John Evans Professor of Chemistry and Inventor of Lyrica
Whether it be through taking a course in organic chemistry, working in labs, passing by Silverman Hall, or hearing about his invention of pregabalin—or better known as Lyrica—, most people have most likely encountered Richard B. Silverman’s name in some form or another during their time at Northwestern University.
Silverman is the John Evans Professor of Chemistry and has made significant contributions to the world of chemistry through cutting-edge research. His commitment to the sciences has won him numerous awards such as the Northwestern University Trustee Medal for Faculty Innovation and Entrepreneurship (2014) and Excellence in Medicinal Chemistry Prize of the Israel Chemical Society (2014). In the same year 2014, he became a fellow of the American Academy of Arts and Sciences and a fellow of National Academy of Inventors.
Whereas most eight-year old boys might be running around outside or in the playground, Silverman at that age was playing a game of a different sort—one that sparked his first flame of interest in chemistry. After receiving a chemistry set as a gift, he and his older brother decided to conduct their first home experiment.
“It was a very simple invisible flame experiment that shows how alcohol burns cleanly,” Silverman said. “We used our bedroom as our laboratory without realizing that the curtain was flammable.”
Sure enough, the flame Silverman and his brother created was invisible—that is, until the curtain caught on fire. His mother heard the noise, promptly put out the fire, and forbade any future household chemistry experiments.
“That was our first experiment,” Silverman said. “It was a lot of fun, but it was five years later that I allowed to have another chemistry set. By that time, I was pretty much hooked on chemistry, and when I took organic chemistry as a college sophomore, I realized that was the area of chemistry that I was really passionate about.”
Later, Silverman attended graduate school with the intention of going into the pharmaceutical industry, only to discover his interest in teaching during his time as a TA.
“My career plans changed during my third year of graduate school. I decided that I wanted to become an academic scientist,” Silverman said. “My interest has always been in medicinal chemistry, so I did a postdoctoral fellowship after my Ph.D. with an enzymologist to learn about how enzymes function and how to inhibit them.”
And so, enzyme inhibition and looking at molecular mechanisms and organic synthesis for practical medicine applications became the focus of Silverman’s research. Specifically, Silverman said he is interested in finding small molecules that will have an effect on neurological and neurodegenerative diseases such as epilepsy, Parkinson’s disease, ALS, and Huntington’s disease.
“We study enzymes that are important to those diseases and try to design molecules that will prevent those enzymes from functioning and thereby have an effect on the disease,” Silverman said.
The Story of Lyrica
Perhaps the most well-known of Silverman’s research is his discovery of Lyrica, a drug whose original design was to treat epilepsy.
The healthy body has a delicate balance of inhibitory neurotransmitter (GABA) and excitatory neurotransmitter (glutamate); excess excitatory neurotransmission or insufficient inhibitory neurotransmission could cause over-excitation of neurons, leading to convulsions. The goal, Silverman said, is to get those neurotransmitters back into balance.
“Our approach was to inhibit the enzyme that degrades the inhibitory neurotransmitter,” he said. “Blocking that enzyme prevents the degradation of the inhibitory neurotransmitter, increasing its concentration, so the convulsions should stop.”
“We also recognized, however, that you cannot interfere with the enzyme that is producing GABA, namely, glutamatic acid decarboxylase, because then you would be lowering the GABA concentration. So we set out to design a molecule that would selectively inhibit the enzyme that degrades GABA but not inhibit the enzyme that is producing GABA,” Silverman said. “We also knew that the molecule had to get into the brain, which required lipophilic properties, so we incorporated that property into our drug design.”
The surprise, though, was that the compounds that inhibited the GABA-degrading enzyme in fact activated the GABA-producing enzyme (glutamic acid decarboxylase). Thus, more GABA is produced.
“That was the ‘eureka’ moment,” Silverman said. “We had found a new mechanism for increasing GABA concentrations, which could be a new class of drugs for treating epilepsy.”
The story of Lyrica, hence, is one that demonstrates the value of being open-minded as a researcher. “When you make some unusual observations, you shouldn’t scrap it just because it is not what you wanted,” Silverman said. “Instead, you should ask, ‘What can I do with this new piece of information?’”
Ultimately, Lyrica became known not just for providing relief from epileptic symptoms. “In clinical trials,” Silverman said, “people with neuropathic pain—the pain you get fibromyalgia, diabetes, or spinal cord injury—reported back to physicians their pain went away. That was not what pregabalin (Lyrica) was originally designed for, nor was that the design of its predecessor, Neurontin.
Through physicians and word of mouth, it became known that Lyrica could be effective for nerve pain. After more clinical trials, Lyrica was approved for providing relief for various nerve pain symptoms associated with diseases such as fibromyalgia, diabetic neuropathy, and post-therapeutic neuralgia.
Silverman’s primary interest, though, remains in neurodegenerative and neurological diseases. Currently, his most advanced project is with the compound CPP-115. “We are working with a small company, Catalyst Pharmaceutical Partners, which has put it into a Phase I clinical trial,” Silverman said. “And they are now designing a Phase II trial.”
“The compound is an inhibitor of a particular enzyme called GABA aminotransferase. It turns out that there is another related enzyme that a group in Israel has been studying for hepatocellular carcinoma, and they asked for samples of some of the compounds we published as inhibitors of GABA aminotransferase to determine if they have an effect on liver cancer. And they do.”
This molecule, CPP-115, is able to inhibit both GABA aminotransferase for epilepsy and ornithine aminotransferase for liver cancer. The plan now, according to Silverman, is to put CPP-115 into a clinical trial for liver cancer.
Qualities of a Researcher and Looking Forward
According to Silverman, research is an essential experience for all undergraduates regardless of academic field. His advice to undergraduates is to keep an open mind when searching for an area of research interest. “Research forces you to think creatively, to expand beyond what you read in a textbook, and come up with solutions that solve problems,” he said. “It doesn’t matter what kind of research you pursue, as long as it interests you.”
There are several qualities that a successful researcher possesses. “First, a researcher cannot be upset by failure,” Silverman said. “Most of your experiments will not work, but the key is to take failure as a challenge instead of defeat—a starting a point to finding a solution. It takes creativity to view a failed experiment as an opportunity to redesign the experiment using a different approach or take it into a different area.”
It takes a flexibility of the mind and the ability to think outside the box to problem-solve in the research world and discover an impactful solution.
“By asking yourself why the experiment did not work, you can make a change and see what happens,” Silverman said. “It may end in worse or better results, but either way, you learn something from the experience. The best researchers are the ones who are willing to take a chance on trying something different.”