By Patricia Calhoun
By William Breathes
By Michael Roberts
By Melanie Asmar
By Michael Roberts
By Michael Roberts
By William Breathes
By Michael Roberts
Doug Ishii watches his wife, Wendy, from across the room as she mingles with her guests. He's traded in his lab coat for a collared shirt, and peppered silver hair is the only indication that the Japanese man grinning toward the hostess could be a day over sixty. Wendy wears violet-blue beads in her ears and around her neck, a perfect match with the party's decor and a sharp contrast to her bright-red hair. As she floats through the lobby, Wendy looks genuinely moved that each person enjoying free wine and appetizers chose to attend her fundraiser, whether or not they ultimately decide to donate to her theater's $3 million capital campaign.
It's rare that the couple would be in the same room during the early evening hours of the work week. Had this been any other Wednesday, Doug would still be in his lab in the physiology building at Colorado State University, studying the impact a special protein has on the brains of diabetic rats and theorizing on what that could mean for humans. Doug has spent his whole career studying this single molecule, and he believes he's finally close to a major medical breakthrough: a cure for Alzheimer's Disease. A small bioscience company in Sacramento, California, is growing Doug's protein in rice plants, and if they succeed, the only major obstacle to clinical trials will be the tens of millions of dollars Doug must raise from grants and investors. Needless to say, evenings spent at home with his wife are rare. Not that Wendy would be there if he did arrive in time for dinner. Her work with Bas Bleu, the 49-seat salon theater she started in 1992, keeps her just as busy, especially now that she has to raise $1.5 million by December in order to buy the 100-year-old warehouse the company has already moved into.
When Wendy has a few moments to steal herself away from the party, she is quick to explain just what a thespian like herself has in common with a molecular biologist, aside from their schedules and the fact that she's managed to spark in him a love for Samuel Beckett's plays. "I'm only as good as my last role," she says. "He's as good as his last experiment. We both survive on grants, and we always have our hand out, fundraising."
Doug laughs in agreement, then pauses before slowly and carefully articulating his thoughts on the subject. "We're both involved in a certain amount of risk-taking," he adds. "And in theater, as in science, you have to be willing to put yourself out there and to take risks. Without taking risks and without courting the possibility of failure, you can't really hope to make significant advances. You can do safe science or you can do risky science, and it's in risky science where you can make large jumps -- and theater is like that as well."
As Wendy returns to her guests, Doug continues to ponder this notion of risk. He and Wendy aren't afraid of taking dangerous leaps with their careers or their livelihood, because they aren't afraid of being poor, he says. Been there. Done that.
Douglas Ishii was born in a stable.
His parents, William Takeo Ishii and Fusaye Hatanaka, were born in the United States, though they both returned to Japan with their families when they were still children. Doug's mother, Fusaye, came back to the U.S. when she was twelve to live with her grandmother, and his father, William, came back to go to medical school. The two met in San Francisco and married in 1939. They had their first child in 1941, before Pearl Harbor was bombed, and Fusaye was pregnant again in 1942, when 120,000 persons of Japanese ancestry living on the West Coast were evacuated from their homes. The family was ordered to sell everything and go to their assigned assembly center, bringing only what they could carry. When William spoke out against the government for incarcerating American citizens who had committed no crime, he was jailed, leaving his twenty-year-old wife to take their one-year-old son and report to the Santa Anita racetrack, where horse stalls had been converted to living quarters. Shortly after they arrived -- carrying just two suitcases, one filled with diapers and one with baby food -- Fusaye gave birth to Doug.
From the racetrack, Fusaye and her sons were moved to what the U.S. government called a "detention center." "But we knew what they were," Doug says. The concentration camp was surrounded by barbed wire and guards armed with machine guns. The barracks, hastily erected in the desert, had sand and snow coming in through the planks. Mess halls and latrines were shared; the only privacy came from the blankets that families put up between the individual quarters. Doug's family was held like this for four and a half years.
When the war was over, the government gave them $25 and a bus ticket, and they used it to get to a housing project in San Francisco. William had contracted tuberculosis in jail and was unable to join his family. That left Fusaye to support the children by cleaning and cooking in wealthy homes. Books were Doug's escape from his bleak, violent neighborhood. He would go to the Bayview branch of the San Francisco Public Library and read six books every two weeks, everything from science fiction to Dostoyevsky. The reading and studying paid off: After high school, he attended the University of California at Berkeley. State schools in California did not charge tuition at the time, so he was able to go for just $76 a semester in incidental fees. (That policy changed after Ronald Reagan became governor in 1967.) Doug started out studying philosophy and creative writing, but he quickly found himself drawn to science and chose a biochemistry major.
