NYT on stem cell trials for islet restoration

‘A Terrible, Terrible Disease’

Dr. Melton had never thought much about diabetes until 1991 when his 6-month-old baby boy, Sam, began shaking, vomiting and panting.

“He was so sick, and the pediatrician didn’t know what it was,” Dr. Melton said. He and his wife Gail O’Keefe rushed their baby to Boston Children’s Hospital. Sam’s urine was brimming with sugar — a sign of diabetes.

The disease, which occurs when the body’s immune system destroys the insulin-secreting islet cells of the pancreas, often starts around age 13 or 14. Unlike the more common and milder Type 2 diabetes, Type 1 is quickly lethal unless patients get injections of insulin. No one spontaneously gets better.

“It’s a terrible, terrible disease,” said Dr. Butler at U.C.L.A.

Dr. Doug Melton, a biologist at Harvard University, did not think much about diabetes until his 6-month-old son started showing symptoms.Credit…Kayana Szymczak for The New York Times

Patients are at risk of going blind — diabetes is the leading cause of blindness in this country. It is also the leading cause of kidney failure. People with Type 1 diabetes are at risk of having their legs amputated and of death in the night because their blood sugar plummets during sleep. Diabetes greatly increases their likelihood of having a heart attack or stroke. It weakens the immune system — one of Dr. Butler’s fully vaccinated diabetes patients recently died from Covid-19.

Added to the burden of the disease is the high cost of insulin, whose price has risen each year.

The only cure that has ever worked is a pancreas transplant or a transplant of the insulin-producing cell clusters of the pancreas, known as islet cells, from an organ donor’s pancreas. But a shortage of organs makes such an approach an impossibility for the vast majority with the disease.

“Even if we were in utopia, we would never have enough pancreases,” said Dr. Ali Naji, a transplant surgeon at the University of Pennsylvania who pioneered islet cell transplants and is now a principal investigator for the trial that treated Mr. Shelton.

Blue Clues

For Dr. Melton and Ms. O’Keefe, caring for an infant with the disease was terrifying. Ms. O’Keefe had to prick Sam’s fingers and feet to check his blood sugar four times a day. Then she had to inject him with insulin. For a baby that young, insulin was not even sold in the proper dose. His parents had to dilute it.

“Gail said to me, ‘If I’m doing this you have to figure out this damn disease,’” Dr. Melton recalled. In time, their daughter Emma, four years older than Sam, would develop the disease too, when she was 14.

Dr. Melton had been studying frog development but abandoned that work, determined to find a cure for diabetes. He turned to embryonic stem cells, which have the potential to become any cell in the body. His goal was to turn them into islet cells to treat patients.

One problem was the source of the cells — they came from unused fertilized eggs from a fertility clinic. But in August 2001, President George W. Bush barred using federal money for research with human embryos. Dr. Melton had to sever his stem cell lab from everything else at Harvard. He got private funding from the Howard Hughes Medical Institute, Harvard and philanthropists to set up a completely separate lab with an accountant who kept all its expenses separate, down to the light bulbs.

Over the 20 years it took the lab of 15 or so people to successfully convert stem cells into islet cells, Dr. Melton estimates the project cost about $50 million.


![Mr. Shelton’s diabetes treatment supplies. He said his new drugs, which suppress his immune system, are far less onerous than the constant blood sugar monitoring and insulin intake.]

The challenge was to figure out what sequence of chemical messages would turn stem cells into insulin-secreting islet cells. The work involved unraveling normal pancreatic development, figuring out how islets are made in the pancreas and conducting endless experiments to steer embryonic stem cells to becoming islets. It was slow going.

After years when nothing worked, a small team of researchers, including Felicia Pagliuca, a postdoctoral researcher, was in the lab one night in 2014, doing one more experiment.

“We weren’t very optimistic,” she said. They had put a dye into the liquid where the stem cells were growing. The liquid would turn blue if the cells made insulin.

Her husband had already called asking when was she coming home. Then she saw a faint blue tinge that got darker and darker. She and the others were ecstatic. For the first time, they had made functioning pancreatic islet cells from embryonic stem cells.

The lab celebrated with a little party and a cake. Then they had bright blue wool caps made for themselves with five circles colored red, yellow, green, blue and purple to represent the stages the stem cells had to pass through to become functioning islet cells. They’d always hoped for purple but had until then kept getting stuck at green.

The next step for Dr. Melton, knowing he’d need more resources to make a drug that could get to market, was starting a company.

Moments of Truth

His company Semma was founded in 2014, a mix of Sam and Emma’s names.

One challenge was to figure out how to grow islet cells in large quantities with a method others could repeat. That took five years.

The company, led by Bastiano Sanna, a cell and gene therapy expert, tested its cells in mice and rats, showing they functioned well and cured diabetes in rodents.

At that point, the next step — a clinical trial in patients — needed a large, well financed and experienced company with hundreds of employees. Everything had to be done to the exacting standards of the Food and Drug Administration — thousands of pages of documents prepared, and clinical trials planned.

