By Elise Lamar, PhD
With modern science splintering into ever more specialties, collaborations across disciplines have taken the place of Renaissance men who could do it all. Today, it takes a team of highly specialized experts to succeed.
Both textbooks and Hollywood often link discovery with out-sized personalities. Students and movie-goers alike learn that Darwin “discovered” where we all came from after a long sea voyage and that Pasteur proved bacteria do not materialize out of nothing by experimenting with beef broth. These stories reassure us that if you give a lone genius time for contemplation and a few simple tools, great insights are sure to follow.
But discovery in the era of post-genomic biology doesn’t happen that way. In the nineteenth century Mendel may have deduced the laws of inheritance while gardening, but in 2001 decoding the human genome took not one, but two, fiercely competitive camps with a collective population of about six hundred contributors. Today’s advances in bioscience are more likely when investigators with diverse talents—and access to highly sophisticated equipment—join forces to tackle a problem, and a recent groundbreaking study by Conaway & Co. is a case in point.
The star of the study, which graced the cover of a recent issue of the prestigious journal Cell, was a group of proteins collectively known as Mediator. The Mediator machinery provides a much-needed boost to RNA polymerase (pol II), the enzyme that copies a gene’s DNA into the RNA intermediaries necessary to construct proteins. In addition to facilitating the assembly of pol II at the start site, Mediator shifts the enzyme into high gear, accelerating the synthesis of those RNA transcripts.
Although Mediator has been dissected biochemically in labs world-wide since its identification in the early nineties, how Mediator juggles seemingly disparate roles as initiator and accelerator of gene expression had eluded researchers. In an unexpected twist, an all-Stowers team led by Joan Conaway, PhD, and Ron Conaway, PhD, discovered one way Mediator does it: When a single component of the massive thirty-protein Mediator machine switches allegiances, pol II shifts from a static state to an active, gene-expressing mode.
The discovery sheds new light on life’s most fundamental process, namely, how information encoded in our genome is transcribed into a blueprint for proteins. Identifying the linchpin involved the coordinated effort of no fewer than seventeen Stowers researchers: the Conaways plus seven members of their lab, including the study’s first author Hidehisa Takahashi, PhD; Investigator Ali Shilatifard, PhD, and two members of his lab; four researchers in the institute’s Proteomics Center; and an in-house research advisor.
Each contributor applied unique skills to the project. The Conaways brought two decades of molecular analysis of both pol II and Mediator. Shilatifard’s lab has an impressive track record of characterizing the factors recruited by Mediator to activate the acceleration phase of transcription. Ron Conaway, who co-leads the Conaway lab in partnership with his wife, Joan, says that while the effort required technical know-how in fields of molecular biology, bioinformatics, cell culture, mass spectroscopy, and microarray analysis, the underlying question was simple. “This paper is, at heart, a mechanistic study of how Mediator recruits factors to a gene that elongate RNA transcripts,” he says. “It’s the kind of experiment we’ve always liked to think about, but not something you can do in your basement.”
Joan Conaway—who, like Ron, was trained as a biochemist—agrees that the paper could only have emerged from a melding of old-fashioned biochemistry with recent proteomic approaches. “This work required state-of-the-art mass spectrometry,” says Joan, the study’s senior author. “And our collaborators in the Stowers proteomics core are among the developers of these techniques.”
Mediator meets MudPIT
Most Stowers faculty members say that the excellence of the core centers—facilities that provide technical and intellectual support—is a major attraction of the institute. Currently, Stowers investigators can consult with twelve core groups, which offer not only state-of-the-art equipment, but a highly trained scientific staff skilled in areas as diverse as cell culture, electron microscopy, and reptile husbandry.
For the Mediator study, no core was more critical than the proteomics center, whose expertise is in assessing interactions between a cell’s protein components—that is, the state of its “proteome.”
The paper reported how a short segment of Mediator subunit #26 recruited mutually exclusive protein partners one tethering pol II to a gene’s start site and the other freeing it to catalyze RNA synthesis. The ability to rapidly identify interactors in small samples of cellular soup and then figure out what part of subunit #26 they stuck to required a mass spectroscopy method called MudPIT, for multidimensional protein identification technology.
MudPIT was developed in part by the proteomics center’s director, Michael Washburn, PhD, when he was a postdoc with proteomics pioneer John Yates at The Scripps Research Institute in La Jolla, California. Both Washburn and Laurence Florens, PhD, who heads the proteomics core and also hails from the Yates lab, were authors on the Mediator paper as were two other members of their team.
