In search of new medicines from plants

Plants have been used as medicine since before the emergence of our species, by early hominids, non-human primates, and even other animals. Homo sapiens has taken this natural apothecary to another level of organization and scale, with perhaps 40% of modern medicines being derived in some form from plants. Our ancestors discovered the medicinal effects of plants by accident, trial and error, and/or learning from effects of similar plants and then experimented with the optimal methods of extraction, combination and application. Bitter plants, for example, were sought after by shaman in the Amazonian rain forests because of previous experience of beneficial effects of other bitter plants (due to the presence of alkaloids). An extraordinary wealth of knowledge in the medicinal properties of plants has been accrued by generations of shamans and their pupils, and much of it tragically has been lost due to the combination of  destruction of indigenous peoples and their cultures,  the lack of a written record of many traditional medicine approaches (many cultures transmitted information solely via oral tradition) and loss of the medicinal plants’ habitat due to logging, farming, expansion of towns and cities, and more recently climate change. 

Fire damage and regrowth in Santa Monica Mountains National Recreation Area. Photo credit: Geoff Abbott.
There are, however, protected places where plants can for now thrive, and furthermore many written records (ranging from patchy to more complete) do exist for the culture and medicine practices of some indigenous peoples, often compiled by anthropologists and ethnobotanists who strove to record or preserve indigenous culture.
Studying herbs and other plants available in local supermarkets and nurseries has led my lab to find potassium channel-mediated anticonvulsant, vasorelaxant and ataxia therapeutic actions in plant metabolites. In all the above cases we were guided by indigenous folk medicine approaches, and also by decades of studying  in the lab the physiology and pathobiology of potassium channels, which are enormously influential in human physiology and disease, and frustratingly underused drug targets (something we hope to address).  More recently, as part of a collaboration, a compound we previously found to activate Kv7.3 and Kv7.5 potassium channels was discovered to stop cocaine-seeking behavior in mice. 

Collecting plants in the wild
While these projects remain ongoing and productive, we have also for the past few years ventured into the field to collect plants under permit from protected wild spaces in the US National Parks and University of California Reserve systems, with an agnostic collection approach that  generally only requires that we identify the species we collect and avoid protected plant species, i.e., we do not actively seek out plants with a previously known medicinal plant history, and for most trips are permitted to collect samples from any non-protected plants. While in many disciplines fieldwork is of course fundamental and a normal and common activity (ecology, archeology, paleontology, to name but a few), it is less common in biomedical research. Our first foray into this approach led to an initial report describing a 40-plant pilot study from species collected with the help and guidance of the Redwood Creek Vegetation Team of the National Park Service; most recently, the results of our first full-scale screen primarily from plants we collected in the wild have also been published, uncovering molecular mechanisms underlying analgesic and anti-inflammatory activities of folk medicine staples including witch hazel and fireweed. 

Results of screening 1,444 plant extracts against two potassium channels. A, screen; B, species from boxed region in A. From Manville, Yoshimura et al., 2024.
In our collecting approach we sample only the leafy aerial parts, and avoid taking tree bark or other sampling techniques that would imperil the plant from which we sample; we only sample plants that are abundant in the locale from which we are collecting.

Dr. Rian Manville collecting plants with the author pre-dawn on Santa Rosa Island, CA. Photo credit: Geoff Abbott.
In this manner we have compiled a still-expanding library of 2000+ plant extracts from a variety of habitats and environments – deserts, coastal and inland chaparral and scrubland, mountains, redwood, pine and deciduous forests, and beaches and surrounding areas in California and the US Virgin Islands.
 
The unique environment of a salt pond in the USVI. Photo credit: Geoff Abbott.

The tangible and intangible benefits of field trips
Stepping away from the computer and the electrophysiology rig and into the field brings an entirely new perspective and appreciation for the plants we collect.  It also reminds us of the challenges and joys posed by the habitats in which they grow and are/were collected for food and medicine by indigenous populations. As biologists, even in biomedical research, we should retain our connection with the natural environment whenever possible. In an era in which almost everything we need in the lab (and in our lives) can be ordered and delivered to our door, we have traded that connection for the convenience it brings, by necessity in most cases (think of behavioral or pharmacological studies using wild-caught mice, or having to extract restriction enzymes from their original bacterial source for each time we wish to cut DNA, for example).  In cases where fieldwork can be conducted sustainably and bring added scientific value, however, it can rewardingly reconnect us to the “bio” in biomedical research, while also offering further arguments in favor of protecting natural habitats, and understanding and addressing climate change. 

View in the Mojave desert on a plant collecting field trip. Photo credit: Geoff Abbott
Beyond the spiritual and philosophical benefits derived from sustainably sourcing plants from their natural habitat, there are other advantages to this approach. Even though we do not plan our collecting around known medicinal plants, these connections often emerge in our hits, which can guide the molecular mechanistic or preclinical studies we conduct when we discover the active compounds involved. Reciprocally, this provides a gratifying molecular rationale and increased understanding of the original folk medicine in cases where the plant was used in this way. Sometimes we discover potentially beneficial in vitro activity in plant extracts for which there is no written record of medicinal use. In some cases this can be explained by other, counteracting toxic effects that might emerge in preclinical studies; in other cases, it is possible that the benefits were not previously uncovered, or else for the anthropological reasons outlined above, all prior written records or oral tradition of their use and benefits have been lost. 

Beach base camp while plant collecting on Santa Rosa Island, CA. Photo credit: Geoff Abbott.
Furthermore, the active compounds we discover in plants have been “pre-approved” for cellular use; in other words, they have existed in plant cells for thousands or millions of years and the plant cells and whole organism can function in and tolerate their presence. In many but not all cases, they have been tolerated by animals and humans that consume the plants. This does not mean they are guaranteed “safe” by any means and indeed some of the most interesting compounds from plants can be lethal to humans depending on the dose and nature of their application. Yet, chemically, the plant compounds we study are at least prima facie compatible with biological systems, providing one advantage of the “blind watchmaker” versus vast libraries constructed primarily from synthetic compounds, or virtual libraries created by artificial intelligence – although their numbers are difficult to argue with!    

The author on a coastal redwood forest plant collection trip. Photo credit: Bo Abbott.

Summary: the future and the past
Science and discovery tend to move forward when multiple approaches are taken, and when investigators from one field apply their knowledge to a different one, bringing diverse perspectives. While we look to the future in eager anticipation of the transformation of drug discovery that AI promises, we believe it is also appropriate to look to the past and continue to learn from the natural world and the discoveries made by shamans and medicine men and women – the original pharmaceutical startup pioneers.