Richard Mailman has a new baby named Dave, a new company named DarPharma, Inc., and a dream so big he’s embarrassed to dream it.

The dream, after almost two decades of monomaniacal work, seems right on the verge of coming true. In this dream, millions of people with Parkinson’s disease or Alzheimer’s disease or schizophrenia or drug addiction or various other neurological afflictions take a pill that would help them lead a more normal life. And in this dream, the pills arrive in time to help Mailman’s friend and long-time research partner, Steve Wyrick, who retired from Carolina because he was diagnosed with Parkinson’s disease.

But Mailman, professor of psychiatry, pharmacology, and medicinal chemistry, doesn’t dare dwell on this dream when he talks to potential DarPharma investors. For the record, when Mailman thinks business, these days, his stated motive is making money, and plenty of it. He has learned the hard way, he says, that investors understand this motive better than, say, impassioned idealism or obsessive scientific quests.

But before there were any investors, before DarPharma was so much as a gleam in Richard Mailman’s eye, there was indeed a scientific quest. Starting in the late 1970s, Mailman and his lab, working with Wyrick and others, took an interest in certain receptors that triggered messages in the brain — receptors for dopamine. This in itself was nothing unusual. Researchers and drug companies all over the world were focused on dopamine, a neurochemical that influences a wide range of brain functions and plays a role in several neurological diseases.

Take Parkinson’s disease, for instance. Parkinson’s affects 1.5 million Americans, and it begins when large numbers of dopamine nerve cells in the brain die. “Because this is a dopamine-deficiency disease, it’s rational to think that if you could somehow replace the dopamine you could make people better,” Mailman says. “The problem is that you can’t just give people dopamine, because it will never enter the brain. So people have tried to use strategies that mimic dopamine. The most effective therapy that’s used today is a drug called levodopa, which the brain coverts to dopamine.”

Oliver Sacks’ 1973 book, Awakenings, which became the basis of a play and a movie, told the story of a Parkinson’s patient who took levodopa and made a miraculous but temporary recovery. Today, most scientists believe that dopamine nerve cells themselves are needed to convert levodopa to dopamine. Because levodopa does not actually cure Parkinson’s, nerve cells continue to die. When there aren’t enough nerve cells to make the conversion, levodopa no longer works. Bill Snider, director of Carolina’s neuroscience center, has hired a group of researchers who are studying the process of brain-cell degeneration and how to prevent it, and others are studying how to repair the damaged brain. But for now, there is no cure or prevention for Parkinson’s disease — only the need for longer-lasting treatments.

Find the Right Mimic

The dramatic effects of levodopa, usually sold in combination with another drug under the trade name Sinemet, affirmed the importance of activating the dopamine receptors. Mailman and others wondered if the right receptors could be engaged without having to rely on dwindling numbers of nerve cells to produce the dopamine. What was needed, he thought, was a drug that would act directly on the critical dopamine receptors just as dopamine does. Trouble was, these receptors belonged to two different families — D1 and D2. The D2 family had gotten most of the attention because common wisdom was that they influenced the widest number of neurological functions. But Mailman wasn’t convinced that D2 was the answer, especially for Parkinson’s disease.

By the mid-1980s, Mailman and his research partner, Dave Nichols at Purdue, had evidence and a strong belief that the less-studied D1 family of receptors offered much greater promise. “No one agreed with us,” Mailman recalls, “mainly because people had misinterpreted some of the data available then, but also because what we were doing didn’t fit the established models.”

The limited number of signaling pathways activated by the D1 family of receptors seemed to Mailman as much an advantage as a limitation. D1 receptors affected such things as movement, thought, memory, and addiction, but they did not seem to cause behavioral disturbances or interfere with pain thresholds, the cardiovascular system, or other vital functions. To Mailman and his colleagues, this meant that drugs targeting the D1 family were less likely to produce dangerous or unwanted side effects.

So Mailman set himself squarely at odds with conventional wisdom and pursued D1 with a vengeance. “It was one of those intuitive kinds of things,” he says. “I just couldn’t leave it alone, so I focused everything on this one direction. In retrospect, it was high risk, but it also seemed right.”

He and Nichols looked for a “full agonist” — a compound that could bind to the D1 receptor and mimic the action of dopamine. Nichols was deft at designing new drugs, so he was a natural complement to Carolina’s basic studies of cell receptors and signaling pathways — studies being conducted in Mailman’s lab as well as in the lab of Alex Tropsha, associate professor in the School of Pharmacy. By the late 1980s, the team had synthesized the first full D1 agonist, a drug they called dihydrexidine. And they were ready to see if it worked.

n a lab-made video from 1990, an African green monkey with experimental Parkinson’s disease lies rigid and unresponsive on the floor of its cage. Moments after an injection of dihydrexidine, he stirs. Soon he is up, moving normally around his cage, interacting with the staff. The response is dramatic, as dramatic as the initial effects of levodopa. In monkeys, at least, Mailman and Nichols were watching their own kind of awakenings.

