Research Revolution Underway at West Campus
At the center of the sprawling 136-acre West Campus are three buildings that will house scientists who are using three distinct technologies yet who share an underlying mission: transforming the way biological research is conducted at Yale.
“New technologies are creating an unprecedented amount of data and providing entirely novel ways to address scientific questions,” says Michael Donoghue, vice president for West Campus planning and program development. “The new cores opening up on the West Campus put Yale in a unique position to capitalize on these advances to answer some of the most fundamental questions in biology.”
By January, the three core facilities — pioneer occupants of the largest acquisition in the University’s history — will be open and assisting Yale scientists in the business of discovery.
Already, the technologies employed by the Yale Center for Genome Analysis, the Center for High Throughput Cell Biology and the Small Molecule Discovery Center have proved to be invaluable in dozens of Yale projects — such as shedding light on the genetic basis of autism, tracking key molecular pathways in inflammatory diseases, and discovering a new cancer drug. The new cores will only increase the computational firepower of bioinformatics systems and allow Yale scientists to conduct experiments that would not have been feasible just a few years ago.
The core facilities will help support the entire University, but will also be linked closely to five new institutes planned for West Campus. The institutes will be in microbial biology, chemical biology, cancer biology, systems biology and cell biology.
(Illustration by Wendolyn Hill)
Yale Center for Genome Analysis: Paving the way for personalized medicine
Shrikant Mane is representative of the directors charged with day-to-day operation of the new facilities. All are scientists whose love of research led them to learn the diverse and powerful new technologies that are quickening the pace of discovery in the life sciences. All are silent partners in labs throughout the university.
On most scientific papers to which Mane contributes, his name usually does not appear in the most prestigious positions — the first or last on a list of authors. However, the backbone of the work of many Yale labs relies on Mane’s technological expertise. In fact, Mane is a collaborator on some of Yale’s most scientifically ambitious projects.
“Intellectually I am fascinated by emerging new technologies, and I am a big user of technology,” Mane says. “All my life I have been doing experiments, so I understand and contribute to the researchers’ needs.”
As a collaborator on several grants, Mane has provided the biotechnological support for projects that seek the genetic basis of autism and age-related macular degeneration; help test novel ways to repair the central nervous system; explore genes crucial to the evolution of the human brain; and look for genes involved in asthma, schizophrenia, bipolar disease, kidney disease and brain aneurysms.
Mane began his science career at the University of Bombay as a cancer researcher in the 1980s. His curiosity about the baffling behavior of cancer led him to do his postdoctoral work in biochemistry and molecular biology at Johns Hopkins University School of Medicine. But once he purified a protein of interest, he was inevitably drawn to emerging molecular biological technologies to identify the genes for these proteins.
His interests coincided with a revolution in genomics. Since the early 1990s, when a global effort to sequence the human genome was launched, genomic technology has become increasingly more powerful. While it took a decade and billions of dollars to create a draft of the genetic alphabet of a human being, new DNA sequencing technology can scan the entire 3 billion base pairs of a person in a matter of months for a cost of a few hundred thousand dollars. As the cost of DNA sequencing continues to fall, it is anticipated that in coming years the price for sequencing a human genome will come down to less than $1,000.
When Richard Lifton, chair of the Department of Genetics at Yale and a Howard Hughes Medical Institute investigator, began his search for a director of the Yale Center for Genomic Analysis he did not have to look far.
Mane, who has been with Yale since 2001, holds many titles. He is co-director of the Keck Biotechnology Resource Laboratory; director of Microarray, DNA sequencing and Oligonucleuotide Synthesis at Keck; and director of the Yale/National Institutes of Health Microarray Center for Research on the Nervous System, established through a National Institutes of Health grant. His duties made him intimately familiar with the work of many scientists, including Lifton.
