With diabetes hitting epidemic levels – an estimated 17 million are afflicted in the U. S. alone – MIT’s Harvey Lodish and his coworkers have found what could become a significant part of medicine’s arsenal of treatments for it.
The agent is a hormone dubbed adiponectin. Lodish, an MIT biology professor and a member of the Whitehead Institute for Biomedical Research, identified it nearly a decade ago while screening for proteins that are made solely by fat cells. But while it was clear adiponectin had many of the earmarks of a hormone, only in recent years have his lab and others shown it plays a key role in controlling fat and sugar levels in the blood.
Like better-known cousins such as insulin and growth hormone, adiponectin makes things happen when secreted into the bloodstream.
Insulin, for its part, is in effect the spark plug that makes our engines run. Its main role is to cause our muscles to take in and burn our most important “fuel,” the blood sugar called glucose. And adiponectin boosts these effects.
“It has a synergistic relationship with insulin,” explains Lodish, “so it seems to be a major player in glucose metabolism.” It also enhances our muscles’ ability to burn fatty acids, the main building blocks of body fat.
And that’s not all, notes postdoctoral associate Tsu-Shuen Tsao, the lab’s point person on adiponectin. He notes, for example, that another group found in work with rodents that if the gene that triggers the making of adiponectin is incapacitated, and the animals are then put on a fatty diet, they no longer respond to insulin.
Given that diabetes is a disease of elevated blood glucose, do such findings make adiponectin a good bet for treating the disease? Lodish’s answer, in effect: maybe – but let’s avoid rash predictions. “Remember, this hormone is part of a network that controls fat and sugar metabolism,” he notes, “and we need to understand more about how the whole system works.”
Medical Connections
Lodish’s caution reflects a career spent doing science with a medical slant. His lab is clearly a basic-research enterprise. But Lodish himself has a strong interest in medicine, too, and in fact can tell you how it got started.
While at Cleveland Heights High School – where his activities included “keeping time as the bass drummer in a 164-piece marching band” – he worked summers in a Case Western Reserve Medical School lab. That critical experience, he notes, taught him what research could do for patients.
Lodish, who later graduated from Ohio’s Kenyon College and from Rockefeller University, has made a career-long specialty of exploring cell membranes. These fatty sheets, a scant few molecules thick, control the entry of many types of substances into cells. The scientist’s achievements include seminal work on the glucose transporter – a molecule that sits on the surface of most body cells, and lets them bind and take in this vital source of energy.
Such work has earned him an impressive list of honors: he belongs to both the National Academy of Sciences and the American Academy of Arts and Sciences, and is the new president of the American Society of Cell Biology.
But the scientist has close ties with the world of medicine, too. He co-directs a research project on red blood cells with a Children’s Hospital colleague, has helped found five biotech firms, and consults with pharmaceutical companies. In addition, he notes, “About half the postdocs in my lab are M. D. s. “So, he has many windows on the obstacles to converting lab discoveries into therapies.
Even if a molecule seems to do helpful things, he notes, you can’t just start giving it to sick people. “You need to know basic things first,” he explains. “What tissues does it act on? What’s its half-life in the body? How is it destroyed? What are its potential side effects?”
Resisting Hype
What happens when this reality collides with a press hungry for news of medical breakthroughs? Two years ago, Lodish found out at first hand.
Working with a biotech firm, his lab was exploring the effects of what they knew to be an especially active chunk of adiponectin on weight gain.
The researchers put lab mice on a diet aimed at boosting their weight. “It’s a mixture of butter, oil, sugar, sometimes chocolate,” says Lodish. “Basically, it’s junk food.”
Like most human junk-food aficionados, the animals gained weight. But when some were injected with the adiponectin fragment, they could keep on consuming like the untreated mice and still slim down.
The researchers’ report that the mice involved had weight losses averaging a dramatic 7.5 percent caused a minor media sensation. “I spent three solid days telling reporters, ‘Look, all we’ve shown is that this hormone causes weight loss in mice,'” says Lodish. “‘We have no idea if it will do the same in humans.'”
Whether the hormone can in fact help obese individuals is still to be seen. But Lodish says that diabetes right now seems like a better target, and that many groups are working on adiponectin with this disease in mind.
The scientist’s lab, for its part, is doing the quiet but crucial work needed to make sure the hormone can be effectively deployed as a drug. A major goal is to find the receptor on the surface of muscle cells that binds the key adiponectin fragment.
Lodish says he’d be delighted if adiponectin does have medical benefits. “People like me do science for all kinds of reasons,” he notes, “but if it actually leads to a useful therapy, that would be terrific. “But he’s not predicting that it will.