Mice, worms, flies, microbes, man -- they're all much more than mere bags of nucleotides and amino acids. Instead, they're actually the result of complex interactions between genes, proteins and cellular organelles. So, while scientists the world over are racing to finish the sequencing of the human genome, others are gearing up to answer biology's next big riddle: How do organisms function as whole, integrated systems?
This new scientific discipline -- systems biology -- is not all about biology, either. For, as Leroy Hood can tell you, biology is information science. And, though biotechnology's tools can and do decodify this information, they need the aid of computers to turn raw data into knowledge. In fact, the next scientific revolution will not and cannot occur without a true merger between biology and computing. "Applied math and computer science are fundamental to modeling and understanding systems properties, even though mathematical models of biological systems do not yet exist," Hood explained last spring. (For more comments made at the Bio '99 meeting on the marriage of biology and computing, including from Compaq Computer Corp.'s chairman Ben Rosen, see the Signals article, "Restless In Seattle.")

Leroy Hood

Even in May 1999, Hood was well on the way to setting up an institute specifically to address questions in systems biology. By mid-December, he'd not only established the new Institute for Systems Biology, but he'd also set up most of the infrastructure necessary to get it up and running. Hood has left his post as chairman of the department of molecular biotechnology at the University of Washington -- a department that was created through a $12 million donation by Microsoft Corp. co-founder Bill Gates and founded by Hood in 1992 -- to devote his energies full-time to the Institute, which is an independent, not-for-profit organization. Hood said that he's hired all the key managers to set up the new (but temporary) facilities in Seattle, and they're moving in Feb. 1, 2000. An anonymous donor contributed $5 million to get the ball rolling; meanwhile, Hood is now in the process of "raising a substantial endowment" to fund construction of the Institute's permanent facilities.

The Institute will take a multi-disciplinary approach to the systematic study of systems biology. Hood intends to hire not only the usual assortment of molecular biologists, geneticists and biochemists, but also computer scientists, applied mathematicians, physicists, chemists and engineers. "We need to be able to integrate leading-edge technologies into biology," he explained. "Breaching the language barriers that exist across these disciplines is an enormous task…but the key in all cases is motivation [on the part of the scientist] to learn about another view of the world."

Support for the research will come from grants -- both those that can be transferred from the university and new ones -- as well as endowments. Because the Institute is not-for-profit, it's neither limited by industry's constraints -- to make money -- nor by those which academia imposes --limited resources, bureaucracy and divergent opinions as to what's "good biology "and "bad biology," he added.


As well, Hood envisions active collaborations between the Institute and the University of Washington and other academic institutions and foundations, including Scandia Labs and Pacific Northwest National Labs. He's also lining up corporate collaborators: Monsanto Co., Illumina Inc., Orchid Biocomputer Inc. and Paracel Inc. have all signed on, and "we're in talks with Immunex and Merck," Hood said. And, he'll be talking to IBM in the future. "IBM clearly wants to get into life sciences," Hood said. Indeed, the computer giant's taken a huge step in that direction in recent months: Just this week, IBM announced that it has joined the SNP Consortium. In December 1999, it announced a $100 million research initiative to build a supercomputer (nicknamed "Blue Gene") to model the folding of human proteins and a grants program to fund research at selected centers working in the field of structural genomics.

In the manner of true visionaries, Hood has always been years ahead of the pack. While at the California Institute of Technology (Caltech), where he earned his Ph.D. in biochemistry in the late sixties, Hood and his colleagues devised the instrumentation that allowed the rapid synthesis and sequencing of both proteins and DNA. Looking for a way to commercialize the first of these instruments, the protein sequencer, Hood helped found Applied Biosystems Inc. in 1981. (It's since been acquired by PE Corp.) The rest, as they say, is history, for these instruments not only changed the face of molecular biology, but also they paved the way for the genomics information revolution. In fact, he was one of the first advocates for the Human Genome Project and continues to be a key player.

According to Hood, the heritage of the Human Genome Project will be nothing less than a "periodic table of life." Armed with that information, and aided by a new set of powerful research tools, including those used in genomics and proteomics, scientists are nearly ready to tackle biology's most challenging puzzle yet. In fact, Hood's goal in creating the Institute for Systems Biology is to "achieve pioneering discoveries that can advance preventive medicine" in the 21st century. That includes the ability to analyze an individual's genes, to create medicines precisely tailored to that individual, and even to pick up genetic flaws that can be corrected (or compensated for through life style changes) before a disease has a chance to get a toehold. There are six to eight institutes emerging across the country to tackle these post-genomics-era challenges, he explained. "The systems approach to disease will lead to a revolution in medicine," he said, and "institutes such as ours will lead the way."


That may be so, but other sorts of entrepreneurs are already catching the fever. Just this week, the first self-proclaimed systems biology company popped up on the radar screen. CIStem Molecular Corp., based in San Diego, was founded a year ago to commercialize a patent-pending technology developed by Stuart Kauffman of the Bios Group LP (whose expertise centers on mathematical models of genetic regulatory networks) and Marc Ballivet, a professor at the University of Geneva, Switzerland (the regulation and developmental role of brain neurotransmitter receptors). The goal is to exploit aspects of the genetic regulatory networks that control gene expression in all organisms.

CIStem is going after medically relevant networks right from the start. CIStem's president and CEO Anne Crossway explained that the company's research efforts will focus on the regulatory regions that control gene expression, rather than the structural genes themselves. The firm claims that its proprietary technology allows it to identify the cis sites (polynucleotide sequences) found within the promoter and enhancer regions of DNA that control the transcription of structural genes as well as the trans-acting factors (proteins) that bind to them. The cis/trans complexes formed as a result modulate gene expression; depending on the particular combination, they are responsible for the differential expression of every gene in the genome, the company says. "We have high specificity molecular methods to identify and clone the regulatory elements," Crossway said. And, although "only a few hundred trans-acting factors have been identified to date, there could be as many as a few thousand to 10,000 [that exist].

"Knowledge of the interaction of the cis sites and trans factors will lead us to the genes," Crossway explained. In this way, CIStem hopes it can cut short the path to gene discovery -- and thus offer potential partners the best drug development targets. "Focusing at the regulatory level is the key to understanding disease circuitry," Crossway explained.

With new initiatives stemming from both academia and industry, it's evident that the study of systems biology is already here, a forerunner of the revolution in medicine that's predicted to occur in the post-genomics era.



Images: Vitruvian and Leda by Leonardo da Vinci