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Molecular and Systems Biology
By Leroy Hood, President, Institute for Systems Biology
Dr. Hood (M.D., Johns Hopkins, 1964; Ph.D., Caltech, 1968) began his career at Caltech,
where he and his colleagues pioneered four instruments that comprise the technological foun-
dation for contemporary molecular biology. In particular, the DNA sequencer revolutionized
genomics by allowing the rapid automated sequencing of DNA. While at Caltech, Dr. Hood
and others worked with Arnold O. Beckman to organize the Beckman Institute in 1986. In
2000, Dr. Hood cofounded the Institute for Systems Biology in Seattle. He has been honored
You need to with numerous academic and scientific awards for his study of immune diversity, continuing
development of instrumentation, improvements to diagnostic methods, and efforts to open
use frontier doors for new treatments and cures. Dr. Hood is a member of the National Academy of
Sciences, the Institute of Medicine, and the American Association of Arts and Sciences.
problems in
I was at Caltech for 30 years--four years as an undergraduate, four years as a gradu-
ate student, and then 22 years as a faculty member. During that time, I participated
biology to in four transformational developments in biology: the creation of new technologies,
genome biology, systems biology, and personalized medicine. Each of these advances
drive the kinds should be seen as nothing less than a paradigm shift in the biological sciences, with all
of these paradigm changes driven by changes in technology.
of technology
When I became an assistant professor at Caltech in 1970, I divided my time equally
between biomedical research and the development of new instruments, despite some
you want to
resistance from the department. However, the two should not necessarily be seen as dis-
tinct. You need to use frontier problems in biology to drive the kinds of technology you
develop. want to develop. And once you've developed those technologies, they in turn allow you
to remove the shrouds of confusion from these frontier areas.
One of the first instruments that my colleagues and I successfully developed was a device
to determine the amino acid sequence of proteins. With a sensitivity much greater than
any previously available instrument, the device allowed us to look at biologically inter-
esting proteins that had theretofore been invisible. With University of California, San
Francisco, professor Stanley Prusiner, we sequenced the proteins involved in prion
diseases--work that helped Prusiner win the Nobel Prize in 1997. We sequenced the pro-
tein erythropoietin, a hormone that stimulates the production of red blood cells and was
one of the first billion-dollar products in the biotechnology industry. We also sequenced
proteins involved in neurotransmission, stem cell development, and immune reactions.
26 INSTRUMENTATION FOR A BETTER TOMORROW
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It was a remarkable time; we had this instrument that let us go out and survey the field
of all these things that hadn't been looked at before.
We also developed a device to synthesize proteins from their constituent amino acids.
This instrument was critical, for example in synthesizing part of an important protein in
the AIDS virus, which in turn led to the development of the first protease inhibitor for
the virus. The protein synthesizer also played a key role in the development of the poly-
merase chain reaction (PCR) because it enabled the construction of the oligonucleotide
primers that are essential to the amplification of targeted DNA regions. PCR never
would have happened if it had not been possible to synthesize DNA very readily.
In the late 1970s, I began thinking about commercializing some of the instruments I was
developing. The president of Caltech emphasized that the fundamental role of the
university was scholarship and education, not the commercialization of instruments, so I
began exploring options on my own. I went to 19 different instrument companies and pre-
sented a vision of how instruments were going to transform biology. I was 0 for 19. In fact, I
went to Beckman Instruments three times, and the last time a manager said, "We're just not
interested." About that same time, Arnold Beckman, who was no longer directing Beckman
Instruments, heard me give a lecture, and his reaction was "This is really interesting. This is
just what Beckman Instruments needs." I should point out, this raises a really interesting
question about companies. What happens when the creative driving force of the company
isn't at the helm anymore? Is it really better to start new companies?
That's what I did. I participated in the founding of a new company, Applied Biosystems,
which commercialized the instruments we were developing and is now a world-leading
company in the field of molecular instrumentation.
One of the most important instruments commercialized by Applied Biosystems was the
automated DNA sequencer, which could determine the sequence of nucleotides in DNA
molecules. This got me into the next big adventure of my life, which was the Human
Genome Project. Launched in 1990, the project completed an initial draft of the human
genome in 2000, and a final draft in 2003. Essential to the project's success was the auto-
mated DNA sequencer developed by Applied Biosystems. The development of the
instrument began in earnest in 1982 through a multidisciplinary effort involving biolo-
gists, chemists, computer scientists, and engineers. I realized that the tools of biology
INSTRUMENTATION FOR A BETTER TOMORROW 27
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1986
First automated DNA sequencer
1980 launches the genomics revolution.
Frederick Sanger awarded 1990
Applied Biosystems commercializes
the Nobel Prize in Chemistry Advances in mass spectrometry
the first automated DNA sequencer,
for inventing the dideoxy enhance protein identification
accelerating the researchers'
DNA sequencing method, and characterization.
ability to unravel genetic secrets.
still used today to identify Time-of-Flight (TOF) MS with
the genetic code of organisms. matrix assisted laser desorption
ionization (MALDI) is introduced,
and becomes an important
technique for understanding large
biomolecules, including proteins.
