PRESIDENT'S LETTER

	Tuan-hua David Ho

Is There a Clear Dividing Line Between Basic and Applied Plant Research?

Basic and applied research used to be distinct from each other. When I was a graduate student in the now DOE–Michigan State University Plant Research Laboratory (PRL) in the 1970s, my thesis research was related to the basic understanding of form and function of plants; that is, the mode of action of the plant hormones GA and ABA. Although the PRL was supposed to have an applied mission related to energy and environment, we were never under any pressure to relate our research to any potential application. “Biotechnology” was a rather remote, and seldom mentioned, concept. I don’t remember the subject of “translational and mission-oriented research” ever being discussed. We routinely exchanged research materials, protocols, and other information without much concern for their possible commercial value. There was little or no attempt to protect intellectual property. I left graduate school with a belief that I would spend my career pursuing basic research, and the applied aspects of research would, and should, be left for others to worry about.

Almost 40 years later, however, attitudes are quite different. Now we are often asked to identify the practical impact of our research whenever we submit a proposal to government funding agencies. We fail to address this requirement at our own peril! Interactions with the biotech industry have become much more frequent. University technology transfer offices used to work almost exclusively on engineering-related cases but now pay much more attention to biotech prospects. We are asked to use an MTA (material transfer agreement) all the time if any research materials change hands even for seemingly trivial reasons. We even instruct our students and other lab members to establish the good habit of carefully documenting research results in case they have future commercial value and to serve as witness to each other’s important research discoveries. In addition to using publications as important markers of specific discoveries, filing for intellectual property protection is becoming an important practice. This change is a global phenomenon; plant biologists in almost every region of the world routinely address biotechnology issues, and the line between basic and applied plant research has become blurred.

Of course, the aforementioned changes did not take place overnight; hints of applications or missed opportunities were discussed throughout this period of gradual change. During my graduate study years at Michigan State University, I had the good fortune of getting to know quite a few luminaries in plant biology. The late Professor Norman E. Good made seminal contributions to understanding chemiosmotic processes as an important aspect of photophosphorylation in chloroplasts. Because having good and reliable buffers was essential in his research, Dr. Good and his associates synthesized and characterized hundreds of dipolar ionic buffers in terms of pKa, stability, buffering capacity, and so on, and these “Good” buffers have become a mainstay of modern biology (1). Suffice it to say, no graduate student in biochemistry/molecular biology nowadays can finish his or her thesis research without using one or more “Good” buffer. For example, Tricine is a commonly used electrophoresis buffer, and HEPES, the most widely used synthetic buffer in the world, is used in many enzymatic reactions and cell culture media. Although quite a few biochemical supply companies have made handsome profits selling the “Good” buffers, Dr. Good and Michigan State University did not apply for a patent for anything related to these buffers because doing so was not part of the research “culture” at that time. Thus, they were not able to share in the profits that flowed from the commercialization of their work.

In the mid-1970s, I was invited to give a lecture at a symposium being held at the University of Minnesota, where I heard the late Dr. Jeff Schell describe the fascinating system of crown gall tumor and its induction by the soil bacterium Agrobacterium tumefaciens. In addition to its intrinsically interesting features, its role in tumorigenesis suggested that this process might provide insights into human cancer development—even then an extremely popular and highly fundable topic. Later, on other occasions, I heard Dr. Mary Dell Chilton describe her team’s efforts to determine whether there was a transfer of bacterial genetic material to the plant genome. They meticulously carried out a series of “driver DNA” renaturation measurements, using various fragments of the large Agrobacterium Ti plasmid renatured faster in the presence of tumor DNA, proving that the plant had incorporated copies of that part of the plasmid (2). From that instant on, the development of both basic understanding of this bacterium-to-plant gene transfer and applications in taking advantage of this process as an effective means to transform plants took off at a fast clip. Both academic and industrial researchers contributed to this period of rapid development in modern plant biology, and it was hard to distinguish basic from applied research in their work. University scientists were filing for patents on their inventions, and industrial scientists were publishing papers in highly visible journals. By the early 1980s, the first transgenic plants were generated and the genes involved in tumor formation were well studied. The first transgenic plant product carrying a fruit ripening delaying gene was marketed in the early 1990s (3). The now well-known herbicide-resistant transgenic soybean was first introduced in 1996, and its market share in the United States is now over 90% (4). It was less than 40 years from the publication of the original curiosity-driven research to the marketing of a new breed of crop plants.

