LEADING MEDICINE

FAMED SWEDISH SCIENTIST JOINS METHODIST TEAM TO DISCOVER NEW APPROACHES TO FIGHT DISEASE

By Patti Muck Like generals mapping a battle strategy, Drs. Jan-Åke Gustafsson, Willa Hsueh and John Baxter talk about the next line of attack against the obesity epidemic.

“Sixty percent of the U.S. population is overweight, and 30 percent is obese,” Hsueh reminds her colleagues as they discuss the war against diabetes, heart disease and other leading killers. “Drugs for these are desperately needed.”

“There’s only one way to move data from the laboratory bench to the bed of the ailing patient, and that is patenting and commercialization — making companies,” Gustafsson points out.

As Baxter and Hsueh talk in the conference room of their laboratory at The Methodist Hospital — joined by Gustafsson via telephone from Sweden — their animated conversation moves from one topic to the next, but the focus remains clear: how to translate scientifi c knowledge into drugs that can help sick people.

“We go from atomic resolution — understanding how the drugs work — to biochemical and molecular biology testing to animal testing, and we’re hoping now to expand our program so that we can develop compounds that will have impact,” Baxter explains.

Just six months since his arrival in Houston from his native Sweden, Gustafsson already has several research and development strategies under way with Hsueh and Baxter. He leads the developing Center for Nuclear Receptors and Cell

Signaling, an integrated joint center between the University of Houston and The Methodist Hospital Research Institute.

The center is partially funded by a $5.5 million grant from the

Texas Emerging Technology Fund.

An expert in nuclear receptors, Gustafsson works closely with Baxter, who heads the Research Institute’s genomic medicine core, and Hsueh, who directs diabetes and metabolism research. This high-powered partnership and crosslaboratory collaboration holds the potential to discover new ways to control nuclear receptors, the docking stations in our cells’ nuclei that regulate cell behavior and control the body’s metabolic and disease processes.

As the Research Institute continues adding leading medical experts to its impressive roster, director Dr. Michael W. Lieberman, looks at this latest hire — Gustafsson holds a joint appointment in the Research Institute — as “a very proud hour.”

Dr. Jan-Åke Gustafsson

“Though this is a new place and a new culture, these are people who know and like and trust one another, and they’ve worked together for a long time,” Lieberman says. “They’re all creative, they’re all smart, they all talk fast, they all think fast. With Willa, Jan-Åke and John in the same room — you stay out of their way and expect them to do great things.” For three years, Jan-Åke (pronounced Yan á key) Gustafsson explored employment opportunities in the United States. He was approaching retirement age in Europe with no will to quit — “I want to be active until I die, which I hope is many years from now,” he says.

He had several good offers, including one from Yale University. But when Baxter, his longtime friend and collaborator, urged him to visit Houston, the next chapter of his internationally acclaimed career started to take shape.

During his recent phone conversation with his colleagues, he was tying up loose ends in Sweden and fi nalizing his permanent relocation to Texas. His wife, Margaret Warner, a fellow research scientist at Karolinska Institutet in Stockholm, is also part of the new team in Houston.

Lieberman says working with higher education through partnerships with the University of Houston, Rice University and others makes sense because each partner gains from the others’ knowledge. The universities offer expertise in biomedical engineering, applied mathematics, chemistry, physics and computational science. Combine that with Research Institute physicians skilled at pathophysiology, clinical trials and translational research, and the collaborative potential is limitless.

“It’s a culture that encourages risk-taking,” Lieberman says. “It’s interdisciplinary research — we do things around disease problems, not around disciplines. We always have our antennae out; we’re always fi ltering new leads. It’s a very heady environment.”

Gustafsson brings with him international fame gained from years of lectures and award-winning scientifi c research. He is former chairman of the Nobel Assembly of the Karolinska Institutet and led studies on receptors and hormonal control of liver and prostate cancer funded by National Institutes of Health grants.

Together, he and Baxter cofounded a biotechnology company in the late 1980s. Now, their careers have converged in a rich intellectual melting pot where brainstorming grows the seeds of new ideas with fi nancial and institutional commitment behind them.

Hsueh, Baxter and Gustafsson are attacking disease on a broad front. Using nuclear receptors like estrogen receptor beta (ER Beta) and liver X-receptor beta (LXR beta) — both discovered by Gustafsson and his team — the scientists hope to develop compounds targeting atherosclerosis and its complications, including bad cholesterol, triglycerides, lipoprotein and atherosclerotic lesions that cause heart attack and stroke. They believe they can develop medicines that will suppress appetite in the brain and attack infl ammation that damages blood vessels.

At least three new pills — including one called the “exercise pill” — are under development. One pill will use a nuclear receptor to reduce bad cholesterol, eliminate body fat and reduce atherosclerosis in the arteries — a statin-plus type of drug that mimics the effects of exercise without the actual exercise.

Hsueh is working to identify diagnostic markers that will pinpoint patients harboring “angry fat,” or fat that seeps out of its own cells and starts invading other tissues, causing a host of problems throughout the body. “I’ve become known as Dr. Angry Fat because we talk about bad fat, and in my opinion, it’s a primary cause of metabolic syndrome,” she says.

All three lament what they see as a regulatory environment that makes it nearly prohibitive to get a new drug to market these days. Most pharmaceutical companies have stopped developing new drugs to combat problems like diabetes and cardiovascular disease, and at a time

when Hsueh, Baxter and Gustafsson say new medications are needed more than ever before.