Washburn and Florens’ association with the Conaway lab is a deep one: They began analyzing protein interactions in samples for the Cell study soon after they came to Stowers in 2003, and have since used MudPIT to analyze approximately fourteen hundred protein samples from the Conaway lab for this and other studies. Those collaborations have produced twenty peer-reviewed publications, including the July 2011 paper and a pivotal 2004 paper published in Molecular Cell that ended controversy as to what subunits Mediator actually comprises.
Although undoubtedly successful, collaborations might seem like the polar opposite from those deeply satisfying eureka moments, where, in a sudden flash of insight, a new idea is born.
But Washburn rejects the notion that a team approach takes the excitement out of discovery. “It’s the drive for dollars that’s taken the romance out of science,” he says. “Stowers has actually helped bring the collaborative spirit back into science by providing resources that enable people to do great work together.”
Joan Conaway agrees, saying that Stowers’ investment in technology is one of the things that make it such an exciting place to work. “More important, Stowers has recruited the very people who helped develop these approaches,” she says. “Here, investigators aren’t limited by technology. If you can think of a good experiment, you will find people here with the expertise and enthusiasm to help you do it.”
People flummoxed by electronic gadgets can take comfort knowing that scientists often feel exactly the same way. Ron Conaway notes that even when highly trained PhDs gain access to state-of-the-art equipment like mass spectrometers or DNA sequencing machines, they can have difficulty making sense of the mathematical output.
“But this is where Stowers does it right,” he says. “They provide money not only for hardware but for salaries of experts who act as an interface between you and the technology.” One of those interfaces on the Mediator paper was Stowers Research Advisor Chris Seidel, PhD.
Seidel champions collaboration, so much that his e-mail signature reads, “Latin: collaborare—to labor together.” Since his recruitment to Stowers in 2002, Seidel has acted as a personal data analysis trainer for any faculty member seeking help. His expertise is in microarray technology—the analysis of genome-wide changes in gene expression—which he gained building microarray robots in graduate school at the University of California, Berkeley, and for Children’s Hospital Oakland Research Institute. “The advent of genomics has changed biology,” says Seidel. “Most biologists don’t have experience interpreting genomic data or know how to effectively harness bioinformatics and computer programming languages.”
To address such needs, a few years back Stowers President and CEO David Chao, PhD, and Scientific Director Robb Krumlauf, PhD, created an intermediate layer of professional scientists called research advisors who work in an in-house freelance capacity. In addition to Seidel, three other advisors help scientists strategize about microscopy and bioinformatics. “We serve as consultants. We may design experiments, analyze data, or develop technology,” says Seidel, who for the Cell paper helped design and interpret microarray experiments testing whether gene expression patterns changed after Mediator subunit #26 was manipulated. “We approach a project at any level and act as a collaborator to bring groups together.”
Like most scientists, Stowers investigators interact closely with colleagues worldwide. But the Mediator paper embodies one of Jim and Virginia Stowers’ founding principles when they created the institute. They were convinced that talented people do their very best when working under the same roof.
Although the Stowers Foundation began as a consortium of labs distributed across the nation, Jim Stowers’ overriding goal—based in part on his business success at American Century—always was to create a research environment where people see and talk to each other every day. That goal was realized when the Stowers Institute opened its doors in Kansas City in 2000. “We don’t think (the consortium approach) is the most efficient way of doing science,” Jim Stowers said in a 2007 interview. “Virginia and I think that science should be done in one place so scientists can help each other.”
Krumlauf attributes the institute’s rapid success to the authenticity of this principle. “What is unusual here is the number of extensive collaborations within the institute. Collaboration is just ingrained in our culture,” he says. “That means that science moves faster, and synergy between investigators can stimulate ideas that might not occur to one person working in isolation.”
Seidel also thinks the idea of the lone discoverer is overrated. “Amelia Earhart had a navigator,” he says. “I don’t think anyone thinks less of her because she wasn’t solo.”
Shilatifard agrees. “The days of Mitchell are over,” he declares, referring to British biochemist Peter Mitchell, who left academia to conduct research at his estate into how mitochondria produce cellular energy—work that (full disclosure) earned him a Nobel Prize in chemistry in 1978. “Science is collaborative now: you aren’t going to make a big discovery in your garage,” Shilatifard says. “There are too many things to understand—biochemistry, genetics, drug discovery, mouse work, bioinformatics—no one person can do it all. Now investigators must be humble enough to ask for help and then be lucky enough to have great colleagues to provide it.”