When the baby vomited again, Gail Melton knew something was seriously wrong with her second child, a son she and her husband, Doug Melton, had named Sam.
She phoned Doug and took Sam to Harvard Health Services in Holyoke Center. Doug hurried to the clinic from his Fairchild Biochemistry Building lab on Divinity Avenue, where, as a professor of molecular and cellular biology, his research through the 1980s had transformed the field of developmental biology by bringing the powerful tools of molecular biology to bear. Together Gail and Doug rushed their infant son to Children’s Hospital Boston.
The specialists at Children’s at first were puzzled by Sam’s condition and hovered around the bed where he lay semiconscious. For Doug and Gail, the waiting was torturous. Their anxiety only increased when the doctors asked them to leave the room. Waiting out of sight of their son, they feared the worst. It turned out that the solution to the mystery posed by Sam Melton’s condition did not lie in high-tech tests, but rather in a very basic one, a urinalysis:
Sam Melton’s urine contained high levels of sugar, which immediately told the doctors that his pancreas wasn’t working properly. Though the condition is rare in 6-month-olds, Sam Melton had diabetes.
Today, diabetes is routinely treated with insulin injections, but insulin does not cure the disease; it only postpones its life-threatening complications. Health officials say the condition is reaching epidemic proportions around the world, afflicting an estimated 23 million Americans and 171 million worldwide.
Sam Melton was diagnosed with type 1 diabetes, the more serious of the disease’s two variations. Unlike type 2, type 1 cannot be controlled by diet and requires a lifetime of insulin injections to replace what the body cannot produce itself.
Though that night was one of the worst of Doug Melton’s life, it may ultimately prove to have been a turning point for diabetics around the world. For Sam’s illness brought a powerful new player into the decades-long fight against the disease, one who has already made important discoveries on the development of beta cells, the cellular insulin factories in the pancreas.
In his most recent work, conducted in mice and published today in the online edition of the journal Nature, Doug Melton and colleagues say that they have been able to use proteins called transcription factors to change one cell type directly into another, essentially reprogramming a cell’s DNA so that it becomes a beta cell. The advance provides a potential way forward in efforts to create a supply of insulin-producing cells that genetically match a diabetic’s other body cells and that can be used in therapy.
For a video of Doug Melton discussing stem cell research with Charlie Rose, click here
Since his now-16-year-old son’s diagnosis, Melton has become one of the top scientists in the field of stem cell and regenerative biology. Together with David Scadden, who heads the Center for Regenerative Medicine at Massachusetts General Hospital, Melton leads one of the world’s premier centers for stem cell science, the Harvard Stem Cell Institute.
Melton is also co-chair — along with Scadden — of a unique new department at Harvard, the Department of Stem Cell and Regenerative Biology, which draws faculty from the Faculty of Arts and Sciences and Harvard Medical School. In recent years, Melton has been both lauded and vilified for his work on human embryonic stem cells, a side effect of his leadership at a time when the federal government sought to restrict the work.
But at the time of Sam’s illness, nobody knew what the future held. Melton admits he was not an expert in diabetes. As a biologist, he knew the disease’s basics, but he had made a name for himself in developmental biology, by examining the forces that instruct a fertilized egg to begin dividing and changing into the enormous array of tissue cells that make up a body.
Melton was in the midst of a promising career. He had come to Harvard as an assistant professor in 1981 and was named a full professor in 1988. But a personal storm raged in him during the days and weeks after Sam’s diagnosis, a storm sparked by his child’s suffering and fed by a father’s feeling of helplessness.
“I did what any parent does,” Melton said of those days. “I asked, ‘What am I going to do about this?’”
When the storm cleared, Melton saw a new way ahead. He could not help Sam the night his bed was surrounded by doctors. He could not spare him the needles from the many blood tests and the insulin injections that followed. He could not even explain to his infant son what was happening. But he was determined to help him in the future:
He would find a cure for diabetes.
