Keith West and John Groopman look at a map of Bangladesh

Proteins: An Army of Me

An army is at work in your body.

Tens of thousands of proteins perform hundreds of thousands of tiny tasks fundamental to human health. Proteins make up muscles and tendons, carry messages between cells and help chemical reactions take place. Without them, your muscles wouldn’t contract, your stomach wouldn’t digest food, your temperature and blood pressure wouldn’t remain steady, and your body wouldn’t be able to fight infection. In Bloomberg School labs, scientists are teasing apart the structure and mechanics of proteins in hopes of ultimately finding successful treatments for diseases ranging from Alzheimer’s to AIDS. 


Proteomics: New Food for Thought

Half the children in the world who die each year die in southern Asia. In this region, where hundreds of thousands of mothers also die, better nutrition is crucial to survival.

This crisis has driven the work of Keith West, DrPH ’87, MPH ’79. The International Health professor has spent years working to prevent nutritional deficiencies in children and mothers in developing countries, supervising studies that involve tens of thousands of participants. Now he and his colleagues are using the field of proteomics to revolutionize how micronutrient studies are done.

Typically, micronutrient interventions take years: The health of study participants is monitored for long periods and blood samples are sent back to the U.S. through complicated logistical and customs processes before being analyzed. Moreover, micronutrient interventions such as zinc or vitamin A supplements work on some people but not on others. Proteomics enables researchers both to reduce the research time and to determine why interventions affect individuals differently.

“It’s frustrating when we see individuals that an intervention doesn’t work well in,” says John Groopman, PhD, chair of the Department of Environmental Health Sciences, who has teamed with West, James Yager, PhD, senior associate dean for Academic Affairs, and Parul Christian, DrPH ’97, MPH ’92, associate professor of International Health. “It would be nice to know how it works on an individual basis so that we can [modify] it.” Proteomics enables researchers to do exactly that because it is based on genetics. Proteomics is the study of the functions of proteins in a cell or organism and their relationship to gene expression. Genes are the bosses of proteins, which are the worker bees of human cells. When genes express themselves differently, proteins respond and changes happen in the body.

Proteomics enables researchers to do exactly that because it is based on genetics. Proteomics is the study of the functions of proteins in a cell or organism and their relationship to gene expression. Genes are the bosses of proteins, which are the worker bees of human cells. When genes express themselves differently, proteins respond and changes happen in the body.

Right now, the researchers are looking at the effects of micronutrients, such as folate, vitamin A and zinc, on the protein profiles of pregnant women in Nepal. By determining how micronutrients affect what proteins are expressed and when, they can determine why certain interventions sometimes produce dramatic benefits and other times don’t.

“For example, some interventions work only if a transport protein works,” Groopman explains. “If you lack the transport protein, the nutrient won’t make it to the [appropriate] site.” And if they know why a micronutrient doesn’t work, they can adjust it.

“This will change the way we assess the nutritional health of populations,” says West. The researchers plan to develop a technique for performing micronutrient testing in the field using a portable fluorometer. “We’re trying to crunch the time lag to [provide] a more rapid response and more rapid interventions.”


When Function Follows Form

A coat hanger bent in the shape of a curly spined frog rests on Ingo Ruczinski’s desk. It’s not modern art or the result of a closet door accident; it is a rough approximation of Protein L, one of millions of proteins found in living organisms.

Proteins’ complex functions belie their humble composition: strings of amino acids that fold up into a three-dimensional shape. The amino acid sequences of millions of proteins have been discovered, but only about 26,000 protein structures are known. 

Scientists can’t just look at proteins and describe their structure—they’re too small to be seen. X-ray crystallography can be useful, but it is time-consuming and doesn’t always work.

That’s where Ruczinski’s coat hanger comes in. It represents the goal of his work: learning how proteins fold and what their shapes are. In the world of proteins, form largely dictates function. Depending on its shape, a protein will bind to a string of DNA, expedite a chemical reaction or guide other molecules to where they’re supposed to be. Knowing just how proteins coil and find their “native” shape could lead to huge breakthroughs in treatment and prevention of disease: from reengineering proteins to prevent Alzheimer’s to designing drugs that stop HIV.

In the field of protein structure prediction, Ruczinski, an assistant professor of Biostatistics, is an expert at ab initio modeling. Latin for “from the beginning,” ab initio modeling uses statistical wizardry and probabilistic search algorithms to build a 3D structure based just on the amino acid sequence. While not yet accurate enough for designing new drugs, the method is, for example, already being used to determine what some genes of unknown function actually do.

Ruczinski and colleagues have developed a software program called Rosetta to speed the ab initio discovery of protein structures and nudge science closer to the delivery of life-saving drugs. Ruczinski, PhD, acknowledges that reengineering proteins to prevent disease is still way down the road. “But,” he says, “if you told someone 70 years ago that we would land a man on the moon…”


A Garbage Disposal for Trashed Proteins

Human cells generate a lot of garbage: proteins that have gone south from exposure to radiation, chemicals and toxins. These proteins can give people diseases, sometimes fatal ones.

So why isn’t everyone sick all the time? Because cells come installed with their own built-in garbage disposals.

The “on” switch for these disposals is ubiquitin, an essential protein made of 76 amino acids that is so named because it is virtually ubiquitous. One of ubiquitin’s functions is to search the body for proteins that are misshapen, damaged or folded incorrectly. When ubiquitin finds a bad protein, it flags it to be destroyed by an enzyme called the proteasome. This enzyme’s constituent parts join together to form a cylinder, suck the flagged protein in and chop it to bits. 

When the ubiquitin-proteasome pathway fails, people can get sick.

“It’s very clear that there are excesses and deficiencies of this enzyme that can be correlated to disease,” says Cecile Pickart, PhD, professor of Biochemistry and Molecular Biology

Pickart’s lab is studying the mechanics of the pathway, especially how ubiquitin signals other proteins to be destroyed. The ultimate goal: guiding the design of drugs to intervene in the pathway and treat diseases including cancer, Parkinson’s, Huntington’s and Alzheimer’s. Pickart is looking specifically at the link to Alzheimer’s. In the neurodegenerative diseases, researchers believe there is too little proteasome activity.

Drug-related therapy would need to boost it.

“We have a lot more to learn,” says Pickart. “Basic research still has such a role to play.”


Wrestling SUMO for Health

Proteins can be altered by their interaction with other molecules and sometimes by other proteins. Until 1996, the only protein known to modify other proteins was ubiquitin (see previous story, above). 

That year, Michael Matunis, PhD, associate professor of Biochemistry and Molecular Biology, found another protein that modifies other proteins. He discovered SUMO (small ubiquitin-like modifier) while studying the proteins associated with the nuclear pore complex, tiny tunnels that allow things to flow between the cytoplasm and nucleus of a cell.

“It was serendipitous,” he says. “I found this protein—RanGAP—and I found that it contained SUMO. It turns out that SUMO is attached to hundreds of proteins in a cell.”

And it performs a myriad of essential tasks: controlling cell division, modifying the proteins that make RNA and helping move proteins between the cell’s nucleus and cytoplasm. 

But SUMO is not always a do-gooder; it modifies the protein that causes Huntington’s disease, a degenerative brain disorder. “SUMO seems to enhance the toxic effect of the protein,” says Matunis. “The more it’s attached to the protein, the more severe the disease.”

Matunis’s lab is working to understand all of SUMO’s functions and the way the protein performs them. The goal: to deliver research that will enable scientists to design drugs that regulate SUMO’s attachment to certain proteins and arrest Huntington’s, malaria and other diseases.