Inner Workings of a Successful Collaboration An Interview with Howard Hughes Medical Institute Professor Manuel Ares, Jr. Manny Ares is a Professor in the Department of Molecular, Cell, and Developmental Biology. He and David Haussler, Professor in the newly forming Department of Biomolecular Engineering, began working together seven years ago to explore genome-wide understanding of splicing and alternative splicing. Their collaborative efforts inspired the formation of the CBSE and led to the development of UCSC's Microarray Facility.

CBSE: What led you and David Haussler to initially collaborate?

Ares: I think it was a mutual realization that we were interested in similar problems from different angles. Back in 1996, we were coming to the realization that what we were doing was going to be transformed by the fact that whole genome sequences were going to become available, and that this presented us with some opportunities. We realized we'd learn a lot that way, but we didn't really have the tools yet.

CBSE: How did the collaboration evolve?

Ares: It grew over a period of time. Haussler was applying mathematical approaches to questions like: How do you find a gene in raw genome sequence? How do you identify protein sequence similarities? I think the first formal engagement I had was sitting on the thesis proposal committee of one of David's students, David Kulp. Kulp and Haussler were trying to predict gene structure including splicing patterns. In those days, bioinformatics grad students sought out biologists to help them see if what they had set up made biological sense. Leslie Grate and Michael Brown were two other computer science grad students I got to know. Leslie was doing computational RNA folding and Michael as well, with an emphasis on comparing sequences from different organisms.

When the yeast genome was first sequenced, an annotation was placed on the sequence and put on the web at Stanford (SGD - Saccharomyces Genome Database). But that first annotation was inadequate for identifying introns in the yeast genome. So Leslie set up a yeast intron database for us as an in-house resource. It was so useful that we published it on the web. It's still ahead of SGD in terms of the extent and accuracy of the annotation, mostly because we care a lot about introns.

CBSE: What has the day-to-day working relationship been like between your groups?

As graduate students, Chuck Sugnet, from the Dept. of Computer Science and Bioinformatics Research Group, and Tyson Clark, from the Dept. of MCD Biology, worked together to develop the technology necessary to establish UCSC's Microarray Facility.

Ares: It's great. Collaborators have to learn from you and you have to learn from them. Teaching someone something always forces you to inspect it more carefully. An intelligent expert in one field might be naive in another field, but they're going to keep you honest and make you produce a better justification for something than you might ordinarily demand of yourself. People who work strictly within a discipline and never get out tend to get lazy, because the only other people they ever talk to accept the same fundamental assumptions.

CBSE: What were the scientific success stories?

Ares: I guess from my point of view the development of microarrays that detect and measure splicing has been successful. Tyson Clark, a grad student in my lab, and Chuck Sugnet, a computer science grad student in Haussler's group worked together to get the microarray technology set up here. At the same time, they went the standard technology one better and produced printed oligo arrays that can discriminate different RNA transcripts from the same gene. This technology has allowed us to see splicing of all yeast introns at the same time. We found some surprising things about splicing this way. For example, different introns have different dependencies on different parts of the splicing apparatus. Thus, the yeast spliceosome deals a little bit differently with each of the substrate pre-mRNAs it has to splice.

CBSE: How does the microarray facility tie into all this?

Microarray specialist Lily Shiue has been indispensible to the smooth functioning of the Microarray Facility.

Ares: The facility was set up from a variety of funds. We first used money from a small grant from NCI, which Haussler and I had for studying introns in the yeast genome. The Deans from Engineering and Physical and Biological Sciences each chipped in. Chuck Sugnet built the robot that spots the arrays, and we bought a scanner and other necessary equipment. Once we got rolling, we went to outside agencies for other money. The W.M. Keck Foundation supported a proposal by the RNA Center to do RNA genomics. The Packard Foundation also came through. The NHGRI support of Haussler has also allowed us to acquire the instruments needed for the Affymetrix microarray platform.

The CBSE brought us faculty positions. For example, we were able to attract Todd Lowe here with a CBSE position, in part because of the flexibility of the Packard funds. As more people use arrays, the capabilities of the facility have expanded. I bought a liquid handling robot with my NIH grant, and got a second scanner. We started attracting attention from industry. We're a beta site for a new array method, and were gifted a new scanner in return for analyzing and comparing the new technology with old methods. Packard funding also allowed us to hire Lily Shiue as our Microarray Specialist. Lily knows nearly everything about arrays, and she coordinates the facility and trains people from five labs in 3 different departments - and that's probably going to get bigger.