He also married at nineteen and had to work at a chemical plant from midnight until 8 a.m. to make enough to feed his family. He would go to class from 8 a.m. to 5 p.m., study for a couple of hours, sleep for a couple more and then go back to work. Still, he would occasionally run out of money and have to quit school to support his three kids, going back when he'd been able to save up enough. It took him seven years to earn his bachelor's degree in biochemistry.
After graduation, Doug got a job with the U.S. Forest Service, working to find a safer alternative to the dangerous pesticide DDT. After two years, the feds asked him to sign and fingerprint a loyalty oath, this being the Vietnam War era. For him, the document was too reminiscent of his parents and other Japanese-Americans being asked to renounce their own country, even their own parents. Unwilling to sign, Doug put his toeprint on the paper and wrote "Hang Ten" instead of his name.
He was fired with just 57 cents in his pocket. He and his wife decided to blow it on gumballs and candy for their kids at the corner store, taking a good thirty minutes to find exactly the right combination that would add up to precisely 57 cents.
Doug found his next job by calling the Biomedical Research Institute listed in the yellow pages. His employer was a doctor who had been awarded a research grant but hadn't done research before. Doug spent $10,000 stocking his empty lab and then designed and conducted the doctor's experiments. He liked the work so much that he considered getting an advanced degree in order to lead his own research. Unsure if he could take four more years of school, he decided to leave it up to fate. He sent one application to Stanford University, knowing they only accepted one out of every 5,000 applicants. If he didn't get in, he would choose a completely new direction for his life.
Doug was that one in 5,000, and once at Stanford, he decided to focus on research instead of medicine. "In the end, what I found was that in research, for a moment or a few days, you are the only person in the world to know the answer to a research question, and that gave to me a feeling that is indescribable, and I've enjoyed that thrill of discovery," he says.
He earned his Ph.D. in pharmacology in 1974 and then started a post-doctoral fellowship in neurobiology. He spent the next few years studying a molecule called Nerve Growth Factor, which is part of a family of proteins called neurotrophic factors. These factors play a role in the development and survival of nerve cells. At the time, scientists believed that NGF held huge promise for reversing the effects of some of the most devastating brain disorders, such as Alzheimer's, Parkinson's and Lou Gehrig's. Although NGF was the first molecule discovered that could regulate growth in the nervous system, there were some significant obstacles to turning it into a feasible drug. For one thing, it was too large a protein to cross from the bloodstream into the brain, and thus any treatment using NGF would require drilling a hole into a patient's skull.
In 1978, Doug was offered a faculty position at Columbia University teaching pharmacology and conducting neurobiology research. His marriage had ended, so he packed up and moved across the country, intent on living in the Village he'd read so much about in the novels of his childhood.
While studying NGF at Stanford, Doug had felt like one of a hundred mice chewing on the same pizza crust, so he set out to find another neurotrophic factor when he started his own lab at Columbia. The molecule called Insulin-like Growth Factor, or IGF, had been previously discovered, but scientists believed it regulated body weight. Doug was the first to discover that it played a role in the nervous system. He showed that IGFs were involved in the communication between nerve cells and could even help a crushed nerve to regenerate and grow, something NGFs could not do. He also found that IGFs had this effect on every type of nerve cell in the body, whereas NGFs only impacted certain neurons. For a moment, Ishii was the only person in the world to know that IGFs could perform these functions. He's been studying them ever since.
As a painfully shy teen growing up in Londonderry, Vermont, Wendy Ishii never wanted to be an actress. She wanted to be a writer and philosopher. One of her high school teachers, a writer himself, would send her to detention every day while the other kids went outside to play baseball or soccer. Wendy was required to write one thing during that period, whether it be a poem, a play, a paragraph or a sentence. That instructor also introduced her to theater, and would sit with her listening to plays on record. "He saw something in me and nurtured that, and actually controlled that, and decided I was going to go to Marlboro College," she says. "He locked me in his bathroom until I'd filled out my damn application and slipped it under the door."
