An Engine for solving societal problems

MIT’s accelerator brings an incubator and funding to startups that matter.


“One of my frustrations as an academic is that over the last twelve years we’ve produced a lot of really useful methods and techniques, and almost none of them has been put into practice,” one prominent MIT professor told me earlier this year. “This is not an unusual problem for academics. But it’s frustrating to have things that you know could help and they’re not helping.”

Generating the intellectual property (IP) is only the very first step on the road to the real world. Established companies often are not very interested in IP, even game-changing IP. They are more likely to want prototypes, and people who know how to build the prototypes.

They want, in brief, to work with startups.

That’s one reason why this professor launched a startup. It’s also one reason why MIT actively spreads the entrepreneurial gospel to students and staff who might not have considered it a few years back, and keeps deepening its “environmental ecosystem” of competitions and advisory networks and resources like the Startup Exchange.

And it’s the thinking behind the Engine, the startup accelerator that MIT president L. Rafael Reif announced yesterday. The Engine will combine an incubator with funding for startups focused on real needs.

“When it comes to the most important problems humanity needs to solve — climate change, clean energy, fresh water and food for the world, cancer, and infectious disease, to name a few — there is no app for that,” as Reif explained in the Boston Globe. “We believe the Engine will help deliver important answers for addressing such intractable problems — answers that might otherwise never leave the lab.”

Venture capitalists do a reasonable job of funding many tech companies, but very few VCs are interested in startups that may take more than five years to pay off. The Engine won’t sponsor quick-turnaround firms, or companies that join the thundering herds of marketing middlemen, or oddities like the outfit that claims to deliver wine matched to your DNA.

Instead the funds might go to biotechs, like Oxalys, which do very well if they can even get their drug candidates into first clinical trials within a few years. Or makers of industrial products, like Dropwise’s energy-saving coatings for power plants, which manufacturers probably will adopt quite slowly because that’s how that industry works. Or any number of truly innovative, truly needed products and services.

It will take a decade or more to see how the Engine’s bets turn out. Many will fail. But these are bets we need.

Beta living through stem cells

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


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.”

The write stuffing


When I graduated from high school, all I really knew professionally was that I wanted to write on many topics. Last weekend when people at my high school reunion asked politely what I wrote about, I did find myself saying, many topics—in fact, way more now than when I worked as a staff journalist. Okay, I’m not covering the full human condition. Much of the universe is unexplored. But so far this year I’ve done stories about medical hackathons and crowdsourced scientific challenges, global data security and global financial crises (still separate topics so far!), drug development crises, the future of suburbia, steam power, gene therapyagricultural particulates, the challenges of small data in healthcare, chemical sensing on a chip, employee cross-trainingurban carbon dioxide release, jet engines, zebrafish brains, surgery by telemedicine and robotics manufacturing, among others.

Hackathon crowd control


Crowdsourced challenges are now an established part of the medical research ecosystem, especially for data analysis problems such as finding the best genomic analysis techniques or new ways to interpret mammography data. Writing a story about these competitions for Nature, I’ve been struck by the rapid spread of their most intense form: the medical hackathon.

Described today in a Science Translational Medicine review, these hackathons (or “datathons”) take place over a weekend or a few evenings, bringing together some mix of medical scientists and engineers, data scientists, clinicians, patients, medical entrepreneurs, public health advocates and other interested parties. Participants “are encouraged to collaborate, fail fast and iterate.”

Hundreds of medical hackathons have been held. Some encourage multiple groups to study the same clinical problem with the same data and compare conclusions. Other hackathons are all about idea generation. The events may target specific threats such as the Zika epidemic, or more general topics such as improved intensive care, or a free-for-all of unsolved medical problems.

Like software hackathons, the medical hackathon “integrates collaboration, idea generation, and group learning by joining various stakeholders in a mutually supportive setting for a limited period of time,” the STM authors say.

Key is the face-to-face mashup of expertise and views, which doesn’t come easily on the outside. “It is difficult to establish a platform for the realtime, respectful, and effective exchange of ideas among specialists who are usually separated by time, space, methods, attitudes, and terminology,” they point out.

