Son’s diabetes diagnosis prompted scientist’s journey for a remedy

Doug Melton’s existence was fundamentally altered the moment his child was diagnosed with a serious illness. Yet, unlike most parents facing such a challenge, he was a molecular biologist who had the unique capability to take action.

Now, over three decades later, Melton and his associates are nearing the development of a new treatment for Type 1 diabetes that utilizes stem cells to create healthy insulin-secreting cells that can be transplanted into patients. Vertex Pharmaceuticals, a biotech firm based in Boston, is conducting clinical studies on techniques developed by Melton and his colleagues at Harvard, along with a startup company he established.

“Few things are more fascinating than tackling an intriguing scientific puzzle,” Melton remarked. “Especially one that entails educating others and that, if successful, benefits individuals globally.”

Recently, Melton was appointed as Harvard’s first Catalyst Professor, a senior faculty position designed to encourage partnerships with the private sector. This role permits distinguished faculty to participate in external ventures while fulfilling their teaching responsibilities and contributions to the University’s academic goals. 

“It is challenging to envision a superior illustration of how fundamental scientific discovery paves the way for medical breakthroughs.”

Hopi Hoekstra

Hopi Hoekstra, Edgerley Family Dean of the Faculty of Arts and Sciences, commended Melton’s endeavors as a prime representation of scientific discovery leading to advancements in medicine.

“In an era when investment in science faces scrutiny, it is tough to conceive a better illustration of how fundamental scientific inquiry paves the way for medical innovations and how research conducted at Harvard can enhance the health of everyday individuals,” she stated.

Nurturing a biologist

As a youngster, Melton found himself enchanted by biology. A particular question consistently perplexed him: How did single-celled eggs evolve into intricate organisms with billions of specialized cells? “I recall as a boy in Chicago pondering how the eggs in the pond determined whether to develop into a salamander or a frog,” he reminisced. “That curiosity truly ignited my scientific journey.”

This inquiry continued to drive his career forward. Melton obtained a biology degree from the University of Illinois and received a Marshall Scholarship to study at the University of Cambridge, where he earned an additional bachelor’s degree in the history and philosophy of science and a Ph.D. in molecular biology. In 1981, he joined Harvard, dedicating a decade to exploring early development in frogs and mice. His aspiration was to investigate how bodies form in vertebrates.

His path took an unexpected turn in 1991 when his infant son, Sam, was diagnosed with Type 1 diabetes, a condition in which the immune system targets and destroys beta cells, the components of the pancreas responsible for insulin production — the hormone that regulates blood sugar levels. Patients affected by this condition are compelled to rely on external insulin sources. “I didn’t fully comprehend what that entailed,” Melton recalled. “But we soon learned. My wife devoted all her time to being Sam’s pancreas, administering insulin to him.”

With two young children, Melton and his wife felt overwhelmed. Half in jest, she turned to her husband and proposed he make himself useful. “She looked at me and said, ‘You know, you’re somewhat ineffective,’” he recalled. “‘You’re expected to contribute. Why don’t you focus on this issue?’”

So he did. Melton redirected his research towards diabetes. His transition wasn’t as radical as it might appear: The development of tissues and organs involved the same enigma that had intrigued him from the start — how did genes encode signals that directed cell division and differentiation? He began investigating how beta cells formed in frogs and mice and eventually delved into a burgeoning area of biology — stem cells. These developmental cells serve as precursors that develop into all cell types within the body. An idea took root in his mind: to manipulate embryonic stem cells to create insulin-producing cells.

“It never crossed my mind that it was impossible,” Melton stated. “I merely didn’t know how to accomplish it.”

Escalating global challenges

Diabetes is a condition where the body fails to properly metabolize glucose, the blood sugar that serves as our primary energy source. Typically, glucose levels are regulated by insulin, produced by beta cells within clusters of endocrine cells known as islets of Langerhans, distributed throughout the pancreas.

In Type 1 diabetes — which can manifest at any age, though often during childhood — the immune system attacks and annihilates beta cells. In Type 2 diabetes — which frequently develops later in life and is often associated with obesity — beta cells become impaired and insufficiently produce insulin.