1991
1989
1985 GenBank and other public
Gene for cystic fibrosis
Robert Gallo and databases begin to show
1983 identified. A mutation
Luc Montagnier exponential growth
Kary B. Mullis develops in the gene sequence
independently in sequence information,
the polymerase chain creates a protein that
publish the DNA as Applied Biosystems
reaction (PCR), cannot function properly.
sequence of HIV, the automated DNA and
a technique that enables virus that causes AIDS. protein sequencers gain
scientists to rapidly in popularity.
amplify DNA. In 1993,
he received the Nobel
Prize in Chemistry
for his accomplishment.
couldn't be developed just by biologists any more; we had to integrate our partners from
other disciplines (see Figure 16 for the development of analytic methods).
This project convinced me that a cross-disciplinary environment could foster major
advances in biology. Such an environment was difficult to establish at Caltech, so in 1992,
I moved to the University of Washington to establish a new department of molecular
biotechnology. The department brought together faculty members working on
proteomics--the global analysis of proteins--cell sorting, protein synthesizers, and other
sensitive, high-throughput instruments. We had good tools, a good computational infra-
structure, and a cross-disciplinary environment, and the idea of biology as an information
science was just beginning to emerge.
With the necessary components of a more comprehensive approach to biomedical prob-
lems becoming available, I turned my attention to the best way to approach complex bio-
medical problems. Systems biology is the idea that we can look at all of the elements of a
system. There are two main types of digital information in biological systems. One is the
genes that make proteins, and these proteins often create networks that do things like sig-
nal transduction of information from outside a cell. The second type of digital informa-
tion is the regulatory elements that interact with a class of proteins called transcription
factors--they regulate the expression of proteins and help to create networks of physio-
logical and developmental order. These two types of information lie at the heart of systems
biology. To take advantage of the many new opportunities offered by this perspective, I
cofounded the Institute for System Biology in 2000.
Instruments now being developed are specifically focused on a systems biology perspective.
For example, we are involved in efforts to use nanotechnologies to sequence single DNA
molecules, which would eliminate the need to produce a large number of identical DNA
28 INSTRUMENTATION FOR A BETTER TOMORROW
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2002
Next-generation mass spectrometers
1998 further improve accuracy of protein
DNA sequencing becomes 2002 identification and characterization.
industrial scale. The ABI Systems increase analysis
1994 Mouse Sequencing
PRISMŽ 3700 DNA Analyzer speed and provide even higher
DNA evidence gains Consortium publishes sequence
becomes the primary platform performance for protein and peptide
acceptance for use of mouse genome, enabling
used to sequence the human identification and analysis of small
in criminal cases, and scientists to compare the contents
genome, enabling molecule drug
is brought to public of the human genome with
the project to be metabolites
attention in the this important animal.
completed years important in
O.J. Simpson trial. ahead of schedule. therapeutics.
1995 2002
1994 Craig Venter and colleagues at 1997 John B. Fenn and Koichi Tanaka
Term "proteomics" TIGR complete first genome "Dolly," a sheep, 2000 awarded Nobel Prize for
coined thrusting protein sequence of a free-living is the first mammal to The Human Genome Project Electrospray
studies into spotlight. organism, Haemophilus be cloned from an adult. and Celera Genomics and MALDI ionization. Applied
independently complete their Biosystems and Applied Biosystems/
1993 influenzae, using the novel drafts of the human genome. MDS SCIEX incorporated these
Huntington disease "shotgun" sequencing method. In February 2001, Celera award-winning techniques into their
gene identified, ending The flu-causing organism Genomics published its results mass spectrometry systems.
the decade long search. contains 1.8 million base pairs in Science, and the HGP
Genome sequencing of and approximately 1,000 genes. published its results in Nature.
a few viruses is complete.
molecules for sequencing. My prediction is that within 10 years we will be able to sequence FIGURE 16 A pictorial timeline
the complete human genome inexpensively and rapidly. We are also working on instru- illustrating the rapid
development of genetic
ments that will be able to analyze the individual RNA molecules in a cell (such instruments analysis techniques.
would indicate which genes are turned on and making proteins) as well as on an integrat-
ed "nanolab" that would subject the contents of a single cell to a variety of diagnostic tests.
In turn, these new instruments will make possible the coming era of personalized medi-
cine. Patients would have their DNA sequences analyzed and undergo a profiling of the
functioning of their cells using material from a simple blood test. We'll look at your DNA
and make predictions about your future health. And we'll look at your blood as a window
to health and disease.
Disease arises as a consequence of modified biological networks. When you modify the
network, you modify the patterns of gene expression, which constitutes a molecular sig-
nature that differentiates health from disease. We can design a drug strategy that moves a
network back toward its more normal behavior.
This new approach to medicine will have profound consequences for the health care and
pharmaceutical industries, I predict. The medicine of today and the medicine of the future
are going to be radically different. For example, I think in the next 10 years big pharma is
going to be entirely restructured. I don't think it will be able to respond to the new kinds
of medicine we will see.
At the same time, the new medicine will have a powerful effect on the lives of individuals.
If you put the medicine of the future, which I think is 10 to 20 years off, together with
things that are happening in aging and neurobiology, I think we're going to significantly
increase the productive lifespan of individuals over the next 20 years.
INSTRUMENTATION FOR A BETTER TOMORROW 29
Representative terms from entire chapter:
dna sequencer