Herbicide resistance research proceeded by the inverse path—that is, from the development of a practical solution to an agricultural problem to the basic understanding of how the process works. Most, if not all, herbicides were identified by random screening of chemicals. Any chemical that inhibited plant growth but had little or no toxicity to humans and low impact on the environment was considered a good candidate for herbicide development. One such chemical, a simple amino acid derivative called glyphosate, was identified by Monsanto from extensive screening. It effectively inhibits growth of all plants, yet has very low toxicity to mammals, with an LD₅₀ higher than that of aspirin; in other words, it takes less aspirin than glyphosate to kill 50% of testing mice in the toxicology study (4). While glyphosate was marketed as a kill-all herbicide with the trade name Roundup^TM, initially its mode of action was not well understood. The involvement of experts in the field of phenolic secondary metabolites was essential in understanding the mechanism of glyphosate action (5, 6). Glyphosate was shown to be a competitive inhibitor of phosphoenolpyruvate (PEP), one of the substrates for an enzyme, 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase, in the biosynthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. Not being able to synthesize these amino acids blocks plant growth, yet many mammals do not even have this biosynthetic pathway and hence no target site for glyphosate. (These aromatic amino acids are among the “essential” amino acids, which need to be acquired by mammals from the food they consume.)

Once the mode of action of glysophate was elucidated, a commercial application of immense value quickly followed, making important crop plants glyphosate resistant by transformation with EPSP genes encoding EPSP synthase variants that are insensitive to glyphosate inhibition. With relevant knowledge and technology readily available, the main hurdle for herbicide-resistant plants turned out to be regulatory approval and public acceptance. While this type of transgenic crop was quickly adopted by U.S. farmers, significant resistance still exists in other parts of the world. Although GM (genetically modified) crops will remain a subject of debate for the foreseeable future, other technologies derived from sound basic research, such as gene stacking, excision of selection markers, plant-origin selection markers, transgene gene containment, and the like, will, we hope, make GM plants more acceptable, with less impact on the environment, and consequently embraced by an even larger majority of the general public.

Does the absence of a distinct separation between basic and applied research pose problems for our discipline? Is the pursuit of fundamental knowledge “tainted” because researchers are addressing issues that could be related to “profits” or “making somebody rich”? This is not an easy issue to analyze. The late Professor Donald E. Stokes, formerly professor of politics and public affairs in the Woodrow Wilson School of Public and International Affairs at Princeton University, argued that basic and applied research could easily go hand in hand under certain conditions (7). In his book Pasteur’s Quadrant: Basic Science and Technological Innovations, Stokes stated that research activities are usually inspired by a quest for fundamental understanding and/or considerations of use. He illustrated the “Quadrant” model (fundamental understanding and/or considerations of use) with three examples. (There is no example to fit into the fourth quadrant since no research would likely be initiated if neither of these driving forces existed.) Niels Bohr’s pursuit of atomic structure was a discovery in basic science, yet later had profound impacts in both basic and applied arenas. Thomas Edison’s research was driven only by potential applications. Although his inventions have greatly changed many aspects of modern society, little advance in science was derived from his inventions. Louis Pasteur’s research was inspired by both the quest for fundamental knowledge and the development of potential applications. Pasteur’s work stands as vindication of Professor Stokes’s thesis: that historically there has been an unfortunate and unnecessary separation between basic and applied research. The fact that basic science was also called “pure” science seemed to suggest that the economic impact of a research project was of no concern to “pure” scientists. However, this paradigm is fast changing in plant biology, as highlighted by the above examples: Good buffers, crown gall tumor, and herbicides. There is no clear dividing line between basic and applied plant research anymore!

