By mid-morning, she must be off to another building to review plans for a student-faculty retreat; then at midday, she'll grab a sandwich and share insights with students in Harvard's M.D.-Ph.D. program. Seminars, committee meetings and other such duties will fill the rest of her afternoon.

That's life as usual for this HHMI investigator. In a typical day, Andrews switches among her roles as associate professor of pediatrics, director of the M.D.-Ph.D. program and attending physician at Children's Hospital in Boston, pausing just long enough to exchange e-mail with collaborators or to coordinate family schedules with husband Bernard Mathey-Prevot, a researcher at the Dana-Farber Cancer Institute.

Although it would be distracting and exhausting to some, Andrews actually thrives on this varied, chock-full schedule. Her knack for seamlessly changing gears—and sometimes even direction—helps explain the researcher's success, and that of her team, in helping to unlock the mysteries of iron-metabolism disorders.

A Sudden Change of Direction
Andrews made her first major gear change in the early 1990s while she was a postdoc in HHMI investigator Stuart Orkin's lab at Harvard Medical School, where she researched globin gene transcription. A seemingly temporary assignment to help a medical student with a literature review on iron metabolism soon became a major new interest and research area for her.

"I knew nothing about iron metabolism," she recalls, "but I was asked to work with him because our lab studied red-cell biology, and iron and red cells are always important to each other" (Iron must continually be recycled in the body to replenish red cells' hemoglobin.) To the medical student, Mark Fleming, the project was no mere academic exercise. His father-in-law had a heritable iron-metabolism disorder, and, coincidentally, a member of Fleming's family had been recently diagnosed with an iron-metabolism disorder.

Together, Andrews and Fleming delved into iron's intricacies and soon realized that even though medical scientists had been studying iron metabolism for nearly a half-century, "some big pieces of the puzzle were missing." Various labs had spent decades trying to identify the proteins involved in iron transport, but the approach used—purifying target proteins—wasn't panning out, probably because the critical transporters were present in very small amounts. When it came time for Andrews to set up her own research program, she and her lab group (which included Fleming as a postdoctoral fellow) decided to take a different tack.

"We figured genetics would give us a different way to get at these missing pieces," says Andrews. "We could isolate transporters by studying mice that were anemic due to mutations disrupting iron transport: We'd simply track the anemia in the animals and the mutations in their DNA and then find transporter genes based on their positions in the genome, rather than their function. This approach bypassed the biochemical step, which was difficult, and took advantage of emerging techniques in gene mapping."

It was a bold decision: Andrews was essentially rejecting the protein-purification techniques in which she was well schooled from her graduate and postgraduate work, to embrace molecular genetics methods in which she was relatively unschooled. What's more, she was still a newcomer to the study of iron-related disorders. The change of course paid off, however. In the seven years since they began exploring the subject through molecular genetics and clinical observations, Andrews and her coworkers have made several important contributions, such as identifying a key protein (DMT1) that ferries iron across membranes and discovering a mutation that interferes with the expression of transferrin, another important iron transporter. (Indispensable as it is, iron is curiously inept at getting itself into and out of cells; it relies on transporters to shuttle it where it needs to go.) At present, the researchers are investigating the roles of other proteins and modifying genes in iron transport and accumulation.

Avoiding Iron Overload
At the most basic level, iron-related disorders are easy to understand—they result from either too much or too little iron in the body. Too little iron leads to the pallor and lethargy of iron-deficiency anemia, a condition that one in ten people will experience some time in life. Genetic defects are rarely to blame; iron deficits usually occur when people don't get enough iron in their diets or when blood loss or intestinal parasites deplete their iron stores.

Iron overload is a bit more complicated. Although iron is essential—it helps hemoglobin carry oxygen through the bloodstream to all the tissues of the body—too much of it can be toxic. Balance is clearly all-important, but avoiding overload is a tricky task.

"There's no pathway for getting rid of iron in the liver or the kidneys," explains Andrews. A smidgen is lost every day through the normal sloughing of skin and intestinal-lining cells, and premenopausal women lose some in menstrual blood, she says, but "for the most part, the iron you take in—either through diet or blood transfusion—is what you have forever."

