Gokhan Hotamisligil

Lying on a fringed blanket, the sweet-faced little girl in the photo looked like any other child, except for her swollen feet and left hand. Far too large for her two-year-old body, the appendages were deformed, discolored and engorged with fat. She had the rare condition Proteus syndrome, which brought her to the attention of Gökhan Hotamisligil. At the time, nearly 20 years ago, he was a promising young pediatrician in Turkey. Many years later, her case would redirect his career to focus on basic science.

Now chair of the new Department of Genetics and Complex Diseases at HSPH, Hotamisligil and his colleagues are determined to unlock the mechanisms by which the environment and genetic material interface to cause disease.

"Our big dream is to establish a system where we can really mechanistically address how the organism interfaces with its environment and how you generate responses to what you eat, what you breathe, what you are exposed to: toxins, radiation, anything that you can think of," said Hotamisligil. "The other component is to carry this research into population genetics, and I think we need to find ways to work with the existing strengths of HSPH and the broader scientific community in that area. This will not all happen tomorrow, but we are excited for the future."

He is fond of recounting the story of the little girl, with whom he is still in touch, as a lesson in turning research disappointment into opportunity.

A Newfound Thirst for Basic Science
Proteus syndrome is marked by traits such as abnormally large skulls, excessive fatty tissue deposits and asymmetrical arms or legs, according to the Merck Manual. John Merrick, the subject of the book and play The Elephant Man, is thought to have had the syndrome. In the case of the little girl, masses of fat cells, or adipocytes, had collected in her hand and feet, making them much larger than her otherwise slim body. These fat cells were reproducing uncontrollably, although they were non-malignant. There is no definitive cure for Proteus syndrome, so Hotamisligil treated the girl's symptoms.

After becoming involved in several other cases, he emerged as a well-informed physician on the condition, which is so rare that current medical literature documents about 50 cases worldwide, according to the Genetics Education Center at the University of Kansas Medical Center.

He brought his experience to Harvard Medical School (HMS) in 1989, where he accepted a fellowship in pediatric neurology and neurogenetics in the laboratory of Xandra Breakefield, professor of neurology at HMS. He became increasingly interested in basic science and entered a PhD program in the Department of Biological Chemistry and Molecular Pharmacology at HMS. At one of the program's retreats, Hotamisligil developed an idea upon meeting Bruce Spiegelman, a professor of cell biology who researches mechanisms of adipocyte differentiation. Perhaps a line of human fat cells could be propagated and sustained indefinitely from the rapidly reproducing fat cells taken from Proteus syndrome patients.

"No human fat cell line exists for research purposes in the lab," said Hotamisligil. "This is a big limitation for researchers in this field."

Because of the abnormal cell growth associated with the condition, patients undergo surgery frequently to remove excess tissue. Hotamisligil collected samples, and experiments followed. At the same time, Hotamisligil worked on additional research into the genetics of monoamine oxidases in neurological disorders, which was proving to be productive. The same could not be said for the adipocyte research.

"It just didn't work," he recalled. "It is very hard to maintain this tissue's ability to make fat cells. There are some conditions that we cannot mimic in cultures. Maybe in this case, there was something outside of the cells that was a stimulant for their growth, maybe circulating factors, that we needed and did not have." To date, human fat cell lines have not been successfully developed and maintained in the lab.

So with progress underway in other research he was conducting, Hotamisligil faced the decision of what to do for his thesis. While the idea of developing human adipocyte cell lines did not pan out, other preliminary observations he made during this time pointed to possibilities in tapping into the mechanisms that underlie type 2 diabetes.

"I thought, maybe I will give up neurogenetics and start going in the direction of metabolic regulation," he said. "That turned out to be a very good decision for me. At that time, the area was very poorly developed, and our eventual discoveries made a significant impact."

Starting Over
The time was the early 1990s, when rumblings of a growing obesity problem in the U.S. were being presented in the media. A concept called the Metabolic Syndrome, a cluster of related illnesses such as diabetes, hypertension and obesity, was being developed, defined and redefined.

For his thesis, Hotamisligil worked in Spiegelman's lab on trying to unravel the mechanisms of insulin resistance, a factor in diabetes. He focused on the immune system and inflammatory mediators. The project led to the discovery of an important role for the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in type 2 diabetes. Later, a mechanism in cultured cells by which TNF-alpha interferes with insulin signaling was elucidated and further confirmed in rats. His thesis work helped lead to his appointment at HSPH.

Since then, his focus has been on understanding the integration of immune and metabolic responses, emphasizing their underlying molecular pathways. He has chosen to tackle major diseases of the Metabolic Syndrome first one by one, trying to elucidate the molecular basis of obesity, diabetes and heart disease, and then understanding them as a cluster.

A Department's Vision
The Department of Genetics and Complex Diseases (GCD), established last September, is being organized by Hotamisligil and fellow GCD primary faculty members Bruce Demple, Karl Kelsey, Guy Reed, Marianne Wessling-Resnick, Dieter Wolf and Zhi-Min Yuan. The department is recruiting several new faculty members.

The advances of the past decades have revolutionized biological sciences, said Hotamisligil. This rapid expansion has provided key information on the cellular and molecular machinery controlling cell formation, development, specialization and functional organization. There is also a deepening knowledge of molecular signaling networks, he explained. These developments have been set against a technological backdrop in which information about proteins, lipids, transcripts, sugars and their derivatives can be incorporated into biological models. These developments present newfound opportunities, he said.

"While the current scientific platform offers limitless opportunities, there are substantial challenges as well," said Hotamisligil. "First, how can these fundamental advances be applied to understanding the organization and integrated function of complex systems and whole organisms? Second, and perhaps most daunting, is how to synthesize existing and increasing knowledge to study human populations-at the intersection of biological systems and their environment-to effectively develop new preventive and therapeutic applications. It is this second area in which we are hoping to establish a presence."