In an effort to treat the 1.5 million Americans living with diabetes, scientists have developed a treatment that uses stem cells that produce insulin.
Type 1 diabetes ruled Brian Shelton’s life.
He would lose consciousness without warning when his blood sugar plummeted. A motorcycle crash caused him to crash into a wall. While delivering mail, he passed out in a customer’s yard. After a quarter century in the Postal Service, his supervisor told him to retire. The 57-year-old man died.
He was taken into his ex-wife’s home in Elyria, Ohio by Cindy Shelton. The thought of leaving him alone all day made her nervous.
This year, she spotted a clinical trial that Vertex Pharmaceuticals was conducting for people with Type 1 diabetes. After his baby son and then his teenage daughter contracted the disease, a scientist vowed to find a cure and developed a treatment over decades.
The first patient was Mr. Shelton. In June 29, he received an infusion of cells grown from stem cells, which functioned similarly to insulin-producing pancreatic cells.
The insulin and blood sugar levels in his body are now automatically controlled by his body.
With a new treatment, Mr. Shelton, now 64, may be the first person cured of the disease, which may offer hope to many of the 1.5 million Americans who suffer from Type 1 diabetes.
“It’s a whole new life,” Shelton said. “It’s a miracle.”
There was astonishment among diabetes experts, but caution was advised. Seventeen people with severe cases of Type 1 diabetes will take part in the five-year study. The medication is not intended to treat Type 2 diabetes, which is more common.
Dr. Irl Hirsch, a diabetes expert at the University of Washington who was not involved in the research, said, “We’ve been looking for something like this for decades.” Further research is needed to verify the results, which have not yet been published in peer-reviewed journals. It would also be helpful if he knew if there would be unanticipated adverse effects and if the cells would last a lifetime or if the procedure would have to be repeated.
“In the end, it is an amazing achievement,” he said.
The same caveats were offered by Dr. Peter Butler, a diabetes expert at U.C.L.A. who was not involved with the research.
Dr. Butler described the result as remarkable. It would be similar to the miracle when insulin became available 100 years ago to be able to reverse diabetes by giving them back the cells they are missing.”
Doug Melton, a Harvard University biologist, began the 30-year quest 30 years ago.
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‘A Terrible, Terrible Disease’
Before 1991, Dr. Melton had never given much thought to diabetes until his six-month-old son, Sam, began shaking, vomiting and panting.
It was so sick, and the pediatrician had no idea what it was,” Dr. Melton said. His wife Gail O’Keefe rushed their baby to Boston Children’s Hospital. Sam’s urine was overflowing with sugar, which was a sign of diabetes.
It usually begins around the age of 13 or 14 when the body’s immune system destroys insulin-producing islet cells in the pancreas. Type 1 diabetes is quickly lethal without insulin injections, unlike Type 2, which is more common and milder. It is impossible for anyone to get better on their own.
At U.C.L.A., Dr. Butler described the disease as “terrible, terrible.”
Diabetes is the leading cause of blindness in this country – patients are at risk of going blind. In addition, it is the leading cause of kidney failure. As a result of their blood sugar plummeting during sleep, people with Type 1 diabetes are at risk of having their legs amputated. They are much more likely to suffer a heart attack or stroke if they have diabetes. Covid-19 weakens the immune system – one of Dr. Butler’s fully vaccinated diabetes patients recently died from it.
Diabetes is exacerbated by the high cost of insulin, which has been rising steadily for years.
Historically, the only cure has been a pancreas transplant or transplantation of insulin-producing cells from an organ donor’s pancreas, called islet cells. A shortage of organs, however, makes such an approach impossible for the vast majority of patients.
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, said, “Even in utopia, we couldn’t have enough pancreases.”
Blue Clues
It was terrifying for Dr. Melton and Ms. O’Keefe to care for an infant with the disease. Four times a day, Ms. O’Keefe pricks Sam’s fingers and feet to check his blood sugar. After that, she had to inject him with insulin. Insulin was not even sold in the proper dosage for a baby that young. It had to be diluted by his parents.
“Gail told me, ‘If I’m doing this, you have to figure out this damn disease,'” Dr. Melton recalled. Their 14-year-old daughter Emma would eventually contract the disease as well, four years older than Sam.
Dr. Melton studied frog development but abandoned it to find a cure for diabetes. As a result, he turned to embryonic stem cells, which can become any type of cell in the body. The goal of his research was to turn them into islet cells that could be used to treat patients.
Among the problems was the source of the cells – they came from unused fertilized eggs from a fertility clinic. Nevertheless, President George W. Bush banned the use of federal money for research on human embryos in August 2001. As a result, Dr. Melton had to separate his stem cell lab from everything else at Harvard. With funding from the Howard Hughes Medical Institute, Harvard and philanthropists, he set up a completely separate lab with an accountant who kept all expenses separate.