Chance intervened. In April 2019, at a meeting at Massachusetts General Hospital, Dr. Melton ran into a former colleague, Dr. David Altshuler, who had been a professor of genetics and medicine at Harvard and the deputy director of the Broad Institute. Over lunch, Dr. Altshuler, who had become the chief scientific officer at Vertex Pharmaceuticals, asked Dr. Melton what was new.

Dr. Melton took out a small glass vial with a bright purple pellet at the bottom.

“These are islet cells that we made at Semma,” he told Dr. Altshuler.


Vertex Pharmaceuticals’ headquarters in Boston.Credit…Bill Sikes/Associated Press

Vertex focuses on human diseases whose biology is understood. “I think there might be an opportunity,” Dr. Altshuler told him.

Meetings followed and eight weeks later, Vertex acquired Semma for $950 million. With the acquisition, Dr. Sanna became an executive vice president at Vertex.

The company will not announce a price for its diabetes treatment until it is approved. But it is likely to be expensive. Like other companies, Vertex has enraged patients with high prices for drugsthat are difficult and expensive to make.

Vertex’s challenge was to make sure the production process worked every time and that the cells would be safe if injected into patients. Employees working under scrupulously sterile conditions monitored vessels of solutions containing nutrients and biochemical signals where stem cells were turning into islet cells.

Less than two years after Semma was acquired, the F.D.A. allowed Vertex to begin a clinical trial with Mr. Shelton as its initial patient.

Like patients who get pancreas transplants, Mr. Shelton has to take drugs that suppress his immune system. He says they cause him no side effects, and he finds them far less onerous or risky than constantly monitoring his blood sugar and taking insulin. He will have to continue taking them to prevent his body from rejecting the infused cells.

But Dr. John Buse, a diabetes expert at the University of North Carolina who has no connection to Vertex, said the immunosuppression gives him pause. “We need to carefully evaluate the trade-off between the burdens of diabetes and the potential complications from immunosuppressive medications.”

Mr. Shelton’s treatment, known as an early phase safety trial, called for careful follow-up and required starting with half the dose that would be used later in the trial, noted Dr. James Markmann, Mr. Shelton’s surgeon at Mass General who is working with Vertex on the trial. No one expected the cells to function so well, he said.

“The result is so striking,” Dr. Markmann said, “It’s a real leap forward for the field.”


Mr. Shelton recalls shedding tears when he checked his blood sugar levels after having a meal following his procedure.Credit…Amber Ford for The New York Times

Last month, Vertex was ready to reveal the results to Dr. Melton. He did not expect much.

“I was prepared to give them a pep talk,” he said.

Dr. Melton, normally a calm man, was jittery during what felt like a moment of truth. He had spent decades and all of his passion on this project. By the end of the Vertex team’s presentation, a huge smile broke out on his face; the data were for real.

He left Vertex and went home for dinner with Sam, Emma and Ms. O’Keefe. When they sat down to eat, Dr. Melton told them the results.

“Let’s just say there were a lot of tears and hugs.”

For Mr. Shelton the moment of truth came a few days after the procedure, when he left the hospital. He measured his blood sugar. It was perfect. He and Ms. Shelton had a meal. His blood sugar remained in the normal range.

Mr. Shelton wept when he saw the measurement.

“The only thing I can say is ‘thank you.’”

If you have to be on immune suppressing drugs not so great. But still I am the point where I can’t stand living this way and think about it. It should be for everyone though if they want it and have a really hard time. Not just for who they consider to be severe.

By ”severe” in general is meant highly unpredictable blood glucose fluctuations with hypoglycaemic unawareness.

Less challenging now with CGMs, I figure.

Progress. Maybe not in my lifetime, but hopeful progress. In the meantime, back to work with what CAN be controlled.

I’m thinking that the word, “severe,” may simply be a way to distinguish type 1 diabetes from type 2. It’s use may stem from the general ignorance that the average reader of this article may have about diabetes and the distinction of T1D from T2D. Have you ever had an initial discussion with someone who wants to know if you have the “bad kind of diabetes”?

I remain wary of this line of research as taking immunosuppressive drugs for the rest of your life is no picnic. I would refrain from using the word, cure, as immunosuppression makes you vulnerable to cancer and various infection vectors.


This technology was first developed in Canada about 20 years ago and a number of patients were put on it. It is called the “Edmonton Protocol”. The major problem with it is the suppression of the immune system to avoid rejection. I have a friend who received islets and it worked reasonably well but I haven’t talked with her recently to know how she is doing.

When I finished my stem cell trial, which was just safety & procedures, they were starting up another one but with full on autoimmune drugs. I asked what type of patient they were looking for. And “severe” is a term they used. And I was told that many endocrinologist never see a patient like this. It is a person that has life threatening lows, like hospital type lows daily. There are people that can not function as a normal person due to wildly and strangely fluctuating blood sugars. These people would probably be ok with drugs if it gave them a life that makes sense most days.
While my early years were severe but that was because we didn’t know any better. If my parents had the things I have things I have now, their life would have been so much easier and not so chaotic.
This treatment is not for most of us but I figure if it helps some try to lead a more normal life, give it a try. And who knows maybe the answer for the rest of us might come out of this trial!

