Searching for a cure for the brain's darkest diseases
By Nicole Sweeney Etter | Photography by Dan Dry
Day after day, Dr. David Baker hunched over his lab bench searching for a sign that he was on the right track. As a post-doctoral fellow, he was engaged in a risky project: deviating from the neuroscience establishment by studying the role of glutamate in addiction, while virtually everyone else focused on another neurotransmitter called dopamine.
It was slow, painstaking work. But it was then that Baker made the most remarkable discovery of his young career, one that propelled him to where he is today. He identified a unique mechanism in the brain that releases glutamate, a key neurotransmitter, in an unusual way. His team was the first to show that extrasynaptic glutamate released by that mechanism is critical for brain function — and plays a part in brain dysfunction.
Now an assistant professor of biomedical sciences in Marquette’s College of Health Sciences, Baker and Marquette colleague Dr. John Mantsch have started their own company, Promentis Pharmaceuticals, that could deliver promising new treatments for schizophrenia and other neurological disorders.
“This is exciting, leading-edge science right in Milwaukee,” says Daniel Lawton, a veteran of the pharmaceutical industry who is CEO of Promentis. “One of the reasons it’s so exciting and one of the reasons it’s daunting is that schizophrenia really is a poorly understood disease. The more we understand about schizophrenia, the more we understand just how desperately necessary new therapeutic approaches are.”
Baker grew up in Montana, just outside of Glacier National Park. Like most science-savvy students, he thought about a career in medicine. He wanted to help people, and as a doctor he could do that every day. Then he fell in love with research. “I thought if I could contribute to a discovery, that could touch millions of lives over years and years,” he says.
Baker’s path seemed bright from the beginning. As an undergrad at Montana State University, he contributed to three scientific papers in academic journals — an extraordinary feat for someone his age. By the time he earned his doctorate, he had written 11 papers — two or three times the production of his peers.
His post-doctoral fellowship at the Medical University of South Carolina was different. The work was slow and filled with trial and error. Baker’s mentor was Dr. Peter Kalivas, one of the top neuroscientists in the country.
“Dave is probably the brightest guy to come through my lab,” Kalivas says. “Dave’s real knack is to see with new eyes. He can see things in different ways, and that was always very impressive to me.”
Kalivas’ lab was researching long-term changes in the brain caused by cocaine addiction and found that glutamate levels in key structures of the brain were reduced by 50 percent. That seemed to indicate that glutamate could be involved in brain function or dysfunction. Kalivas assigned Baker a project: find out where this extrasynaptic pool of glutamate is coming from and how it’s released.
Most neurotransmitters, including glutamate, are released between synapses, the gaps between nerve endings. But the mechanism that Baker identified bathes the entire nerve in glutamate. That’s important because it could reveal a new molecular target for drugs to treat a host of major neurological disorders.
Baker and Kalivas were confident that extrasynaptic glutamate could answer mysteries of the brain, but until a few years ago, most people did not agree. The deck was so stacked against their research that at an international conference in Dublin, one of the leaders in the field declared that extrasynaptic glutamate was in no way involved with neurotransmission — end of story. Kalivas presented the opposite viewpoint.
“It was really interesting being at odds with some very prominent neuroscientists,” Baker says. “At that early stage, it was certainly a high-risk project and slow-developing story.”
Plunging into uncharted territory has its disadvantages. “It was difficult and frustrating for months. It was like stepping into a room, and it’s completely dark, and all you have to navigate through the room is the light from your watch. We stumbled around in the dark for a long time,” Baker says. “But we really felt like if we were right, this would have the potential to be a significant development.”
One of Baker’s first studies showed that by inhibiting that unique brain mechanism, one could alter glutamate levels. Proving that fact was half the battle. Next he decided to see if it could affect dopamine levels. It did.
“It was really just incremental gains — we were lighting candles along the way,” Baker says. “A lot of things didn’t take. A lot of things didn’t make sense. But once we knew that we could stimulate the receptor and affect glutamate, that was huge.”
Soon, Baker, Kalivas and their colleagues were publishing high-profile papers that were heralded as far away as England and India. One 2002 paper in the Journal of Neuroscience has since been cited by other scientists more than 200 times. A 2003 paper published in Nature Neuroscience has been cited more than 100 times. “It has had a major impact,” Baker admits.
Now when Baker goes to www.clinicaltrials.gov and searches for studies targeting this mechanism, scores of projects come up. The explosion of interest didn’t bother him at first, but then doubts started to creep in. He wondered: “What if this isn’t real? What if I’m leading people down a dark alley, and it’s going to be a dead end?” But as clinical data showed that targeting that mechanism did help people, he learned to relax. “For me that was the real confirmation,” he says.
By the time Baker published the lion’s share of data, he was already at Marquette. “Here you have a department where it’s a priority to bring in people who study disease, understanding what goes wrong and how to treat it. I think it was kind of inevitable that we’d get someone like David who was working in a hot area,” says Mantsch, an associate professor of biomedical sciences and fellow addiction researcher. “I think he’s probably one of the most important faculty we have on this campus, and what he’s doing just amazes me.”