Lessons in team-building and science
Now a fit 54, Doug Melton says he became a scientist because he didn’t feel he could make original contributions as a philosopher of science — his first career choice.
He grew up in the 1960s just outside of Chicago, the oldest of three children of a grocery store manager and a court reporter. He recalls attending Dwight D. Eisenhower High School in Blue Island, Ill., in the period after Martin Luther King Jr.’s assassination.
The school was wracked by race riots, he said, bringing traditional academic learning to a halt. Rather than learning facts from books, though, Melton said he learned from classroom discussions about racial differences and about how to live and work together.
“What we mostly talked about in high school was ‘What’s the difference between being black and white?’” Melton said. “The teachers couldn’t teach because there were all these fights, so we talked about team play, getting along.”
Though Melton wanted to attend college, Ivy League schools such as Harvard weren’t on his radar screen. His aspiration was to attend the University of Illinois, which he did in 1971.
Throughout his career, Doug Melton has shown a talent for taking available lessons from whatever situation he was in. His turbulent high school years were no different. Rather than bemoaning the lost academic opportunities, Melton said he learned things that, though nonacademic, were important nonetheless.
“It was a very interesting experience because of the tumultuous social times. There was a lot of discussion in my school about race and discipline and not a lot about education,” Melton said. “That circumstance teaches you a lot about people and motivation, about focus on mission. Though I didn’t know as much science and chemistry as other students who entered the University of Illinois with me, I think I knew a lot more about getting people to work together.”
At the university, Melton could indulge the scientific interest he had harbored for years. Even as a small boy, he remembers, he would visit ponds and wonder how the frogs’ eggs he saw knew to make a frog and not, for example, a salamander.
Melton entered the honors biology program and worked in the lab of David Stocum, who was studying limb regeneration in amphibians. Stocum — today the head of Indiana University’s Center for Regenerative Biology and Medicine — remembers Melton as very mature, a good athlete who made a mean spaghetti sauce, and as someone who had a “quiet forcefulness” about him. Stocum recalls that Melton was one of a handful of undergraduates Stocum has mentored who published a scientific paper while in the lab. Melton’s work, on the tissue that forms over a wound at the beginning of the regeneration process, was a significant advance, Stocum said.
“He developed the ability early on to be very rigorous and critical. He demonstrated a unique flair for research,” Stocum said. “It’s absolutely gratifying that he’s done much more than I. That’s the way you would like it, for the students you taught to go out and do big things. He’s done big things.”
Off to Cambridge
When Melton graduated from the University of Illinois in 1975, he won a prestigious Marshall Scholarship that let him study at the British university of his choice. Melton chose Cambridge University and flew across the Atlantic Ocean with the intention of becoming a philosopher of science and spending his career pondering science’s underlying principles. He eventually realized, however, that — as he put it — “being a real philosopher was beyond me.”
That left Melton looking for alternatives. One place he looked was in the lab of Cambridge University’s eminent biologist John Gurdon, who, in the 1960s, became the first person to clone an animal using the nucleus from fully differentiated adult tissue. Gurdon’s work provided an important foundation for studies involving cloning, proving that each cell, whether for muscle, skin, or another specific tissue, contains within it the instructions for the full animal.
Gurdon recalls working in the lab one day when there was a knock on the door. Outside was Melton, who, Gurdon recalls, explained that he was studying the philosophy of science but wanted to get back into a lab. Melton asked whether he could come in on weekends and clean up. For free.
The request was a bit unusual, Gurdon said, but needing the help, he agreed. During casual conversations in the ensuing weeks, Melton shared more of his background and Gurdon learned who he had on his hands.
“He would come in and start washing glassware on weekends. After a while you realize this was no ordinary person. Glass-washers don’t come like this,” Gurdon said. “And after a long time it emerged he had a spectacular record of achievement as a student and had been offered graduate studentships all over the place.”
Gurdon and others in the lab began to get Melton involved in experiments, and, when Melton asked to do a graduate program there, they enthusiastically accepted him.