Like a remote island where castaways must cleverly conserve precious resources in order to survive, a healthy body uses finely tuned mechanisms to continuously recycle iron. The body has strict controls on the uptake of iron in the digestive tract and its subsequent distribution to organs. If something goes awry with the control mechanisms, however, the delicate balance is upset and iron builds up in the body, with harmful consequences. When it accumulates in the liver, for example, the likely results are cirrhosis, liver failure or liver cancer. In the heart, irregular beat and reduced ability to pump blood may result. Excess iron can also cause diabetes and problems in sexual development when it collects in the endocrine tissues.

Still, patients with iron-overload disorders aren't doomed to deteriorating health. When recognized, the problem can be treated by regularly removing blood from the body—a process called phlebotomy. "It's a simple, safe and effective treatment that's been done for more than 50 years," says Andrews. There's just one problem, she notes: "Patients hate it." Clearly, learning how to prevent or treat the disorders—rather than just managing iron buildup—could improve the lives of millions of affected people.

In one line of research, Andrews and her colleagues are gaining new insights into an ancient iron-overload disorder, HFE-associated hemochromatosis, that originated some 2,000 years ago as a mutation at a single point on a gene carried by a Celtic man or woman. The mutation, which produces a defective form of a protein called HFE (see page 44), spread throughout the world along routes of Celtic migration, eventually becoming common in the British Isles, Australia, the northwestern coast of France and the United States.

Today, in the Andrews lab, the use of mice with the same mutation is helping to show exactly how the gene defect leads to the disease. Experiments with these mice have revealed, for example, that iron buildup in the animals is caused by increased iron flux through the usual absorption pathway and not by the activation of some alternative pathway—information that could eventually prove useful in devising treatment strategies. The researchers also are zeroing in on genes that influence the severity of the disease.

Strains of mice with this and other mutations—both natural and engineered—are helping the Andrews team tease out the details of iron metabolism. Yet the researchers always keep human patients in mind.

"The fact that Nancy is a physician—that she sees patients and goes to conferences and hears about these problems—really keeps us on track when it comes to addressing questions that are the most relevant," says Angel Custodio, a doctoral student in the Andrews lab. "My conversations with her in the laboratory put my experiments in the context of what's happening in the clinic. Without that, it would be easy to invest time following avenues that wouldn't take us to the answers we really want."

"The 'why' [of research] can't just be that 'it's interesting,' or 'it's a major biological process,' although I think those things are very important," explains Andrews. Part of the 'why' also has to be 'how does this help advance medicine?' "

From Patients to Mice and Back Again
Andrews' dual roles as physician and scientist not only help her students and postdocs avoid blind alleys, but also lead to whole new paths to explore. For about a year, for instance, postdoctoral fellow Cindy Roy had been trying to develop a mouse model of an iron-deficiency disorder called anemia of chronic disease—the most common type of anemia in hospitalized patients. "Certain cells in the body—called macrophages—are responsible for recycling iron," says Roy, "but in chronic disease, the macrophages hang onto the iron instead of recycling it back to developing red blood cells." So although there's plenty of iron in the body, anemia results because much of the iron is trapped inside the macrophages, and there's not enough available for making new red blood cells. Roy realized that she had to breed mice genetically predisposed to this condition; trying to induce it in standard mice was "difficult to do without making them super sick," she says.

Meanwhile, as Roy labored in the lab, Andrews was learning from clinician colleagues about young patients with a metabolic disease that causes them to develop benign liver tumors. The intriguing connection to Roy's work was that patients who developed the liver tumors showed symptoms just like those seen in people with anemia of chronic disease. "Even if you give these patients intravenous injections of iron, they still can't make enough red blood cells," says Roy. "But if the tumor is removed, the anemia corrects very quickly."

The liver tumors, it seemed, were producing something that interfered with iron absorption and recycling, and the researchers speculated that this same substance might have a role in anemia of chronic disease as well. Comparing samples of tumor tissue with normal tissue, Roy found that the tumors contained abnormally high levels of a particular protein—one known to be involved in regulating iron absorption. Apparently, the tumors produce so much of the protein that iron recycling and absorption are completely shut off.

Armed with that knowledge, Roy now has a "candidate" protein—a handle on the fundamental cause of the condition—to look for in her mouse model system, once she establishes it. "It's kind of backwards," she laughs. "Usually the mice help us figure out what's going on in the patients, but in this case, the patients have helped us with the mice."

Whatever the order, progress has been made. Patients are a step closer to better health. Once again, shifting gears has helped Andrews and her lab move forward.

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Reprinted from the HHMI Bulletin,
March 2002, pages 18-21.
©2002 Howard Hughes Medical Institute