Building Bridges, Fighting Illness

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Researchers in Richard Silverman's lab are working on an exciting compound that might someday prevent cerebral palsy.

SiS is proud to feature the work of Tom Schroeder, Science in Society's 2009 Fellow Assistant Research Award (FARA) recipient. This award, sponsored by Northwestern's Residence College system, provides funds for an undergraduate student to author content for the site in collaboration with the SiS editorial team. Schroeder is a first year student majoring in chemistry and English.

The iconic image of a scientist alone in the lab, working steadily in isolation toward the world’s next big discovery, doesn’t quite paint the full picture. Instead, most scientific and medical advance can only happen because of a dynamic network of diverse researchers working together, both within their own laboratories and across institutions. The problems they tackle are complex, requiring specialized, complementary expertise and a lot of teamwork.

This is particularly true of finding solutions to treat disease. The process of bringing a drug from the lab to the clinic involves collaboration between not just chemists and medical professionals, but also experts in biology, engineering, and even physics. Richard Silverman, John Evans Professor of Chemistry at Northwestern University, is especially experienced in assembling networks of researchers for this purpose. Credited with the discovery of the blockbuster pain drug Lyrica, Dr. Silverman’s most recent focus is on a small molecule implicated in neurodegenerative disease and cerebral palsy.

Cerebral palsy, which affects more the 750,000 Americans, impairs muscle coordination and overall body movement, because the areas of the brain that control these functions have been damaged. Often, cerebral palsy is the result of hypoxia, or a period without oxygen, often late in a woman’s pregnancy or during delivery. During hypoxia, nitric oxide (NO) builds up in the baby’s brain, resulting in severe damage. Many other neurological conditions, such as Alzheimer’s, Parkinson’s, Huntington’s, and strokes, can also be caused by a surplus of NO.

However, NO is essential to other processes of the human body, such as regulating blood pressure and the immune defense system. The key, then, is to slow down nitric oxide production in the brain when it’s too high without disturbing levels in these other systems. This could be done by creating a compound that interferes only with the molecular machinery that produces NO in the brain, an enzyme known as neuronal NO synthase.

Unfortunately, the different enzymes in the body that produce NO for its various purposes are very similar, making this more complicated than it sounds. Drug companies had tried to do just this for a long time, but without success.

When Silverman first became interested in inhibiting NO synthase, the enzyme was new to him, so he turned to those with experience to gain the necessary expertise for his research team. He found his collaborators as many scientists do, by reading the literature produced by other scientists in various fields. After finding material from a team at University of Michigan on their work with NO synthase, he started the first of the project’s many partnerships by sending a member of his lab to Michigan to learn how to isolate and analyze the enzyme. When the lab member returned, he showed Silverman’s team the techniques he had acquired. After many experiments, Silverman was able to exploit minute differences in enzyme structure by designing a series of compounds selective for the brain.

In a biochemical sense, a drug is like a puzzle piece—it must be of a certain shape and size to react with its specific target and not with others. It is important, then, to be able to visualize the interactions between a drug and its target to ensure that it has the correct shape. The leading method for documenting these interactions is known as X-ray crystallography. In this technique, scientists bounce X-rays off of crystallized forms of the enzyme and drug together, recording where they land. This yields information used to reconstruct a molecular image of the pair.

A group in Irvine, California is particularly well versed in applying this technique to NO synthase and its inhibitors. Once Silverman had identified promising compounds, he found the Irvine team’s publications and reached out to them. They welcomed the collaboration, so he sent his compounds to California for imaging. The Irvine scientists were able to determine minute but critically important differences in interactions between Silverman’s compounds and the different enzymes, revealing why they were so selective in the first place. After they could see how the drug candidates were interacting with the enzyme, the Northwestern group was able to further refine their compounds for medicinal potential.

During this period, Silverman published his findings in a leading scientific journal, which caught the eye of Dr. Sidhartha Tan, a neonatologist at Evanston Hospital. Tan had developed a method of testing anti-neurodegenerative drugs on animals in which he induces cerebral palsy. The discovery that Silverman was working on a project so similar was a fortunate revelation. “He had published an article in the Journal of Medicinal Chemistry,” said Tan, “and we looked at the address and said ‘this fellow is right in our backyard!’” He called Silverman, who was very interested in testing his promising drug candidates in Tan’s animal model, and the partnership began there.

The results were better than expected. Not only did the drug prevent the onset of cerebral palsy in the vast majority of cases, it did so without affecting other NO-dependent functions such as blood pressure regulation. Silverman and Tan published their results this February.

There is still much work to be done. For one, there are many differences in human and animal systems. For this reason, the compound will be tested in additional animal models to ensure safety and performance. Another collaboration is being established with a toxicologist in Europe to determine how the compound will affect humans. Clinical trials will only be possible once the medicines are safe enough for testing.

Given that NO is such a power player in neurodegenerative disease, further testing of the inhibitor could reveal other potential applications. Silverman says that they will test the drug’s effect on every disorder they possibly can. This process has begun already: a London company,  reached through Northwestern’s Technology Transfer program, is currently interested in the compound’s applications for Parkinson’s disease.

Even if all goes as planned, it will still be a long time before we see Silverman’s compound hitting the shelves. Every pharmaceutical drug must be subjected to a rigorous battery of clinical trials before it becomes generally available. According to Silverman, it usually takes around fifteen years to get from the discovery of a promising compound to its availability as a drug. He refers to 2009 as “year one” of the process. No matter the fate of this new cerebral palsy preventor, a long period of further collaborations awaits.

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