Learning from frogs
Melton received his doctorate in molecular biology in 1980, coming to Harvard shortly after, in 1981. At around that time, recent Massachusetts Institute of Technology graduate Cliff Tabin — today chair of Harvard Medical School’s Genetics Department — was looking for a postdoctoral fellowship. Melton was suggested to Tabin as someone who was “clearly doing things at the edge of future questions of developmental biology.”
Intrigued, Tabin visited Melton and recalled seeing a basketball in his office, a good sign to sports fan Tabin. He signed on and worked in Melton’s lab for the next year and a half as a postdoctoral fellow. Tabin called Melton a “very rigorous scientist” with high standards, but also someone with a wry sense of humor. One of Melton’s strengths, Tabin said, is a combination of creativity and practicality that leads him to pursue not just important questions, but ones that can be answered.
“He knows what’s important,” Tabin said. “I learned a lot from Doug.”
Malcolm Whitman, another former fellow in Melton’s lab who has since joined Harvard’s faculty, echoed Tabin’s assessment, calling Melton a “very creative, very determined, and very confident thinker.”
Melton, he said, gave his postdocs room to pursue their interests and, in Whitman’s case, provided training and support that let him pursue his goals. “It was a great place to be a postdoc,” said Whitman, who is today a professor of developmental biology at the Harvard School of Dental Medicine.
While Melton can be humorous and supportive, he’s also no pushover, particularly when it comes to scientific points. He can be tough when he believes an issue is important, showing what Whitman described as a “directness without aggression” that can be very effective. Whitman recalled Melton helping him inject a batch of frog embryos, which Whitman then left on the lab bench overnight without changing the culture medium. He came in the next morning to find his experiment ruined. He also found a note from Melton expressing the importance of changing the medium so the experiment could progress.
“He was not going to yell, but he was also not going to let it go,” Whitman said.
Melton conducted much of his research on the African frog, Xenopus, whose eggs are particularly large, making them easy to work with. Several colleagues credited Melton with transforming the field of developmental biology by bringing to bear the powerful techniques of molecular biology. Melton himself said his most notable accomplishment during those years was the discovery of a type of messenger RNA whose concentration in part of the fertilized egg kicks off the process of differentiation. He also determined that nervous system cells are the easiest for the developing animal to create.
Melton was named an associate professor in 1984, the John L. Loeb Associate Professor of the Natural Sciences in 1987, and full professor of molecular and cellular biology in 1988, the same year his daughter Emma was born.
From frog cells to stem cells
In 1992, after Melton made the decision to shift his research focus from developmental biology to diabetes, one of the first things he had to do was tell people. One of the most difficult audiences was closest to home: in his lab. The research assistants, post-doctoral fellows, and students had come to Harvard to work with a brilliant developmental biologist, not a diabetes researcher. Melton would be starting over in a new field where the fame and — from a more practical standpoint — the grants went to proven names, other names.
But having stepped onto this road, Melton would not be dissuaded. Today, he recounts the time philosophically, and, though he does not want to be seen as someone ruled by his emotions, he makes no apologies for his decision. He also said he was blessed, in a way, by being in a related field and at Harvard, a place that would allow him to shift his professional interests.
Though colleagues asked about Doug Melton invariably cite the impact he has had in not one but two fields, Melton downplays his shift in research focus. True, he had to begin by educating himself about the state of diabetes research and take on new students and fellows interested in his new direction, but he says he had already spent years studying how early cells begin to change into bone, blood, heart, and brain. Focusing his attention on the pancreas and how beta cells develop was different, he said, but it’s not as though he was doing something entirely foreign.
“I was in an extremely fortunate position to have the training and resources to say, well, I could switch my career and work on this problem,” Melton said. “This isn’t like I was an economist or a physicist where I really had to change everything. I was already studying animal development. I switched to how you maintain an organism in its adult form. How is the pancreas not only made but maintained and, with these pancreatic insulin-producing cells — these beta cells — how can we make more of them?”