This difficulty holds even for global crises like Zika. But hackathons around the world are addressing the rapidly spreading virus, among them one held at Massachusetts General Hospital earlier this month. Among the resulting proposals:

  • An app for crowdsourced mosquito surveillance data collection, with games
  • Larvicide automatic dispensers
  • A public health online rumor-squashing campaign
  • Hairnet-like nets to cover open water containers
  • Applying new diagnostic technology to detect the virus in pregnant women
  • A mosquito larva finder, with a microscope add-on to a smart phone that samples standing water, analyzes for type of larva and adds GPS location data.

As often with more established crowdsourcing competitions like the Dream Challenges, we don’t know which if any of these early results will be driven all the way into the clinic. But the promise is real.


The U.S.S. Monitor, which launched a revolution in battleships, was a child of other revolutions. Without new iron-making techniques, iron ships were impractical. Without rifled cannons, the two-gun Monitor would have been a toy. Without railroads to transfer men and materials, she could not have been built in a little over three months. And without the telegraph, she could not have been built at all or sent to arrive in time for her shootout in Chesapeake Bay.


Telegraphs only became practical in the 1840s but spread with astonishing speed across America. By the Civil War, they were part of the landscape. (And seascape: news of the Monitor’s arrival in Hampton Roads, carried by telegraph cable under the Chesapeake to a land station and then on to Washington, made the day for Lincoln’s nervous cabinet.)

Among the changes brought by this almost-instant messaging, daily newspapers often became surprisingly timely. The day after the Monitor and the Virginia (a.k.a. Merrimac) fought, details were splashed across the front page of the New York Times.


The Union War Department’s telegraph office was a short walk from the White House. Lincoln spent many hours there, following and responding to battle news, getting away from the crowds seeking attention, and writing the first drafts of the Emancipation Proclamation during downtimes.

The Department’s head telegrapher went on to run Western Union, which dominated telegraphy in this country for well over a century. Wikipedia tells me that the company would still deliver a personal telegram as late as 2006, but of course decades before that the telephone had turned it into a curiosity. I was dumbfounded to receive one when I was 20 and had no phone. The yellow sheet of paper with a sentence in capital letters came from a friend who was changing plans. Lincoln knew what that was like.


The Monitor and the Virginia slug it out. My great-great-grandfather, a German immigrant in a New York regiment, watched the battle. No telegrams or other written documentation survive for him. We don’t even know his full name.

Mooning cancer

Buzzing aroundBuzzing around Tranquility Base.

We can only applaud a big push to add resources for attacking cancer, but it’s a mistake to call this newly announced federal initiative a moonshot. We won’t land on the cancer cure moon in a decade.

Never mind what it says about our society that our only common metaphor for a large successful national effort is more than a half-century old. The metaphor doesn’t work here.

The actual moon shot built on existing engineering. And the National Aeronautics and Space Administration created its infrastructure from scratch. That’s not possible in our health system, and its irrationalities are increasingly slowing down the grand march toward more personalized medicine.

If the space program had been run like our current health system, computers at Mission Control in Houston and the launch site at Cape Canaveral would not have talked to each other.

Promising efforts like the American Society of Clinical Oncology’s CancerLinQ program are threatened by our inability and unwillingness to share clinical data. As Otis Brawley, chief medical and scientific officer for the American Cancer Society, wrote this week in STAT, “real or perceived privacy issues, along with difficulties connecting disparate electronic health records, may scuttle it.”

As cancer research rockets ahead in the lab, clinical studies may lag years or decades behind. We can take steps to speed them up, but there’s no quick fix.

If NASA had worked like our medical system, the rocket engine makers would have charged whatever they liked. Contrast that with the famous quote from astronaut John Glenn about how he felt before liftoff: “you were sitting on top of two million parts — all built by the lowest bidder on a government contract.”

And if we had run space like medicine, all engineering decisions would have been second-guessed by non-engineers.

The world’s largest cancer center, MD Anderson in Houston, launched its own Moon Shots cancer program three years ago. The initiative helped MDA raise about $300 million, sharpen its priorities and add a few important efforts. And it seems to have achieved progress in a few fairly narrow treatment areas. That’s good news and about what we should expect so far.

There’s nothing theoretical to me about the suffering that cancer inflicts on human lives. I’m happy to see our vice president bringing in the best and brightest to plan an initiative, and especially to figure how to connect the data silos.