Seeing that video footage was a rare event for a basic researcher — you can work a whole career and never see something so dramatic,” Mailman recalls. “We knew that the monkey model was predictive. Everything that works in the monkeys works in people. So we were absolutely convinced that this drug was going to be a key to potentially helping Parkinson’s patients, and possibly people with other diseases, as well.”

Ironically, just as they were seeing these optimistic early results from the monkey studies, Steve Wyrick was diagnosed with Parkinson’s disease. Suddenly, the quest was not just scientific or humanitarian. It was also personal.

Steve is my long-time buddy,” Mailman says. “So this news hit us hard. And Steve has been on our minds every step of the way since then.”

Mailman and Nichols assumed that the animal results from dihydrexidine would create a sensation. But scientists and pharmaceutical communities, still largely committed to dopamine models for the D2 family of receptors, were skeptical, Mailman says. “While drug companies did approach us, the questions they asked were, ‘How long do the effects last, and can you give the drug by mouth?’ And we knew that the answers were not pleasing. We knew that this drug couldn’t be given orally, and we knew it had a very short duration of action — only an hour or two.”

Mailman and Nichols were disappointed, but they went back to work in their labs, focusing on the basic scientific question of what happens when a drug binds to a receptor. Working also with Tropsha, they used techniques including computer modeling that allowed them to test the designs of various molecules and simulate their effects on receptors.

Dave Nichols sat down at the computer, and he started sketching out molecules to test this model,” Mailman says. “And he came up with a totally novel backbone that never had been made before. First, he sent us the structure, and we modeled it on the computer, and it looked beautiful, and we were really excited. So Dave’s lab made up a sample of the drug and sent it to us, and we tested it immediately. But when we got the results back, they were totally negative. The drug didn’t bind to the receptor or cause any activation at all. And this was astounding to us because we were convinced it should work.”

Mailman didn’t believe that the problem lay in their models — or, for that matter, in their pharmacological methods. “So I called up Dave’s lab, and I said, ‘Someone made a mistake, Dave. This is not the drug you designed. I’m going to call this stuff you sent me uncertamine. Go back and check out what your lab made.’ So Dave looked back at the tests and in fact he found an anomaly in what a student had done, making him realize that the wrong molecule had been sent.”

Nichols’ lab made the correction, and this time, the drug behaved exactly as the model predicted it would. And there was more good news when Mailman tested this new drug, dinapsoline, in animals. Unlike dihydrexidine, dinapsoline’s effects lasted a long time — 10 hours.

We’re not the smartest people in the world,” Mailman says, “but we knew immediately that there were some practical implications of having the drug work for ten hours. And then we gave the drug orally to animals, and lo and behold it also worked orally.”

So Mailman and Nichols believed that they had a hot property on their hands. Their universities’ technology-transfer offices filed a patent application on dinapsoline, now known as DAR-201, and the team signed an agreement with Bristol Meyers Squibb to develop the drug. But when the researchers found themselves at odds with the company about scientific issues, Mailman and Nichols extricated themselves from a hot deal gone cold.

Impatient for Action

Meanwhile, the team had several new compounds in the works, and they were growing impatient for action from the business world. In 1999, as Mailman was beginning a sabbatical in London, he told Nichols that the only way to control the scientific fate of their work was to start a company. “I told Dave Nichols that someone was going to do this sooner or later, and without us it would be later, not sooner. I also told him that if it was someone else, we were going to get lost in the shuffle, and all the work we’d done for fifteen years was going to amount to one or two little citations. And I said, candidly, at this point in my life, my ego couldn’t take that.”

While Mailman was in London, he began circulating what he called a “prospectus” for his new company, unaware that a prospectus, in business parlance, is what you prepare when your company is ready to go public. He laughs, now, at how naïve he was about the business world. In his zeal to show all of the elegant science behind their new compounds, he now realizes he scared away business types by giving too much detail about the elaborate biochemistry of receptors and signaling pathways.

For business people, he says, this was a total turnoff. “We probably hurt ourselves because, before I learned what I was doing, we made pitches to a lot of local venture capitalists, and I think we were seen as naïve — you know, these scientists up in their ivory tower without any understanding of reality. They assumed that we were impractical, that we didn’t have the necessary business sense. But in fact, Dave Nichols and I are very practical people, and know how to take our scientific knowledge and turn it into clinical products. But the business people didn’t know that, and they just couldn’t take it on faith.”

Having worked through Carolina’s Office of Technology Development to form DarPharma, negotiate a license agreement, and navigate the perilous waters of launching a venture, Mailman began to realize that he needed more than his own expertise as a scientist. In a class for aspiring entrepreneurs at the Kenan-Flagler Business School, Dean Robert Sullivan and his faculty hammered into Mailman the basics of business — everything from how to write a business plan to hiring the management. He was learning, but he was still a scientist doing business part-time.

Then Jeff Segal, a successful neurosurgeon who also had started two successful medical software businesses, showed up on Mailman’s doorstep — literally. Segal had been looking for a way to help his son, who has autism. After studying the medical-research literature, Segal had concluded, on his own, that the most promising avenue for treatment might be through the type of D1 drugs Mailman and Nichols had developed. Segal found Mailman’s address, traveled to Chapel Hill, and waited on Mailman’s doorstep, offering to do whatever he could to help develop the drugs. After several months working for the company under a handshake deal, Segal became co-founder and the first president and CEO of DarPharma, raising $3.6 million in startup capital last winter in a tough economy. Operating in Chapel Hill, the company now has eight employees studying many new drugs.

