Helen Hobbs

Helen Hobbs never devised a grand plan for her career. Rather, she has built a grand career on an extraordinary capacity to reevaluate and shift directions. This relentless flexibility and fresh thinking helped her pioneer a novel idea in the field of human genetics. Her work on heart disease, the leading cause of death in the U.S. and the world, has already led to the development of trailblazing therapies that reduce dangerously high cholesterol levels.

In high school, Hobbs enjoyed science, but her image of researchers was a caricature. Knowing that she gravitated toward people, she could not see herself as a solitary white-coated figure hunched over a lab bench. By college, she was studying art history. While writing about the use of color and space in a particular painting, she realized that even her most penetrating analyses would be subjective. Uncomfortable with the idea that her work would never reveal absolute truths, she decided to pursue art as a hobby rather than a profession.

Hobbs had enjoyed the one biology course she had taken in her first university year, so she turned to medicine, an arena that united her interests in people and science. After an internship at Columbia-Presbyterian Medical Center in Manhattan, she embarked on a residency at the University of Texas Southwestern (UTSW) Medical Center in Dallas. There, she was selected to serve as chief resident by the head of medicine, Donald Seldin. Hobbs relished unraveling the mysteries that ailed her patients. The mix of meaningful human contact and intellectual puzzles suited her perfectly, or so she thought.

Seldin saw Hobbs differently. He insisted that her mind would wither if she did not engage in experimental science.

Hobbs demurred, but her mentor was hard to ignore. Seldin knew her well and he had a knack for recognizing talent, so perhaps his advice was worth heeding. Indeed, she had noticed that almost every attending physician at UTSW ran a laboratory—and her mind percolated with questions after the impromptu lessons they imparted about their research.

Although Hobbs still didn’t envision a future in the lab, she joined Michael Brown and Joseph Goldstein’s in 1983. They would win the Nobel Prize in Physiology or Medicine two years later for their discoveries about the mechanisms by which the body controls cholesterol levels. This lipid plays essential structural roles in cell membranes and serves other vital purposes, but it turns hazardous when it builds up in the arteries.

Bench work did not come easily to Hobbs, and she frequently considered quitting. She had trouble sticking to protocols and tried to multitask too much, an approach that helped her in medicine, but not in experimental science. Still, she recognized others’ excitement when their results illuminated a crucial issue, and she wanted to persevere until she had that experience.

On a visit to her husband, who was training with the accomplished biochemist Efraim Racker at Cornell University in Ithaca, NY, she watched the senior scientist. At age 70-something, he was still pipetting away; at every step, he referred to a protocol tacked up in front of him.

If Racker needed to follow precise instructions, Hobbs realized, maybe she did too.

Her experiments started to work.

Hobbs was attempting to define abnormalities in the receptor that normally sucks a particular type of cholesterol particle—LDL cholesterol—from the bloodstream. Such defects underlie familial hypercholesterolemia, an inherited disorder characterized by extremely high LDL cholesterol levels, hardening of the arteries, and heart disease. Brown and Goldstein had identified a group of individuals who manufacture no detectable LDL receptor; in a subset of these individuals, Hobbs found, the LDL receptor’s messenger RNA was missing entirely.

When Hobbs looked up the names of the patients from whom these samples were taken, she realized that four out of five of them were French. Further exploration revealed that the individuals were French Canadian. A captivating thought struck her. Maybe they were missing a single common piece of the LDL receptor gene; if so, perhaps a common ancestor had bestowed this genetic quirk on all of them.

As Hobbs registered that possible meaning of the French names, she had her “aha” moment. Her subsequent investigations upheld the scenario she envisioned.

In 1987, she established her own lab at UTSW. Over the next thirteen years, she published dozens of papers and generated important information about cholesterol-containing proteins in the blood.

Then she realized that her research was on the wrong track.

At a scientific meeting, other investigators announced that they had pinpointed the genetic culprit for a rare inherited disorder marked by unusually small amounts of the so-called “good” cholesterol, high-density lipoprotein (HDL), which is associated with health rather than disease. As she listened to the talk, she realized that she should have made that finding, which uncovered new information about how cholesterol moves among tissues. In principle, she was perfectly suited to have done so, given her training as a human geneticist with expertise in lipid biology. Her work, however, had led her into studies on cells grown in culture dishes. En route back from the meeting, Hobbs decided to shift her focus to her professional sweet spot: She would use her clinical acumen in combination with genetics to expose DNA aberrations that underlie inherited medical conditions.

