Profile of Richard Dixon

Organic Interest

Growing up in Burton-on-Trent, England, Dixon had to decide the course of his life at an early age. In the British school system in the 1960s, students were required to choose by age 14 whether they were going to study arts or sciences.

“I was a timorous schoolboy, and it was a really tough decision whether to go into the arts or sciences,” Dixon recounts. He easily could have gone on to study literature, he says, without some helpful advice from his headmaster. “[He] was a chemistry Ph.D., and he called me up on the phone one day and told me, in no uncertain terms, ‘you're going to be a scientist!”’

Chemistry grabbed Dixon's attention during his last two years of secondary school. “I had a chemistry lab upstairs in my bedroom. I probably burned several carpets distilling acids,” he says. “I was fascinated with synthetic chemistry. I made noxious compounds in the garage and once nearly poisoned my father.”

At that time, the idea of going into plant science had not crystallized for Dixon but it soon came time for picking a major in college. “Physics wasn't my favorite subject, but biology and chemistry, I loved.” Dixon entered the University of Oxford (Oxford, U.K.) in 1969 to study biochemistry. “That probably reflected the fact that I couldn't make up my mind between biology and chemistry. It was best of both worlds,” he says.

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Richard Dixon

Dixon was fascinated with the complexity of organic molecules and how they are produced. In his third year at Oxford, his interest in plants—and plant chemicals—blossomed after he took an elective course in plant biochemistry. “When I looked at the structures of some of the more complicated plant natural products, like morphine for example, it really amazed me. I was asking myself way back then ‘how on earth do plants put these things together? How do they do the chemistry?”’

In that class, Dixon learned about the synthesis of lignin, a complex polymer that confers rigidity to plants. The class, taught by Vernon Butt at Oxford's Botany School, made Dixon appreciate how an understanding of enzymology could explain the chemistry underlying natural product pathways. “I saw how we could begin to dissect natural product biosynthesis, even for complex polymers, at the enzyme level. It got me feeling that plant biochemistry was where I wanted to go.”

The next year, Dixon completed his senior thesis on the mobilization of storage polysaccharides, such as galactomannans, in legume seeds. After graduating with a bachelor's degree in biochemistry in the summer of 1973, he was accepted into Keith Fuller's plant biology laboratory at Oxford and planned to continue his graduate studies on the processes he studied during his senior year. In the interim between graduation and the first day of graduate school, Dixon got his first harsh lesson about academic life.

“I went home for that summer vacation and spent the whole time reading up all around this subject of carbohydrate mobilization in seeds,” he recalls. When he showed up at Oxford in October ready to start his Ph.D. project, he discovered that no less than four papers had been published during the summer by another group, doing the studies he had planned to do over the following three years. “That was message number one,” he says. “If you have a good idea, get moving quickly because there is always someone out there who's had the same idea.”

After his disappointment subsided, his advisor offered an alternative course for his doctoral studies: using plants as factories for making molecules of value. Fuller had developed cell suspension cultures of several plant species to produce specific molecules and suggested that Dixon try to develop cell culture systems that could generate enhanced levels of antimicrobial molecules.

“I said that was fine, but I was a little disappointed because it wasn't really what I'd planned on doing. But it really was fortuitous,” he says, noting the increasing interest in natural plant products and genetically modified crops in recent decades.

Dixon commenced working on French beans, looking to boost the plant's production of a chemical called phaseollin, an isoflavonoid compound that acts as an antimicrobial defense. The compound is usually induced by pathogens that attack the plant, which can also be mimicked with pathogen extracts. “So I did my Ph.D. optimizing culture systems, mainly cell suspension cultures, and evaluating different types of inducers for turning on this pathway (2),” Dixon explains.

Just before completing his doctorate in plant biochemistry in 1976, Dixon met Chris Lamb, a postdoctoral fellow who had recently arrived in the laboratory and who planned on studying the mechanistic aspects of light induction of early enzymes in the same pathway Dixon was studying. Their brief overlap set up a collaboration between the two that has spanned decades.

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Dixon tending cacti, one of his hobbies.

Dixon soon departed for his postdoctoral fellowship in the department of biochemistry at the University of Cambridge (Cambridge, U.K.), working in the laboratory of Derek Bendall. There he continued the work he had started in Fuller's laboratory, and his close collaboration with Lamb took root. While working in Bendall's laboratory, Dixon began to define the molecular responses of the legume cell suspension system that he and Lamb would use for the next 15 years to study the molecular biology of defense gene induction (3).

