In recent years, however, Lifton's group has made a series of important findings establishing the powerful role of genes—in particular, mutations that alter salt metabolism—in this devastating disorder that affects one in four Americans.

The change in perspective resulting from Lifton's genetic studies, carried out by an energetic team of clinician-researchers at Yale's Boyer Center for Molecular Medicine, is reverberating throughout the biomedical community. "Thanks to Lifton's landmark research, hypertension is now in the mainstream of molecular medicine," says Joseph L. Goldstein, professor and chair of molecular genetics at the University of Texas Southwestern Medical Center and corecipient of the 1985 Nobel Prize in physiology or medicine for his research on cholesterol metabolism. Goldstein also heads HHMI's medical advisory board. It was, indeed, the prospect of overturning conventional wisdom that tantalized Lifton 15 years ago when he emerged from a residency at Boston's Brigham and Women's Hospital pondering where best to concentrate his energies. The young physician-scientist was already well equipped scientifically, having done graduate research in the Stanford laboratory of molecular biologist David Hogness. There, isolating genes in fruit flies, he learned new techniques of genetic manipulation and analysis. He also established an indefatigable, independent-minded research style, often working until three in the morning to chase down a result, grabbing a few hours' sleep and then returning to the bench at dawn to launch his quest for the next piece of data.

"I came out of residency and saw that there were a lot of smart people doing very good work on the molecular genetics of cancer, cholesterol disorders and diabetes," the soft-spoken HHMI investigator recalls. "Yet, here was this very common trait, hypertension, that affects 50 million Americans and is one of the leading causes of morbidity and mortality. And we knew almost nothing about the primary determinants of this disease." When he proposed to explore the genetic basis of hypertension, Lifton immediately encountered skeptics. He remembers people telling him, "Hypertension is just much too complicated to try to apply these tools to, and you should think about something else." Lifton recalls that such remarks "just made me all the more convinced that this was the right thing to be doing."

Rather than tackle the massive puzzle of hypertension in the entire population, he decided to narrow his focus to genetic disorders affecting blood pressure—choosing just those distinctive medical puzzle pieces that he could most readily fit together to begin building a picture of the disease. The approach echoed that of Goldstein and fellow Nobelist Michael Brown, who in the 1970s tackled the complexities of cholesterol metabolism by tracing the cause of familial hypercholesterolemia. Their discovery that people with the disorder lack receptors for low-density lipoprotein and thus cannot remove this form of cholesterol from the bloodstream led to a radically new molecular understanding of the illness and set the stage for the multibillion-dollar market for cholesterol-lowering drugs.

"I figured the genetic approach might allow us to get our foot in the door in terms of understanding some of the fundamental pathways that affect blood pressure," Lifton says. So he decided to search for rare, single-gene forms of high and low blood pressure, using them to gain clues to the overall pathways involved in blood pressure regulation. Lifton recalls that there was also doubt that even the targeted approach would prove fruitful. "The leading textbook on hypertension at that time made almost no mention of single-gene disorders that related to blood pressure, and there was a lot of skepticism that some of the diseases reported as single cases even existed as distinct entities," he says. "So it was a pretty murky start."

At that time, Lifton had taken a visiting faculty post at the University of Utah, but Brigham and Women's Hospital had also invited him to retain his clinical position there. This affiliation proved crucial when a colleague at the hospital, Robert Dluhy, encountered a patient with a rare form of hypertension called glucocorticoid-remediable aldosteronism, or GRA. Lifton immediately began a genetic study of the patient and her family.

"We began an investigation of this patient's family and fairly quickly acquired evidence that the disease was caused by a mutation in a particular gene," Lifton says. "However, the nature of the mutation proved elusive. We finally suspected that the mutation might be an unusual gene duplication that fused pieces of two normal genes to create a new gene with a different function. We devised an experiment to test this hypothesis. It was one of those seminal moments—coming back into the lab at three in the morning to look at the results. The autoradiogram was unequivocal and clearly showed that the head of one gene had been fused to the body of the other. This resulted in abnormal regulation of a critical steroid hormone. These are the rare moments of discovery and insight that we thrive on."

With this success under his belt, Lifton launched studies of every inherited form of high or low blood pressure for which he could recruit patients. After moving to Yale in 1993, he and his colleagues began studying a form of hypertension known as Liddle's syndrome, finding it to be caused by mutations affecting the renal epithelial sodium channel. Specifically, they focused on a defect that allowed a flood of salt into the bloodstream, raising blood pressure. Another key target for study became the gene encoding the mineralocorticoid receptor (MR) for the steroid hormone aldosterone, which regulates those sodium channels.

The first clue to MR's key role in salt balance came with the team's studies of a disease that had little apparent connection with high blood pressure. David Geller, a physician-scientist in Lifton's laboratory, was exploring a genetic disorder called pseudohypoaldosteronism type 1, which produces life-threatening loss of salt from the bloodstream at birth, along with other metabolic abnormalities. Geller discovered that the underlying cause of this "salt wasting" was a loss-of-function mutation in MR.

The scientists reasoned that if mutations causing loss of MR function produced salt wasting, perhaps mutations that increased the receptor's activity might cause salt retention and hypertension. Sure enough, when Geller began to study patients with early onset of severe hypertension, he became the first to pinpoint the specific mutations that overactivated MR, producing hypertension.

In one striking discovery, Geller, Lifton and colleague Paul Sigler reported last July in Science that a mutation in MR makes the receptor exquisitely sensitive to progesterone. They proposed that this finding explains why some pregnant women experience dramatic spikes in blood pressure: their mutant, progesterone-sensitive MR is activated by the 100-fold progesterone increase that occurs during pregnancy. Geller is now probing the molecular details of this mutation and scouting the possibility that mutations in other "nuclear receptors" resembling MR might cause entirely different metabolic disorders. Such mutations might affect the receptors for hormones, such as glucocorticoid, androgen and progesterone itself.

Researchers in Lifton's laboratory have also pinpointed mutations that lower blood pressure by impairing salt reabsorption in the kidneys. They have shown, for example, that diseases known as Gitelman's and Bartter's syndromes, which feature low salt retention and low blood pressure, can arise from mutations in any of four genes. These include genes that encode cotransporters that mediate reabsorption of sodium and chloride ions, as well as genes that encode specific potassium and chloride ion channels involved in this same process.

Studies of the salt-regulation pathway by Lifton and his colleagues have revealed mutations in four genes that raise blood pressure and in eight that lower it. That body of work has unequivocally established the genetic contribution to hypertension, says Oliver Smithies, an Excellence Professor in Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill and a leading hypertension researcher. "Dr. Lifton's research papers are a joy to read," says Smithies. "They go right to the heart of the problems he investigates."

Lifton's group is now zeroing in on an entirely new pathway that regulates blood pressure. Lifton says that he and his colleagues "have just started to crack one of the last remaining single-gene forms of hypertension." This pathway "looks like it's going to be more interesting than any of the others," he says. "It's almost impossibly exciting because we know the genes involved and the clinical consequences of the mutations. However, we have none of the lines to connect one to the other. It's like a skier seeing, after a fresh snowfall, nothing but virgin powder as far as the eye can see."

Clearly, Lifton still delights in scientific exploration. "What I find immensely exciting and satisfying about science," he says, "is just learning something new—figuring out the way nature has been working for millions or billions of years, the way a particular human disease has worked ever since people have been on the planet. Those rare moments of crystallization where you suddenly see into the problem—those are priceless. Those are the moments that drive you."

Photo: Harold Shapiro

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Reprinted from the HHMI Bulletin,
May 2001, pages 22-27.
©2001 Howard Hughes Medical Institute