Marlboro College, in Marlboro, Vermont, near the New Hampshire/Massachusetts border, had a whopping 117 students when Wendy attended, and a renowned reputation for theater and music. By her second play her freshman year, King Lear, she had become an actress. "It was passion, and it never stopped," she says. "And I always got the great roles, so that made it easy." At eighteen, Wendy was a leading lady and a character actor, able to convincingly play a sixty-year-old woman.
During the summer of 1966, Wendy and John Farrow, Mia's younger brother, started a little company called the New York Popular Players. They toured the fishing villages of Newfoundland with two Molière plays and lived in a tent. They didn't know what they were doing, but it was fun. By 1969, their tiny company had become the Marlboro Theater Company. During the world-class Marlboro Music Festival each year, the Marlboro Theater Company held performances in a barn. "We as young artists cut our teeth on a very sophisticated audience," Wendy says. "It was an incredibly creative time in my life, and a lot of people who are still in the industry came out of there, because I think there was a commitment to doing plays worth doing and never just trying to do warmed-over Broadway musicals or what was popular. We were really challenging ourselves as artists." She worked with Chris Noth -- better known today as Carrie's Mr. Big on Sex and the City -- as well as Ted Levine, whom she calls "Teddy" and who played Buffalo Bill in Silence of the Lambs.
After she graduated, Wendy stayed with the company, which would later be called the Marlboro Guild Theater. The players toured for much of the year, had seasons in Boston, and then would return to Marlboro to study and prepare. She lived alone in a summer cabin near Marlboro with kerosene lamps, no running water and 300 acres between her and civilization. One year she was so broke waiting for the summer season to start that she had no food left in her house. So she shared dog food with Ho Ho, her Shepherd/retriever mix. "It was fine," Wendy says. "I heated it up, put in a lot of garlic salt, and I would sit on the floor with Ho Ho. It was nice to have dinner together. We would eat out of his bowl -- a bite for him, a bite for me."
Though Wendy never minded the gypsy lifestyle, she gave in to peers who wanted her to give it a go in New York City. And because a lot of influential people -- including Ernest Kilroy, who wrote the script for TV's Roots -- knew her work from Marlboro, she never had much trouble getting in doors. She made good money doing commercials and standing in on soap operas, but, to her agent's chagrin, she was always skipping town to do regional theater and guest-star at Marlboro. "That's my passion, and that's what sustains me emotionally and artistically and humanely," Wendy says.
At Christmastime in 1980, Wendy went to a craft show at New York University where her sister was exhibiting. When she came across some beautiful handblown glasswork, she struck up a conversation with the artist. They were engrossed in conversation, flirting really, when Doug Ishii saw Wendy for the first time. Looking for a way to divert the glassblower's attention, Doug decided to make him choose between talking to the beautiful young lady and making a sale. Doug still owns that vase.
Doug was already in the next booth when Wendy wandered in. Since he was the only one there, she assumed he was the artist, though she was surprised that such kitschy trinkets as country "Bless Our Happy Home" signs could be the work of a Japanese artist. When Doug commented on how beautiful the glasswork at the previous booth was, Wendy replied, "Yes, and I like yours, too." He told her it wasn't his booth, that he was just there because he loved craft shows.
"What do you do?" Wendy asked him.
For the next 53 minutes -- "and I know it was 53 minutes, because across the room was a big clock," Wendy says -- Doug talked to her about neurons and ganglia and Silent Spring, the book Rachel Carson had written about DDT, and anything he could think of to say. "I was completely smitten," Doug says. Though Wendy didn't have the slightest idea what he was talking about, she was struck by him. "It wasn't like bells went off, but I knew I wanted to know him for a long time," she explains. At the end of the conversation, she gave him her home phone number, something she rarely did.
A few days later Wendy's Honduran doorman, Julio, was visiting in her apartment. Julio was like a protective brother to Wendy, always watching out for her and taping her television appearances since she didn't have her own VCR. He was adorably starstruck. Wendy had dated actor and salsa singer Ruben Blades, and the doorman nearly hyperventilated when Blades came to the building. Julio always asked Wendy when she was going to get married, and her standard response was, "I'm never going to get married, but if I ever were to get married, I'd marry a Japanese man." So it was fitting that Julio was sitting beside Wendy when her future husband called for the first time.
