Romancing the Genome

GENOMICS—a field most of us hadn't heard of a few years ago— promises to be the next scientific revolution.

By Karen Guin

At first it was just big science. An international group of researchers announced in 1990 a multi-billion dollar plan--the Human Genome Project--to determine the entire sequence of the three billion chemical units that make up human DNA. The U.S. government, specifically the National Institutes of Health and Department of Energy, would conduct and fund much of the work over a period of 15 years.

Now it's fast science too. The Human Genome Project has accelerated its schedule and anticipates it will complete a "draft" version of the human DNA sequence this year and a final draft by 2003, two years ahead of schedule. Yet in a stunning development, it appears that a private interest may reach the sequencing finish line even sooner. Celera Genomics, a Maryland-based biotechnology company, announced in April that it had "completed the sequencing phase of one person's genome" and was "3 to 6 weeks" away from assembling the data into a draft of the human genome.

	DOE Human Genome Project

It's really no surprise that sequencing machines are running 24 hours a day in both public and private laboratories. The stakes are enormous. Knowledge of the human genome--and of the specific sequences that make up the 80,000 to 100,000 genes within the genome--promises to permanently change biology and medicine. Although less than 1 percent of the sequences vary across the human population, the variations that do occur can have a major impact on how humans respond to disease; to environmental insults such as bacteria, viruses, toxins and chemicals; and to drugs and other therapies.

"Human genomics will significantly affect the practice of medicine," says Joseph Silva, dean of the UC Davis School of Medicine. "We're anticipating a new age in medicine in which genetic information will allow individualized therapeutic approaches and facile new strategies for drug discovery."

Sequencing efforts have by no means been restricted to human DNA. The Human Genome Project has coordinated federal funding for genome sequencing of a number of organisms that are important model systems for biological research. Already sequenced are the relatively small genomes of the bacterium Escherichia coli, baker's yeast Saccaromyces cerevisiae and the microscopic worm Caenorhabditis elegans. And in March, a team of publicly and privately (read Celera) funded researchers, including UC Davis geneticist Kenneth Burtis, reported in Science that it had deciphered virtually the entire genome sequence of the fruit fiy Drosophila melanogaster--a major achievement in the world of biology. A big push is currently under way to sequence the genome of the mouse, the most widely used mammalian model for biomedical research. The availability of these sequence data is enabling scientists to analyze and compare entire genomes of different organisms. This new field of inquiry, "genomics," is shedding light on fundamental processes in biology and medicine.

Some think the greatest gains will come from our knowledge--and manipulation--of plant genomes. Teams of scientists in the United States, Japan and Europe have sequenced about 90 percent of the genome of the small fiowering plant Arabidopsis thaliana, a widely studied model of higher plants. This increased understanding of plant biology will enable scientists to improve the quality, quantity and drought and pest resistance of plants that are important sources worldwide for food, fuel and fiber.

In laboratories throughout UC Davis, scientists have been closely following and evaluating developments in genomics. Many realized early on that advancements in gene studies could benefit their own research programs. They also recognized that the campus, with its enormous strengths in the sciences, could make significant contributions to the field. "Davis biologists are particularly adept at determining the function of genes and comparing the genomes of different organisms," explains Dean Mark McNamee of the Division of Biological Sciences. "We also have a broad base of talent in computational sciences. There are computer scientists here who are actively developing tools to manage and analyze the massive data sets generated by genomics research."

In June 1999, a campuswide committee of 13 faculty members proposed that UC Davis fund a major initiative in genomics. Their proposal called for the recruitment of dozens of new faculty members--at an estimated cost of $40 million over a five-year period--and for a new center that would be a focal point for genomics-related activities. The plan was enthusiastically endorsed in October by the campus's Academic Planning Council.

"We concluded that it is critical that UC Davis undertake this very ambitious initiative to ensure that the campus maintains its international position as a leader in the biological sciences," says Robert Grey, provost and executive vice chancellor and chair of the council.

Within days of the initiative's approval, the campus announced its plans to establish a UC Davis Genome Center and to recruit 25 state-funded faculty members in genomics and in the related computer science fields, bioinformatics and computational biology. In addition to launching a major faculty recruitment effort, administrators began to fast track plans to significantly increase the campus infrastructure for genomics research. Central to these plans is the construction of a new $95 million Genome and Biomedical Sciences Building that will house the UC Davis Genome Center and several biomedical programs.

McNamee says the genomics initiative contains two critical elements. One is the addition of genomics faculty in units throughout the campus. "This approach will ensure that all schools, colleges and divisions on campus benefit from an infusion of genomics expertise," he says.

Equally important, says McNamee, is the creation of a central home for genomics on campus. The UC Davis Genome Center will house a core group of faculty members working at the forefront of genomics and bioinformatics. This group will rigorously assess advancements in gene studies and provide guidance to researchers campuswide who want to incorporate the latest genomic techniques into their research programs or want to incorporate information about genomics and bioinformatics into their courses.

Efforts to recruit a director and an associate director of the genome center are currently under way and could be completed this year, says Larry Hjelmeland, a professor of ophthalmology and of molecular and cellular biology who was appointed by Grey to coordinate the planning phases of the genomics initiative. The associate director will both help oversee the center and head up its bioinformatics arm, which will include a core computer facility. Once on board, the two directors will be heavily involved in efforts to recruit other talented scientists with expertise in genomics and bioinformatics.

