In my last column, I discussed herbaria and my newfound interest in them (Flannery, 2011). Even though this month's theme is human health, I'm not ready to leave my new love yet, and I think I can justify sticking with the topic, at least peripherally. After all, it was human health that for centuries drove the study of plants, and to a certain extent it still does, as botanists travel the world seeking plants with medicinal properties. The first herbaria were tied to medical schools.
Helen Hewson (1999) noted that botanical illustration, botanical gardens, and herbaria all developed at about the same time in the mid-16th century and all met the need of helping botanists compare species from different localities. As printed tomes on medicine became available, there was the concomitant need to ensure that two authors were talking about the same plant. Nomenclature had yet to be regularized, so drawings, dried specimens, and growing plants were a big help in identifying species. But drawings didn't become useful until the publication of the first great printed and illustrated herbals of Brunfels in 1530 and Fuchs in 1542 (Arber, 1912). The first botanical garden was established in Pisa in 1544 by Luca Ghini, who is also credited with creating the first herbarium of pressed plants and with founding the second botanical garden at Padua in 1545. So the mid-16th century was a very exciting time for botany — and for medicine. Anatomy and botany were the two major areas of study in medical schools of that time, and it was at Padua in 1544 that Vesalius published his On the Fabric of the Body, with the amazing illustrations that are still reproduced so frequently today. Anatomy aided in understanding what was going on inside the body, and botany aided in a more practical way: providing chemicals that would help right what was wrong in the body.
These two areas of biology were tied together at an even more fundamental level, in that they were both about observing form, understanding structure, being able to detect subtle differences. If a physician was going to prescribe a particular plant product as a medication, he or she had to be sure that the correct substance was actually used: two plants could look similar and yet be very different chemically. Being able to compare the plant in hand with a reliable source — a specimen in a botanical garden, a dried plant in a herbarium, an illustration in an herbal — was a great boon and a new idea that suggested that botany was becoming a science and was contributing to medicine's heading in the same direction.
This linkage between medical knowledge and plant collections extended beyond Italy and remained an important spur to the development of botanical gardens for centuries. The medical school at Montpelier in France founded a botanical garden in 1593, though it had a physic garden for several centuries before that. In this sense, "physic" means healing and refers to plants grown for medicinal purposes. This tradition extends back to ancient times and long predates the term "botanical garden," which was first used for gardens like those at Padua and Pisa that were connected to universities. The distinction is not always clear for some of these older gardens; it often has more to do with the founding body than with the garden itself.
The Chelsea Physic Garden, still flourishing today in London, was founded in 1673 by the Worshipful Society of Apothecaries, which kept it as a private preserve until 1983, when it was opened to the public. The land for this institution was originally the garden of John Danvers, who owned the home that had earlier belonged to the British Lord Chancellor, Thomas More, the man beheaded by order of Henry VIII for not acquiescing to Henry's way of dealing with his marital problems. In the 16th and 17th centuries, Chelsea was a suburb of London where the wealthy lived and had lush gardens; More's was right on the Thames. In 1713, Hans Sloane purchased the manor next door to the Physic Garden and in 1722 leased 4 acres to it; he also provided financial assistance to get the faltering garden back on its feet (Wulf, 2009). Sloane, besides being a wealthy man, was himself a doctor and early in his career spent 18 months on the island of Jamaica serving as physician to the Governor. During this stay he collected plants extensively and created a herbarium, which he brought back to England and continued to augment throughout his life, mostly by buying the specimens and collections of others, as well as trading some of his specimens for ones he didn't have. Though the herbarium can be seen as related to his profession, which he continued to practice throughout his life treating three British monarchs, Sloane had other collections that included everything from shells to stuffed animals. These collections became the nucleus of what eventually became the Natural History Museum, London, where they are still housed.
Physicians & Botanists
As seems to have happened to many botanist/physicians, what may have begun for Sloane as a professional interest in medicinal plants grew into what might be considered a collecting obsession. His herbarium is composed of thousands of sheets of pressed plants, and, as was the standard practice in his day, he had them bound — into 270 volumes. Carl Linnaeus changed all that. He rightly argued that binding prevented reshuffling of the sheets when plant classifications were changed. To replace the book, he invented the herbarium cabinet in which related plants could be filed by genera and family, much as they are to this day. I should note that Linnaeus himself was trained as a physician and, like Sloane, practiced medicine along with doing his extensive classification work. This link between botany and medicine is seen again and again well into the 19th century. Erasmus Darwin was a physician and also the author of several botany books, some in prose but others, more famously, in poetry (Darwin, 1791). Although by the time his grandson Charles became an adult the tie between the fields was beginning to weaken, Charles did begin his higher education studying medicine for two years in Edinburgh and had a lifelong interest in plants that only became stronger with time (Kohn, 2008).
