| Perspectives on Texas

Heart disease is the No. 1 killer in Texas and the U.S., but thanks to an important discovery made at UT Southwestern Medical Center, it could one day be a thing of the past. The pioneering Dallas Heart Study launched by UT Southwestern geneticists Dr. Helen Hobbs and Dr. Jonathan Cohen yielded invaluable findings that led to a new class of drugs called PCSK9 inhibitors — the next generation of cholesterol-controlling medications. Clinical studies have shown these drugs dramatically lower LDL cholesterol levels and reduce heart attacks. The groundbreaking discovery has brought world renown to Dr. Hobbs — whose work is partially funded by the State of Texas — and placed the state among the leaders in heart research worldwide. It’s a true Texas story with heart.

Your risk of heart disease could be largely eliminated by mutating just one gene.

Until recently, there hasn’t been a major breakthrough in the treatment of heart disease since the 1970s, when two UT Southwestern Medical Center scientists discovered the low-density lipoprotein (LDL) receptor, which controls the level of cholesterol in the blood and in cells. Their discovery led to the development of statins, which are now used daily by millions of people to help lower cholesterol levels and reduce the risk of heart attack and stroke.

But while the LDL discovery has had a tremendous impact on extending human life (not to mention earning the two scientists, Dr. Michael Brown and Dr. Joseph Goldstein, a Nobel Prize), what has remained elusive — perhaps constrained to the realm of medical science fiction — is an outright cure for heart disease. After all, how do you cure a condition that’s caused gradually, over a lifetime? Could it be prevented from ever forming?

At the time Dr. Hobbs began working in Brown and Goldstein’s molecular genetics lab at UT Southwestern in the 1980s, the best answers doctors had for the prevention of heart disease were behavioral: Don’t smoke; watch your diet; avoid fatty foods and food containing large amounts of bad cholesterol; exercise regularly; and take statins. It was not clear what role blood cholesterol levels had relative to other risk factors in the development of heart disease. This was a question that Dr. Hobbs would answer.

It was while working in the Brown and Goldstein lab that Dr. Hobbs had her first taste of what it felt like to make a breakthrough, participating in a study that uncovered gene mutations that inactivated the LDL receptors, causing abnormally high levels of cholesterol. She discovered individuals who had the same mutation in the gene coding for the LDL receptor.  

“That was interesting and immediately raised questions,” she says. “Why did all of these people — if they’re not related — why do they all have the same mutation in the gene?”

She discovered that all those people with the same LDL receptor mutation came from the same region in Canada, and their ancestors traced their roots back to the same small region of France.

Research for Dr. Hobbs became more than experimental trial and error. Genetic research was an entrée into a larger story about the evolution of the human species. It was a story about the way our genetic markers are passed down through generations, expressed or isolated in cultural subgroups. And to answer the question of why any group of people displayed a certain genetic characteristic meant cracking a code that could have larger implications for the future of human health.

By 1999, Dr. Hobbs had established an independent laboratory at UT Southwestern, when another colleague, Dr. Sandy Williams, then the Chief of Cardiology, approached her with an idea.

The Donald W. Reynolds Foundation, a charitable organization that funded capital grants to research aging and quality of life as well as cardiovascular clinical research, was offering a decade-long grant at a whopping $6 million per year to a single research center to work in cross-disciplinary cardiovascular medicine.

They had six weeks to complete the proposal. To write it, Dr. Hobbs teamed up with Dr. Cohen and Dr. Ronald Victor, a hypertension specialist. They knew that the largest and most distinguished medical research facilities in the nation would be gunning for the grant — and that the chances of winning it were slim. To distinguish their proposal, they would have to take advantage of the flexibility and collaborative dynamic of their relatively young medical institution.

“We thought, ‘Well, if we’re going to do this, we have to really go for broke,’” she says. “’We have to write the best possible study we can think of, to ask the most important questions.’”

The first key to their proposal was an emphasis on genetic diversity. Dallas has a large, multiethnic population, which is attractive to geneticists because the oldest populations, and African-American populations in particular, possess the most genetic diversity. In order to increase their chances of finding mutations that might yield revelations, Drs. Hobbs and Cohen designed a longitudinal study that over-sampled from the African-American sector and had the flexibility to bring subjects back repeatedly to take new tests and follow up on any new developments if any interesting mutations were found.

The second key was an advanced and detailed approach to epidemiology. Most genetic studies seek to capture as large a segment of the population as possible, which can be costly and can favor the number of subjects over the quality of data collected from them. Drs. Hobbs and Cohen’s proposal instead opted to direct resources toward creating the most detailed subject profiles possible.

“We decided that for everything we measured, we would use the best, most accurate assay available,” Dr. Hobbs says. “We would have very precise phenotype traits. When we looked at the heart, we would use magnetic resonance imaging — the very best imaging modality of the heart. When we looked at fat in the liver, we didn’t use sonography but rather another methodology called proton magnetic resonance spectroscopy, which is much more accurate at measuring liver fat.”

When Dr. Hobbs decided she wanted to use an electron beam computerized tomography scanner that UT Southwestern didn’t have, she phoned the dean and asked him to commit to purchasing the million-dollar machine if they got the grant. He agreed. The final grant proposal told a compelling story of a medical institution coming together around a population-based genetic study of heart disease that would capitalize on its genetically diverse local gene pool and invest in collecting the most detailed medical assessments of any study of its kind. Drs. Hobbs and Cohen, joined by other colleagues from Dallas, flew to Las Vegas to present their proposal in the final round of considerations. They won.

“We were more surprised than anybody,” she says, “though we thought we had written a really great grant.”