A focal point of activity in the UC Davis Genome Center will be the use of automated technologies to measure and analyze gene expression, says Charles Langley, a population geneticist in evolution and ecology who has also been involved in the center's planning. Until recently, tests to measure gene expression--the degree to which a gene is "on" or "off"--were relatively slow and labor intensive. Now scientists can use "gene chip" and "microarray" systems to measure the expression of thousands of genes in a single experiment. "The ability to characterize an organism at the level of gene expression and gene function will be of great interest to scientists in the center," notes Langley. Their interests will also extend to "proteomics," an emerging field that focuses on the expression and function of proteins.

Hjelmeland says it is likely that members of the center will pursue collaborations with scientists at national laboratories and at biotechnology companies in California. "Big science, like genomics, often requires a collective effort. Some projects are simply too massive to undertake without drawing on outside resources." To encourage partnerships with the private sector, the campus is working to streamline its technology transfer and intellectual property rights processes. Administrators are also considering long-range partnerships with companies that might locate in one of two "enterprise" zones, areas the campus has set aside for industry collaborations.

Genetic research in the revitalized pharmacology and toxicology department should yield new approaches to drug development and the design of clinical trials, according to Fitz-Roy Curry, associate dean for research in the medical school. Natural variations in the human genome--the most common being single differences in the chemical units of DNA, or "single nucleotide polymorphisms" (SNPs)--can affect the way in which humans respond to drugs. Understanding these minute differences may enable scientists and physicians to tailor drug treatments to genetically distinct populations. Such knowledge may also help identify individuals who are likely to experience severe side effects from specific drugs.

Knowledge of SNPs will also help researchers better understand how sequence variations affect an individual's susceptibility to disorders such as cancer, hypertension, diabetes and mental illness.

As scientists zero in on SNPs that are associated with a particular disease, they will likely turn to model organisms to learn how these variations contribute to the disease pathway. The model of choice for many scientists will be the laboratory mouse.

"The mouse is the preeminent research tool for understanding gene function in the context of the whole mammalian organism," says veterinarian Stephen Barthold, director of the UC Davis Center for Comparative Medicine and of the Mouse Biology Program. With Barthold's help, the campus is quickly becoming a national leader in comprehensive mouse biology. He catalyzed discussions that led to the establishment of JAX Research Systems at UC Davis, a collaborative program between the campus and the Jackson Laboratory of Bar Harbor, Maine, to produce and maintain genetically customized mice at a new facility on the Davis campus. Barthold was also instrumental in landing a $5.4 million grant from the National Institutes of Health that names the campus one of four Regional Centers of Excellence in Mouse Biology. The grant supports and expands genetic research using mice and focuses on minimizing the number of animals needed for studies.

Genomics is also a high priority for the College of Agricultural and Environmental Sciences, according to its dean, Neal Van Alfen. This year the college will further strengthen its programs in the plant sciences by hiring two new plant geneticists. One of these scientists will focus on comparative plant genomics and the use of information from model species to learn about the genetics of crop plants. The other will focus on functional plant genomics and the use of genome sequence information to identify and possibly manipulate important traits in crops.

"These positions refiect fundamental changes occurring in agriculture," says Van Alfen. "Breeding programs traditionally have been the engine of agricultural development. However, new crop products will be developed based on knowledge of the organization, structure and function of plant genomes."

Cotton, the world's most widely used natural fiber, is the subject of research in the laboratory of plant geneticist Thea Wilkins in agronomy and range science. California is the third-largest cotton-growing state, but yields have not increased in 30 years. With a $3.8 million grant from the National Science Foundation, Wilkins is leading a team of researchers that is attempting to identify all 50,000 to 60,000 cotton genes, particularly those that determine the length, strength and texture of the cotton fiber. Knowledge of the cotton genome may enable scientists to develop better plants for cotton farmers.

The potential benefits of genome sequencing are many--as are the societal implications and the need to proceed thoughtfully. As efforts to sequence the human genome near completion, concerns are growing over the ownership, distribution and use of the sequence information. Though scientists participating in the Human Genome Project pump their sequencing results into public data banks, those at Celera send their raw data to corporate databases--and extract information from the public data banks as well. If Celera completes the sequencing job first, for a period of time knowledge of the human DNA sequence will be held by a private venture. This raises the question: Who should own and control such precise information about human genetics? Those committed to the Human Genome Project are in agreement that the data belong in the public domain.

To explore these issues and other implications for individuals and society, the Human Genome Project has established the Ethical, Legal and Social Implications Research Program, or ELSI. The program is composed of biological and social scientists, healthcare professionals, historians, legal scholars and others who develop materials to promote education and help guide policy-making. Among ELSI's concerns is how knowledge of the genetic differences among individuals will affect society.

"We are going to know the differences," says Hjelmeland, "and they will raise many questions." A scientist with a penchant for ministry, Hjelmeland says he is personally challenged to be involved in a public discourse about issues related to genomics. In recent months he has spoken at events sponsored by the UC Davis Interfaith Council and at a UC Berkeley course on science and religion about the availability of genetic information. In one example, he points to the commercial availability of a blood test that can determine if a woman carries a heritable mutation that puts her at greater risk for developing breast and ovarian cancer. "Who has the right to see this information--insurers, employers, courts?" asks Hjelmeland. "And how does this information affect the individual? How does it impact her decisions regarding treatment or family planning?"

Hjelmeland thinks the university is one of several appropriate forums for discussions of questions like these. Earlier this year he encouraged the campus to support the development of a yearlong lecture series on biotechnology, policy and society that will begin in October.

As genome projects continue to reveal the genetic framework of humans and other species, the need for public forums like this will grow. "We are in the middle of a revolution in the biological sciences that is akin to the industrial revolution," says Hjelmeland. "New technologies are enabling us to take a very different look at biology. They're also presenting us with some serious issues." UC Davis' ambitious new genomics initiative is certain to be one of the campus's most fascinating ventures of the early 21st century.