By Douglas Jones II

The Birth of Biotech

    In the late 1970s Genentech pioneered technologies that transformed translational biomedical research. Genentech was founded in 1976 based on the idea that the genetic information encoding for a given protein could be transferred – or quite literally cut and pasted – for production in bacterial cells. Thirty years ago, the notion of synthesizing a human protein, such as insulin, from a bacterial cell was a revolutionary concept. Using this protein as a therapeutic in humans was even more revolutionary and also perceived to be highly risky. But this was exactly what Genentech aimed to do. Genentech successfully pioneered recombinant DNA technologies for production of human insulin from bacteria and showed this protein to be identical in function to insulin produced in humans. Synthetic human insulin, the first ever genetically engineered therapeutic agent, was approved by the FDA in 1982, and the age of biotechnology was born. 
 

    Dr. Richard Scheller is heading research and development efforts at Genentech as they venture into new and exciting areas. Prior to his time at Genentech, Scheller was a professor of Molecular and Cellular Physiology at Stanford and an Investigator of the prestigious Howard Hughes Medical Institute. In 2001 he moved to Genentech to serve as Senior Vice President of Research. Following Genentech’s merger with Roche in March 2009, Scheller assumed the role of Executive Vice President of Research and Early Development and now oversees all research and clinical development activities at Genentech. Scheller sat down for a discussion with me about the past, present, and future of research at Genentech.

The ‘Genentech Culture’

    Dr. Arthur Levinson rose from head of research to president and CEO of Genentech in 1995. A molecular biologist by training who had never headed a company before, he shifted the focus at Genentech to the laboratory, and is credited by many for instilling the unique culture at Genentech. I asked Dr. Scheller to comment on this unique ‘Genentech culture’.
 

Scheller: With a large percentage of our research devoted to basic science discovery I think there is a unique culture here that doesn’t exist in a lot of other companies. But you might ask us, ‘What do you get out of that? Why do we do it?’ Imagine having a group of people coming in from all over the world as post-docs: different backgrounds that bring in different technologies, different ideas. Mixing this in with the Genentech science keeps us up to date with new technologies and new ideas. It keeps us rigorous. A lot of the scientists who are here wouldn’t be here if they couldn’t do basic science as well as translational science.
 

    How is it that Genentech was able to effectively instill this culture, while other companies may have tried and seen less success?
 

Scheller: It’s really a unique culture here. We’re not asked by commercial folks to make a particular drug for ‘x-y-z’ disease. We assess the scientific opportunity, so in a sense the model is a little bit backwards… or different, let’s say 180 degrees, not backwards – we find a scientific opportunity and develop that into a therapeutic. We’re not asked to find a therapeutic where there may not be a particularly unique scientific opportunity that presents itself, which is the way many companies work. So I think entire the culture is quite unique: science driven and data driven, with a very high percentage of rigorous basic science that doesn’t exist at other places.
 

    Upon news of the recent merger with Roche, many people were concerned this might spell the end of the ‘Genentech culture’. Could this culture truly persist under the umbrella of a big pharma company such as Roche?
 

Scheller: Roche indicated from the start that the research and early development group would remain an independent entity, which is exactly what happened. We receive a budget from Roche, which is a substantial one, and then we manage that budget as we wish. We of course have a set of goals, which is not only to make new medicines, but part of the goals are to stay an exciting place for post-docs to come, part of the goals are to publish papers, part of the goals are to maintain high scientific standards. I report to the CEO of Roche directly, and have a set of folks who report to me. I distribute the budget to them and they manage the budget in the same way that they would have if we were an independent Genentech.

Academia vs. industry vs. Genentech

    The research environment at Genentech seems to lie somewhere in between that of academia and industry, making it an attractive place for scientists and researchers. This is likely a major factor in Genentech being named the “top employer in the biopharmaceutical industry” by Science magazine for seven of the last eight years. What are some of the similarities and differences between life at Genentech and life in academia?
 

Scheller: In academia the goal is to discover something really interesting and important, but it doesn’t matter as much exactly what it is you discover. Some serendipitous things can happen that lead to a really exciting discovery, and that’s fine. We’re interested in discovering cool things here as well, but we’re also interested in making medicines. And that is a process that we really need to follow and be successful at in order to help people. So that’s a more directed mission than following your instincts in basic science discovery. However, at Genentech we do both. We have a post-doc program and the goal of the post-doc program is for people to discover cool things, whatever it might be. But we also have translational programs and the translational programs are more focused on making a medicine for somebody with a particular disease.
 

Scientists here are encouraged to have basic science research programs, largely through the post-doc program, but the scientists here also have translational programs. Sometimes people ask me ‘what percent of a scientist’s time do they have to pursue their own ideas?’ There isn’t really a formula for the scientists; we try to find the right balance for each individual. Some people aren’t interested in the basic science and want to do more translational work, and other people are mostly basic science oriented. So there isn’t a formula, but we encourage folks to do both. The difference is that we really encourage almost everyone to have a translational project to help patients and to help our pipeline.

The Future of Research at Genentech

    Genentech has had substantial success in the past, what does the future hold?
 

Scheller: In the next five years I hope that we can continue to make great medicines for people with cancer, immunological disorders, and infectious diseases. Neuroscience is another disease focus area we are entering. To be quantitative about it, I hope that we can deliver at least ten new products to late-stage research folks [Phase III clinical trials] over the next five years and we’ll try to have diagnostics associated with as many of those as possible to focus on appropriate patient selection.
 

    Antibody-drug conjugates, or so-called ‘armed antibodies’, are getting a lot of hot press right now, will these bring the next generation in therapeutic medicine?
 

Scheller: We’re very excited about our molecule that’s furthest along, which is an antibody that’s well-known in the clinic, Herceptin, conjugated to a drug that is a toxic substance for cells. This molecule is called trastuzumab-DM1 (TDM-1), and it has performed extremely well in early stages of clinical development and we are seeing response rates that are very promising. This molecule is being used to treat Her2+ patients that have failed all the other therapies, so there is little left for these patients, and we are seeing very nice durable responses. So as a proof of the concept, this looks very promising.

But what one has to remember is this is an old idea – arming antibodies with a drug. People called it the ‘magic-bullet’ if you will: the bullet that only went to the right place. It took us almost a decade, of studying all of the variables involved: What drug should we use? What antibody should we use? How should the drug be connected to the antibody? We tested all of this to understand the principles behind making this magic-bullet a really effective medicine. Now that we think we understand these principles we have a large pipeline of what we call ‘armed antibodies’ coming forward for a variety of the other cancers as well: lung, colon, other non-Her2+ breast, prostate, and ovarian cancers. We’re quite excited that this could provide great benefit to patients.

In retrospect…

    Prior to your time at Genentech, you were a successful professor at Stanford, and here at Genentech you have clearly seen continued success. What advice would you give to younger students and researchers at earlier stages of their career?

Scheller: The most important advice is to really, really do something you are passionate about, to do something that you really enjoy. If you do that, you’ll be fine. It’s simple advice, but absolutely the best thing I could recommend to people. If you try to force yourself to do something that you’re not passionate about, it usually just doesn’t work. Science is hard, science takes extreme dedication, science takes passion; and if you’re not truly excited about something, if it’s not what you want to do, then it becomes extremely difficult to put in the devotion and dedication that’s needed to be successful. Even if you could make yourself work that hard, you’d still be doing something that you just didn’t enjoy. So do something that you love.