Today's bioentrepreneurs at the University
of California have predecessors dating to the early decades of the 20th
century. An early example is Karl F. Meyer, whose work on botulism and
plague saved the California canning industry and produced a successful
vaccine for commercial distribution. More recently, Berkeleyans figured
prominently in the history of the first Bay Area biotechnology companies
that developed ground-breaking techniques and products. They include Kary
Mullis and Donald A. Glaser, two Nobel Laureates associated with Cetus
Corporation, where a major biotechnology tool (PCR or the polymerase chain
reaction) was invented. Cetus was later acquired by Chiron Corporation,
co-founded by another Berkeleyan, Ed Penhoet. He retired as Chiron's CEO
and returned to UC Berkeley in 1998 to serve as Dean of the School of Public
Robert T. Tjian (1949- ) & Tularik, Inc.
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.
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
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 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
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.
First human transcription
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.
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
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
|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
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