Botany's link with medicine was also firmly established in the New World. The first American textbook on botany was published in 1803 by Benjamin Barton, a Philadelphia physician; he also trained many of the next generation of practitioners in both these fields. In New York, David Hosack was a prominent physician who was an early advocate for smallpox vaccine and for the use of the stethoscope in physical examinations. In addition, he was — you guessed it — an accomplished botanist who in 1801 purchased a parcel of land in the middle of Manhattan Island and created the Elgin Botanic Garden, which later became the first publically owned garden in New York State. However, it was considered too far north from the city's center, so the land was eventually sold for other uses, and in the 20th century it became the site of Rockefeller Center. Botanically, the property didn't fare as well as the Chelsea Garden did, but the vacuum its demise created was eventually filled by botanical gardens in each of the other four boroughs, with the gardens in the Bronx and Brooklyn having extensive libraries and herbaria.
David Hosack worked with Amos Eaton, who became a prominent botanist in New York and who interested John Torrey in the science. Torrey, in turn, inspired and collaborated with Asa Gray. The latter two were both trained as physicians, but Gray gave up medicine for botany and represents the turn that botany took in the 19th century, as it began to become a separate enterprise from medicine, which was also changing. By the end of the century, medicine had become professionalized thanks to the work of, among others, William Osler (1849—1920), the Canadian physician who is considered the father of modern medicine. He was one of the founders of the Johns Hopkins Medical School and developed the idea of internships for physicians after they graduated from medical school. This was a departure from the much looser apprenticeships that had been the norm until then.
Two Separate Fields
This weakening of the bonds between botany and medicine, with the practitioners of each going their own way, meant that doctors came to know less and less about the medicinal properties of plants and thought of medicines more as specific chemicals. Where those chemicals came from was less important than their effectiveness in treating disease. On the other hand, botanists were occupied with issues other than human health. One of the spurs for the development of this science was the Morrill Act of 1862, which called for the creation of land-grant colleges that would, as part of their mission, foster the development of agricultural education (Ertter, 1995). Botany was obviously an important part of such training, and, in addition, there was a crying need for botanical research to support the agricultural enterprise. Food plants, not medicinal plants, became the focus for many botanists, as they also continued cataloguing the new species being discovered in the western part of the United States. This latter enterprise reached its peak in the second half of the 19th century, when another type of botanical research was also developing. Botany was moving away from taxonomy and toward experimentation. Improved microscopes were making cellular investigations feasible, and the hunt for plant growth factors began. Charles Darwin's simple plant experiments, including those on how plants moved toward the sun, suggested the way botany was heading (Kohn, 2008).
Then came the dawn of genetics at the beginning of the 20th century, as well as the development of medicine as a scientific discipline, making the link between botany and medicine ever weaker. This was despite the fact that many of the most important medicines, including aspirin, which was first marketed in 1899, were based on plant chemicals. In the case of aspirin, it was a derivative of the salicylic acid found in the bark of the willow, Salix. And, of course, there was quinine from the cinchona tree, Cinchona pubescens, to say nothing of cocaine, morphine, and nicotine. Still, the stress in research was not on plants, but on creating synthetic forms of these drugs or chemically synthesizing novel substances, as in Paul Ehrlich's search for a chemical "magic bullet" that would cure syphilis (Witkop, 1999).
The focus on chemistry continued, even though the great magic bullet of the 20th century, penicillin, was a plant product — at least, Penicillium chrysogenum and its fellow fungi were considered plants when Alexander Fleming discovered the mold's antibacterial properties in 1928. Of course, there were still people who saw plants as great sources of medicines. For example, two important classes of anticancer drugs are plant derivatives. First, there are the related compounds, vincristine and vinblastine, discovered in 1950s in the Madagascar periwinkle, Catharanthus roseus. Out of all the plants in the world, how did this one get singled out for investigation? Those who drank a lot of tea made from this plant had low white-blood-cell counts. Researchers who investigated the effect discovered that these two substances prevented creation of the mitotic spindle in cells attempting to divide, thus aborting the process — just the ticket for slowing down leukemia and other cancers.
