Controlling Growth Factors
Who you are is largely dictated by a group of biochemicals called growth factor proteins. Growth factors orchestrate embryological development, guide our maturation from infant to adulthood, regulate immune function, direct the ever-changing alterations to our brains that underlie personality and learning, and enable us to repair damage to our bodies and minds.
"Effectively and selectively controlling growth factor function is one of the holy grails of medicine," says Joe Harding, Washington State University professor of physiology and neuroscience.
Too much or too little growth factor action is the hallmark of our most devastating diseases--from cancer, where over-activation of growth factors leads to uncontrolled cell division and the loss of cell adhesiveness associated with metastasis, to neurodegenerative diseases where augmented growth factor activity would be helpful in halting degenerative processes and restoring lost mental and motor functions.
But the development of useful, affordable drugs has been difficult. While there have been some notable successes that block specific growth factor systems, these drugs suffer from a lack of specificity, the development of drug resistance, an inability to reach the brain, or exorbitant costs. The ability to activate growth factors with pharmaceuticals has been even less successful, and no FDA-approved drugs are available.
"Our laboratory has developed a technology that targets a process common to many growth factors," Harding says. "We have successfully built molecules that can either activate or inhibit growth factors. These small-molecule drugs are inexpensive to manufacture, highly specific, and can be designed to reach the brain."
"We've developed a molecule called Dihexa that shows promise at halting and perhaps reversing the devastating effects of Parkinson's disease and dementias," Harding continues. "In animals, we are seeing therapeutic effects attributable to a combination of neuro-protection from the offending insult, the generation of new connections among surviving nerve cells, and the production of new nerve cells from stem cells that reside in the brain."
Harding and his colleagues see potential for this technology to reach far beyond the treatment of neurodegenerative diseases.
"There is a potential here to develop innovative treatments for almost every major human disease," Harding says, "including cancer, diabetes, and congestive heart failure."
The development of Dihexa has been progressing for over 20 years. Drug development requires a village, and Harding's invention is no exception. Dihexa (and its cousin molecules) were screened from hundreds of candidate compounds. One of Harding's former graduate students is a key member of that village--Leen Kawas is now CEO of M3 Biotechnology, the WSU spin-off company that is attempting to commercialize Dihexa.
By the time she was 7 years old, Leen Kawas knew she wanted to cure cancer. The native of Jordan had a deeply personal motive: her beloved grandmother was deteriorating before the young child's eyes.
"As a child, seeing that leaves a significant message that someone needs to do something," Kawas says. "I wanted to study chemistry and accounting, and my mom convinced me pharmacy was a combination of both of those things."
Kawas's mother ran the biggest hospital in Jordan and held managerial positions at the University of Jordan as well.
"She influenced us a lot--we're all over-achievers," Kawas says of herself and her siblings. She has two sisters. One works as a researcher with IBM, while the other teaches at the University of Washington. Her 23-year-old brother just graduated from medical school.
Kawas earned a doctorate of pharmacy in Jordan and worked as a clinical and retail pharmacist in Jordan, an experience she found valuable but which also left her itching to get back into academia.
"Learning the drug approval process, understanding reimbursement issues, and patient interaction were all very helpful," Kawas says, "but I needed a new challenge and wanted to do work with more impact."
Kawas began investigating graduate programs on the East Coast, where her uncles live, until a University of Jordan professor and WSU alumnus approached her and suggested WSU.
"It was two hours before the deadline to submit my application, but he said Pullman was a great town, had some researchers in my area, so I went for it."
Once Kawas found Joe Harding's lab, the choice was easy.
But even as she prepared to move half way around the world, her mother suffered a stroke that resulted in seizures and hospitalization. The experience of her mother's illness shifted Kawas's focus from cancer to neurology.
"I always have the patient in mind in the drug development process," Kawas says--which is why developing Dihexa in a cost-effective way is a major priority for both Kawas and Harding and the third member of M3's executive team, Jay Wright. That is also one of the reasons M3 Biotechnology has proven so attractive to investors.
Harding says that Kawas's research was instrumental in the early development of Dihexa and helped set the foundation for the development of M3 Biotechnology. Her background informs her appreciation of the interplay between the chemistry and biology that underlies M3's platform. That same background also gives her the credibility to lead the company and guide its drugs to clinical trials and, ultimately, the therapeutic marketplace.
The Wright Brother
After finishing a neurochemistry postdoctoral program with Frank Margolis at the Roche Institute in New Jersey, Joe Harding and his wife, Barbara, headed for Pullman in 1976.
"We drove out here with our screaming five-week-old baby," Harding recalls. "We had a house that we'd rented in advance but, when we arrived, we discovered there was someone living there!"