In 1994, shortly after his decision to change his research focus to pancreatic development and diabetes, Melton received a major boost: He was named a Howard Hughes Medical Institute investigator, a designation that not only put him among a prestigious group of scientists, but that also came with funding, a critical factor for someone competing for research dollars in a new field.
To Doug Melton, the one whose life was really changed by Sam’s condition was his wife, Gail. “I’m almost ashamed to say I made a big change, because for Gail … it’s almost indescribable what it’s like to be the mother of a 6-month-old with diabetes,” Melton said. “She dropped everything to manage Sam. She became his pancreas. She measured his blood sugar and gave him insulin. Instead of having an organ inside his body, he had Gail.”
Diabetes presents those seeking to treat and cure it with two main problems: the first is how to replace the beta cells destroyed by the body so the pancreas can again produce insulin; the second is how to stop the body from destroying beta cells.
Melton decided to focus on the first part of the problem — how to produce more beta cells — since it related more closely to his earlier work. He was content, he said, to let other researchers focus on the autoimmune aspect of the disease. Any cure for diabetes, he believed, would be rooted in a deep understanding of how the pancreas and the insulin-producing cells within it develop. In reviewing the research on the topic, he said he found many possible questions to be explored. Chief among them was how a beta cell develops, starting with a fertilized egg and the embryonic stem cells that multiply and change and slowly become the myriad tissues in the body.
Stem cells fascinate Melton and other scientists because of their unique properties to both divide and propagate themselves and to turn into fully developed tissues. There are two different kinds of stem cells. Adult stem cells are the source of specific tissue types, blood or bone, for example, and are dedicated to making only that type of cell. Embryonic stem cells, on the other hand, have the ability to develop into any cell in the body. Their immense regenerative capacity has raised the possibility of curing a host of degenerative diseases afflicting nerves, blood, bone, and other types of tissues. Researchers studying everything from diabetes to heart disease to Alzheimer’s disease have taken up stem cell research, making it one of the hottest scientific fields in the new century.
But the source of embryonic stem cells has embroiled the field in controversy. The cells are typically extracted from an embryo just several days old, a tiny lump of cells called a blastocyst. The fact that the blastocyst is destroyed in the process has triggered a religious and political debate over whether human life was being destroyed to promote scientific research. The debate has raged on despite the fact that many of the embryos were surplus, left over and kept in freezers in in vitro fertilization clinics, slated eventually to be destroyed.
On Aug. 9, 2001, President George W. Bush signed an executive order saying that though research could continue on embryonic stem cell lines that were already in existence, federal funding could not be used on any research involving lines created after that date.
Researchers across the country protested that the restrictions would choke off an avenue of research with enormous potential to end many forms of human suffering. They also argued that the approved pre-existing lines, for several reasons, were not as useful as the president contended. Further, even if research proceeded using private funds, the executive order created an administrative nightmare by forcing researchers to effectively create separate labs to conduct the same work: one that met the criteria for federal funds and a second for research on nonapproved cell lines and on which federal money — and anything paid for through federal grants — could not be used.
A year later, Melton’s 1992 nightmare replayed itself. Though there was no known family history of the disease, his 14-year-old daughter, Emma, developed type 1 diabetes.
“It makes you think about the concept of fairness and why you ever thought life would be fair,” Melton said, then adding: “Gail and I have a lot of good things for which we’re both grateful and fortunate in our lives. Compared to other people, we’re in very good positions to deal with this. Professionally, if someone wanted to start work on the disease, what better place to be than Harvard and the Boston community? What if I had accidentally become a philosopher?
“Every family has some life-changing events and I don’t like to think we’re very special,” he said. “When I think of all of my friends who have children with autism or cancer or something else, I feel, ‘Shame on me for drawing attention to our problem.’”
But Melton continued to push ahead in his work. In 2004, he unveiled a direct challenge to the government’s attempt to discourage embryonic stem cell research: He announced he had created 17 new embryonic stem cell lines that he would make available to other researchers.