But in those premolecular biology days, Dixon and Lamb had to use old-fashioned biochemical techniques such as density labeling to address whether the increases in enzymes involved in the synthesis of antimicrobial compounds were due to de novo synthesis or activation of the enzyme. Soon after Dixon moved to his first faculty position in the department of biochemistry at Royal Holloway College, University of London (Surrey, U.K.), they showed that the enzyme induction was associated with synthesis of new enzyme molecules as well as changes in the turnover of existing enzyme molecules (4).

“Just as we were asking those questions, the tools of molecular biology became available,” Dixon recalls. “The new molecular technology set me on one path of my career, which has been to identify—at the molecular genetic level—the whole biosynthetic machinery for making complex isoflavonoids and related compounds.”

In later years, Dixon and his colleagues would become the first to clone many of the genes in pathways leading to legume defense compounds, including the critical enzyme for making isoflavonoid antimicrobials in soybeans (5). Later, he and Lamb elucidated the role of reactive oxygen species in the induction of plant biochemical defenses (6).

A Noble Move

Their collaboration, which produced more than 100 articles, also helped bring Dixon to the United States. In early 1987, Dixon traveled to the Salk Institute (San Diego) to do part of his sabbatical with Lamb, who had moved there a few years earlier. From Lamb, he heard about the Noble Foundation, a philanthropic organization that had provided funding to establish the plant biology program at Salk. The foundation had decided to develop a plant biology program at its research campus in Ardmore, OK, and was looking for someone to lead it. By the summer of 1987, Dixon accepted a position as director of their new plant biology division.

As Dixon hired the foundation's first set of investigators, he also set up a joint postdoctoral program between the Noble Foundation and Salk to help “overcome the potential recruiting difficulties of having a division that was starting from zero in a location that was not, at the time, an obvious one for people to go to do plant science,” he says.

“If you have a good idea, get moving quickly because there is always someone out there who's had the same idea.”

While building the program, Dixon continued collaborating with Lamb on plant defense gene induction but also shifted his focus from isoflavonoids. “[I returned] back to the thing that had turned me on all those years ago back in college: the lignin pathway,” Dixon recalls.

In 1994, Lamb, Dixon, and their colleagues showed that the down-regulation of one of the early enzymes in the lignin pathway, called phenylalanine ammonia-lyase, reduces the amount of lignin in plants (7). The findings made Dixon think about new applications for such genetic manipulation.

“For most of my career up until then, my interest in plant natural products had focused on their roles as antimicrobials,” he says. “I began to start thinking of other plant traits that were going to be important to the clientele that the Noble Foundation serves.”

The foundation, located in the heart of the beef “cattle belt” of southern Oklahoma, has a clientele that includes farmers and ranchers interested in enhancing the value and quality of forage crops for their cattle. Dixon began to wonder how lignin modification might be applicable to these issues.

“Lignin shields cellulose—a major source of carbohydrates for animal nutrition—from degradation by microbes and microbial enzymes in the rumen of cattle and sheep,” he explains. “Reducing lignin, or altering lignin composition, should therefore improve forage digestibility, so essentially you get more weight gain per unit [of] forage.”

Dixon's work on altering lignin biosynthesis in alfalfa—a major forage crop for beef cattle—was largely funded by Forage Genetics International, which was interested in his approach. Along the way, however, he also discovered new basic information about the enzymology and molecular genetic control of the lignin synthesis pathway.

Through this research, Dixon found that “what I was taught as an undergraduate about lignin biosynthesis was a huge oversimplification. The pathway that people believed to operate, based on doing limited in vitro biochemistry, is actually far more complex than what was first presented.” Dixon's work, for example, showed alternate routes to lignin biosynthesis through enzymatic activities whose basic reactions had been known for many years (8).

His group also generated large numbers of genetically modified plants in which either lignin content or composition was altered. “Some of these modifications improved forage quality,” he says. Specifically, he found that down-regulating the expression of certain cytochrome P450 enzymes of the lignin pathway greatly improved the digestibility of alfalfa (9).

Plant Power

These modified crops might one day benefit not only cows, but also cars, Dixon says. He notes that lignin modification also has a significant impact on the efficiency of processing necessary to get fermentable sugars out of lignocellulosic materials (10). “This is a major [advance] for bioethanol production,” he says, because the presence of lignin reduces the access of enzymes and chemicals to the plant sugars that are fermented during ethanol production. Dixon is using his genetically altered alfalfa lines to explore which features of lignin are most detrimental to sugar release and fermentation during bioethanol production. Using this knowledge, he predicts that it will be possible to design an optimal strategy for genetically modifying plants that will facilitate biofuel processing.

