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A Tradition of Mentoring
by Susan Sample

Wise Words from the Past Help Sung Wan Kim See the Future of Drug Delivery, Train New Scientists

Black-and-white photographs of two men stand out among the many accolades, penned in languages from around the world, in the office of Sung Wan Kim, Ph.D.

"They are my teachers," explained the distinguished professor of pharmaceutics and pharmaceutical chemistry at the College of Pharmacy.

One man, shown in front of a blackboard, has died; the other just celebrated his 90th birthday thousands of miles away. Yet Kim uses the present tense to describe his relationship to both with the same precision he designs complex polymeric gene carriers. That's because the late Henry Eyring, Ph.D., and Willem Kolff, M.D., Ph.D.-two of the greatest mentors at the University of Utah-will always be Kim's teachers: their words of advice not only have inspired the pharmaceutical scientist to reach the same high academic standards, but also have enabled him to envision the future direction of his science.

"Henry taught me to be bold in my thinking and approach each problem from a fundamental point of view," said Kim. "Pim Kolff showed me how to plan research and obtain funding, conduct research effectively and remain at or beyond the cutting edge of a research field."

Those challenges continue to motivate Kim, who has helped define the field of drug delivery. For nearly 20 years, he and Jindrich Kopecek, Ph.D., D.Sci., co-directors of the University's Center for Controlled Chemical Delivery (CCCD), have chaired a biennial international symposium on drug delivery. The published proceedings have become the subject's textbook.

"Gene therapy is the ultimate research scientists can do. The genome sequence is almost finished," said Kim. "The next stage is functional genomics, which will identify many proteins produced in our body. Then, we can learn their functions and use the proteins for therapy.

"There will be no more new drugs," Kim predicts. "Gene therapy is the highest technique physicians will use to treat patients."

That's where Kim is working now. He is one of two researchers whose work on nonviral vectors was described in the Nov. 23, 2001, issue of Science as offering "a glimpse of future gene therapies." The article described the TerplexDNA system Kim designed, which successfully delivered therapeutic genes to rabbits with heart disease, and another that used a soluble degradable polymer to deliver DNA to the white blood cells of mice, preventing the onset of type 1 diabetes.

"Despite the complexity," acknowledged the journal, "it's beginning to work."

Just five years ago, few journals would accept Kim's work on nonviral vectors. "They told me the transfection was too small," he said, referring to the amount of DNA the polymer is able to transport into the cell, where the gene can produce proteins to correct or modulate disease. "But I showed in animals that it was working," said Kim, now a member of the Gene Therapy editorial board.

"The maxim of pharmaceutical science is: the smallest dose with the greatest efficacy. We have 50 publications to prove that a small amount of transfection is effective. I'm very optimistic that our system will be used successfully in human patients."

Others are, too. "Sung Wan wants his science to improve human health care," noted John W. Mauger, Ph.D., dean of the U College of Pharmacy. He'll succeed, he said, because "Sung Wan knows what's important. A lot of people can identify a problem but can't pose it as a viable research problem with a methodology that tests a premise. Sung Wan provides an environment for good training and the high standards to reach it."

At the Second Asian International Symposium on Polymeric Biomaterials Science, held in Korea two years ago to honor Kim on his 60th birthday, the dean told the audience of 400, "Dr. Kim has built his drug delivery research program around the idea that it must be linked with new and needed therapeutic strategies. I find that his research is particularly rich, since it couples basic science with strategies for the treatment of disease, such as insulin-dependent diabetes."

"A tablet was a tablet was a tablet" is how Mauger described the state of drug delivery 25 years ago. "What was important was the drug itself." If the correct amount of a drug was prescribed, it was assumed that the effect would be standard among all patients. But a study of digoxin in the early 1970s found that the tablets weren't delivering all of the drug, and the time frame for the tablets' effectiveness varied among brands.

"Tablets were discovered to be more than inert delivery vehicles," said Mauger, professor of pharmaceutics and pharmaceutical chemistry. As a result, the academic discipline of pharmacy began to evolve, focusing "not only on the pharmacology and chemistry of drugs, but how to safely and selectively deliver drugs, reduce toxicity and be effective."

Kim was one of the first researchers in the world to consider using biomaterials for drug delivery. His academic background uniquely qualified him. A graduate student at Seoul National University, he met Eyring in 1963, when the distinguished professor of chemistry was visiting Korea. Eyring helped Kim obtain a fellowship to the U, where he received his Ph.D. in physical chemistry six years later.

"My next fortune was to study with Willem Kolff," said Kim. Kolff, distinguished professor of both medicine and surgery, and research professor of bioengineering, directed the Institute of Biomedical Engineering, where he was investigating the biocompatibility of polymers and pioneering artificial organs. "I was immediately interested in his research," recalled Kim.

Considering himself "too old to go to medical school," the 29-year-old Kim sat in on a number of medical school courses. "I acquired enough knowledge in hematology and physiology to carry out research in blood-compatible polymers." The Hematology Study Section of the National Institutes of Health agreed, granting Kim a Research Development Award in 1976.

By that time, he had joined the faculty of the U College of Pharmacy. "I felt strongly that biomaterials research could be combined with pharmaceutics research, with the primary aim of improving therapeutics through improved drug delivery systems," said Kim.