During the 20 years it took the lab of 15 or so people to successfully convert stem cells into islet cells, Dr. Melton estimated the project cost about $50 million.
We had to figure out what chemical messages would turn stem cells into insulin-producing islet cells. The research involved unraveling normal pancreatic development, figuring out how islets are made in the pancreas and conducting endless experiments to steer embryonic stem cells to become islets. The process was slow.
One night in 2014, a small team of researchers, including Felicia Pagliuca, a postdoctoral researcher, were in the lab doing one more experiment.
Despite our optimism, she said, “we weren’t very optimistic.”. In the liquid where the stem cells were growing, they had put a dye. A blue liquid would result if insulin was produced by the cells.
Her husband had already called to ask when she would be home. She then noticed a faint blue tinge that became darker and darker. It was an ecstatic moment for her and the others. From embryonic stem cells, they made functioning pancreatic islet cells for the first time.
A cake and a party were held to celebrate the lab’s anniversary. They then made themselves bright blue wool hats with five circles colored red, yellow, green, blue, and purple to represent the stages stem cells had to go through to become functioning islet cells. Up until then, they had always hoped for purple but had been stuck with green.
In order to make a drug that could reach the market, Dr. Melton decided to start his own company.
Moments of Truth
Semma, a combination of Sam and Emma’s names, was founded in 2014.
We had to figure out how to grow islet cells in large quantities using a method others could replicate. It took five years to accomplish that.
Bastiano Sanna, a cell and gene therapy expert, tested the company’s cells in mice and rats, showing that they functioned well and cured diabetes.
In order to conduct a clinical trial in patients, a large, well-financed and experienced company with hundreds of employees was needed. In order to comply with the Food and Drug Administration’s exacting standards, thousands of pages of documents had to be prepared, and clinical trials had to be planned.
It was chance that intervened. Dr. Melton ran into his former colleague, Dr. David Altshuler, who was a professor of genetics and medicine at Harvard and deputy director of the Broad Institute, at a meeting at Massachusetts General Hospital in April 2019. Dr. Altshuler asked Dr. Melton what was new at Vertex Pharmaceuticals over lunch.
A purple pellet was found at the bottom of Dr. Melton’s glass vial.
He told Dr. Altshuler, “These are islet cells we made at Semma.”.
ImageVertex focuses on human diseases whose biology is understood. “I think there might be an opportunity,” Dr. Altshuler told him.
Several meetings followed, and eight weeks later, Vertex acquired Semma for $950 million. Dr. Sanna became an executive vice president at Vertex after the acquisition.
Until the diabetes treatment is approved, the company will not announce a price. There is a likelihood that it will be expensive, however. Vertex has enraged patients with high prices for difficult and expensive drugs.
It was Vertex’s challenge to ensure that the production process worked every time and that the cells were safe to inject into patients. Sterile conditions were used to monitor vessels containing nutrients and biochemical signals where stem cells were transforming into islet cells.
Vertex began a clinical trial with Mr. Shelton less than two years after Semma was acquired by Vertex.
Like patients who receive pancreas transplants, Mr. Shelton must take drugs that suppress his immune system. According to him, they do not cause any side effects, and he finds them less stressful and risky than constantly monitoring his blood sugar and taking insulin. To prevent his body from rejecting the infused cells, he must continue taking them.
However, Dr. John Buse, a diabetes expert at the University of North Carolina who is unaffiliated with Vertex, said the immunosuppression is concerning. It is imperative that we carefully evaluate the trade-off between the burden of diabetes and the potential complications associated with immunosuppressive medications.”
Mr. Shelton’s treatment, called an early phase safety trial, required careful follow-up and began with half the dose that would be used later in the trial, said Mass General surgeon James Markmann who is working with Vertex on the trial. He said no one expected the cells to function so well.
“The result is so striking,” Dr. Markmann said, “it’s really a leap forward.”
Vertex revealed the results to Dr. Melton last month. There was not much he expected.
“I was prepared to motivate them,” he said.
In what felt like a moment of truth, Dr. Melton was jittery. On this project, he had devoted decades and all of his passion. After the Vertex team’s presentation, he broke out in a huge grin; the data were real.
After leaving Vertex, he went home for dinner with Sam, Emma, and Ms. O’Keefe. The results were announced by Dr. Melton when they sat down to eat.
I’ll just say there were a lot of tears and hugs.”
The moment of truth for Mr. Shelton came after he left the hospital a few days after the procedure. His blood sugar was measured. Everything was perfect. A meal was shared between him and Ms. Shelton. He maintained a normal blood sugar level.
When he saw the measurement, Mr. Shelton wept.
My only response is ‘thank you.'”