Wendy's compassion drew Doug in. The first time he went to her apartment, he saw that she not only cooked her dog's food, but she fed him with a spoon. And she was non-competitive in a way he had never seen before. "In New York City, you have these cattle calls of hundreds of actors auditioning for a single part," he remembers. "The night before, she'd be calling friends, telling them how wonderful they would be in that part and encouraging them to audition."
Wendy had lived with boyfriends before, but had always kept her own apartment. This time she knew "this was it" within a few weeks. Still, she was panicked that Doug would realize she wasn't as smart as he was. "Don't you want to be with somebody smart who can understand what it is you do?" she blurted out one day while they were riding the subway together.
"You're incredibly intelligent," he told her. "You don't have a quantitative mind."
Wendy had to look up "quantitative" when she got home. He was right. They were married in 1982.
In March 1985, Doug was offered a job at Colorado State University in Fort Collins, a place he and Wendy had never heard of. When they looked at the map, they noticed how close it was to Yellowstone and the Grand Tetons and decided to come out for a free vacation. Wendy was looking forward to three days in a hotel room watching I Love Lucy reruns and not talking to an agent or learning any lines. But when she arrived, she was given an itinerary. The search committee, upon discovering that she was a classically trained actress, had arranged for Elizabeth Elliot of the local opera to take her around and tell her how fabulous theater in the area was.
Wendy instantly liked Elizabeth and was impressed with the tour, but back in New York, her career was taking off. She had her own character on All My Children, and she was just starting to open doors that people wait their whole careers to get through. She knew Steve Zuckerman -- now a TV director who's worked on such hits as Friends and Everybody Loves Raymond -- from his work in theater, and she went to dinner at his house when she returned from Colorado. "Who's your competition?" he asked her. "Your competition is Meryl and Sigourney. They're known and you're not, so you'd be nuts if you go to Colorado."
When she got home, Doug told her he had just accepted the job. Wendy shed a few tears that night, but she never hesitated to follow her husband. "Maybe had I not already played most of the great roles that had ever been written, it would have been more difficult," she says. "I had so much already, but what I hadn't had was this deep, constant, abiding, exciting love affair with a husband. I am so head over heels in love with Doug Ishii. He still knocks my socks off."
When Doug Ishii started working at Colorado State University in 1985, he wanted to investigate what role Insulin-like Growth Factors, or IGFs, might play in disease, starting with diabetes. Diabetic neuropathy -- a painful burning sensation in the hands and feet that can lead to amputation, impotence, incontinence and gastrointestinal problems -- was the result of nerve damage in diabetic patients. This nerve ailment was a logical place to start testing a large protein such as IGF: The molecule wouldn't have to cross from the blood to the brain, because the problem isn't in the brain, it's in nerves throughout the body. Using experiments with rats, Doug found that injecting the animals with IGF prevented nerve damage. He applied for a patent to treat diabetic neuropathy with IGF injections in 1988 and then continued to work on his theory, not publishing it until 1995. The patent -- which Doug would need in order to take the next steps toward developing an actual drug and testing it in humans -- took another ten years to be approved.
In the meantime, Doug knew that finding a practical way to get IGFs into the brain could have huge implications for treating and preventing disease. Even though conventional wisdom told him that large molecules couldn't cross the blood-brain barrier, he wanted to be certain. His students, though, were too well trained. They knew big proteins wouldn't cross, and they didn't want to waste their time on such an experiment. It took a couple of years before Doug convinced a graduate student, Cynthia Armstrong, to give it a try. She made an IGF molecule radioactive by hooking radioactive iodine onto it, then injected it into a rat. When she subsequently pulled cerebral spinal fluid from the rat, radioactivity showed up. In 1995, Doug applied for a patent to treat diseases of the brain using IGFs across the blood-brain barrier. He didn't release the results until 2000, and today the process is patented in Germany, France, Italy, Spain, the U.K. and Canada, but pending in the U.S.