Applications based on acquired knowledge have played a pivotal role in the evolution of human civilization. The development of agriculture some 8,000 to 10,000 years ago was apparently derived from knowledge about plants and animals acquired by our ancestors, who were originally hunters and gatherers. The adoption of this earliest form of biotechnology—agriculture—led to an expanded and more diverse human population, which in turn facilitated more knowledge acquisition and technology development. Jared Diamond, in his famous book Guns, Germs, and Steel: The Fates of Human Societies (8), pointed out that the rate of incorporation of new knowledge-based applications decisively influenced the evolution of human civilization with certain early technology-adopting societies dominating over others. Although the explosion of new knowledge in our time allows us to imagine a wide range of new and often high-impact technologies, prudence requires us to attempt to balance these new possibilities with the protection of resources. Ignoring this principle has resulted in the collapse of some ancient civilizations, such as those in Greenland Norse and Easter Island societies (9), and it is conceivable that the same situation could happen among modern societies. Furthermore, Hawken et al. (10) suggested that modern economies have already shifted from the emphasis on human productivity to focus on resource productivity. With the rapid depletion of natural resources, it is imperative that we increase our investment in “natural capital.” In the conventional economic wisdom, if a major supplier is overextended, immediate action is called for to prevent a meltdown of the system. A case in point is that conventional energy sources are expected to run out by the end of this century, and the current energy basis of our economic system is not sustainable. The essential energy-source transformation will require large investments in alternative energy such as biofuels. These considerations put plant biology at the center stage, as our profession is clearly related to food security, human nutrition, alternative energy, protection of the environment, and sustainable development. The plant biology community worldwide, in both the public and private sectors, has to follow a multidisciplinary approach combining both basic and applied research to meet these daunting challenges.

What are the roles of ASPB during this paradigm shift in plant biology? In addition to campaigning for the value of basic plant science, the Society has been actively highlighting the contributions of plant biotechnology in enhancing the quality of our lives and environment. We constantly reach out to the government, legislative bodies, and the general public to highlight the contributions of basic and applied plant biology research. Furthermore, we are collaborating with plant biology societies around the world to form the Global Plant Council (GPC), whose task is to publicize what basic and applied plant biology can do for the world community. The shifting paradigm of plant biology is also reflected in the programs at our annual meetings. Decades ago, ASPB meetings were focused only on basic research. However, more application-related topics have been included in recent ASPB meetings. The upcoming Montréal meeting has two symposia on applications: “Impact of Plant Biology on Human Health and Medical Research” and the “Next Wave of Plant Biotechnology.” We sincerely hope that attendants at this meeting will enjoy the combination of basic and applied plant biology research that is at the forefront of our profession and blazing the trail to the future.

Tuan-hua David Ho

Acknowledgements
I thank Nikolaus Amrhein, Mary Dell Chilton, Danny Kohl, Don Ort, Ralph Quatrano, and Paul Versleus for their comments and suggestions.

References

1. Good, N.E., Winget, G.D., Winter, W., Connolly, T.N., Izawa, S., and Singh, R.M.M. (1966). Hydrogen ion buffers for biological research. Biochemistry 5: 467–477.
2. Chilton, M.D., Drummond, M.H., Merio, D.J., Sciaky, D., Montoya, A.L., Gordon, M.P., and Nester, E.W. (1977). Stable incorporation of plasmid DNA into higher plant cells: The molecular basis of crown gall tumorigenesis. Cell 11: 263–271.
3. Martineau, B. (2001). First fruit: The creation of the flavr savr tomato and the birth of biotech food. New York: McGraw-Hill.
4. Duke, S.O., and Powles, S.B. (2010). Glyphosate-resistant crops and weeds: Now and in the future. AgBioForum 12 (3, 4): Article 10.
5. Amrhein, N., Deus, B., Gehrke, P., and Steinrücken, H.C. (1981). The site of the inhibition of the shikimate pathway by glyphosate: II. Interference of glyphosate with chorismate formation in vitro and in vivo. Plant Physiol. 66: 830–834.
6. Schonbrunn, E., Eschenburg, S., Shuttleworth, W.A., Schloss, J.V., Amrhein, N., Evans, J.N.S., and Kabsch, W. (2001). Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail. Proc. Nat. Acad. Sci. 98: 1376–1380.
7. Stokes, D.E. (1997). Pasteur’s quadrant: Basic science and technological innovations. Washington, D.C.: Brookings Institution Press.
8. Diamond, J. (1997). Guns, germs, and steel: The fates of human societies. New York: W.W. Norton.
9. Diamond, J. (2005). Collapse: How societies choose to fail or survive. New York: Viking Press.
10. Hawken, P., Lovins, A.Q., and Lovins, L.H. (1999). Natural capitalism: Creating the next industrial revolution. New York: Little, Brown and Company.