In the brutal “publish or perish” world of academia, competition can kill camaraderie. But Baker found a different environment at Marquette, where a group of young neuroscientists works alongside more-veteran colleagues. The biomedical sciences professors eat lunch together and routinely meet to discuss their research and share ideas. They want to see each other succeed. “It’s not like a lot of other places — faculty here really take a team approach,” Baker says.
It was the perfect place for Baker to flourish.
Eager to follow up on his discoveries, Baker applied for three major research grants during his first year at Marquette. As a junior faculty member, he is required to divide his time equally between teaching and research, and he asked what would happen if he received all three grants. His bosses and colleagues laughed at the unlikely prospect. Then Baker won all three grants, worth nearly $2 million.
He made it work, even though the combination of teaching and research added up regularly to 80 hours a week. That’s not unusual, says Baker, who points to other driven young colleagues who regularly clock 80- to 100-hour weeks.
Despite his lab’s continuing progress, Baker started to feel frustrated. He continued to publish papers, but outside of academic journals, nothing was happening. “The real value of these findings wasn’t being realized,” he says.
Although Baker’s focus at the time was on addiction, he hypothesized that this brain mechanism could also be involved in other neurological diseases, such as Parkinson’s. In 2004 he decided to turn his attention to schizophrenia, one of the top 10 most disabling neurological disorders. Though it occurs in only 1 percent of the population, the disease is so disruptive that most schizophrenics can’t function in society, and 10 percent commit suicide. But the medications for the disease are so debilitating and ineffective that compliance rates are abysmal. By finding a better treatment for schizophrenia, Baker hoped to have a real impact.
Because he’d never worked on the disease, it was unlikely his grant proposal would win funding. He began digging through the research anyway. “The field was a mess — there were a myriad of potential causes, and they really seemed at odds with each other,” he says. Baker sat down and sketched a table of all the opposing hypotheses. Then he considered the possible role of his mechanism. If it was involved, it appeared to resolve all the other hypotheses. He made such a compelling case that the National Institutes of Health funded his grant request on the first submission.
He started to collaborate with a psychiatrist from the Medical College of Wisconsin and a chemist from the University of Wisconsin-Milwaukee. The trio applied for the biggest grant offered by Wisconsin’s Biotechnology Alliance — $250,000 — and won. Using an existing drug in a small clinical trial, the researchers found they could restore normal levels of extrasynaptic glutamate and alleviate some schizophrenia symptoms.
But Baker thought they could do better. He wondered: How could he transition from the discoveries he was making in his lab to technology that was commercially available? Should he patent his findings and sell the license to another company?
Then he and Mantsch came up with a crazy idea: Why not create a spinoff company? They talked to Tim Keane, entrepreneur in residence in the College of Business Administration, about how to found a company. Keane encouraged them to enter the Kohler Center for Entrepreneurship Business Plan Competition. Baker and Mantsch took first place, winning the support of Marquette’s Golden Angels Network, and then were finalists in the state business plan competition. With the help of colleagues, including UWM chemist Dr. James Cook, their pharmaceutical company was born.
They decided to call their company Promentis, which means pro mind or healthy mind. They applied for NIH’s small business innovative research grant — which typically is no more than $100,000 — and received $500,000. Then Baker and Mantsch recruited three industry veterans from Schwarz Pharma: Lawton as CEO, Steve Pollock as vice president and Dr. Klaus Veitinger as chairman of the board. Baker and Mantsch, who both hold the title of founder and director, will head up the science along with UWM’s Cook.
Drug discovery is often a haphazard process. “The typical model is that someone makes a serendipitous discovery, and it seems to work,” Baker explains. A pharmaceutical company might realize that a drug for one disease seems to alleviate symptoms of another, so then a similar drug is created. But no one knows why those drugs seem to work. That can lead scientists to jump to conclusions about the root causes of disease. Baker’s approach is different — understand the neurobiology of a disease first, then create the drug that corrects the problem.
It can take $100 million or more and a decade to turn the germ of an idea into a marketable drug, Lawton says. Promentis has already made substantial progress in a promising area. “But there’s no doubt it’s a long, expensive and uncertain path forward,” he says. “This isn’t the sort of project you can self-finance and produce in your garage.”
Baker says if he and Mantsch knew what they were getting into, they might have thought twice about starting their own company. Still, Baker hopes to guide other Marquette faculty through the entrepreneurship process. “I could really make a convincing argument that my story couldn’t have happened at other universities,” he says.
At a large research university, could a junior professor walk into the dean’s office or the Office of Research and Sponsored Programs and say, “I think I’m really onto something”? Could he have captured the attention and support of an angels investor group? Would he have the university president and provost as advocates? Maybe not. It’s been a learning experience for Baker and the university.
“Marquette up until recently hasn’t had a history of this entrepreneurship culture. ... I really think it’s going to change the way the university looks at intellectual property and tech transfer,” Mantsch says. “This is really something that could define Marquette as a research-intensive institution. It’s a shift in mindset.”
In the meantime, Baker and Mantsch have a lot of work ahead, and the clock is ticking. “We know more about this mechanism, and we have a head start on everybody,” Baker says. “It won’t stay that way.”