Over the past ten years, Doug has narrowed in on how IGFs affect learning and memory, intent on finding a way to slow the progression of Alzheimer's. He already knew that IGFs regulated the connections between nerve cells, called synapses, and that learning and memory was believed to be encoded in those exchanges. Clinically, it had also been shown that elderly people with the lowest levels of IGFs do the poorest on learning and memory tests. At the same time, important findings were changing what the scientific community thought it knew about Alzheimer's Disease. In the '80s, the dominant theory had been that the disease was caused by deposits on the brain called plaques and tangles, but studies have since suggested that those deposits could emerge as a natural consequence of aging, possibly aggravating Alzheimer's but not causing it. At the same time, diabetes was being shown as a major risk factor for the development of Alzheimer's. A clinical study done in the Netherlands showed that diabetic patients are at near double the risk for dementia, and that 80 percent of Alzheimer's patients have either diabetes or impaired glucose tolerance, a precursor to diabetes.
Doug wanted to test the hypothesis that IGFs regulate learning and memory. He and a graduate student at the time, Sean Lupien, infused the brains of rats with an antibody that blocks IGFs, and the rats "became dumber than fence posts," he says. From there, Doug wondered if Alzheimer's is caused by a diabetic state in the brain resulting from low levels of IGFs. "If this hypothesis was correct, we should be able to return IGF levels back to the brain and prevent learning and memory disturbances," he explains.
For the next experiment, they put rats in a water maze that required the animals to memorize a path. Every day, the normal rats navigated the maze in less time. Then the researchers made a group of rats diabetic by injecting them with a chemical that kills the pancreatic cells that produce insulin; their performance declined immediately. But when they took a separate group of diabetic rats and injected them with IGF, their cognitive decline was prevented. Like the normal rats, the diabetic rats that received IGFs continued to navigate the maze faster each time. "It reads directly on the clinical problem in dementia," Doug says. "You can take Alzheimer's patients and give them a virtual water maze on the computer, and they show exactly the same problem of not being able to navigate."
As a followup, they weighed the brains of the diabetic rats and those of the diabetic rats that had received IGFs. While the brains of the rats that had not received IGFs had shrunk, indicating protein loss, the IGFs had prevented shrinkage, or atrophy, in the other set. "We suggest this may be very important clinically," Doug says. "Learning and memory requires the ability to synthesize proteins, and the present drugs that are out there don't prevent the continued brain atrophy in these patients."
Doug's findings have been published in several peer-reviewed journals over the past three years, and he's been funded by the National Institutes of Health and Centers for Disease Control. He is optimistic that his discoveries will lead to the first effective treatment for Alzheimer's, which would impact the 27 million patients around the world and slash the $200 billion it costs to care for them.
Experts and peers approve of his methods and findings thus far but are skeptical about whether Doug's work will result in a new treatment. Dr. Greg M. Cole, associate director of the University of California at Los Angeles Alzheimer's Disease Research Center, says the basic findings are sound and cites a 2005 paper from the Laboratory of Neuroendocrinology at the Cajal Institute in Madrid showing that when IGFs are blocked in mice, their brains develop the characteristic plaques and tangles and poor learning of Alzheimer's. However, Cole cautions, because IGFs trigger cell division, a treatment with the protein could produce severe side effects, even tumors. "So, it is unclear that you would want to inject IGFs rather than relatively safe methods," he writes via e-mail from an international Alzheimer's Association conference in Spain. Such safer methods include Cole's own theory that Omega-3 fatty acids can slow the progression of Alzheimer's, and a separate theory that the diabetes drug rosiglitazone could have the same effect. Both are already in trials.
Doug says such research has been sparked by the recognition that diabetes is related to Alzheimer's. "We think it's very fortunate that these trials have begun," he says. "However, our belief is that we need both insulin and IGF for the appropriate treatment."
If she was going to move out to the prairie, Wendy Ishii told her husband, she planned on being a kept woman, spending her days lying in a hammock, memorizing all of Shakespeare. And she wanted a horse. That's the only way she could imagine surviving Fort Collins. Before her mother visited for the first time, she wrote her a letter to prepare her for how ugly it was: "It's practically a desert. There's no green. It's just olive browns and mustards and pinks. It's hideous." Her mother, who is from Australia, thought Colorado looked like heaven when she arrived.
It took Wendy a couple of years, but now she can't imagine living anywhere else -- except maybe Australia -- and she never got around to memorizing Shakespeare or buying a horse. Within weeks of moving to Colorado, she was asked to be a radio host for the classical station, then asked to teach in CSU's theater department.
In 1992, Eva Wright, a Swedish thespian whose scientist husband had also brought her to Fort Collins, invited Wendy to lunch because she wanted to direct her in the play Duet for One. Four hours later, Wendy stopped their discussion.
