are thought to clump together in the body rather than wander off in the bloodstream, doing their duty like a tiny pancreas.

The current commercial champion for smart insulin, though, began back in 1999 with research by Todd Zion, then an MIT graduate student in chemical engineering. Zion came up with a design that combined modified insulin with a sugar gel, and worked dramatically well in rats. He and his colleagues spun out a startup firm called SmartCells in 2003 and honed the technology well enough to get the attention of Merck, which snapped up SmartCells in 2010. Last spring, Merck remarked that it would bring a L-490 smart insulin based on the company’s technology into a clinical trial this year.

But there’s been no news from Merck since, and the National Institutes of Health’s clinicaltrials.gov site doesn’t mention a trial for L-490.

So we’re still in the animal labs.

But I’m still encouraged by last month’s paper in the journal PNAS on a different approach to smart insulin, developed by a team led by MIT’s Daniel Anderson and Robert Langer. This group found that an engineered insulin with the sprightly name of Ins-PBA-F performed very well, maintaining good glucose levels in the blood of mice without functioning pancreases over more than 12 hours and also behaving itself in normal mice.

Which sounds like L-490. But the researchers suggest that the approach Ins-PBA-F spearheads may offer better control and safety in the long run than L-490 because it’s more like normal insulin.

Ins-PBA-F starts with a molecular structure of a long-acting synthetic insulin, and adds a chemical group called “phenylboronic acid” (PBA) that binds to glucose and other sugars. When the surrounding glucose levels climb high enough to occupy the PBA group, the insulin itself is released for action. (Curiously, though PBA is often used to sense sugars and other carbohydrates, the PNAS paper acknowledged that the exact mechanism by which Ins-PBA-F responds to higher glucose levels in the blood isn’t yet clear.)

In theory, such a directly modified insulin molecule may be safer from immune reactions and other side effects than smart insulins that add gels or other types of protein barriers for glucose, as do L-490 and most other approaches. If so, that benefit will appeal mightily to the FDA, which will give extremely tight scrutiny to a radical new drug that could be used around the clock by many millions of people.

A successful smart insulin will be very far from a niche product. Anderson and Langer (who may well hold the world record for co-founding biomedical startups) have the attention of the venture capital community. I hope that successors to Ins-PBA-F will indeed move toward clinical trials, and eventually the clinic. That might be a very smart bet.

Update: Merck actually but very quietly moved its smart insulin into a two-part clinical trial in fall 2014.