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I realize that the term “brittle” is no longer used, because people have a better understanding about treating diabetes. The CGM has really changed everything.

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Keep in mind that the most frequent posters in tudiabetes fall into the top 1% of well-controlled diabetics. We are not a representative sample of the world of diabetics at all.

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Ya, these stories of “cures” are a waste of time for most of us.

I wish I had a filter for posts on diabetes sites where the word “cure” was in the same news article as the words “immunosuppression” or “immunosuppressive drugs”.


Don’t instantly knock all immunosuppressants or transplants as off-the-table forever. Sure I’ve had way too many health care professionals assure me in the past half century that “the cure is only 5 years away” and I’m uber-cynical as a result BUT someday it’ll happen for someone.

I’m already a transplant recipient (cornea transplant for Fuch’s dystrophy, non-D related) and while that is a very trivial case where the immunosuppresants can be delivered specifically to the foreign tissue, and the drugs used do require some management, it’s not a big deal. My wife has had rheumatoid arthritis for decades and again targetted immunosuppressant drugs have often been part of the treatment for that.

Visiting the doc every few months for checkups related to these specialized (and not cheap) drugs is quite a bit different than taking insulin many times every day which we regulate ourselves on a 24x7 basis. I happen to be really good at adjusting my insulin for normal bg’s (not as good as some others here who frequently boast about flatlining) but others are not so lucky.

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Thanks for the reminder, Tim, that immunosuppression exists across a spectrum and we should consider the actual situation before making a conclusion. I had not considered cornea transplants and treatment for rheumatoid arthritis. I appreciate your perspective.

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For some immunosuppressants is worth the risk. For those who just can’t control their sugars.

I know a guy who had a kidney pancreas transplant.
He says he would rather lose the kidney and deal with dialysis than to lose the pancreas.

Of course it was poor control of his diabetes that got him to this place.

He needed immunosuppressants for his kidney anyway so adding a pancreas makes sense.

I was offered this study for encapsulated islet cells.
I almost thought I might, then came covid and it seemed like it was a bad idea for me.

Even thought it was a 2 year study and the implants removed at the end. The risk was more than I wanted

The Edmonton Protocol uses islet cells from cadaveric donors. These are injected into the recipient T1D’s liver. Two injections are needed and are spaced apart by a short time period. Success has been mixed; a friend underwent the Protocol about 18 years ago and had working islet cells for about 12 years. She’s currently still producing some insulin but has to supplement with injections. She was delighted to be 12 years insulin-free. She was immunosuppressed and remains so.

I’ve been T1D for 52 years and had a kidney transplant in 1987, so have been on immunosuppressants for 34 years. They cause me no problems at this stage; the worst that occurred was osteopenia, because of the heavy Prednisone dose they socked me with immediately post-transplant. The subsequent maintenance dose is very low and causes me no trouble. Yes, immunosuppressants increase the chances of several unwanted side-effects, but as my mother, an MD, used to say: if you read all the side effects of Aspirin you’d never touch the stuff.
I have mixed feelings about the erstwhile “cure” but stem cells are miraculous and it’s certainly some progress. One of the biggest pitfalls is t hat this “cure”, once sorted out, may be unaffordable. It won’t be like Banting and Best selling their patent for $1. And that was a centigrade dollar to boot! :canada:

Thanks for reporting your long term real world experience with immunosuppressants, @AuntieFi. Hearing from patients about this persuades me much more than hearing from people with conflicts of interest.

Since you received a kidney transplant, any reason why you didn’t get a pancreas transplant at the same time? I’m impressed that your kidney transplant has endured for 34 years. Is that a long time as far as kidney transplants go?

I’ve been following Dr. Melton’s research on growing new beta cells. Based on everything I’ve read I feel like this has the best chance of being a functional cure one day.

I’m not saying this will work but it seems like one of the only things that is a “functional cure”.

Personally I don’t expect I’ll be interested until there is a method not involving immunosuppression.

I don’t think in the next 50 years they will be able to correct the multiple reasons our immune systems go off the tracks or replace our beta cells with our own cells so I feel like the “functional cure” is the best I can hope for.

I’m happy to see the NYT writing about this. Hopefully it helps them get more attention and support.

Hi Terry,

That many years ago they weren’t doing too many combo transplants. I did subsequently look into a pancreas transplant 15 years ago but was told that I was doing so well that they wouldn’t recomment the risk of another transplant. I was also dissuaded from trying the Edmonton Protocol because of its less-than-impressive results. The doc whom I consulted in Toronto had actually been on the research team in Edmonton and gave me an article from the American Journal of Transplantation that did not speak favourably of the procedure.

I was transplanted in Toronto although I live in Ottawa. I think I’m currently the longest-living graft in the city and there are quite a few of us.

With my adoption of the Omnipod pump and Dexcom CGM my sugars are steady but naturally sometimes I’d like to chuck all this bumph out the window!


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