At UConn, two key players’ paths cross again

The first time they met, in the early 1980s, Frank Torti and Edison Liu were newly minted doctors, Liu training to be a cancer specialist at Stanford University and Torti a young oncology professor who taught him.

Soon after, they would both shift their focus to basic science, motivated by what they expected would be tremendous changes in the way cancer could be studied and treated.

Their careers continued to evolve in parallel in the three decades that followed. Both went to work for research universities in North Carolina. Liu would later develop and run a genome institute in Singapore, while Torti spent time running the U.S. Food and Drug Administration.

Now, Liu and Torti’s paths are crossing again, this time as key players in two of state government’s biggest investments — critics say gambles — for Connecticut’s economic future.

Last month, Torti took the helm of the UConn Health Center, where the state is investing $864 million to expand the medical and research capabilities. Since January, Liu has led The Jackson Laboratory, the Bar Harbor, Maine-based genomics firm developing an institute on the health center’s Farmington campus with $291 million in state funds.

It comes at what both Torti and Liu see as another turning point for scientific research.

“The very interesting thing is that you can track the careers of Frank Torti and Ed Liu as a little bit of metaphor for where oncology, and to a certain degree experimental oncology, has evolved,” Liu said.

“We’ve known each other a long, long time. We have great respect for each other,” said Torti, UConn’s vice president for health affairs and medical school dean. “Even more than the friendship is the sense of a common vision about the future of medicine.”

That vision is rooted in the increasing capability of researchers to decipher the genetic codes for living organisms and study the complex factors that contribute to disease and how people respond to treatment.

“My feeling about this is that medicine of the 20^th century, and medicine even of these first years of the 21^st century, will be laughed at some years from now, and not many years from now,” Torti said. “Just the way we sort of chuckle when we remember that people were doing bloodletting…We even laugh at some of the treatments of just 50 years ago, as just not having any basis in scientific evidence.”

Liu calls the changes in biology at the start of their careers an “inflection point.” Now, he said, science has reached another one — something at which he hopes Jackson Laboratory and Connecticut’s research universities will be poised to lead.

New tools, methods

Both men started their careers as cancer doctors, Torti with a medical degree from Harvard, Liu with one from Stanford.

Torti said he chose the career for a simple reason: “I’ve always wanted to cure cancer.”

Liu said he was influenced by a mentor they shared at Stanford, Dr. Saul Rosenberg. “He was a real mensch,” Liu said, using the Yiddish term for good guy.

Rosenberg was the sort of doctor who could walk into a room and, even if he could do nothing to cure the cancer, made patients feel better, Liu said.

Soon, the tools oncologists had to help their patients would change significantly, enabled by the shifts in biology that led both Liu and Torti to alter their career paths.

For the first time, researchers were beginning to understand how genes functioned normally, and how certain genes could transform a normal cell into a cancer cell, Torti said. Liu described a shift from a science based on observation to one in which researchers focused on understanding the individual parts of the biological system, identifying and sequencing individual genes to see how they worked within cells.

Thinking the future of cancer treatments lay in molecular biology and genetics, Torti decided he should be retrained and took on a fellowship in 1984 to learn molecular techniques so he could run a basic science laboratory.

Liu, who had planned to be a clinician, found himself curious about molecular biology and decided to seek training at the University of California San Francisco. He got “swept up in the beauty” of the science, he said.

Increasing complexity

Liu left California in 1987 for a position at the medical school at the University of North Carolina at Chapel Hill. Six years later, Torti moved to North Carolina to direct Wake Forest University’s comprehensive cancer center.

The two kept in touch from time to time, even after Liu moved to the National Cancer Institute and then overseas to build and lead the Genome Institute of Singapore.

The institute focuses in part on the emerging fields of genomics and computational biology — that is, studying how all the genes in an organism interact, and using mathematical techniques to make sense of the massive amount of data that is now being produced about those genes and their interactions.

Liu’s time in Singapore gave him a close-up view of the intense focus Asian countries place on science, which is seen as a way out of poverty.