Even though Parkinson’s disease remains DarPharma’s number-one focus, Mailman believes that the company’s compounds also have promise in treating several other psychiatric and neurological diseases, as well as substance abuse.

A whole variety of different substances including cocaine, amphetamines, alcohol, nicotine, morphine, and other kinds of opioids all work by different mechanisms, but they all seem to go through a common pathway that involves our favorite neurotransmitter, dopamine,” Mailman says. “In fact, the National Institute of Drug Abuse has stated publicly that the same kinds of drugs we’re developing as potential anti-Parkinson’s drugs are very promising in terms of anti-cocaine medication.”

The drugs also have promise in the area of cognition and memory. Jeffrey Lieberman, professor of psychiatry, has found that D1 receptors in the prefrontal cortex (the front part of the brain) affect aspects of executive function, which involves self-regulation, including the ability to plan, integrate ideas, or manage working memory.

The range of potential applications for DarPharma’s drugs also expands the range of potential markets. A company whose drugs were effective treating Parkinson’s and several other neurological problems could help millions of people and tap markets worth billions of dollars, Mailman says. This potential has helped DarPharma attract several large financial commitments. The Stanley Foundation, which supports research into schizophrenia and bipolar disorders, became DarPharma’s largest single investor when it kicked in $750,000. Late last year, DarPharma applied for a federal grant under the National Institutes of Health’s Small Business Innovative Research program. Recently, the company received word that its application received the highest score, and would be given an award of $850,000 to support its research. These funds will help the company increase its supply of drug compounds for testing and for sharing with other academic labs.

But DarPharma will need more than good reviews and early startup money to shepherd its drugs into the clinic. Any new drug must run a gauntlet of tests before it is ready for trials in humans. Toxicology testing has only begun for DAR-201. So far, results are favorable. But what if things go wrong? “We are lucky that we have many excellent backup candidates, but it also means we would have to start safety testing all over again with a different drug,” Mailman says.

Meanwhile, his lab at Carolina pushes ahead with its studies of dopamine receptors and signaling in brain cells. A part of this research is focused on the problem of tolerance — the tendency of a long-lasting drug to lose its effectiveness as the system adjusts to its presence on the receptor.

What you need is a drug that lasts for most of the day but basically has worn off by the sleep hours,” Mailman says. “And we think we have ways of doing that.”

If the effects of a drug wear off each day, will the signaling system in brain cells reset to normal, avoiding the problem of tolerance? “That’s a very interesting scientific question,” Mailman says, “and it’s something we’re studying. While this is basic research supported by the NIH, DarPharma helps by providing quantities of these drugs to my lab — drugs that otherwise would be prohibitively expensive. This has really helped my students because they are getting the compounds they need for research.”

On the day of our interview, Mailman kicks back in a T-shirt imprinted with a photograph of Dave, his brand-new baby son. Yes, Dave is named for Dave Nichols, Mailman’s partner in business and research, his friend, and also his matchmaker. A few years ago, Nichols cleverly rigged it for Mailman to meet Xuemei Huang, a neurologist specializing in movement disorders. As usual, Nichols knew exactly what would trigger his partner’s receptors. Xuemei Huang is now also Mrs. Mailman and baby Dave’s mom.

So today, Mailman is basking in the glow of fatherhood. People drop by to congratulate him and gush about the picture on his T-shirt. For the moment, at least, all is right with the world. Baby Dave is safely at home with his mother. And DarPharma is safely in the hands of Jeff Segal, Michael Jacobson, DarPharma’s vice president for finance, and Laurene Wang-Smith, vice president for drug development. So Mailman can relax for an hour or so, tell a few stories, philosophize a bit.

For Dave Nichols and me,” he says, “the whole point was to be able to write a review article that carried something from the earliest ideas that this receptor was important to the fact that you could create novel drugs that would make it into the clinic and help people. People like Steve Wyrick and like Michael Jacobson, who, in addition to having an MBA and a Ph.D. in organic chemistry, also happens to have Parkinson’s disease. It was very hard for us to learn to say that the major reason we should be doing something like this is because we could make millions of dollars.”

But he is learning to say such embarrassing things, and dream such embarrassing dreams. Because without the promise of many millions of dollars, no one would invest the kind of money it takes to see a drug all the way into the clinic. So, on the record, Richard Mailman intends to be fabulously wealthy, some day. But off the record, he would be just as happy to have some good news the next time that Steve Wyrick calls. And even though he’s gotten good at talking business, he’ll keep talking molecules and receptors back in the lab.

I love the Carolina community,” he says. “I like the collegiality here. I like the fact that you don’t have to keep secrets — that you can always talk about what you are doing. I like the fact that I’ve gotten help from so many of my colleagues over the years. So I am not going to suddenly forget who I am and stop doing the things that have always been so rewarding. This is where I belong, and this is where I plan to stay.”

Neil Caudle was the editor of Endeavors for fifteen years.