Scientists and academic medicine have a big gap to fi ll. “We must develop data that becomes so compelling that surely people are going to scream, ‘We need these drugs,’” Baxter says. A partnership like theirs, they hope, gives them the necessary resources and wherewithal to do what pharmaceutical companies have been unable to do. “What really counts in our souls is if we can say that we have helped patients,” Gustafsson says. “If we can say our research contributed to developing a drug that really helped patients from suffering, then our careers will have been successful. That’s what we are trying to do in Houston now — to set up structures where this might be possible. !

Jan-Åke Gustafsson, M.D., Ph.D.

Professor, Department of Biosciences & Nutrition

Education

Ph.D., Dept of Chemistry, Karolinska Institutet, 1968 M.D., Karolinska Institutet, 1971

Career/Academic Appointments

1964 Bachelor of Medicine, Karolinska Institutet, Stockholm 1971 Associate Professor in Chemistry, Karolinska Institutet 1976 Professor of Chemistry, Karolinska Institutet 1978 Professor of Chemistry, University of Gothenburg 1979 Professor of Medical Nutrition and Chairman of the Dept of Medical Nutrition, Huddinge University Hospital, Karolinska Institutet 2006-2008 Professor of Medical Nutrition and Chairman of the Dept of Biosciences and Nutrition, Karolinska Institutet

Administrative Positions

1985 Director of the Center for Biotechnology, Huddinge University Hospital, Karolinska Institutet 1987 Founder of KaroBio AB (a campus-situated biotechnology company sponsored by pension and governmental funds with about 80 employees) 2004-present Coordinator for the EU funded CASCADE Network of Excellence

Board Certifi cation

Has been member of the Faculty Board of the Karolinska Institutet and regularly carries out various assignments for the President’s Offi ce of the Karolinska Institutet Awards Committee Member, Endocrine Society, USA 2002-06 Elected Member of Council (Board) of Endocrine Society, USA, 2007

Professional Honors & Recognition

International/National/Regional

2008 International Member American Philosophical Society 2005 Descartes Research Prize for excellence in scientifi c collaborative research 2005 2nd Ernst Knobil Memorial Lecture, San Diego, USA 2004 Medal from Biomedicum Helsinki 2004 Bristol-Meyers Squibb/Mead Johnson Award for Nutrition Research 2003 FEBS Lectureship Datta Award 2002 Commandeur dans l’Ordre des Palmes Académiques 2002 Foreign Honorary Member of the US National Academy of Sciences 2002 Chairman of the Nobel Assembly of the Karolinska Institutet 2002 Fred Conrad Koch Award (Endocrine Soceity USA) 2001 The AF Group Prize for the creation of Novum Research Park 2001 Lorenzini Gold Medal, Lorenzini Foundation 2001 Vice chairman of the Nobel Assembly of the Karolinska Institutet 2000 One of ISI Top 258 Researchers in Biology & Biochemistry 2000 Garvan International Fellow 2000 Burroughs Wellcome Fund Lecture 2000 Foreign Honorary Member of the American Academy of Arts and Sciences 2000 European Medal, British Society for Endocrinology 2000 Curt Nicolin’s Prize for Achievements for the Development of South Stockholm 1999 Medal of the IngaBritt and Arne Lundberg’s Research Foundation 1999 Fogarty Scholar NIH 1998 Adjunct Member of the Nobel Committee of the Karolinska Institutet 1998 The Söderberg Prize in Medicine 1998 Member of the Swedish Academy of Engineering Sciences 1997 Member of the Swedish Academy of Sciences 1994 Gregory Pincus Medal and Award, Worcester Foundation 1992 Keith Harris Lecture, Australian Endocrine Society, Adelaide 1992 The Anders Jahre Prize, Oslo 1992 Medal from Collège de France, Paris 1990 Honorary Member of the American Society for Biochemistry and Molecular Biology 1986 Honorary Member of the Japanese Biochemical Society 1986 Member of the Nobel Assembly of the Karolinska Institutet 1983 The Fernström Prize of the Karolinska Institutet 1982 The Svedberg Prize in Chemistry, Stockholm

University

2008 EMD Serono President’s Distinguished Lecture: “Estrogen Receptor-Beta and Reproduction”. Annual Meeting of the Society for Gynecological Investigation, San Diego. 2008 Honorary Professor at the Beijing Normal University 2008 Honorary doctorate in Medicinal and Pharmaceutical Chemistry at the University of Milan 2007 Honorary Professor at the University of Chongquin, China 2007 Honorary doctorate in Medicinal and Pharmaceutical Chemistry at the University of Milan 2004 Guest Professor at the University of Science and Technology of China, Hefei 2003 J.G. Moore Visiting Professor, UCLA, USA 2003 Marius Tausk Visiting Professor at the Leiden University Medical Centre (LUMC) 2003 McDowell Lecture in Physiology, King’s College, London, U.K. 2002 Burroughs Wellcome Fund Visiting Professor in the Basic Medical Sciences at the University of Texas Medical Branch School of Medicine 2000 Center for Bioenvironmental Research Distinguished Visiting Professor, Tulane University, New Orleans 1995 Sterling Visiting Professor, University of Pennsylvania, Philadelphia 1991 Consultant to The Rockefeller University Hospital 1987 Adjunct Full Professor at the Department of Cell Biology, Baylor College of Medicine, Houston, Texas

Bibliography

Has more than 1,300 peer-reviewed publications