"Eva, it sounds like we're talking about starting a theater, and there's nothing in the world I would rather do less," she said.
"Why not?" Eva responded.
She couldn't come up with a reason, and Bas Bleu was born.
The concept for the theater wasn't hard. Wendy would be the leading lady and talent magnet, bringing in the friends and colleagues she'd worked with around the country; Eva would carry the brunt of the responsibility as the artistic director. They both wanted an intimate salon theater. They wanted to measure their success not by the numbers, but by the conversations they would have in the process, and afterwards with audience members. They chose the name Bas Bleu in homage to a group of women in eighteenth-century England who hosted literary conversations instead of playing cards. "It was the idea of being in a room together with people exploring a work, an antidote to e-mail and sound bites and all those things we live by these days," Wendy says.
Her vision -- including the decision to open with a double bill of Samuel Beckett -- was lost on Doug. "How stupid are you?" he asked. "First, you name it Bas Bleu, so nobody can say it or knows what it is. Then you put it on Pine Street, so nobody can find it. You have 49 seats, so you have no hope of breaking even, and you're opening with Samuel Beckett, that if people do know who he is, they hate him."
That was fourteen years ago, Wendy reminds her husband, smiling coyly. And while the theater was such an immediate success that she had to extend the first run, not everything went according to plan. Eva went through a difficult divorce and left Colorado, passing the artistic directorship on to Wendy. Then two of Wendy's friends who were on the board and connected to the space she was renting died in a tragic murder-suicide. "There was lots of trauma -- not because of Bas Bleu, but around it," she says.
Today Bas Bleu has won national and statewide awards and garnered an international reputation for its interpretation of Beckett's works. Last year it moved into the Giddings Building, built in 1910 for the Western Steel Headgate Company on the grounds of the original fort at the corner of Willow and Pine streets. To accommodate manufacturing the large headgates, it was designed with an open space of 6,600 square feet with no support beams, instead bearing trusses across the sixty-foot width of the building. "There's nothing like it," Wendy says. "It's perfect for a theater, and it still keeps the intimacy that is Bas Bleu's hallmark. What audiences love is you can see a lip quiver, or a tear go down a cheek, or a muffed line."
Realizing the potential in the space, philanthropist and former Beirut hostage Tom Sutherland guaranteed a bank loan to allow Bas Bleu to move in and start productions. Once the company pays back the loan in December and owns the building, another $1 million will need to be raised to complete renovations.
Wendy never planned on being a fundraiser for a major theater, but then again, she never planned on getting married, moving to Colorado, starting another theater or being an artistic director. But she's proud of Bas Bleu's reputation and excited that it's taken the first step "across the tracks" toward revitalizing a historic part of Fort Collins. "If you want to live life fully, you have to be open to those possibilities that might happen and let go of that feeling of entitlement that we make plans and those plans are going to happen," Wendy says. "You inherit positions that you never thought you would do and find out that you are capable of doing them."
Maybe someday she'll find the time to memorize all of Shakespeare, but right now she plans to keep acting as long as she's breathing. "I would be ecstatic if I could spend the rest of my life playing Blanche in A Streetcar Named Desire, Yeliena in Chekhov's Uncle Vanja, Celimene in Molière's The Misanthrope, and Winnie in Beckett's Happy Days," she says. "If I could do just those four plays over and over again, I don't think I would ever become bored or complacent. I don't think I've ever been bored. I don't believe in boredom. It's kind of a useless state."
Doug -- now a Becketteer, as Wendy refers to Beckett's fans -- thinks the success of the theater speaks to Wendy's intuition and charisma. Since science is a field that so often lacks a moral compass, he says it's art that grounds him. "Both of us do the kind of things we do in large measure because we want to make some sort of difference," he says. "For me, it is the hope to develop a new treatment. For the theater, it's really about asking the question: 'What do we value in society?'"
Before Doug Ishii can develop a new treatment, he has some big, expensive hoops to get through. "There's a huge gap between basic science findings in the lab and bringing a new treatment to the public," he explains. "It's not sufficient just to make a discovery, because it will fall by the wayside. It makes me very sad to think that there are many scientists out there that by their inclination are not business people, so there's many wonderful discoveries which will never fully benefit mankind."
