A new generation of bioentrepreneurs emerged at Berkeley in the 1990s. They include Robert T. Tjian, Gerald M. Rubin, and Corey Goodman, all sharing an unusual combination of attributes: mid-career basic scientists and professors, Howard Hughes Medical Institute investigators, and co-founders of "start-up" biotechnology companies developing promising new tools and technologies. A prime example is Robert T. Tjian, co-founder of Tularik, Inc. 

Biography

Robert T. Tjian was born in Hong Kong in 1949. Fleeing the Communist revolution, his family moved to South America where his father, a Shanghai industrialist, had business interests. Eventually several dozen family members settled in Buenos Aires, moved to Rio de Janeiro, and finally, to Collingswood, New Jersey in 1964. Tij (and several siblings) attended UC Berkeley where he worked as an undergraduate with Daniel E. Koshland, Jr., Professor of Molecular and Cell Biology, and received a degree in biochemistry in 1972. Harvard awarded him a Ph.D. in biochemistry and molecular biology in 1976, and he spent three years as Harvard Junior Fellow and Staff Investigator at Cold Spring Harbor Laboratory, where he worked with James D. Watson. In 1979, Tjian returned to Berkeley as Assistant Professor of Biochemistry. In 1982 he was promoted to Professor and in 1987 was appointed Howard Hughes Medical Institute Investigator, an honor which assures long-term funding for his laboratory. Tjian is a member of the Academia Sinica of China (whose president is former Berkeleyan and Nobel laureate Y. T. Lee), the U.S. National Academy of Sciences, and the American Academy of Arts and Sciences. 

In 1991, Tjian co-founded Tularik, Inc., a biotechnology company in South San Francisco which is a leader for its approach to human disease based on regulating gene expression by targeting transcription factors and other proteins involved in DNA transactions. Tjian chairs Tularik's Scientific Advisory Board. He also serves on the editorial boards of several journals and chairs the Chancellor's Advisory Council on Biology. 
 

Robert Tjian, Cold Spring Harbor Laboratory, 1978.

Tjian and "transcription factors"

Transcription factors are proteins that switch genes on or off, causing them to be expressed or repressed. If gene expression is faulty, the cell malfunctions and disease may result. Tjian's group at UCB is focused on identifying transcription factors regulating genes which may cause diseases.
 

This page from Tjian's first graduate school lab notebook (1973) records his discovery of phage SP-01 sigma factor, a bacterial transcription factor. It represents an important step in his career as a scientist and entrepreneur. Tjian and his colleagues have since identified more than 50 transcription factors and they are a foundation of the Tularik, Inc. drug development program.

In 1978, when Tjian had a postdoctoral fellowship at Cold Spring Harbor, he discovered his first non-bacterial transcription factor – a tumor antigen produced by a monkey virus, SV40. 
 

In this article, "Molecular machines that control genes," published in Scientific American (February 1995, pp. 54-61), Tjian describes how disease may be treated by regulating gene expression and repression with transcription factors.

In further testing, scientists isolate chemical compounds that cause the transcription factors to switch the gene on or off. Promising compounds are tested in animal and human trials which may result in a marketable drug. Faulty gene expression or repression appears to be a factor in cancer and various viral, cardiovascular, and inflammatory diseases. 

First human transcription factor
 

This notebook, compiled in 1985-1986 by Jim Kadonaga in Tjian's Berkeley laboratory, records the critical experiment that identified SP 1 (Specificity Protein 1), the first human transcription factor that could be regulated to cause gene expression.

Tularik, Inc.
 

The Tularik logo is a stylized image of the trout fishing river in Alaska where David Goeddel and Tjian first conceived of founding a new biotechnology firm.  Later, Goeddel (former chief scientist at Genentech) drafted a seven page business plan  for the venture (below), addressing such topics as Mission; Competition; Hiring Plans; Financing; Proprietary Position.

Beginning in 1992 with 60 employees, 20,000 square feet of space, and $3.9 million in capitalization, by 1999 Tularik had grown to 184 employees (including 12 in a Long Island facility) in 144,000 square feet, and a market value estimated at $350 million. In 1999, Tularik launched a highly successful initial public offering of its stock.
 

The Founders: Robert Tjian, David Goeddel, Steven McKnight. Tjian became chair of the Scientific Advisory Committee, while Goeddel and McKnight ran the laboratories. Goeddel later succeeded Mark Levin (who went on to found and become CEO of Millennium Pharmaceuticals) as president. Completing the executive team was Robert A. Swanson, who joined as Chairman, a position he also held at Genentech, one of the most successful biotechnology companies.

In this letter to McKnight, Thomas D. Kiley, a lawyer formerly with Genentech, assists Tularik with a key recruitment. Kiley suggests that McKnight's participation is critical to recruiting Goeddel, whose record as an industrial scientist at Genentech, in turn, would help assure venture capitalists that Tularik was a worthwhile risk. As a further aid, Genentech, Inc., agreed to supply Tularik critical materials – thereby making explicit the linkage between a highly successful corporation and its newborn cousin.

Capital had to be secured before Tularik would be viable. It would have to be venture capital because it would take years - perhaps a decade - before Tularik would have a product on the market. Conventional financing through the sale of public shares was ruled out due to the shakiness of the market at the time and the desire of the co-founders to retain control.

A critical patent
 

Tularik holds patent 5,591,825 for "methods and compositions for identifying pharmacological agents useful in the diagnosis or treatment of disease associated with the expression of a gene modulated by an interleukin 4 signal transducer...," which is another way of describing gene regulation with transcription factors. With this patent in hand, Tularik aims to develop and market drugs that direct transcription factors or signal transduction molecules to regulate malfunctioning genes.
Robots run critical operations
	Computers, test tubes, robots, people and a library of 500,000 natural and synthetic compounds and extracts inhabit the laboratories in Tularik's South San Francisco headquarters. Five robots conduct the all-important automated assays which test the compounds' effectiveness in regulating genes; if successful, they could become marketed drugs.