Barbara Harding walked by the house every day and eventually met one of the renters, Donna Wright. "Donna saw Barbara walking by all the time, so she came out and they started talking. Barbara and Donna quickly became friends. They decided we should all have dinner together, and that's when I met Jay."
Over the course of that first evening together, Harding and Jay Wright discovered that both couples were paying rent on the house. The two young men decided to pay a visit to the rental agent to have a discussion--and to get their money back.
"That was the beginning of a life-long friendship and an important collaboration," Harding says.
Jay Wright had already been a member of the WSU psychology faculty for a year or two. His specialty was memory, a perfect complement to Harding's burgeoning interest in neurochemistry.
The pair frequently met over tea to discuss ideas for experiments. Harding feverishly pitched ideas while Wright, taking notes on the back of napkins, grounded them in the practicalities of behavioral psychology. In 1977, they founded a joint lab, an act that raised a few eyebrows in their respective departments because, in those days, interdisciplinary research projects were far from the norm.
But, as Harding points out, this was neuroscience, a field of study that inherently transcends any one discipline.
By the mid-1990s, though, Harding was following a trail that had led him deep into the chemistry and physiology of heart disease. He and his team were racing to identify the target for a powerful cardiovascular peptide that they thought could lead to a useful treatment of cardiac disease. (Peptides are small chains of amino acids that share some characteristics of proteins.)
Harding lost that race but discovered that, along the way, he and his team had another peptide with some curious properties. In talking over the results with Wright, the pair devised a means to uncover the peptide's function. And that, eventually, led to the development of Dihexa and the publication of several key papers.
This work by Harding and Wright led them to a vice president for research at Eli Lilly, the pharmaceutical giant. At a scientific conference, the VP sought out Harding and Wright and offered to fund their research on the promising peptide.
"And that," says Wright, "eventually led, with much help from WSU's Office of Commercialization and a small army of undergraduate and graduate students, to the intellectual property that is at the heart of M3 Biotechnology."
Getting into Science--and the Business of Science
"When I was a kid in New Jersey," Harding says, "we got the Star Ledger. And on Sundays, they published a science section. That and the sports page were all I was interested in. I used to cut out the science pages and catalog them away, rereading them over and over."
By the time he was in 6th grade, Harding was nuts about chemistry. "I used to get on my bike, ride 10 or 12 miles over to the headquarters of Baker Chemical, a big chemical supply company. I'd buy bottles of nitric acid and other supplies I needed, and then bike home with this stuff in the basket of my bike."
The reason the chemistry-kit kid needed dangerous substances like nitric acid was because he was on a mission to isolate as many chemical elements as he could from common compounds. Things didn't always go as planned. Twice, he blew out the windows of his parents' basement. Fortunately, no people or pets were harmed as the young scientist learned his craft.
"I was just really attracted to the idea of making things no one had made before," Harding says, a statement that goes a long way toward explaining his life-long entrepreneurialism.
"I've always had my own little businesses," Harding continues. "In high school, I had a window cleaning business. I'd go into local housing developments being built and get the contract for cleaning all the windows. I had ladders and all the equipment, so I hired my high school friends."
Then there was the fish business. "All through junior high, I raised fish--angel fish, discus, other tropical fish--that I sold to local pet stores." There were tanks everywhere in the Hardings' home. "I'd scavenge busted tanks on community trash days, bring them home, fix them up, and put them into service."
The Path Forward
Harding, Wright, and Kawas hope to move Dihexa into preclinical and clinical trials in the near future. Taking a drug from the lab bench to human therapeutic applications is an arduous and expensive process, however, and there is no guarantee that the trio's invention will make it to market.
"Our initial development work has been supported by grants from both the Michael J. Fox Foundation and the Alzheimer's Drug Discovery Foundation," Kawas says.
"That financial support stemmed from their understanding that our technology represents a novel paradigm in the treatment of neurodegenerative diseases," Harding adds.
The team, and especially Kawas, shuttles from meeting to lab to meeting, scrambling to find time to meet submission deadlines for grants and papers, all the while seeking the support they need to move their invention through the development pipeline.
"We don't know if the drugs we're developing are going to be ultimately successful," Harding concludes. "But they represent a totally new approach to potentially treating some of the most devastating diseases we have. There is hardly a family that isn't touched by a neurodegenerative disease at some point. We can't guarantee success, but it's an approach that looks like it has promise, and we'll see where it goes over the next couple years.
"So that's why we started M3 in Seattle. The long-term goal has been to establish a biopharmaceutical company in Washington that employs Washington residents. And we want to produce pharmaceuticals that people can afford. That was one of our core tenets when we started this. We didn't want $100,000 treatments. We want treatments that everyone can afford, that insurance companies will be happy to pay for."