A recent collaboration between Mane and Lifton illustrates the power of the new technology and provides a glimpse of its potential clinical value. For the first time they made a clinical diagnosis using comprehensive DNA sequencing of all the protein-coding genes in the genome. The technology, which selectively analyzes the 1% of the genome that encodes for proteins, allowed the scientists to pinpoint mutations in the genes of a five-month-old Turkish boy that cause congenital chloride diarrhea, a rare birth disorder in which the gastrointestinal tract fails to properly absorb chloride and water.
For now, Mane says he plans to harness the power of 12 sequencers at West Campus to aid the work of Yale researchers. “We have no doubt that one day the technologies that are being employed at the new West Campus facility will pave the way for personalized medicine by providing critical insights into identification of genetic risk factors, diagnosis, prevention and treatment for a host of human diseases,” Mane says.
Center for High Throughput Cell Biology: A ‘marriage’ designed to speed research
While Lifton, Mane and others are pushing the limits of genomics technology, James Rothman, chair of the Department of Cell Biology, recently has his own vision for the Center for High Throughput Cell Biology. Rothman, one of the top cell biologists in the world who was recruited to Yale last year from Columbia University, wanted to create a center that married several distinct technologies that together would give scientists an unprecedented view of the inner workings of the cell.
In the summer of 2008 the center became the first of the three West Campus cores to open for business. Rothman recruited Columbia colleague Lars Branden to become director of the core. The facility, which employs 13 people, helps researchers assess how genes function in a cell by selectively silencing genes in highly automated, genome-wide screens. The latest in optical microscopes assess the effects of gene expression in living cells and the deluge of data is fed into banks of computers. The bioinformatics system helps researchers develop a picture of how those genes interact in living cells.
“We can do this for any field of biology you can imagine,” Branden said. “We want to be a hub of the Yale community’s efforts to decipher complex biological processes.”
While most of the individual and robotic technologies housed at the center have existed for years, Rothman envisions marrying the technologies in a way that will create something entirely new.
“The marriage of genomic, optical and bioinformatics screening technologies can shave years off research time as well as give scientists new insights into cell biology that will drive research forward,” Rothman said.
Small Molecule Discovery Center: Finding tiny keys to major diseases
By contrast, chemical screening is a well-developed technology that has been a key part of the drug discovery process for years. But it is rare for university scientists to have easy access to such technology, says Janie Merkel, who runs the Yale Small Molecule Discovery Center, scheduled to open on West Campus in late November.
Using high throughput experiments capable of analyzing tens of thousands of possible future drugs a day, the five-person team at the center is in the business of looking for small molecules that affect many biological processes such as inducing or repressing the expression of genes, inhibiting the interactions of proteins or the activities of enzymes. In terms of medicine, this could mean using a chemical at the DNA, RNA or protein level to correct the behavior of diseased cells to simulate health.
The great potential of the technology for academic researchers was illustrated by the recent sale of the biotechnology company Proteolix, developer of a drug to combat multiple myeloma, to Onyx Pharmaceuticals in a deal potentially worth $851 million. The basis for the new drug, now in Phase II clinical trials, originated in the lab of Craig Crews, executive director of the Small Molecule Discovery Center. Crews has appointments in Yale’s Departments of Molecular, Cellular and Developmental Biology; Chemistry; and Pharmacology.
While compound screening is commonly used by drug companies to find molecules that affect known biological processes, sometimes compound screens can also trigger whole new avenues of research by identifying novel activity, Merkel says.
Like Mane, Merkel began her science career on the bench, gaining her Ph.D. in molecular biophysics and biochemistry at Yale in 2000. Like her colleagues at the other cores, she became fascinated with the technologies that are increasingly propelling research in life sciences. After stints with several biotechnology companies, however, she has become convinced that outstanding science depends upon a much older skill. Outstanding science still depends upon researchers talking to each other, she says.
“We can tailor how we advance the research goals of the scientists,” Merkel says. “Our product is not just technology, but communication.”
— By Bill Hathaway