Lab Holiday Wish List

Illustration: ©2002 Ned Shaw Editor's Note: With the gift-giving season upon us, The Scientist wanted to know what today's life scientists would be most grateful to receive this holiday season. We queried researchers throughout the world for ways to push life sciences to the next level, whatever that level might be. The final list has eight interrelated items. KNOWLEDGE INTEGRATION One of the most commonly expressed wishes was the desire for broader integration of knowledge among disciplines. As Werner Dubitzky, school of biomedical sciences, University of Ulster, Coleraine, Northern Ireland, puts it, "There is a growing need to integrate 'vertical' disciplines in the life sciences, ranging from the physical to the biochemical, all the way up to the neuroscience and cognitive science levels." Today, the life sciences could be said to be on a meat-and-potatoes diet; integration would add some much-needed variety to the menu. The result would be a delicious mélange of projects and breakthroughs in genetics, cell biology, chemistry, physiology, and other disciplines--a mincemeat pie, if you will, that fosters insights that might never occur otherwise. Photo: Courtesy of Marcia Ledford, UM Photo Services Alan Saltiel One place that's spicing up the meal is the Life Sciences Institute at the University of Michigan, Ann Arbor. Next September its 230,000-square-foot "lab without walls" should be completed. There really are walls, of course, but this football-field-sized, six-story facility is based on sharing equipment and space among groups of about 30 scientists and giving investigators the choice of working in a project-driven lab or in an open environment among scientists of different disciplines and disparate projects. The head chef in this endeavor is Alan Saltiel, the institute's director. His wish is to attract future Nobel laureates who are looking for something more than just lab space, thereby advancing research and boosting research funding. Photo: Courtesy of Development Counsellors International Pete Kissinger The integration of knowledge sought by Saltiel in the lab-without-walls extends to making sense of the information that is already known. Pete Kissinger, Purdue University chemistry professor and CEO of West Lafayette, Ind.-based Bioanalytical Systems, defines the challenge as "the difficulty of integrating information from the different domains in which scientists work." In other words, says Kissinger, scientists must see the forest as well as the trees. "We now have so much data that does not seem to lead to much information with respect to the function of entire organisms," he says. "For example, we can develop drugs based upon focusing upon one receptor, but it is hard to consider all the others. Thus, side effects surprise us. The more we know about the details, the less we seem to be able to put it all together." DATA MANAGEMENT Part of the problem in putting it all together is that discovered information and available information are not synonymous. Oftentimes, relevant data simply cannot be retrieved in the face of overwhelming quantities of data. It's the classic needle-in-the-haystack problem, for which researchers turn to bioinformatics and data management specialists. "Life sciences must spend more time and interest in managing ... data," insists Don Gilbert, associate scientist in the biology department, Indiana University, Bloomington. Gilbert wants a computer for the holidays this year--a supercomputer, that is. Specifically, he's looking for open-source grid computing. Grid computing is a way of linking PCs to form an ad hoc supercomputer, in which each computer crunches one piece of a task when not busy doing its owner's work. This approach squeezes greater productivity out of available resources--sort of a computational nod to the environmental movement. Scientists have applied this approach to such problems as the SETI (Search for Extraterrestrial Intelligence) project, protein folding, and protein-small molecule docking.1 Today's informatics challenge, however, extends beyond raw computing power. The goal is to "use this available and fast-growing body of life science knowledge in more sophisticated, computer-based ways," says Dubitzky. "This, essentially, is a challenge for computer science--fields like database technologies, artificial intelligence, human-computer interaction, machine learning, data mining, and soft computing," he adds. "Grid computing, artificial life, and computational creativity will be key areas in this endeavor." Dubitzky wants money for molecular imaging studies that "will complement the conventional reductionistic mode of analysis with a holistic dimension." In other words, Dubitzky desires more than a photomicrograph. He wants the big picture. THE RIGHT