38 million

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

According to data from the U.S. Centers for Disease Control, over 38 million Americans, approximately 11 percent of the population, were diagnosed with diabetes in 2021. It ranks as the eighth leading cause of mortality in the nation.

The impact of diabetes is also escalating worldwide, especially in low- and middle-income nations. The International Diabetes Federation reports that nearly 589 million adults globally suffer from the condition, equating to about 11 percent of the global adult populace.

For Melton, this worldwide mission took on even greater significance. Approximately a decade after his son was diagnosed with Type 1, his daughter, Emma (then 14), was also diagnosed with the same illness.

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Endorsed through Bush-era reductions

A significant advancement took place over a century ago with the creation of exogenous insulin therapy, initially administered via injections and now largely through insulin pumps. Nevertheless, these innovations still rely on outside sources of insulin and serve as treatments — not definitive solutions.

Melton has pursued a remedy by uncovering the developmental biology of beta cells. What were the developmental milestones that transformed a stem cell into a beta cell that synthesized insulin? Is it possible for scientists to replicate those processes to engineer beta cells suitable for transplantation into patients?

His investigations were daring, and Harvard was a unique environment where he could conduct them. He reminisced about the University’s backing when, in 2001, then-President George W. Bush halted federal funding for human stem cell research and later restricted federal financing to existing stem cell lines. The University established a new lab for Melton to ensure his research remained distinct from federally funded projects. In 2004, Melton and his colleague David Scadden established the Harvard Stem Cell Institute, a partnership now encompassing over 350 research faculty.

“I take pride in saying that Harvard supported my work, resulting in approximately 300 stem cell lines that we distributed to researchers globally at no cost,” Melton stated. “That significantly facilitated the advancement of the entire field.”

Imitating nature

Throughout the years, Melton and his associates made a series of findings that paved the way for a novel treatment to revive insulin production in individuals with Type 1 diabetes.

Melton likens this stem cell-derived islet therapy to “educating” a stem cell and its progeny — providing the protein signals that initiate or halt developmental processes. Ultimately, the approach introduces 15 signaling proteins at precise times and locations in six phases over 30 days to convert a stem cell into an insulin-producing beta cell. These cells are subsequently transplanted into individuals with Type 1 diabetes.

“I take pride in saying that Harvard supported my work, resulting in approximately 300 stem cell lines that we distributed to researchers globally at no cost.”

Doug Melton

After showcasing a technique to produce beta cells in 2014, Melton launched Semma Therapeutics (named after his two children) to foster a commercial application. In 2019, Vertex acquired the company, which now runs clinical trials for Type 1 diabetes patients. Melton noted that over a dozen participants have completed the trial, and “more than a handful” who have undergone this novel treatment are now “insulin independent” — meaning they have not demanded additional external insulin thus far.

Continuous glucose monitors check blood sugar levels every 15 minutes, while a beta cell does it 1,000 times per second. “I’m not creating anything,” Melton asserts. “I’m attempting to mimic nature.”

A hub for science

The new stem-cell-derived therapy marks the first instance of a fully differentiated human cell being cultivated in the lab from stem cells and subsequently introduced into human clinical trials. Melton indicates that this technique may eventually be adapted for treating Type 2 diabetes. The method also offers insights regarding how stem cells could be leveraged for other treatments, such as generating dopamine-producing brain cells for Parkinson’s disease therapy.

“Harvard is the type of institution where you can tackle a problem that might not be resolved in a year, five years, or even a decade,” Melton remarked. “I believe that’s one of the remarkable advantages our institutions can offer.”

Harvard has also been an exceptional venue for fostering young talent — and learning from them, according to Melton. The scientist has engaged around 50 undergraduates, graduate students, and postdoctoral researchers in his lab. He has also relished teaching courses like developmental biology and “Frontiers in Therapeutics: Science of Health,” which investigates how fundamental science can address unresolved medical issues.

“I enjoy teaching undergraduates because, generally, they arrive with fewer biases or preconceived ideas about what’s valuable and how to pursue it,” Melton expressed. “That prompts me to reconsider what we are doing. There’s an added motivation — to inspire some of the bright young undergraduates to consider a future in science.”

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