Chipping away at the genome
New laboratory ups the ante in the rush to fingerprint human cells

By Diane Ainsworth, Public Affairs

John Ngai, left, a molecular biologist and director of Berkeley's new Functional Genomics Laboratory, adjusts a scanning laser fluorescent microscope to read information from a microarray, or gene chip, while staff research assistant Vivian Peng looks on. Each spot from the cell sample will help determine whether a particular gene related to health or disease is being expressed. Peg Skorpinski photo

11 OCTOBER 00 | Deciphering the function of each human gene is a daunting prospect that will continue far past the projected 2005 deadline for completing the Human Genome Project.

Scientists at drug firms, biotech companies and university laboratories are rushing to make inroads using an array of powerful new tools: DNA chips and microarrays that let them see at a glance which of thousands of genes are active in a given tissue sample; software that organizes thousands of gigabytes of genetic data; huge databases of genes, disease-tissue samples and RNA "messenger" molecules, those that actually initiate the work of constructing proteins.

From these cutting-edge technologies, molecular biologists like John Ngai, director of Berkeley's new Functional Genomics Laboratory, will be able to fingerprint different cells and tissues based on a precise survey of gene expression.

"How cells in the human body differ from each other, whether they're from different organs like the heart, stomach or brain, or from diseases such as breast cancer, melanoma, schizophrenia or diabetes, is largely a function of what subset of genes they express," said Ngai, a faculty member in the College of Letters and Sciences. "It's like building an FBI profile of a cell. Finding out about which genes a particular cell expresses can tell us a lot about the molecular properties of that cell."

To learn what makes the human body thrive or falter, scientists must know the genetic code - the famous DNA strand of more than 3 billion chemical "letters" that spell out instructions for how to build a human being. The genomes of fruit flies, yeast, worms and bacteria - simple organisms - have been sequenced. Their DNA chips, called microarrays, range from several thousand to about 20,000 genes. Complex vertebrates, such as mice and humans, possess more - on the order of 100,000 genes - some of which behave differently under healthy and diseased conditions.

Researchers use microarrays, or genes on a glass chip, to sense which genes are turned on or off in sample tissues. In studying various kinds of breast cancers, for instance, they are searching for clues to tell-tale molecular fingerprints. In each case, they have found genes that are expressed at different levels in cancerous versus normal cells, and also found variations between different types of breast cancer tumors. This kind of information should ultimately give doctors biochemical identifiers to guide their treatments.

Currently, many laboratories invest an enormous amount of time, money and resources to isolate, verify the identity of, and prepare thousands of genes for study on a microarray platform - all before scientists can begin analyzing the genes' relationship to health and disease.

"In conducting fundamental research, we'll be making our own microarrays to monitor and analyze the expression levels of 10,000 to 20,000 genes in a single experiment," said Robert Tjian, a molecular biologist in the College of Letters and Science who helped Ngai secure the initial seed money for the laboratory equipment. "The biotech industry relies on that basic research to develop pharmaceuticals that will fight or cure a given disease."

Under the dome of Berkeley's new Functional Genomics Laboratory organized research unit, Ngai and his colleagues from a broad range of the physical, life and health sciences, as well as statistics, will be able to tap the virtually unlimited potential provided by information pouring in from genome sequencing projects.

"These recent advances now allow the dissection of biological processes at unprecedented levels of detail," Ngai said. "The beauty and power of functional genomics is that, by allowing us on a large, genome-scale to sweep through the molecular inventory of a cell, we will be able to discover novel molecules - which may constitute potential molecular targets - that may be involved in specific diseases."

At the level of basic science, functional genomics allows scientists to understand what drives different cells in a most fundamental way. In terms of human health and medicine, Ngai said, new genomics strategies will help researchers to identify rapidly new molecular targets - and, in turn, therapeutic strategies - for intervention in the battle against many different diseases.

The work requires state-of-the-art imaging instruments, computing power and robots to perform large-scale repetitive tasks. To support undergraduate, graduate and post-doctoral researchers, technicians are needed to run the machines and prepare the microarrays.

Over the next several months, Ngai's collection of high-tech instruments will be moved into a central facility in the Life Sciences Addition from their current locations in his Molecular and Cell Biology lab and another laboratory run by Functional Genomics Laboratory co-founder Tito Serafini.

This new collaboration will be particularly valuable for many laboratory researchers who spend significant amounts of time and money to manufacture custom microarrays for gene expression research. Scientists will benefit from using an integrated system that will improve their ability to replicate and validate study results.

"For reasons of cost and scale, it would be very difficult for individual faculty to initiate and sustain these kinds of projects on their own," Ngai said. "The commitment by the campus administration to fund this organized research unit represents a strong and important first step toward keeping research on the Berkeley campus at the very forefront of the biological and biomedical sciences. This commitment will arm our faculty with the infrastructure to leverage additional funding and explore the basis of normal biological processes as well as human diseases."