The story of another mitosis inhibitor and anticancer drug, taxol, suggests how a new rapprochement between medicine and botany began in the mid-20th century (Goodman & Walsh, 2001). In the 1950s and 60s, the National Cancer Institute (NCI) began to do mass screening of substances for anticancer properties. Most of these were synthetic chemicals, but Jonathan Hartwell, who was involved in the project, had experience with natural products and thought that plant substances deserved more attention. He developed informal relationships with botanists who provided him with material to test. In 1960, NCI formalized this process by contracting with the U.S. Department of Agriculture to have its botanists collect a thousand specimens a year for screening. One of the specimens was the bark of the Pacific yew tree, Taxus brevifolia, which turned out to harbor the anti-mitotic agent taxol, which stabilizes the mitotic spindle so that it doesn't disassemble as it normally would. Taxol was eventually shown to be effective in treating lung, ovarian, and breast cancer, among others. There was, however, a supply problem: T. brevifolia was not a plentiful species and harvesting the bark killed the trees. Because yew trees don't grow very rapidly, a taxol shortage and perhaps extinction of the species loomed as possibilities, but chemists were eventually able to take a chemical in the more abundant European yew, T. baccata, and synthesize taxol from it. Now the drug is made with a plant cell fermentation process. It's also been discovered that a fungus found in T. brevifolia also produces taxol, and this has provided a supply of the chemical for researchers.
The taxol story focused light on the importance of plants as sources for drugs and led to increased funding for plant research by drug companies. There was also an increased interest in ethnobotany, another area that for many years had been outside the mainstream of plant science — until the recreational drug revolution of the 1960s and 70s. One of the most prominent ethnobotanists of this era was Richard Evans Schultes (1915—2001), a Harvard professor who did field work in Central and South America. He not only studied plants, but drew on the knowledge of indigenous peoples who used these plants in healing, in religious rites, and in a host of other ways. Schultes is considered the father of modern ethnobotany because he brought attention to the wealth of botanical information that indigenous peoples possess and emphasized that this was a resource that was rapidly disappearing as once-isolated tribes were touched by civilization. Exposure to the larger world led to the assimilation or, in many cases, the death of these tribes from a host of causes, but particularly from infections against which they had no immunity.
One reason Schultes became so well known was that he recorded the hallucinogenic effects of a number of plant products and coauthored The Plants of the Gods: Their Sacred, Healing, and Hallucinogenic Powers (1979) with Albert Hofmann, the German chemist who discovered LSD. In other words, Schultes made the study of plants interesting, if not downright exciting. Plants entered our consciousness in a new way and, combined with the discovery of plant-based anticancer drugs, made the connection between botany and medicine again an intriguing one. Of course, the link between the two had never been completely broken. Besides indigenous peoples continuing to utilize the botanical riches that surrounded them, many in the developed world still looked to what came to be called "herbal medicine" to find substitutes for and additions to products of the pharmaceutical industry.
I was brought up in a home in which medicines were used only when absolutely necessary and were always purchased at a pharmacy. This was usually on the advice of a physician, except for such staples as aspirin and Pepto-Bismol. We were definitely not into "herbal remedies"; the term itself seemed old-fashioned. In the 1960s and 70s, however, there was a move toward more "natural" medications, and herbal medicine began to come back into favor, at least among certain portions of the population. I wasn't one of them, and I am still suspicious of them, even with my newfound interest in botany and respect for the power of plant chemicals.
Yes, I think plants are wonderful sources of potent drugs, and that's precisely why I'm wary of herbal medicines, which are often sold as nutritional supplements to circumvent the drug regulations of the Food and Drug Administration (FDA). I have heard too many stories about people becoming enamored of some herbal tea or other elixir only to suffer ill effects from overuse. If herbal medicines are effective, then overdose is possible just as with any other medicine. While indigenous peoples have generations of experience using plant materials in treating illness, many of those touting these substances don't. There are issues of purity, effectiveness, and dosage that need to be carefully addressed. The FDA may have its faults, but it does have a history of dealing effectively with all these issues.
I am not arguing that herbal medicines shouldn't be used; each of us has to weigh the risks and benefits for ourselves. Rather I am contending that we need to learn more about the plant world and its chemistry so that we can use its medicinal riches more effectively. One approach is to read the herbal literature of the past, because there is so much information that has accumulated over the millennia that these substances have been used (DeBear-Paye, 2000). A lovely introduction to this world is an old book, Medicinal Plants and Their History, by Edith Grey Wheelwright (1974; originally published in 1935). She really digs into the old literature and also draws on the strong herb use and gardening tradition of Britain. She presents a very different perspective from the plant hunters of today, the ethnobotanists. In this field, anthropologists, botanists, and physicians are collaborating with indigenous peoples to document the plants they live with and how they use them. They are working in many different parts of the world, as opposed to Wheelwright's narrow European frame of reference. These researchers are obviously walking a fine line between supporting local cultures and exploiting them. There is a great deal at stake here, for some plant substances may one day be developed into drugs worth millions to pharmaceutical companies.