“There’s no natural resources in Asia,” he said. “Manufacturing is technology applied, and so everything is based on management of human capital and harnessing the scientific trends. And they do it, quite frankly, not even for human health. They do it primarily to ensure that their countries are rising, because as far as they’re concerned, you can’t have health unless the economy is stable.”

Liu returned to the United States in January to become president and CEO of Jackson, an institute aimed at studying genetics, primarily in animals, as a way to understand human diseases. The creation of Jackson’s Connecticut institute is intended to give the firm a larger role in studying human diseases and treatments — something for which UConn’s access to patients and clinical expertise will play a key role.

Of his relationship with Torti, Liu noted, “It’s fallacious to think that just because we know each other it’s going to guarantee success, or that we would be devoid of conflict because we represent institutions that have their own interests.”

But, he added, “There’s no question that if you do know each other and trust each other and have a long history of trust, that you tend to work out problems faster and easier.”

Torti said it’s “delightful” to be working with a partner with a common vision.

“It makes the whole job that I have so much easier, because we don’t have to sort of forge or negotiate a common vision,” he said. “We both know what the next steps need to be, and we both have an appreciation of what really good people and good recruits are in these areas.”

Cancer and beyond

The advances that led Torti and Liu back to basic science three decades ago had implications for how doctors targeted cancer. The chemotherapy they had been using was imprecise, targeting cells indiscriminately.

“It was a little bit more like carpet-bombing at that time,” Liu said.

Being able to identify specific genes that produced mutations that drove cancer growth gave researchers targets for more precise therapies.

Now, the next step, Torti and Liu said, involves being able to study the entire genome of a creature and understand how the pieces interact.

“We’re ready for that next inflection point, where we can now ask the question, ‘If you have a disease, tell me how all genes interact to give you that disease, and if that’s the case, then why is it that some people respond to therapies and others don’t?’” Liu said.

Why does someone live to be 100? It’s not because of one gene, he said, but a robust system. Studying all the genes in an organism and how they interact, something fast-evolving technology now allows researchers to do, can offer clues about why some people with a disease respond to therapies and others don’t.

Liu likened it to going from being blind and feeling an elephant’s tail to seeing the entire elephant.

Torti described it as moving from looking at one gene under a microscope to looking through a telescope at a galaxy.

While cancer treatment is more precise than in the “carpet-bombing” days, it’s still imprecise; most patients with a certain type of cancer are likely to get a treatment that will work in some of them, but not all, while exposing them all to toxicities.

“Now, is it worth doing that? Yes it is, because some patients really benefit enormously,” Torti said. “But is that the future? I don’t think so.”

The future, he, Liu and others believe, is to better identify which patients will respond to particular treatments, based on their genetics as well as other factors. The concept is frequently referred to as personalized medicine.

It could mean determining that a drug won’t work in a particular person because his or her genetics causes the drug to be metabolized too quickly to be effective. Or it could focus on drug delivery; perhaps a treatment isn’t working because a tumor is blocking the blood supply that would carry the treatment there. To determine that, patients could get a very low dose of the drug that wouldn’t cause toxicity, allowing clinicians to see if it can reach the target.

Liu noted that the same principles can be applied to fields beyond biomedicine and human health, including agriculture, animal husbandry and environmental studies. He and his former oncology professor now represent two institutions with focuses far broader than cancer, and both say the advances in medicine will stretch beyond their original field.

Torti hopes UConn will build on the drug delivery aspects of personalized medicine, and develop work on the interface between genetic and environmental factors in disease. As an example, he cited prostate cancer. The disease is far less common among Asians than Caucasians, but when Asians move to the U.S., within a generation they become far more susceptible to prostate cancer, a change that occurs far too quickly to be genetic. Some experts believe it could be related to diet; perhaps the Asian diet is protective against prostate cancer, while the Western diet makes men more susceptible.

“There’s this connection between diet, which is a kind of environmental susceptibility, and the genetic,” Torti said. “How do you tease those out?”

Scientists understand much of what makes normal cells behave, and often know just what genetic abnormalities occur in cancer, Torti said. The challenge now is to figure out how to develop treatments that will intervene.

“We’re right on the cusp now,” he said.