Genome Mapping Progress Catapults Plant Research

Plant researchers appear to be catching up with the efforts of those scientists in the better-funded and more visible Human Genome Project. With a critical mass of information forming on the genome of a model plant, Arabidopsis thaliana, including libraries of gene sequences and a number of important chromosome maps, molecular biologists working with plants are at the threshold of important breakthroughs on previously intractable problems. They are on the brink of understanding the mechanisms of disease resistance and of creating plants that produce novel substances like biodegradable plastics. Chris Somerville, a molecular biologist with the Plant Research Laboratory at Michigan State University, is out on that leading edge. He coauthored a recent paper in Science (V. Arondel, et al., 258: 1353, 1992), which was something of a breakthrough because it demonstrated the power of the currently available genetic maps and libraries. "We demonstrated that you could isolate a gene just on the basis of the genetic map location of a mutation of that gene," says Somerville. "Now anything we can mark with a mutation, you can just go and get the gene now." In this research, they used a mutated strain of Arabidopsis that was unable to produce omega-3 unsaturated fatty acids. The culprit was a gene coding an enzyme they dubbed fad3, a fatty acid desaturase. The discovery of fad3 is important because it demonstrates the ability to use the genetic resources currently available to locate and sequence genes with relatively little effort, and it indicates, in Somerville's mind, that one of the big breakthroughs of plant science disease resistance is not far behind. Somerville says that with about 1,000 professors in the United States working in the area of plant disease resistance, it's obvious that interest is keen, but not one of the genes controlling this trait has been identified in any plant. Now, thanks to the mapping efforts combined with other powerful tools of molecular biology, it looks like a number of groups both in the U.S. and abroad are very close to identifying a resistance gene. "It will be a first-class breakthrough when it happens," he says. Joe Ecker, a molecular biologist at the University of Pennsylvania, devotes half of his efforts to mapping the Arabidopsis genome and the rest to working out the signal transduction pathway for the plant hormone ethylene. His latest results, published in the February 12 issue of Cell (J.J. Kieber, et al., 72:427-41, 1993) are the culmination of work he started in the early 1980s and give "the first feel for what a plant signal transduction pathway looks like." It turns out it's very much like the pathway found in humans and fruit flies. Most of the molecular biologists now studying Arabidopsis did not start out working on plants. Ecker got interested in plants while investigating herpes viruses for his Ph.D. At the time, he harbored a strong desire to get involved in hormone research. He says that was also about the time when one of the first big plant molecular biology reports hit the mainstream scientific press (M.D. Chilton, et al., Cell, 11:263, 1977). The paper appearing as it did in Cell, with an accompanying photo on the cover had a big impact on Ecker. "When you're in a medical school, you don't get a lot of plant journals. It was basically telling you you could now introduce genes into plants, " he says. It was an exciting time, a time when "basically nothing was known about how plant hormones worked," he says. "From then until now, we've been pursuing the goal of how plant hormones work, and now we're at the tip of the iceberg on that." Arabidopsis began to emerge as the agreed-upon model for basic plant researchers about 10 years ago because its genome is small in size, about 100 million base pairs of DNA in five chromosomes, compared with the 3 billion base pairs on 23 chromosomes in the human genome, researchers say. The plant has a short life cycle compared with crop plants such as corn or rice. In addition, the seeds are tiny and the seedlings can easily be grown in the lab. For instance, Pablo Scolnik, a plant geneticist for E.I. Du Pont de Nemours & Co. Inc.'s Experimental Station Laboratory in Wilmington, Del., says that in the basement of his building he has as many Arabidopsis seedlings growing as there are corn plants in Iowa. Du Pont has a large agrichemical business and an expanding interest in agricultural biotechnology. Why is Du Pont interested in this particular plant, a relative of cauliflower that has a pronounced noncommercial, academic reputation? "The ability to clone genes affects all of agricultural research right now," explains Scolnik. "And when you have the genome for Arabidopsis, you have the genome for all plants. They're that homologous." As with others in this field, Scolnik started out in another division of life sciences in his case, as a bacterial geneticist who completed his Ph.D. 12 years ago. Explaining his transition to Arabidopsis, he quips, "I was working with photosynthetic bacteria, and when you grow up you move on to plants." One prominent researcher who also moved on to plants is Howard Goodman, a molecular biologist at Massachusetts General Hospital's genetics department. He was recognized by the Philadelphia-based Institute for Scientific Information as among the top 1,000 cited scientists in the period 1965-78 for his work in cloning the gene for insulin. But since he switched from humans to the field of plant molecular biology about 10 years ago, he says, his citation prowess has declined. Part of the appeal of plant research was that the field was "new and less crowded," he says. "And a lot of the techniques that had been coming up through the animal world hadn't been applied to plants yet." But the study of the molecular biology of plants has been picking up increasing momentum in the past few years. "There's been an explosion of interest in this field," he says. "And it's been very open and very collegial. It's a nice feeling to work in a field where people are so open." He sees both pros and cons to the choice of Arabidopsis achieved through international consensus as the focus of worldwide research efforts in the physiology of plants. While it's beneficial to have a common organism, there are a lot of reasons not to work on Arabidopsis. "For one, it has