Then there is the ethnobotanical interest in how plants are used as food. This is obviously of anthropological significance, but may also be useful in solving some health problems. Oliver Sacks's (1996) book, The Island of the Colorblind, tells the complicated (and yet to be completely resolved) story of the cluster of neurological diseases called "lytico-bodig" that afflicts the Chamorros, natives of the Pacific island of Guam, though only those born before the 1950s. Some individuals have symptoms similar to Parkinson's disease, others suffer from dementia, and still others from something akin to amylolateral sclerosis (ALS). The Chamorros, particularly those living in rural areas, traditionally ground seeds of the cycad, Cycas circinalis, to make flour. They were aware that the seeds have a toxic coating and washed them carefully, but doctors working among the Chamorros still thought the cycad was the likely source of toxin. They reasoned that younger people weren't afflicted because after World War II there was importation of wheat flour, which was cheap and easily available — no grinding required.
However, there are problems with this hypothesis, as Sacks describes in his book. First, C. circinalis is found on other islands where the disease isn't seen. It could be that the Chamorros have a particular susceptibility to it, but there is also the issue that neurotoxins usually act relatively fast, within a matter of weeks at most, not the decades that seem to be involved in lytico-bodig. For example, people who emigrated from Guam when young developed the disease in their 50s and 60s, even though they hadn't eaten cycad flour for decades. Sacks goes into many details like these and describes what he learned when he traveled around Guam visiting patients with a resident neurologist. The tale he tells has elements of a mystery story but one without a satisfying conclusion. In the end, Sacks wonders if the disease will disappear entirely before its cause is identified — not the worst of endings, but an unsatisfying one.
Since writing this book, Sacks has done more work on the mystery and published a paper with Peter Cox (2002) in Neurology detailing a new hypothesis. This time the culprit is a fruit bat called a flying fox, Pteropus tokudae, which was eaten by Chamorros for special occasions until the populations of these animals diminished sharply in the 1960s, which could explain the freedom from the disease among younger people. The bats feed on cycad seeds and don't seem to be harmed by the toxin, which accumulates in high doses in their muscles. The disappearance of this culinary delight is correlated with the disappearance of lytico-bodig, but those who have been suspicious of other cycad-related hypotheses are suspicious of this one as well. All this is a good reminder that seeking active substances from plants can definitely be a double-edged sword, just as from any other source, including synthetic chemistry labs in pharmaceutical companies.
Although I have dwelt on this cautionary tale, I am hardly arguing that we should not go to plants for novel medicines. Their track record is just too good to ignore them. If nothing else, the wonderful ethnobotanical stories of how plants are used around the world are fascinating. This is yet another area of botany that I've just begun to explore, and I'll only mention one jewel of the ethnobotanical literature here: Gary Paul Nabhan's (1985) Gathering the Desert. This book ranges over much more than just the medicinal uses of plants. Nabhan looks broadly at the Native Americans of the Southwest and the plants they use as food, as tools, as medicines, and for dozens of other reasons. As in several of his other books, he is trying to preserve a way of life that is intricately connected to the plant world — to save the cultures of the people living with these plants, but also to enrich the broader culture. If Native Americans no longer live intimately with plants, their generations-old knowledge will disappear and we will all be poorer — and perhaps less healthy.
Early in the book, Nabhan has a chapter entitled "The Creosote Bush Is Our Drugstore." This plant, called greasewood by the Papago, who use it medicinally, is Larrea tridentata. It's used to relieve coughing, intestinal problems, poor circulation, and even postnasal drip. The FDA has investigated one of its active ingredients, the antioxidant NDGA, but two studies found that it could cause kidney problems, so further research was halted. Those who appreciate the medicinal value of the plant argue that extracting a single chemical and administering it in high doses cannot replicate what complex plant extracts can do. This is an age-old issue dividing the medical community from herbal-medicine advocates, and I am obviously not going to solve the problem here. All I wanted to do in this article is to remind you that botany and medicine have had a long relationship —and one that continues in the 21st century.