Son’s diabetes diagnosis sent scientist on quest for cure

Doug Melton’s life irrevocably changed the day his child was diagnosed with a life-threatening disease. But unlike most other parents in that situation, he was a molecular biologist uniquely positioned to do something about it.

Now, more than 30 years later, Melton and his colleagues are within sight of a new treatment for Type 1 diabetes that uses stem cells to make healthy insulin-producing cells that can be transplanted into patients. Vertex Pharmaceuticals, a biomedical company headquartered in Boston, is running clinical trials on methods pioneered by Melton and his colleagues at Harvard and a startup company that he founded.

“There are few things better than having an interesting science puzzle,” Melton said. “Especially one which involves educating people and that, if you’re successful, does some good for people in the world.”

Melton recently was named Harvard’s first Catalyst Professor, a senior faculty role that aims to foster collaboration with the private sector. The professorship allows distinguished faculty to engage in external opportunities while maintaining their teaching commitments and contributions to the University’s academic mission. 

“It is hard to imagine a better example of how basic scientific discovery paves the way for breakthroughs in medicine.”

Hopi Hoekstra

Hopi Hoekstra, Edgerley Family Dean of the Faculty of Arts and Sciences, hailed Melton’s work as a prime example of scientific discovery generating an advance in medicine.

“At a time when investment in science is under attack, it is hard to imagine a better example of how basic scientific discovery paves the way for breakthroughs in medicine, and how the research done at Harvard can improve the health of everyday people,” she said.

Hatching a biologist

As a child, Melton became captivated by biology. One question especially puzzled him: How did single-celled eggs grow into complex animals with billions of specialized cells? “I remember as a boy in Chicago wondering how the eggs in the pond knew whether to make a salamander or a frog,” he recalled. “That really started me on a career in science.”

That question continued to propel his career. Melton graduated with a biology degree from the University of Illinois and won a Marshall Scholarship to study at University of Cambridge, where he earned another bachelor’s degree in the history and philosophy of science and a Ph.D. in molecular biology. In 1981, he landed at Harvard and spent a decade studying early development in frogs and mice. He planned to spend his career investigating how bodies formed in vertebrates.

His life took a sudden turn in 1991 when his infant son, Sam, was diagnosed with Type 1 diabetes, a disease in which the immune system attacks and destroys beta cells, the parts of the pancreas that produce insulin, the hormone that regulates our blood sugar. Such patients are forced to rely on external sources of insulin. “I didn’t really even know what that meant,” Melton recalled. “But we quickly found out. My wife was spending all her time really being Sam’s pancreas, injecting him with insulin.”

With two young children, Melton and his wife were overwhelmed. Half in jest, she turned to her husband and suggested he make himself productive. “She looked at me and said, ‘You know, you’re kind of useless,’” he recalled. “‘You’re supposed to be able to do something. Why don’t you work on this?’”

So he did. Melton switched his research to diabetes. His jump was not as radical as it might seem: The development of tissues and organs involved the same mystery that had captivated him from the beginning — how did genes encode the signals that guided the division and differentiation of cells? He began researching how beta cells form in frogs and mice and eventually came to an emerging realm of biology — stem cells. These developmental cells are the precursors that differentiate into all cell types in the body. An idea hatched in his imagination: taking embryonic stem cells and manipulating them to become the cells that produce insulin.

“It never occurred to me that it couldn’t be done,” said Melton. “I just didn’t know how to do it.”

Rising global burden

Diabetes is a disorder in which the body cannot properly metabolize glucose, the blood sugar that is our main source of energy. Normally, glucose is regulated by insulin, produced by beta cells in clusters of endocrine cells called islets of Langerhans scattered throughout the pancreas.

In Type 1 — which can appear any time but often during childhood — the body’s own immune system attacks and destroys the beta cells. In Type 2 diabetes — which often appears later in life and frequently is linked to obesity — beta cells become dysfunctional and fail to supply sufficient insulin.