Success came quickly, and by the early 2000s, she had hit her stride. She not only identified genetic mistakes that cause rare familial illnesses, but also produced key insights into the disorders’ mechanisms.

Hobbs wondered, however, whether she could also figure out what sets cholesterol levels in the community rather than the clinic. Perhaps she could even find DNA changes that enhance rather than compromise health. To achieve these goals, she needed to look in the general population. With Ronald Victor, she had established the means for conducting such an inquiry. They had designed and launched the Dallas Heart Study, which was collecting detailed medical information from thousands of adults in the area.

With this potent resource, Hobbs and her scientific partner, Jonathan Cohen, set out to test a bold idea. Prevailing wisdom held that common maladies such as heart disease arise from widespread genetic variations that collude with diet and other environmental factors. In this view, each DNA tweak exerts a small effect; in combination, they generate a discernible trait. But Hobbs knew that single gene alterations cause serious problems and that people with the same illness do not necessarily share the same DNA flaws; sometimes the same clinical presentation even maps to different genes. She reasoned that the same phenomenon—infrequent single-gene errors—could promote common attributes such as risk-prone or risk-resilient cholesterol profiles.

As a first step toward homing in on rare genetic signatures that act in the general community, Hobbs identified people from the Dallas Heart Study with the lowest and highest HDL cholesterol levels. Then she and her colleagues searched for perturbations in genes that might contribute to these traits—genes known to underlie diseases characterized by dangerously low levels of HDL cholesterol. Changes in the same genes showed up disproportionately among people with very low HDL levels in the general population, thus providing support for Hobbs’s proposal.

The first journal to which Hobbs and Cohen submitted their results rejected the work without review. Apparently, the idea that uncommon genetic peculiarities could exert significant physiological effects—low HDL levels—in relatively healthy individuals seemed preposterous enough that the publication didn’t seriously consider accepting the paper. Science did, though, and it appeared there in 2004. The data created some tension because they contradicted the popular view that common diseases arise from multiple common variants, a premise that was motivating huge research projects.

Hobbs and Cohen stuck to their approach and deployed it to fuel their next major finding. By then, intriguing observations about a protein called PCSK9 were emerging. A defect in the PCSK9 gene had been associated with hypercholesterolemia, and it mimicked the effects of extra PCSK9. Surplus protein apparently instigates trouble by removing LDL receptors from the surface of liver cells, thus slashing quantities of the molecular machines that normally drain circulating LDL cholesterol.

If too much PCSK9 provokes high LDL cholesterol levels, Hobbs reasoned, perhaps too little would deplete the artery-clogging substance. If so, she might be able to unearth beneficial versions of its gene by analyzing DNA from people in the community with exceptionally low blood cholesterol levels. Once again, she and Cohen turned to the Dallas Heart Study. This time they sought flaws in the PCSK9 gene among people with the lowest LDL cholesterol levels from diverse ethnic groups. In 2005, they reported that seven African Americans possessed one of two distinct DNA anomalies in PCSK9. Then they checked the entire population—not just those with the lowest cholesterol levels. One in 50 black people in the Dallas study had one of the two PCSK9 alterations and, on average, significantly lower LDL cholesterol levels than those without one of the variants. Furthermore, the genetic irregularities are linked to an even more dramatic reduction in the incidence of heart disease. Because individuals without fully functioning PCSK9 carry small amounts of LDL cholesterol for their entire lives, these results suggested that modestly dampening LDL cholesterol level over many decades can slash the risk of heart disease.

By establishing that PCSK9 glitches are associated with low LDL cholesterol levels and protection from heart disease, the researchers presented an attractive therapeutic target. The promise of such a strategy gained steam when Hobbs identified a healthy individual who had two faulty copies of the PCSK9 gene, no detectable PCSK9 in her blood, and extraordinarily low levels of LDL cholesterol. This discovery suggested that a PCSK9-inactivating drug would be safe and effective. Several companies picked up the idea, and the U.S. Food and Drug Administration approved the first two PCSK9-targeted treatments last summer.

Hobbs’s open mind about herself as well as her science has helped her chart a new course for genetic studies of human metabolism. By showing that rare genetic deviations can deliver large effects in the general population, she has established a powerful tactic for elucidating biological processes that wield a tremendous impact on human health.

Author: Evelyn Strauss, Ph.D.