no commercial value," he says. "That makes it easier to work on in an academic sense," because the plant has no value in the marketplace and so there's less incentive to jealously guard information. "But there's not as much money available as a result." The National Science Foundation, one of the major funding sources for Arabidopsis genetics, supplied $7.7 million in fiscal year 1991 for all types of research on this organism, not just genome- mapping efforts. By comparison, Congress in the same year provided the National Institutes of Health $87 million for the more saleable effort to map the human genome. And that allocation has since grown to $106 million for FY 1993. Plant researchers report, however, that instead of feeling overshadowed, they benefit by being able to take advantage of the biological tools that are developed as part of this massive effort. Du Pont's Scolnik says the problem of funding will be around for a while: "I believe we have a problem. It's a lot easier to convince Congress to fund cancer research than it is to get funds to do plant research." Plus, in the U.S., farmers are paid enormous amounts not to grow certain crops, he says. "We're faced with the question of: `Why should we invest in plant research when we grow more than we need?' " Somerville's answer to that nettlesome question is: "Man does not live by food alone." A lot of our needs, such as for biodegradable plastics, could be supplied by transgenic plants, as he demonstrated in an April paper in Science (Y. Poirier, et al., 256:520, 1992). Corn starch, for instance, costs about 5 cents a pound to produce, while it costs about 50 cents to produce petroleum-based plastics. If plants can be successfully induced to produce alternative products at a similar econom-ic advantage, they will be the factories of the future, according to Somerville. Scolnik says that the openness that has been the hallmark of the Arabidopsis genome effort is what's responsible for the fast progress made toward identifying key genes. Despite his company's bottom-line interest in research, he plans to continue to freely share his laboratory's findings. "My policy is to share all the relevant information and basic technology we generate with the rest of the Arabidopsis community," he says. "I think there a misconception that academic labs are more open than industry labs." He says some companies share, others don't, and the same is true of academic labs. "And remember, this is pretty fundamental research. The funds a company will invest in this type of research are limited." It's this paucity of funding that makes it especially critical not to hold onto information. For instance, Scolnik's group published a paper in February 1992, summarizing their progress in chromosome mapping (R.S. Reiter, et al., Proceedings of the National Academy of Sciences, 89:1477, 1992). An even more vital communication link than publishing papers in journals is the electronic Arabidopsis newsgroup that was established two years ago, just after the long-range plan for an international plant genome effort was established (see The Multinational Coordinated Arabidopsis thaliana Genome Research Project Progress Report: Year Two, Publication No. NSF 92- 112, National Science Foundation, Washington, D.C., 1992). Researchers in this field report that this electronic bulletin board is extremely useful for communicating with their colleagues no matter where their location or time zone. "Also, my phone rings everyday," says Scolnik. "We [Arabidopsis researchers] talk a lot." The continued openness of this international effort is also a delight for Somerville, who says the gene-patenting issue that has infected the Human Genome Project has been "very destructive." The international collegiality is now a thing of the past in that project. "This is exactly the kind of thing we want to avoid with Arabidopsis," he says. Right now, there's a tentative agreement between most European groups and the U.S. to share information openly. There are Arabidopsis sequencing efforts under way in the U.S. at Michigan State and Harvard universities, as well as in France and the United Kingdom, says Somerville. But what he finds potentially exciting is the proposal by former NIH researcher Craig Venter to sequence the entire library of Arabidopsis cDNAs. Venter is known for generating the partial cDNA sequences of neural genes, which formed the basis of the controversial gene patent application being pursued by NIH (Scott Veggeberg, The Scientist, April 27, 1992, page 1). He is currently president of the Institute for Genomic Research, a private group in Gaithersburg, Md., devoted to gene sequencing, which has the capacity to sequence 1,200 cDNAs per day. Arabidopsis has about 20,000 cDNAs, each of which correspond to active genes in the plant. "Venter has spoken to me about doing all the Arabidopsis cDNAs in a matter of a few months. In fact, that remains a distinct possibility," says Somerville. Venter would have the right to hold back and patent a few potentially valuable genes, but the rest of the effort would spill over into the public domain, he says. In Arabidopsis, these cDNAs account for about 30 percent of the total DNA, with the rest being primarily regulatory genes and inactive DNA. Somerville says this approach would close off an alternative pathway, whereby a few big labs generate these sequences. Instead of putting the bulk of them into the public domain, they might play them close to the chest and distribute them to "friends" as favors, or compete directly with the people doing the original research on these genes. For instance, the group of researchers working on Arabidopsis at Michigan State have a lab devoted to sequencing, and the effort is big enough that they could afford to sit on their own sequences. But the 10 principal investigators there are really committed to getting the work out into the open, he says. He says that the large-scale sequencing techniques are out there and that somebody is going to do it. The challenge is to make sure that the groups doing it are regularly releasing their results. "If Craig Venter were to do it, even if he kept back a few dozen very important genes, it would still be a tremendous boon to the Arabidopsis community," says Somerville.

Genome Mapping Progress Catapults Plant Research

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