Dr. Maria Schumacher and Proteins: Up Close and Personal
2004 - Maria Schumacher looks at life at the most fundamental level. “You could call me a minimalist,” she says. “I’m interested in understanding cell growth and development from a structural level. What I specifically want to understand is how the proteins involved in transcribing DNA into the countless other proteins involved in cellular activity carry out their functions at the atomic level.”
To piece together this atomic picture, Dr. Schumacher, a 1999 recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences and an assistant professor of biochemistry and molecular biology at Oregon Health and Science University, uses x-ray crystallography. The concept is simple; the execution complex.
Using biochemical and genetic tools, she first isolates and purifies crystals of the protein in question. She next bombards the crystals with x-rays, and then uses mathematical techniques to analyze the “diffraction patterns” that result as the x-rays are scattered by the electrons in the crystals. “What you get is a picture of the protein’s electron density, and we then do further computer modeling to produce a more detailed ‘snapshot’ of the protein’s three-dimensional atomic structure,” Dr. Schumacher says. “By examining crystals obtained from different stages of the protein’s operation in the cell, we can essentially get pictures of the protein in action. These images are often quite beautiful.”
The images also hold a wealth of information. “They really let us see at a structural level how the protein works,” she says. “Proteins don’t simply keep their same shape at every stage of their action. Rather, they continually change shapes, and these structural changes are crucial to their performance. The images we produce not only give us important information about some basic life processes. Knowing the atomic structures of the proteins also may let scientists begin to design specific drugs to target these molecules in cases where their malfunction leads to disease.”
Dr. Schumacher says she developed her interest in “the basic questions of life” as a child growing up on a farm in southern Washington. “This curiosity lead me into chemistry during my undergraduate years at Portland State University, and ultimately to my current university, where I got a Ph.D. in biochemistry in 1995 and then was a postdoctoral fellow until being appointed to the faculty in late 2002.”
As part of her postdoctoral work, Dr. Schumacher concentrated on imaging a protein involved in genetic regulation in the pathogenic bacterium Staphylococcus aureus. Her findings may prove valuable in helping to design strategies for coping with an increasing health problem: the proliferation of pathogens that are resistant to numerous drugs. “We determined the atomic structure of a regulatory protein that enables the bacterium to resist multiple drugs,” she says. “We also were able to work out precisely how this protein functions.”
This work explained for the first time how a protein is able, from a structural standpoint, to bind several structurally different drugs at once. “It turns out that the protein we imaged operates in an unusual manner,” Dr. Schumacher says. “Most proteins have specific “binding pockets” that enable them to attach to only one type of molecule. But this protein has really expansive pockets—actually there are many pockets within one larger pocket—that enable binding to numerous chemical structures. This insight has helped to open up the field in terms of understanding multidrug resistance, and people are now looking for more structures like this in other systems.”
The path to practical application of these findings is still long, Dr. Schumacher cautions. “It is always a lot of work to move from basic research to medical applications,” she says. “But at the same time, this process almost always must start with understanding at a very detailed level how something works.”
Among her current projects as a new independent investigator, Dr. Schumacher is focusing on how the process of genetic transcription, the conversion of DNA into proteins, begins in the parasitic protozoan Trichomonas vaginalis. “This is an ancient organism, and the transcription process it uses is relatively simple,” she says. “This feature, combined with some other technical issues, makes T. vaginalis an excellent model system for asking questions that would be almost impossible to ask in higher organisms.”
Dr. Schumacher collaborates on this project with Dr. Patricia Johnson of the University of California at Los Angeles School of Medicine, who is a 1998 recipient of a BWF Scholar Award in Molecular Parasitology. “I do the crystallography, the structural work, and Dr. Johnson does the laboratory work to assess actual protein function,” Dr. Schumacher says. “We’ve now worked out the structures of a key protein, called the initiator binding protein 39, or IBP39, that initiates the transcription of nearly all of the genes in the organisms. It’s really interesting that this single protein is responsible for so much of how the organism carries out this basic function.”
Further, the scientists have determined some of the intricate—and until now mysterious—details of just how IBP39 kicks off the transcription process. “We found that IBP39 ‘recruits’ another protein, called RNA polymerase, and brings it to a specific site on the DNA,” Dr. Schumacher says. “This is critical, because it is the RNA polymerase that actually carries out the transcription process that leads to making other proteins. All by itself, then, IBP39 brings RNA polymerase to the correct site and orients it in the correct manner so that it can start its job. That was exciting to see, since this protein appears to do all of the jobs in this protozoan that tens or hundreds or thousands of proteins might be required to do in higher organisms.”
Building on this work, the two scientists have recently targeted proteins in some higher organisms that seem to operate in a manner similar to IBP39. “These proteins have been known for some time, but what we’ve done is to identify their structural region that might be similar to the region we study in our primitive organism,” Dr. Schumacher says. “We’re going to be continuing these studies, and we’re hoping this will add to the knowledge base of how transcription works in higher organisms.”
There also may be a therapeutic payoff. T. vaginalis can be transmitted sexually from person to person, and many people, mostly women, develop the disease. “There are good drugs to treat this disease, but there also is some evidence that the protozoan is starting to develop multidrug resistance,” Dr. Schumacher says. “This needs more study. But in any event, understanding protein structure in the organism may help to identify new targets to attack with new drugs.”
When the lab walls seem to be closing in a bit too much, Dr. Schumacher takes off running. “I’ve been running for roughly 20 years now, without missing more than a day or two in row,” she says. “I started for health reasons—running made me feel better.” She has since been diagnosed as having type 1 diabetes, and she keeps running as a way to help control the disease.
“Running has another advantage, too,” she says. “I get some of my best scientific ideas when I’m out there pounding away. If I’m bogged down in front of a computer, I go for a run and often come back with solutions I didn’t think I would have come up with otherwise.”