Since then, Kim has researched hydrogels, biodegradable drug conjugates, self-regulating drug delivery and stimuli-sensitive polymers. He has published more than 450 scientific papers and owns 25 U.S. patents for his discoveries. Among the numerous honors he's received are the Dale Wurster Award from the Association of Pharmaceutical Scientists, the Controlled Release Society Founders' Award and the Clemson Basic Biomaterials Award.

In 1999, he was elected to the Institute of Medicine of the National Academy of Sciences, the only member nationwide from a pharmacy college.

Adhering to his mentor's advice, Kim continues to look beyond: to gene therapy. While he estimates that 90 percent of gene therapy researchers are focusing on the use of viral vectors to deliver gene therapy, he is among the 1 percent investigating polymeric carriers. "I believe," said Kim, "that novel polymeric materials can solve many different types of drug delivery problems.

"There are 200 clinical studies under way using the viral vector concept. But the drawbacks we are facing at the moment are toxicity and immunogenicity, which affect the gene adversely."

Viruses, by their very nature, are excellent carriers. They can "bud" or fuse with a cell and transfer DNA into the nucleus, where it produces RNA, which, in turn, makes the therapeutic protein. However, viruses pose long-term safety concerns.

"How long does one injection last? We don't know the effective dose," said Kim. A patient in a 1999 clinical gene therapy trial in Pennsylvania died, because his immune system overreacted to the virus.

"We also don't know the fate of the virus. Some of it is integrated into the chromosome. We don't know what the consequence of that will be in 10 years."

Polymeric carriers, on the other hand, are nontoxic, biocompatible and biodegradable, according to the U researcher. They are less expensive and easier to mass-produce and handle, and they are smaller than viral vectors. Although the transfection rates of polymeric carriers have been criticized by some as too low, Kim sees the issue as an advantage.

"Expression of the therapeutic protein is smaller with polymers, but optimal delivery means the smallest dose with the greatest efficacy. Our approach is repeated injection: once a month for three months, for safety reasons," he said. "The worst case scenario with our delivery system is that the doctors would have to go back and offer conventional therapy."

Kim considers the polymeric carrier he designed for delivering interleukin-4 (IL-4) to diabetic mice his most important work in gene therapy so far. PAGA is a water-soluble biodegradable polymer that is injected, along with the therapeutic gene IL-4, into the bloodstream, where it is targeted for T cells. The gene produces proteins that circulate to the pancreas, where they block the auto-immune response that causes type 1 diabetes. He found that one injection was enough to stop the diabetic process.

"The best treatment," Kim feels, "would be to administer this to newborns and young children," who most frequently are diagnosed with type 1.

In another recent trial with animal models, Kim collaborated with David A. Bull, M.D., associate professor of surgery at the U medical school, to show that a novel nonviral gene carrier Kim designed successfully delivered therapeutic genes to rabbits with cardiovascular disease. Specifically, the researchers used the TerplexDNA system-derived from stearyl-poly(L-lysine)(stearyl-PPL), low-density lipoprotein (LDL) and plasmid DNA-to deliver VEGF (vascular endothelial growth factor) directly to the heart tissue of rabbits with myocardial ischemia. They compared transfection rates with those obtained through the injection of naked plasmid DNA (which doesn't use any type of vector) and found that transfection was 20- to 100-fold higher with TerplexDNA.

The polymeric carrier also produced more widespread and uniform transfection at the injection site. In studies with rats, the researchers found the TerplexDNA transfection rates remained higher for 30 days. Next year, they hope to begin clinical trials using TerplexDNA to treat about six patients with ischemic heart disease.

Kim and Bull also used TerplexDNA to deliver genes to various organs in rats through repeat injections. Their studies indicate that, due to the unique properties of the polymeric carrier, it is possible to achieve effective transfection rates with repeated therapy, which may have clinical applications for the treatment of human heart disease.

Several of Kim's other gene therapy projects also could significantly impact future clinical treatments. He is collaborating with Wolfram E. Samlowski, M.D., professor of internal medicine in the medical school's Division of Oncology, to treat several types of cancer. In studies of mice with renal carcinoma and lung cancer, the researchers used WSLP, a water-soluble lipopolymer Kim designed, to deliver interleukin-12, a gene that has been found effective in retarding tumor growth. They also used PAGA, a biodegradable polymer-based cytokine gene delivery system, to carry interleukin-12 to colon cancer cells. In both studies, gene therapy was administered through injections directly into the tumors.

As proud as the distinguished professor is of his research, Kim feels that "my greatest accomplishment is the training of young scientists and watching their careers blossom. I take considerable pride in the success of my students and postdocs."

Two shelves in his office overflow with bound dissertations of his students. Kim has trained more than 100 scientists from 10 countries: a legacy that will influence pharmaceutical science worldwide.

"You really live through your students," said Mauger. "Unless you've written a seminal paper, the literature can die with you. It's your students who propagate your science and carry on your philosophy.

"Each lab has its own personality and culture, the quality of work and the way you think through problems. Sung Wan is mentoring by example. He trained under men who were tough and demanding. They gave at the highest level, and he does it himself."

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