In 2006, the pharmaceutical giant Pfizer released a state of the art clinical study of a new drug designed to treat high cholesterol, torcetrapid. The results were puzzling. The compound lowered low density lipoprotein, aka LDL or “bad” cholesterol. It also substantially pushed up high density lipoprotein, or HDL, the “good cholesterol.” By all accrued medical wisdom, torcetrapid should have lowered the rate of cardiovascular events—heart attacks, strokes, and, ultimately deaths.
But it did not. Instead, it increased both—by 61 percent. Worse: more heart patients died than those in a control group. What had happened? Why hadn’t the “good” cholesterol improved their odds of living longer? The entire cardio-establishment went, well, tachycaric.
Not UCLA Professor Alan Fogelman. A subdued, compact man who cogitates quietly in an ornately decorated office full of Churchill portraits and custom chess boards, Fogelman has pursued the elusive molecule for nearly 40 years. His quest is not unlike that of a zoologist tracking down some strange and wondrous bird. Or, perhaps more precisely, a chameleon. “The reason HDL is constantly throwing a wrench into the whole business of cholesterol management is that it is not one thing all the time. It changes,” he says, “like a chameleon.”
Fogelman’s trek commenced in the late 1960s, when the recently graduated physician was interning at China Lake Naval Weapons Center. There he was struck by a peculiar aspect of the patient population: a disproportionate number of them were dying of heart disease. “It didn’t make any sense,” he recalls. “I mean, here was a pretty young population, guys in their thirties and early forties, and they had all kinds of heart problems. I kept coming back to that picture in my mind and asking myself: what is happening here? The great minds of the day were mainly focused on heart failure, which was important, but I kept asking `can’t we find some way to prevent it?’”
Fogelman next landed in a perfect place to find out: UCLA Medical School, then commandeered by the innovative Sherman Mellinkoff. Early work by UCLA pioneers and others had already elucidated the chemical structure of LDL cholesterol and showed how it might inflame arteries. What followed was a mammoth effort to characterize exactly what the molecule consisted of and how it worked.
What Fogelman et al found was mind boggling. LDL, at its core, is part of our innate immune system. It once had an important beneficial function. By oxidizing in a sudden burst, it allowed humans to fight off the enormous number of pathogens—virii, bacteria, etc—that were present in the pre-modern world, before better sanitation and antibiotics made such a robust system unnecessary. But LDL-driven inflammation led to plaque build-up, rupture and artery clogging. “LDL problems will be with human beings for a long, long time,” Fogelman says. Evolutionary processes have yet to eliminate it, he says, “because its ill effects come so late in life—long after the typical evolutionary sorting before reproduction takes place.”
Eventually, things like lifestyle modification and drugs, mainly statins, were found to lower LDL levels and cardiovascular risk. Similarly, LDL’s sister molecule, High Density Lipoprotein, or HDL, was found to have beneficial qualities: it seemed to transport bad cholesterol back to the liver, and, like a fireman, tamp down all the inflammatory molecules that the LDL had activated in the first place. There were more drugs, and more lifestyle recommendations. HDL levels went up in sizeable populations of Americans.
But by the late 1990s, Fogelman was asking a very uncomfortable question: if statins and such were so good at driving up HDL and driving down LDL, why did we still have so much heart disease? He theorized that HDL might be much more complicated than previously imagined, and then launched a new effort to characterize the molecule, from outer membrane to nucleus. What emerged was a complex ball of proteins--fats on the outside and enzymes and other anti-oxidants in the middle. The stuff in the middle constituted a powerful LDL “attack” system, one that could invade the insides of bad cholesterol and sweep the worst particles back to the liver before they did any damage. That’s what made HDL “good.”
In the process, however, Fogelman discovered something else: in a number of scenarios, HDL morphed into something entirely different. After the trauma of a surgery, for example, good cholesterol behaved even worse than the bad cholesterol. Why? Using bootstrap lab bench techniques—making his own chemical assays that can isolate specific proteins and enzymes—Fogelman began teasing out the phenomenon. He found that for several weeks after someone comes down with the flu, the “fighter” enzymes inside HDL become dysfunctional. The same held in kidney disease patients.
That wasn’t all. Bad HDL started popping up in the blood of patients with common chronic diseases—uncontrolled diabetes, kidney disease, rheumatoid arthritis and even sleep apnea. “We came to see that, in modern life, what was once a trauma-specific acute response had become one that was chronic, sometimes low level, but continuous.” Hence the higher levels of HDL-caused inflammation and atherosclerosis.
Perhaps this was why torcetrapid had failed as a cardiovascular drug: the compound pushed up the HDL in such a way as to make it pro-inflammatory. “HDL is a kind of chameleon in that it samples, say, a break in the skin, takes it back to the liver and `announces’ an acute phase reaction,” he says. “It is like a shuttle, and that shuttle can become pro-inflammatory under the right conditions.” Although he cautions that these observations are hardly ready for use in public health policy, they may have an impact on post-surgical care, wherein standard practice now encourages physicians to prescribe statins.
Fogelman’s expertise in HDL dynamics has also enabled UCLA to define a huge and promising new medical discipline: environmental cardiology, the study of how one’s surroundings interact with genes and behavior to instigate heart disease. A remarkable example was a study that came out in 2008 by the UCLA researcher Jesus Araujo, a Fogelman associate. Like Fogelman,
Araujo was taken with the question: why had heart disease remained so prevalent? Perhaps, he thought, it might have to do with smog. Epidemiologists had long posited a link between the two, but never came up with a causal explanation for it.
To find out, Araujo placed cages of genetically altered mice in two distinct locations—one alongside the Harbor Freeway, one in Santa Monica. He then used a machine to collect and analyze the exhaust fumes the animals were breathing. When Araujo later examined the mouse arteries, he found advanced artery disease in the ones parked next to the freeway.
One other thing: their HDL had become inflammatory.
Might there be a way to restore HDL’s good characteristics? That is exactly what Fogelman and colleagues are now trying to do. Currently there is at least one commercial study of a Fogelman invention—a molecule that “mimics” HDL’s fighter enzymes. Another, dubbed D-4f, was able to turn bad HDL into good HDL in lab monkeys. Both compounds are being developed by Bruin Pharma, a commercial venture headed by Fogelman and his UCLA associate Benjamin J Adsell.
What are D-4fs’chances? “It is so early to try to tell something like that,” he says. “We have no idea where that effort will take us, or whether it will hit the target we hope. We have to wait for the trials.
“After all, HDL—it’s a chameleon.”