PEOPLE If these bioinformatics problems are to be addressed, the field will need additional personnel. This discipline needs men and women with a gift for life sciences coupled with a passion for computing--a rare combination. "Bioinformatics is a black hole," says Brad Thompson, president and CEO of Oncolytics Biotech, in Calgary, Alberta, Canada, suggesting that the field--like a department store in the middle of the holiday season--can never have enough good workers. Thompson notes that this problem extends throughout the life sciences. Samuel F. Hulbert, president of Rose-Hulman Institute of Technology in Terre Haute, Ind., concurs. They both wish for better-educated and better-trained scientists. As Hulbert writes, "Educating people who can bring advancements in the life sciences quicker is one of the critical needs facing our society and the engineering profession. We are limited by a lack of technical talent more than we are by actual dollars available to spend to solve those problems."2 "There are lots of very smart people, but a dearth of properly trained people," Thompson adds. "The distinction is important, because biotech is a fast-moving industry. Half of our patents have priority dates of one to two weeks on our competition," he explains. "Days mean something." A day spent getting a new hire up to speed can, conceivably, mean the difference between gaining and losing a patent. THE RIGHT QUESTION Unlike many of his scientific colleagues, Doug Green, division head of cellular immunology at the La Jolla Institute for Allergy & Immunology in San Diego, is not wishing for a better-trained staff, more complete data integration, or even a more powerful lab. His holiday wish is more elemental. "Our biggest problem is coming up with really good questions," Green says. One should not infer a lack of curiosity on his part, however. Green's holy grail is a "discovery that can't be easily explained, so we can unravel a deep biological problem." It could be said that Green's lab is on a deathwatch. It explores apoptosis at the single-cell level. Cell death, however, cannot be predicted or synchronized. So, Green says, "Having the tools and the technology to deeply probe biochemical events at that [single-cell] level in real time, using primary cells, is high on my wish list." THE RIGHT TOOLS Other disciplines, such as zoology, can only dream of probing the deep, underlying questions. The labs in this field, however well funded, still lack the basic tools that other disciplines take for granted. In zoology, that means fundamental assays and noninvasive testing methodologies. A bear or lion just won't stick out its paw and wait patiently while blood is drawn, observes Terri Roth, animal sciences vice president, Center for Conservation and Research of Endangered Wildlife at the Cincinnati Zoo & Botanical Garden. Fecal or urine samples provide alternatives, and infrared heat-sensing devices are being designed for hands-off testing, she says. Yet even if animals cooperate during testing, "you have to do a lot of research to gather data and establish baseline hormone levels." Simply determining whether an animal is pregnant is a challenge. "For example," Roth explains, "hormonal levels vary greatly throughout pregnancy depending upon the species and even the individual." Additionally, for many other species, "we lack the basic data and established assays to diagnose pregnancy." Another challenge is sperm sorting, a process that weights the coin toss that determines whether progeny will be male or female. The process is fairly straightforward in people, but as Roth explains, the shape of the sperm head is different among species, requiring significant recalibration of any sorting mechanism used. Furthermore, the sperm quality after sorting often is poor. In the wild, this wouldn't be much of an issue. In animal parks, however, the gender ratio in herds is critical. "We have a limited amount of space for wildlife in captivity and need a genetically viable population," Roth says. Because male herd animals typically have harems, parks need more females than males. Sperm sorting can help achieve the proper ratio. AUTOMATION X-ray crystallographers are better off than zoologists, but their technology could use a yuletide boost all the same. Yousif Shamoo, assistant professor of biochemistry and cell biology at Rice University, examines the atomic structure of protein and RNA in his lab. Shamoo's graduate assistant has the tedious and unenviable job of examining 37,000 images manually, one at a time. At five seconds per slide, it takes more than 51 hours to glance at them all. The potential for error is immense. Shamoo is hoping that someone will commercialize an instrument to automatically scan the images to, at the very least, look for edges (a feature