Over the next three years, the team sent 50 people out into the field to knock on doors and ask questions about the family histories of random Dallas residents. The project eventually created detailed physiological profiles of 3,500 individuals and became known, famously, as the Dallas Heart Study. The team narrowed down which household member might make the best candidate for the study, and when the subjects were chosen, they underwent an array of tests. By 2003, Drs. Hobbs and Cohen and a team of other scientists at UT Southwestern had amassed a database of detailed medical profiles on a small but critical cross section of the population. They began analyzing their data by sorting their subjects into phenotypes and looking for extremes in the distribution of various traits. The first trait they looked at was high-density lipoprotein (HDL) cholesterol levels, isolating individuals with the highest and lowest HDL levels and sequencing the genes in the hope of finding shared mutations.

“We were asking whether there might be sequence variations that cause low HDL, not just in individuals with rare genetic diseases but in the general population,” Dr. Hobbs says. “And we found that was the case. We found that healthy people were riddled with mutations.”

At about the same time, a team of researchers in France discovered several French families with hypercholesterolemia, a condition of extraordinarily high cholesterol, who all shared a similar genetic mutation. The French researchers isolated the gene, which produces a protein called proprotein convertase subtilisin/kexin type 9, or PCSK9. When the French team published its research in 2003, Dr. Hobbs wondered if she could find similar connections between PCSK9 and cholesterol in the Dallas Heart Study participants. If the French researchers found that a high level of PCSK9 is related to high cholesterol, Dr. Hobbs wondered, were any of the Dallas Heart Study participants benefiting from the opposite effect? Was there a mutated form of PCSK9 that could result in low cholesterol?

After the discovery of the PCSK9 gene, several researchers were working to figure out how it affected cholesterol.

Another UT Southwestern scientist, Dr. Jay Horton, expressed the gene in the livers of mice and showed that the LDL receptors disappeared and the plasma level of LDL cholesterol increased dramatically. He concluded that expressing PCSK9 caused the cholesterol in the blood to increase. Hobbs and Cohen hypothesized that inactivating PCSK9 would have the opposite effect. To test that possibility, they sequenced the PCSK9 gene in the individuals in the Dallas Heart Study with the lowest LDL cholesterol levels to see if any had a PCSK9 mutation.

It wasn’t long before they found something interesting. Among African-Americans, the population that the study had over-sampled, the scientists found that PCSK9 mutations were relatively common, occurring in one of about every 50 African-Americans.

Not everyone who had the mutation had extremely low levels of LDL cholesterol, but individuals with the mutation possessed on average cholesterol levels that were 40 percent lower than the general population’s. What Drs. Hobbs and Cohen’s study had delivered was a direct correlation between the mutated PCSK9 and lower levels of LDL cholesterol. They took this discovery and used it to analyze the subjects in a similar heart study conducted out of the University of Texas Health Science Center at Houston, which had data going back to 1987. With their collaborator in Houston, Eric Boerwinkle, they found that subjects in the Houston study with the PCSK9 mutation had dramatically lower rates of heart disease.

“Like an 88 percent reduction in heart disease,” Dr. Hobbs says. “So, what does that tell you? That tells you, if you have a low LDL from the time you’re born, you’re basically protected from heart disease.”

The discovery raised plenty of questions. If PCSK9 played such a significant role in how cholesterol is distributed in the body, could the mutated gene be a key to future treatments that could regulate cholesterol levels, paving a way toward drug treatment regimens that could dramatically reduce the rates of heart disease? Perhaps, but there were still a lot of unknowns. For example, if eliminating PCSK9 could reduce cholesterol levels and help prevent heart disease, would it also increase the likelihood of other health complications?

“The beauty of human genetics is that you can see directly the effect of inactivating a gene,” Dr. Hobbs says. “In this case, we knew that inactivating PCSK9 would lower LDL levels. But the thing you worry about when developing a therapy is what will be the effect of inactivating a protein too much.”

To address this potential problem, Drs. Hobbs and Cohen looked for someone among their subjects who had no PCSK9 and found an aerobics instructor in her 40s. She had inherited the mutated PCSK9 gene from both parents. Her good physical and mental health indicated that the mutated gene did not have major adverse health effects, at least in one individual.

Through the Dallas Heart Study, the team found that 2 percent of African-Americans in Dallas had a mutation in PCSK9 that inactivated the protein, an anomaly that correlated with a markedly lower plasma cholesterol level. They discovered that this group was protected from heart disease despite risk factors such as smoking, diabetes, and hypertension. The revelation paved the way for the development of a new strategy to prevent heart disease, based on this one genetic trait that Dr. Hobbs had found. Her research earned her the Breakthrough Prize in Life Sciences and blew open the field of cardiovascular science.

Based on the findings of the Dallas Heart Study, drug companies have now developed treatments for reducing cholesterol by replicating the way the mutated PCSK9 inhibits the destruction of LDL receptors.

But adapting science that works in a test tube into clinical treatments is never simple. Because of the biochemistry behind the way PCSK9 interacts with LDL receptors, it’s unlikely such a treatment could be packaged in a pill, and attempts to do so have been abandoned. However, two companies have developed an anti-PCSK9 monoclonal antibody that can be injected; these are now approved for use by the FDA. Clinical trials show that these treatments reduce LDL cholesterol levels dramatically and also reduce heart disease. The dream for pharmaceutical researchers is a treatment that would essentially function as a new statin.

Dr. Hobbs consults for the pharmaceutical companies working to develop new medications based on her discovery, and, meanwhile, she and Dr. Cohen continue research that will benefit Texans in other areas as well. The Hobbs-Cohen laboratory at UT Southwestern identified the first genetic cause of nonalcoholic fatty liver disease, an increasingly common disorder that is associated with cirrhosis and liver cancer. Liver disease is especially prevalent in Texas — making it an important target for new discovery and therapies by this groundbreaking team.