HomeOur ScientistsDaniel E. Goldberg

Our Scientists

Daniel E. Goldberg, MD, PhD
Investigator / 1994–Present

Scientific Discipline

Microbiology, Parasitology

Host Institution

Washington University in St. Louis

Current Position

Dr. Goldberg is also a professor of medicine and of molecular microbiology at Washington University in St. Louis School of Medicine.

Current Research

Survival of Malaria Parasites in the Human Host

Daniel Goldberg is interested in the biochemistry and chemotherapy of parasitic diseases.

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Malaria parasite exiting its host...

Biography

For more than a decade, Daniel Goldberg has been unraveling the biochemical pathways that take place inside the parasite that causes malaria, enabling it to feast on human blood. A paper by Margaret Perkins, a parasitologist at Rockefeller…

For more than a decade, Daniel Goldberg has been unraveling the biochemical pathways that take place inside the parasite that causes malaria, enabling it to feast on human blood. A paper by Margaret Perkins, a parasitologist at Rockefeller University, first drew him to this research. In 1981, she reported that the parasite gains entry into red blood cells through a receptor on the cells' membranes called glycophorin A.

At the time, Goldberg was carrying out the research component of his M.D./Ph.D. program with Stuart Kornfeld at Washington University in St. Louis, studying glycoproteins, the same family of proteins that glycophorin A belongs to. "I read the article and thought it was a really interesting function of a glycoprotein," recalls Goldberg. "I knew malaria was one of the world's most important medical problems, yet so little was known about it."

After completing his M.D./Ph.D. and residency, in 1998 Goldberg went to Anthony Cerami's lab at Rockefeller University to study the malaria parasite. Malaria is caused by an organism called Plasmodium, which is passed on to humans in the saliva of an infected insect. When Plasmodium penetrates red blood cells, it breaks down their oxygen-transporting protein, hemoglobin, inducing bouts of anemia and fever in the infected person.

The first question Goldberg wanted to ask was How do parasites degrade hemoglobin? After learning from another Rockefeller malaria researcher, William Trager, how to culture Plasmodium falciparum, the most deadly variety of Plasmodium, in a medium of human blood, Goldberg isolated the parasite's food vacuole, the compartment where digestion takes place. From there, he purified a protease, called plasmepsin, responsible for degrading hemoglobin.

Later studies Goldberg conducted in his own laboratory back at Washington University showed that P. falciparum, unlike other Plasmodium species, contains four distinct food vacuole plasmepsins that can stand in for one another. "By duplicating plasmepsin the parasite gained a growth advantage," says Goldberg. "It could chew hemoglobin faster and grow faster."

Plasmepsins make the first cut in hemoglobin, unraveling the molecule so that it can be further degraded by other proteases. What Goldberg found is that many enzymes in this degradation pathway can perform similar functions. "There is enormous redundancy in P. falciparum. There is redundancy among plasmepsins, redundancy between plasmepsins and other enzymes in the food vacuole, and even redundancy among the enzymes that activate plasmepsins," he explains.

Such redundancy helps the parasite survive, and it makes its study more challenging. "The redundancy made things confusing for us," says Goldberg. "It took a decade to figure out the hemoglobin degradation pathway." It may also make it more difficult to develop compounds that can kill the parasite. "It may mean that we will need to develop more than one compound to knock out several components of a pathway at once," says Goldberg.

But Goldberg discovered another possible target for antimalarial drugs—not an enzyme required to break down hemoglobin, but rather one to build proteins. Making proteins requires amino acids. Goldberg discovered that the parasite can do without all amino acids except isoleucine. "It's interesting because isoleucine is the only amino acid that is not found in the hemoglobin of primates, including humans. It is possible that it evolved this way in primates to slow the growth of the parasite," he says.

P. falciparum gets isoleucine from the blood via an "isoleucine transporter," which Goldberg is in the process of tracking down. Once isoleucine is inside the parasite, it is incorporated into proteins, using one of two enzymes called isoleucyl tRNA synthase. One enzyme resides in the cytoplasm and the other in the apicoplast, an organelle inside the parasite. Goldberg discovered that blocking isoleucyl tRNA synthase in the cytoplasm does not kill parasites because a signaling mechanism inside the cytoplasm tells the parasite that it has run out of isoleucine and that it needs to "stall" and wait for more nutrient. When the enzyme is blocked in the apicoplast, however, this signal is not generated. "The parasites go merrily along and eventually die," explains Goldberg. Thus, compounds that block this enzyme's function may provide new antimalarial drugs.

Although Goldberg's research is pointing the way to promising new drug targets, he says that is not what motivates his work. "I am realistic about it. If you identify a possible antimalarial target, the chances that it will lead to an actual drug are small. If you focus your whole emotional effort on developing a drug directly, chances are that you will be disappointed," he says. "You have to be motivated and excited by the basic biology that you are working on. In the case of the malaria parasite, this is truly fascinating."

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Education

  • AB, magna cum laude, biochemistry, Harvard College
  • PhD, molecular biology, Washington University
  • MD, Washington University

Awards

  • Burroughs Wellcome Molecular Parasitology Scholars Award
  • Outstanding Faculty Mentor Award, Washington University in St. Louis

Memberships

  • American Society for Clinical Investigation
  • American Association of Physicians
  • American Association for the Advancement of Science, Fellow