But we need another metaphor to help us conceptualize the effort. (And no, not the War on Cancer.) Maybe we can try a title based more closely on another major healthcare initiative (Obamacan? Bidencare?). Grand national projects can live or die by their metaphors.

Unlocking the combinations

tsMouse regulatory T cell and human T cell, courtesy NIAID.

The autoimmune attack that triggers type 1 diabetes has been beaten in the non-obese diabetic mouse, the best animal model of the disease.

More than 500 times, in fact, notes Jay Skyler, professor of medicine at the University of Miami.

But in humans: never.

Researchers have painstakingly picked apart the genetics of the disease and many of the intricacies of the immune attack that wipes out insulin-creating cells in the pancreas. And recent studies suggest that we might, just might, have a smoking gun in the form of disease-triggering populations of gut microbes. But we don’t really know the trigger mechanisms and we really can’t stop the disease.

However, as Skyler reviewed the disappointing decades of type 1 trials in a lecture last week at Joslin Diabetes Center, he pointed out research approaches that might lead closer to a cure.

Among them: examining the effects of treatments by subgroups (such as age), coordinating dosing with the timing of immune events, and administering multiple doses or higher doses of a drug.

Given the unending complexity of the immune system, though, maybe the most promising strategy is to hit it at multiple points. That’s the thinking behind Skyler’s upcoming Diabetes Islet Preservation Immune Treatment (DIPIT) trial.

DIPIT will compare two groups of people recently diagnosed with type 1, one group given five drugs and the other a placebo. The drugs, all giving hints of helpfulness in earlier type 1 trials and approved by the Food and Drug Administration for other conditions, are

• anti-thymocyte globulin (an antibody used to prevent rejection in organ transplants)
• etanercept (which inhibits tumor necrosis factor, a master regulator of immune response)
• pegylated granulocyte colony stimulating factor (a growth factor that boosts production of certain white blood cells)
• Interleukin 2 (a cytokine whose effects include increasing growth of the regulatory T cells that can guard against autoimmune onslaughts), and
• exenatide (a synthetic hormone that boosts glucose-dependent insulin secretion).

As Skyler told the Miami Herald, “we have one drug to stop the cavalry; one drug to stop the artillery; two drugs that help bring in support systems that favor the immune response; and one drug that helps beta cell health so they can resist the attack better.”

When he first proposed this kitchen-sink idea, “everybody said I was crazy,” Skyler remarked to his Joslin audience. The trial did get FDA approval. He’s still looking for funding, though.

Okay, let’s contrast these combinations with those in another arena of biomedical research that’s almost the reverse of type 1: cancer immunotherapy.

This field tries to activate (rather than suppress) the immune system at multiple points. Also unlike the case with type 1 and other autoimmune diseases, it is awash in drug-discovery money.

In fact, we’re living in the breakthrough decade for cancer immunotherapy. The two clear winners so far are CAR-T cells (chimeric antigen receptor T cells, in which a patient’s own cells are re-engineered to seek and destroy blood cells gone bad) and checkpoint blockade drugs (which prevent tumors from presenting false IDs).

The first checkpoint blockade drug approved by the FDA targets CTLA-4, a surface receptor on T cells and B cells. About a fifth of advanced melanoma patients given the drug survive for ten years with no further treatment. And in clinical trials, combining a CTLA-4 inhibitor with a drug that clogs up another checkpoint receptor, PD-1, has significantly broadened the population of survivors.

Combination is a familiar theme in cancer treatment, since tumors are so adept at evolving to resist whatever you throw at them. There are very high hopes for adding immunotherapies to the mix.

And in that mix, proven treatments like checkpoint blockaders will be joined by other drugs that hit different points of immune activation. There’s much excitement, for instance, about agents that activate the STING (stimulator of interferon genes) pathway, which can kick off defenders in both the innate and the adaptive immune systems and maybe act as a kind of cancer vaccine.

In both cancer and diabetes, nothing will be easy in bringing combination therapies into clinical trials and then ideally into regular practice. Researchers must identify exactly which patients might benefit from which combos, juggle drug dosages and timing, watch for serious side effects and struggle to quantify any improvements in health. These will be long rough roads. But for some patients, we hope, combos will lead to cures.