“We're going to have to do something about this issue,” he says. Although lignin-modified switchgrass, which he is working on, may provide a better source of ethanol than the commonly used corn crop, “what ultimately proves the most effective is, of course, going to be determined by the market.”

“If other approaches for environment-friendly biofuel feedstocks prove to be economically superior, we've still had a great time looking at how plants make lignin,” Dixon says.

Bypassing Gas

Although high in protein, alfalfa presents a deadly problem for livestock. “Alfalfa is a fantastic forage [food], but, paradoxically, it's almost too rich in protein,” Dixon says. The high levels of protein cause a potentially deadly condition known as “pasture bloat.” If cattle eat too much alfalfa, “they get a lot of wind,” he notes. “It can be lethal, and you can have exploding cows.”

One reason that alfalfa and other protein-rich legumes cause excessive methane production is that the parts of the plant that the cows eat, the leaves and stems, lack compounds known as condensed tannins, which are naturally produced in the seeds. In forage crops, condensed tannins can slow down the rate of protein degradation in the cow's rumen, reducing methane production.

“I was familiar with the condensed tannins inasmuch as I knew that we understood everything about the early steps in their synthesis and nothing about the late steps,” Dixon says. “It wasn't clear how the building blocks were made or how they were put together.”

A suggestion from Forage Genetics led Dixon to investigate the molecular biology and genetic modification of condensed tannins, with the goal of inserting them into forage crops. Dixon's group soon determined a key step in tannin production: that the enzyme anthocyanidin reductase converts anthocyanidin, a flower pigment, to a building block of tannins known as epicatechin (11). Their studies revealed that, contrary to previous belief, the pathways for the flower pigments and the pathway for tannins both go through anthocyanidin.

“That was really quite exciting, as we had discovered a new biosynthetic pathway,” Dixon says. “Since then we've been working very hard to understand a lot of the later things that happen [after] that reaction and to move this pathway into the leaves of alfalfa plants.” With the newfound biochemical knowledge, Dixon's group recently has been able to produce alfalfa plants containing lower levels of tannins. He notes that much further study is needed to better understand the pathway and how to optimize its expression in nonseed tissues.

Food and Feedback

Dixon has recently returned to research on antimicrobial isoflavonoid compounds. With the advent of genome-wide techniques like DNA chips, Dixon now can delve deeper into the molecular biology of isoflavonoid biosynthesis.

In his Inaugural Article, he turned to a cousin of alfalfa, the model legume Medicago truncatula. He shows how two different events damaging to the plants—one a chemical that mimics an invading pathogen; the other a chemical released by physically wounding the plant—induce the production of an antimicrobial isoflavonoid called medicarpin via two different pathways (1). He found that the pathogen signal activated all the genes in the antimicrobial production pathway, whereas the wound signal appeared to skip many of the early steps. The chemical released by the wound signal, methyl jasmonate, induces intermediates that had been stored in the cell's central vacuole. Though it is not clear how this process is controlled, Dixon posits that “the plant probably has a reasonable amount of time to mount a defense response and seems to do it by de novo synthesis” in the case of a pathogen attack, but it is immediately compromised and must use the most rapid method possible to make these protective compounds when it is wounded.

Dixon notes that these isoflavonoid pathways can be manipulated to generate plants capable of producing compounds with human health benefits. He points out that many isoflavones are also phytoestrogens, hormone-like compounds that have potential benefits for cancer, cardiovascular disease, cognition, and postmenopausal ailments. Having developed a strategy to introduce these compounds into plants, Dixon foresees a future with human and animal diets designed to treat or prevent specific maladies and functional foods tailored to a person's genetic or metabolic profile.

“I suspect that maybe 100 years from now, there will be genetically modified designer diets for chemoprevention of many of the common diseases,” Dixon remarks.

Dixon is not worried that lignin modification—or any of the other applications of his research—may never come to market. The potential for useful applications has driven his work in interesting and unexpected directions.

“I've been surprised how thinking in a more applied manner has led me to make some basic science discoveries I might not have made,” he says, noting that he probably would not have looked at condensed tannin biosynthesis if not for his corporate partner's interest in the topic.

While he reveals that it is immensely rewarding to see a product borne from your research, his ultimate reward is discovery. “It's really exciting to go out and see whole fields full of a product that initiated from an idea you had in the lab,” Dixon says. “But a part of me has always been the pure scientist. What I enjoy most of all in science is discovering something new—a new gene or a new biosynthetic pathway—that's the most exciting thing there is.”