Developing a new drug can cost as much as half a billion dollars, and the big pharmaceutical companies don't step in until a Phase I clinical trial has shown a drug to be safe in humans and a Phase II trial has shown that it works. To get there, university researchers and the small biotech companies they create must attract investors. That starts with the slow patenting process. "No one is going to put the money toward the development of a new drug unless there's a patent," Doug says. Since CSU actually owns Doug's inventions, the CSU Research Foundation loaned its money and expertise toward pursuing both of his patents, while he created his own small biotech company, Aurogen, in 1992 as a venue for attracting investors. CSURF then licensed the university's patent rights to Aurogen.
Aurogen exists solely to develop Doug's patented IGF technology into actual treatments for diabetic neuropathy and brain disorders. Doug won't disclose how much money has been invested in the company, saying it could put him at a competitive disadvantage, but he will reveal that funding is provided by "high-net-worth individuals" from the greater Fort Collins area who have prior relationships with the company's boardmembers.
Thus far, his biggest challenge, paid for with a Colorado Commission on Higher Education grant, has been figuring out a way to mass-produce the IGF protein. "The normal method of manufacture by production in bacteria, for example, is just too expensive, and more than that, there's probably insufficient manufacturing capacity in the world to make enough IGFs to treat the millions and millions of patients with Alzheimer's disease. Therefore, we're beginning an initiative to construct the human IGF gene and to insert that gene into rice plants."
Biotech companies looking for less expensive means of manufacturing new drugs have turned toward genetically engineered crops in recent years, since plants such as rice and corn have the ability to mass-produce human proteins when part of their genetic code is replaced with a human gene. In fact, Ventria Bioscience, the company Aurogen has partnered with for its IGF endeavor, has already had success growing human proteins in rice. The small, eighteen-employee biotech company out of Sacramento has made headlines in the New York Times, Business Week and the Associated Press for the promise of its technology, but also because of the controversy it presents. Its CEO, Scott Deeter, lives in Fort Collins and is the former president of CyberCrop, a Fort Collins-based software company.
Ventria is developing a drug using two human proteins found in mother's milk, saliva and tears that can lessen the severity and duration of diarrhea, a top killer of children in developing countries. Despite the drug's potential, some environmentalists and farmers fear Ventria's rice could mix with conventional crops and threaten food safety. Even the perception of such a possibility could scare off overseas customers, who account for 50 percent of the rice industry's $1.18 billion in annual sales, according to the Associated Press. Japan, a major exporter, is particularly wary of genetically engineered crops.
The company has insisted that it's highly unlikely that their rice could cross breed with other crops because rice pollinates itself, and the protein is extracted before it leaves the farm, but groups like the Union of Concerned Scientists have argued that there is no way to completely eliminate the risk of contamination. "There are lots of places in the production chain where things can be contaminated," says Karen Perry Stillerman, a senior analyst with the UCS's food and environment program. Thus, the UCS wants the USDA to ban all production of human proteins in food crops grown outdoors.
Stillerman doesn't believe such a ban would come at the expense of patients or slow the development of drugs, because despite fifteen years of testing, no company has ever received FDA approval for a single drug grown in food crops, she says.
Founded in 1997, Ventria first planted rice fields in California but faced mounting opposition from environmental groups and ceased its farming experiments there. Last year the company abandoned plans to plant in Missouri's rice belt after Anheuser-Busch threatened to boycott Missouri-grown rice. Ventria has since started growing its rice in North Carolina, with USDA approval to expand the operation to 335 acres -- and just last month the company was offered $2 million in incentives to build a processing plant in Kansas after the financing to build at Northwest Missouri State University fell through.
For now, Doug's rice is still growing in a lab in California, but he estimates that enough IGFs for the first phase of clinical trials could be grown on two or three acres of land. "That may be done almost anywhere," he says. "It may be done in Missouri. It may be done in South America. We don't yet know if the IGF is going to be produced in the rice kernels, and we can't know that until the plants mature and the rice grains are produced, and that will happen this fall, so we're on pins and needles."
If it works, Doug still needs millions before trials, and getting that far doesn't guarantee a positive outcome or a new drug. There are thousands of small biotech companies like his around the country, each with their success riding on just one or two products. Except for those few that get a positive clinical trial, most of the companies will fizzle and die.
As Doug points out, "You don't get any points for being second in science."