Battling the scourge of malaria

Daniel E. Goldberg, M.D., Ph.D., is known internationally for his work to stop this deadly parasite in its tracks

What do you do when a parasite that's invisible to the naked eye has eluded efforts to eradicate it for centuries? If the bug causes malaria, a killer of two million worldwide each year, and your name is Daniel E. Goldberg, M.D., Ph.D., you do everything you can to stop the parasite in its tracks.

Goldberg, professor of medicine and of molecular microbiology and a Howard Hughes Medical Investigator, has gained international recognition for his work on how the malaria parasite survives in humans. He also directs the Medical Scientist Training Program, one of the country's largest M.D./Ph.D. programs to develop the next generation of medical researchers.

His own interest in malaria began when he was an M.D./ Ph.D. candidate at the School of Medicine in the early 1980s. Studying carbohydrates -- sugars -- in the lab of Stuart A. Kornfeld, M.D., professor of medicine and of biochemistry and molecular biophysics, he came across an article about the malarial parasite Plasmodium falciparum. The article described the parasite's ability to invade human red blood cells by sticking to sugar-coated proteins on the cells' surface.

"I thought that was a fascinating interaction, and that led me to read more about malaria," Goldberg said.

Daniel E. Goldberg, M.D., Ph.D. (left), discusses a sample of protein fragments from hemoglobin that M.D./Ph.D. candidate Ritu Banerjee is injecting into a chromatography machine, used to purify the protein fragments. Katherine King, a fellow M.D./ Ph.D. candidate, looks on.

The chronic disease causes periodic waves of fever and chills that occur when the parasites break out of red blood cells in unison. In Goldberg's medical school days, it was still unclear how antimalarial drugs such as chloroquine work, or what tricks the parasite uses to survive and multiply inside red blood cells.

"This was one of the most important diseases in the world," Goldberg observed, "and there was little research being done on it."

Understanding the malarial parasite is a worldwide concern because certain strains are becoming resistant to chloroquine-like drugs. Even in the United States, where malaria is kept at bay, about a million people a year bring the disease back from travel overseas.

Goldberg decided to learn more about the parasite's activities inside red blood cells in hopes of fostering efforts to develop new antimalarials.

Huge impact

The red blood cells Goldberg studies normally carry oxygen to our tissues. But for the parasite, they serve more as a sit-down dinner. Once Plasmodium attaches to a red blood cell, it pushes its way inside. The parasite then takes in the cells' internal fluid, which is chock-full of hemoglobin, the oxygen-binding protein. The bug transfers the hemoglobin into structures called food vacuoles where it degrades it to create amino acid building blocks for making new parasites. Researchers knew Plasmodium used proteins called proteases to degrade hemoglobin. But it was difficult to tell which proteases play this role.

Goldberg set out to find the needle in this biochemical haystack. After graduating from the medical school, he completed a residency at Brigham and Women's Hospital in Boston in 1987 and then returned here for a year-long fellowship in infectious diseases. Next, he went to the Laboratory of Medical Biochemistry at Rockefeller University in New York to begin learning how to work on malaria.

He joined the Washington University faculty in 1990 and identified two malarial proteases, plasmepsins I and II, that initiate the breakdown of hemoglobin.

Just like certain human proteases, the plasmepsins worked by cutting a target protein into pieces at a physical landmark on the protein. Goldberg hoped to develop a drug that mimicked this site, tricking the parasite out of its true source of nourishment.

A malaria-infected red blood cell is filled with the parasite that, according to the 1998 Guiness Book of World Records, has "probably been responsible for half of all human deaths, excluding deaths caused by war and accidents, since the Stone Age.

However, if the plasmepsins were too similar to their human counterparts, the drug might cause side effects. John Erickson, Ph.D., director of the Structural Biochemistry Program at the National Cancer Institute, took plasmepsin II that Goldberg sent him and used X-ray crystallography to generate images of the protease. The images showed that the protease bound its target in a different way than the human proteases.

Using the information he gathered, Goldberg has collaborated with investigators in industry and at other universities to screen potential anti-malarials. He tests the best candidates on infected red blood cells grown in his laboratory. "We're coming up with some potent plasmepsin inhibitors that kill the parasites in culture," Goldberg said, noting that he enjoys exchanging ideas with collaborators.

Others credit Goldberg for filling in details of Plasmodium's life to bring these efforts to fruition. "He's taken difficult systems and cut through all the confusing things and gotten to the answer," Rathod observed.

Goldberg also determined what makes chloroquine-like drugs work. When Plasmodium digests hemoglobin, it releases a toxic substance called heme. To neutralize the heme, the bug links it into a long chain, which resembles a sharp-edged, crystalline mountain range on images of infected red blood cells.

Goldberg showed that chloroquine-like drugs halt the extension of the chain by binding to one end. He is working with David R. Piwnica-Worms, M.D., Ph.D., professor of radiology and of molecular biology and pharmacology, to develop new drugs that kill Plasmodium strains that resist chloroquine-like compounds. "If you stop them from detoxifying the heme, they drown in their own waste products,'Õ Goldberg explained.

He also is investigating a hemoglobin from the Ascaris worm, which infects about a billion people worldwide. The worm survives in low oxygen conditions in the intestines, possibly due to the hemoglobin's ability to bind oxygen with 20,000 times the strength of the human version.

Understanding the protein could lead to new drugs. But Golberg's laboratory studies it for a simpler reason. "We were fascinated by this molecule," he said.

Goldberg's enthusiasm and dedication carry over to his leadership of the M.D./ Ph.D. training program. He advises 150 students on course work, laboratory training and medical rotations. "It's great to interact with them and see them develop into physician-scientists," he said.

Jeffrey I. Gordon, M.D., Alumni Professor and head of the Department of Molecular Biology and Pharmacology, said Goldberg's appointment as director of the program last year reflects his many strengths. "Dan is an absolutely spectacular scientist, an outstanding physician and a great teacher. He has an essential humility despite his brilliance that inspires students, motivates colleagues to seek his advice and makes him a wonderful role model."

A terrific mentor

In his spare time, Goldberg plays tennis several times a week and watches major league baseball avidly. He also enjoys cooking, reading and spending time with his wife, Mary K. Cullen, M.D.

A research associate in cell biology and physiology at the medical school and a practicing dermatologist, Cullen also has been coordinating science activities for the University City School District. Goldberg, a fan of chili peppers and fine foods, says she adds wonderful flavoring to his life.

But outwitting malaria is what keeps him motivated. "It's such a clever bug -- much cleverer than the humans who are trying to outsmart it," Goldberg says.