By Laura Bonetta

In the late 1990s, Sam Reich grew frustrated with the obstacles that he encountered in trying to deliver therapeutic molecules using viral vectors. As a graduate student in a gene therapy lab at the University of Pennsylvania, Philadelphia, PA, he turned his attention to a budding area of science, RNA interference (RNAi).

At the time, most experiments using RNAi had been done in invertebrates, but Reich, who was working in the department of ophthalmology, showed that RNAi could effectively knockdown the expression genes in the mammalian eye. A chance meeting with colleague Michael Tolentino, also at Penn, presented a way to apply this technology to therapy. Tolentino had discovered that hyperactivation of a protein, vascular endothelial growth factor (VEGF), was involved in age-related macular degeneration (AMD), the leading cause of blindness among aging individuals. This protein contributes to the growth of abnormal blood vessels in the eye, which start to leak and dim central vision. Tolentino was looking for a way to inhibit VEGF, and the RNAi technology developed by Reich provided an ideal candidate. Reich licensed the technology from the university, and Acuity Pharmaceuticals of Philadelphia was created in 2002. Now, only 5 years later, the company is poised to bring the first RNAi-based therapeutic to market.

Many diseases, like AMD and cancer, involve the increased expression of particular genes, and short interfering RNAs (siRNA) can specifically inhibit the expression of these harmful genes and provide a therapeutic benefit. “As a class of drugs, siRNAs are comparable to monoclonal antibodies, although they have a different effect,” says Reich. Like Reich, Jeremy Heidel of Calando Pharmaceuticals in Pasadena, CA, and Jim McSwiggen of Nastech Pharmaceutical Company in Bothell, WA, left stellar research programs in academia to pursue the therapeutic potential of these molecules.

An Agonizing Decision

Reich's decision to move from academia to industry was a particularly difficult one. He had not yet completed his Ph.D. thesis, and joining Acuity would mean not getting his degree. “I spent a lot of sleepless nights agonizing over the decision,” he recalls. But in the end, he decided to follow his research. “The VEGF program was moving so much faster than my Ph.D. would have. It had taken a life of its own, and I decided to stay with it to maintain the momentum,” he explains. “The research was more important to me than a title.”

Reich became Acuity's executive director for research and development and started to put together a team of “top-notch individuals” to deal with the various aspects of bringing a product to market. The new role did not come easily, but it was something he looked forward to doing from the start. “Taking really exciting basic research and then trying to figure out how to make a product based on it presented a whole new list of questions and problems that needed to be solved and that you never think about in the lab, such as applying for patents, fundraising, and human resources. It was exciting to me,” he recalls. “I really enjoy being at junction of business and science.”

To learn the business side of things, Reich relied on his own intuition as well as the expertise of others at Acuity, such as the chief executive, Dale Pfost, who had joined the company in its earliest days. “Dale replaced my Ph.D. advisor in a way,” says Reich. According to Reich, obtaining and maintaining the necessary funds for the different programs in a changing market and economy makes up one of the more challenging aspects of managing a biotech start-up. “So far, we have been successful in staying on track and maintaining momentum,” says Reich. “But it can also be a distraction.”

The Team Approach

The diversity of roles and challenges faced by researchers working in start-up companies is what persuaded Jeremy Heidel to join Calando Pharmaceuticals in 2005. Having completed a successful Ph.D. thesis, he had several career options to pursue, but the idea of working for a start-up biotech company was particularly appealing to him. “Each of the professors I worked with had founded their own companies, and I had worked in one of them for a couple of summers as a student. The experience gave me a sense for what life might be like,” he explains.

Heidel liked the excitement among the people working at these companies and the fact that the roles of employees were not precisely defined. “A lot of start-ups begin lean and mean; there is rarely an excess of manpower. As a consequence, every employee has to be able to adapt,” he says. “If we don't have someone with a particular expertise, you have to step up to the plate and learn what needs to be done.”