38 million Americans were diagnosed with diabetes in 2021, according to the CDC

According to the U.S. Centers for Disease Control, more than 38 million Americans, roughly 11 percent of the population, were diagnosed with diabetes in 2021. It is the eighth leading cause of death in the country.

The burden of diabetes also is rising around the globe, particularly in low- and middle-income countries. According to the International Diabetes Federation, the disease afflicts some 589 million adults around the world, or about 11 percent of the global adult population.

For Melton, this global mission became even more personal. About 10 years after his son was diagnosed with Type 1, his daughter, Emma (then 14), developed the same disease.

Supported through Bush-era cuts

A breakthrough occurred more than 100 years ago with the development of exogenous insulin treatment, originally delivered by injections and now commonly by insulin pumps. But these advances still require external sources of insulin and are treatments — not cures.

Melton has sought a cure by deciphering the developmental biology of the beta cells. What were the developmental steps that turned a stem cell into a beta cell that produced insulin? Could scientists reproduce those events to engineer beta cells that could be transplanted into patients?

His research was bold, and Harvard was the rare place where he could do it. He recalled the University’s support when, in 2001, then-President George W. Bush suspended federal funding for research on human stem cells and later limited federal funding to existing lines of stem cells. The University constructed a new lab for Melton to ensure that his research remained separated from federally funded work. In 2004 Melton and his colleague David Scadden founded the Harvard Stem Cell Institute, a collaboration that now involves more than 350 research faculty.

“I’m proud to say Harvard supported me and we created about 300 stem cell lines and sent them to researchers throughout the world for free,” said Melton. “That really helped the whole field grow.”

Copying nature

Over the decades, Melton and his colleagues made a series of discoveries that laid the groundwork for a new treatment to restore insulin production in patients with Type 1 diabetes.

Melton compares this stem cell-derived islet therapy to “educating” a stem cell and its descendants — introducing the protein signals that trigger or inhibit developmental processes. All told, the method delivers 15 signaling proteins at specific times and places in six stages over 30 days to turn a stem cell into an insulin-producing beta cell. These cells are then transplanted into patients with Type 1 diabetes.

“I’m proud to say Harvard supported me and we created about 300 stem cell lines and sent them to researchers throughout the world for free.”

Doug Melton

After demonstrating a method to create beta cells in 2014, Melton founded the company Semma Therapeutics (the name is a combination of the names of his two children) to develop a commercial application. In 2019, the company was acquired by Vertex, and it now conducts clinical trials for people with Type 1. Melton said more than a dozen patients have completed the trial and “more than a handful” who have taken this new treatment are “insulin independent” — meaning they have not required additional exogenous insulin thus far.

Continuous glucose monitors measure blood sugar every 15 minutes, but a beta cell does so 1,000 times per second. “I’m not inventing anything,” says Melton. “I’m trying to copy nature.”

A place for science

The new stem-cell-derived therapy represents the first time a fully differentiated human cell has been cultured in the lab from stem cells and then introduced into human clinical trials. Melton says the technique might eventually be adapted to treat Type 2 diabetes. The method also provides insights into how stem cells might be used for other therapies, such as making dopamine-producing brain cells to treat Parkinson’s disease.

“Harvard is the kind of place where you can take a problem that you might not solve in a year, or even five years or maybe 10 years,” said Melton. “I think that’s one of the great things our institutions can do.”

Harvard also has been a great place to nurture young talent — and learn from them, Melton said. The scientist has employed about 50 undergraduates, graduate students, and postdocs in his lab. He also has enjoyed teaching classes such as developmental biology and “Frontiers in Therapeutics: Science of Health,” which explores how basic science can be applied to unsolved medical problems.

“I like teaching undergraduates because, on the whole, they come with fewer prejudices or preconceived notions about what’s worth doing and how to do it,” said Melton. “That challenges my own thinking about what we’re doing. There is an additional motivation — to entice some of the bright young undergraduates for a career in science.”