found in most crystals). That would reduce the work by nearly one-third, allowing researchers to spend their time more creatively. EFFICIENT DRUG DISCOVERY Some of that creativity is being directed towards developing more efficient drug-discovery strategies. In terms of trends, "Researchers are developing tools and models for early prediction of drug failure--prior to animal trials--to model new antibiotic agents using all strains that could possibly be generated, saving years of work and tens of millions of dollars," says Mary Campbell, general partner at EDF Ventures, Ann Arbor, Mich. Another approach studies the binding affinity of a lead for its target before studying efficacy, logically noting that if the lead will not bind, its efficacy does not matter. Among such new endeavors is the emerging field of transcriptomics, which studies mRNA and regulation of its production, lifetime, and destruction. "Until now," explains Bruce Seligmann, president and CEO, High Throughput Genomics (HTG), Tucson, Ariz., "RNA expression profiles were basically 'yes/no' assays. They weren't highly quantitative." HTG has developed an RNA assay that offers "the same level of sensitivity as a biochemical array," measuring one gene per cell using 1,000 cells, compared to the million cells typically needed for arrays. The goals, he says, were to provide reproducibility and simplicity at a cost comparable to that of PCR. The assay actually is the embodiment of some of Seligmann's previous wishes. Production scientists have had some of their wishes granted, too, in the form of large-scale preparative electrophoresis capabilities. "The idea is to produce large volumes of proteins with the same purity and resolution of electrophoresis," says Hari Nair, executive vice president and US chief operating officer of Sydney, Australia-based Gradipore. Excessive heat production and membrane clogging have been the stumbling blocks. Gradipore's system, called GradiFlow, uses a combination of molecular size and charge to "purify molecules you otherwise couldn't, in one or two steps, quickly and with high levels of purity and recovery," says Nair. For example, GradiFlow can remove viral and bacterial pathogens and purify proteins simultaneously. Nair says Gradipore sees this as an adjunct to--and in certain instances, a replacement for--chromatography. IMPROVED LICENSING Such advances often are conceived in university research labs and born into joint ventures, license agreements, or other agreements facilitating outright commercialization. It's rarely an easy birth: the tech-transfer process can be quite byzantine. "It can take up to three years to fight [a license agreement] out of the institution," says William D. Paiva, partner in Tulsa, Okla.-based Chisholm Private Capital Partners. The problem is so bad that one university lost a $13-million venture-capital deal because it spent nine months negotiating the license. The university thought it was fast-tracking the deal, says Paiva. The problem of rocky tech transfers is exacerbated because there is little standardization within a university and none among universities. Therefore, standardization tops Paiva's wish list. Standardization, he says, "would help with relationships with the academicians and the outside investment community and allow [tech-transfer departments] to focus on throughput rather than spending months and even years 'tweaking' a licensing agreement." It would also "free up time they could spend on more value-added activities," he adds, like driving intra- and interdepartmental communication, which could stimulate deal formation that might not otherwise happen. Despite many challenges, life science continues at its breakneck pace. Thompson predicts that, "This [time] will be known as the Golden Age of human biology." Michael Kurek, of Biotechnology Business Consultants, in Ann Arbor, Mich., says that "in the broader sense, the very term 'life sciences' will take on a different connotation as the new biology touches almost every aspect of modern life." He cites potential benefits in healthcare, agriculture, and environmental quality. To realize these challenges, Kurek says, will require yet more multifaceted scientists--ones with acumen in such fields as business, law, and public policy. Perhaps, if such researchers step up the challenge, next year's holiday wish list will be a little bit different. Gail Dutton (gaildutton@gi-wireless.net) is a freelance writer in Mayne Island, British Columbia. References 1. A. Adams, "Supercomputing in the life sciences," The Scientist, 16[17]:41-3, Sept. 2, 2002. 2. S.F. Hulbert, "Life sciences developments must reach marketplace quicker," TekNext, Rose-Hulman Institute of Technology newsletter, Oct. 8, 2002.

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