Later that same year, Melton became founding co-director of the Harvard Stem Cell Institute, an entity that since that time has brought together more than 700 principal investigators, postdoctoral fellows, and students from diverse fields across the University. The institute is dedicated not only to studying stem cell science, but also the ethics, policy, and other topics rippling out from the field.
Michael Sandel, a Harvard government professor and author of “The Case Against Perfection: Ethics in the Age of Genetic Engineering,” explores ethical issues raised by stem cell and other science in a class he co-teaches with Melton. Melton, he said, hasn’t completely left the philosopher in him behind.
“Though he claims not to be a philosopher, he actually has a natural gift for asking hard philosophical questions that seem simple on the surface but that invariably go straight to the heart of the matter,” Sandel said. “He poses questions in a most self-effacing manner, but the questions are always razor-sharp and go quickly to the most important and difficult issue.”
As the world focused its attention on embryonic stem cell science, Melton’s ability to clearly explain technical scientific topics became essential as lawmakers, government officials, and the public sought to understand the work that was going on.
“I’ve heard him speak about stem cell research to other scientists and donors alike. I’ve heard him use these words over and over. It’s like hearing a virtuoso performer,” said Kevin Eggan, a leading stem cell researcher who came to Harvard as a junior fellow in 2003 and who works closely with Melton. “His tireless advocacy in this area has been critical.”
Melton spent more and more time addressing donors, politicians, and other groups far from the place he saw as most central to the fight to cure diabetes: the lab. “His message is to let the science speak for itself. Not the politics or the advocacy,” said Ronald Goldstein, chief scientific officer for the Juvenile Diabetes Research Foundation International (JDRF), which has funded some of Melton’s research. “I don’t think he sought that role, but neither did he shirk it. He doesn’t want to go to another meeting. He wants to stay in his lab and find a cure for this damn disease.”
Although Melton declines to discuss specific incidents, his introduction to the rough-and-tumble world of politics was a rude one. He was unprepared, he said, for the exaggeration of scientific facts and sometimes outright lies that he feels were told about stem cell research during the national debate.
While best known outside scientific circles for his advocacy of embryonic stem cell research, Melton’s lab is actually pursuing three different research avenues. Each has the goal of replenishing a diabetic’s lost beta cells, but only one involves embryonic stem cells.
The embryonic stem cell work aims to understand the steps it takes to cause one of those cells to develop into an insulin-producing beta cell. Melton said recently that perhaps five or six steps are involved. At each one, researchers have to figure out what cues, such as the presence of certain chemical signals, the cells use to take the next step.
Another research thrust builds on his 2004 finding that the vast majority of beta cells are created by duplication of existing beta cells, not from adult stem cells, as is the case in some other tissues. He’s trying to understand the capacity of beta cells to divide so he can determine whether they’re a good potential source for surplus cells for diabetic therapy.
The third line of inquiry — direct cell reprogramming — has resulted in the most recent discoveries. Melton said his team has succeeded in finding three critical transcription factors that, when injected into mice, cause a different type of pancreatic cell to morph into a beta cell.
JDRF’s Goldstein said Melton’s “quest” to cure type 1 diabetes has not only led to several important findings, but, through both example and critique, “has elevated the quality of the science in the field, set an example of sharing of resources and data, and has done everything that a scientist can do to expedite the path to discovery.
“Nobody knows how close a cure is,” Goldstein said. “We’re closer than we used to be because of people like Doug.”
Despite those successes, 16 years after that critical decision to become a diabetes researcher, Melton is not satisfied with his progress.
“It’d be stupid of me not to admit it’s gone too slowly. I’d hoped Sam would be cured, as would all type 1 diabetics,” Melton said.
Still, he said they’ve learned a lot, and can take hope from the fact that nothing he has seen in the past decade and a half has convinced him that diabetes can’t be cured.
“I’d like to think my lab has made as much progress as any research lab. We haven’t learned anything that makes me think this is not a solvable problem,” Melton said.