Harvest of Healing

Written references to malaria date as far back as the sixth century BC, but it was less than 150 years ago that scientists discovered its cause: a parasite, of the genus Plasmodium, transmitted to people by female Anopheles mosquitoes. Today the disease affects about 200 million people each year, primarily in large swaths of Africa and Asia, resulting in over 400,000 deaths.

Malaria parasites, in a form known as sporozoites, first infect the liver, then attack red blood cells. Many of malaria’s symptoms—including anemia, chills, fatigue, fever, and muscle pain—stem from the destruction of these cells. Some parasites differentiate into a sexual stage known as gametocytes. When a mosquito ingests blood from an infected person, the gametocytes reproduce inside its body, producing new sporozoites that can begin the infection cycle anew.

Modern medicine’s battle against malaria has been a game of cat and mouse. Starting with quinine, a drug made from the bark of the cinchona tree, a series of antimalarial medications have been rolled out, only to lose their effectiveness as the parasites became resistant to them.

The current frontline drugs date to the late 1960s. At the request of North Vietnam, which was losing more soldiers to malaria than to combat, China assigned a team of scientists, led by Youyou Tu, to comb through records of herbal remedies looking for potential antimalarials. Learning that people had for centuries been treating fever with an infusion made from Artemisia annua, Tu produced extracts from the plant and ultimately isolated a compound that worked against malaria in animal and human trials. Her discovery of artemisinin won her the Nobel Prize for Medicine in 2015.

Today artemisinin, combined with one or two other antimalarial drugs to guard against resistance, is the first-line treatment recommended by the World Health Organization (WHO). But artemisinin combination therapy (ACT) is too expensive for many poor patients, and it is not infrequently in short supply in the areas where it is most needed. More worrisome, resistance to ACT has emerged in Asia, and may be appearing in Africa, as well.

Weathers, a plant biologist, joined WPI in the late 1970s. “One of the things I discovered right away was that, as a plant person, it was hard to get students to work in my lab—particularly undergraduates,” she says. “They thought plants were boring.”

By the 1990s her research revolved around turning plants into living factories for commercially valuable chemicals. She had co-invented a bioreactor, the Mistifier, which used ultrasonic energy to generate a nourishing mist to feed plants through their exposed roots, and was using a microorganism known as Agrobacterium to genetically transform the plants so their roots grew tiny hairs, which increased the surface area from which chemicals could be extracted.

While looking for interesting plants to grow in the reactor, she recalled reading about Artemisia annua and the antimalarial it produces. She thought that might be the hook she needed to lure students looking for research opportunities. “And it worked,” she says. “They were interested because it was an important medical problem, and not just fundamental work.”

Despite the international focus on artemisinin, Weathers found there was a dearth of literature about the organism that makes the drug, a plant more commonly known as sweet wormwood or sweet annie. She and her students quickly expanded that literature by becoming the first team to genetically transform Artemisia annua and to show that artemisinin can be extracted from its roots, potentially paving the way toward a new, more economical way to produce the drug.

“Our focus was on making artemisinin, and lots of it,” she says, “but in retrospect that was absolutely the wrong way to think about it, because malaria is a disease of poor people, and it’s costly to make drugs in a bioreactor.”

In 2015 Weathers and WPI biochemist Kristin Wobbe attended a Gordon Conference on synthetic biology, where the buzz was about a team at UC Berkeley that had inserted the gene for producing artemisinin into the yeast genome.

“We had a lightbulb moment,” Weathers says. “We wondered, what if we could put the gene in an edible plant, and then people could get the drug by eating the plant.” PhD student Patrick Arsenault worked on that challenge for two years, “but in the end,” Weathers says, “it proved to be a monumental task and too technically challenging for our small group.”

In the midst of that project, Weathers completed a sabbatical in the lab of biologist Carole Cramer at Arkansas State University. “It was Carole who wondered, instead of putting the gene in another plant, what would happen if you just ate the leaves of Artemisia?” Weathers recalls. “We thought, people have been making a tea infusion with this plant for 2,000 years, so it must be safe. We did some research and determined that, in fact, it is quite safe to consume.”

That revelation was a turning point. Since then, Weathers and her team have focused on using the Artemisia plant, itself, as a medication. They have bred cultivars that produce high levels of artemisinin, and they have determined how best to grow, harvest, and dry the plant. And they have learned to grind the leaves to produce a fine powder that can be poured into capsules or pressed into tablets. They call this material dried leaf Artemisia, or DLA.

They have also studied the chemistry of those leaves, which are veritable living pharmacies. Like all of the members of the Artemisia genus, Artemisia annua produces a complex mixture of chemicals, including other bioactive compounds like terpenes, flavonoids, and polyphenolic acids, along with essential oils. Some of these compounds have shown antimalarial activity, though they are far less potent than artemisinin.

From a pharmacological viewpoint, the activity of each individual chemical is less important than what happens when they are all ingested together. As Weathers’s research has shown, the synergistic interactions of the ingredients in that phytochemical stew create a therapy that actually surpasses artemisinin and ACT in important ways.

For example, they found that 40 times more artemisinin gets into the bloodstream when it is contained in DLA than when it is administered as a pure drug (pharmacologists call this bioavailability). This may be due, in part, to the fact that the compound dissolves in the plant’s essential oils, which may help it move more readily through the intestinal lining.

Working with Stephen Rich, a molecular parasitologist at the University of Massachusetts Amherst, they showed that DLA reduces bloodborne malaria parasites more completely than does pure artemisinin, which is almost certainly a function of that greater bioavailability, but is also likely due to antimalarial effects of the plant’s other phytochemicals.

In other work, Weathers and Rich fast-forwarded through the evolutionary process that can produce drug-resistance by following parasites through multiple generations of mice that were treated with either DLA or pure artemisinin. With a single dose of artemisinin, resistance appeared after 16 generations; a double dose warded off resistance for another 24 generations. But with DLA-treated parasites, Weathers and Rich stopped the experiment at 49 generations having observed no apparent sign of resistance. Weathers says DLA’s mix of antimalarial compounds—it’s a natural combination therapy, she notes—likely accounts for its resistance to resistance.

Better bioavailability, greater potency against the malaria parasite, and a built-in shield against resistance make DLA a promising candidate for the next frontline antimalarial medication. But there are other reasons Weathers and an international alliance of scientists, doctors, and non-governmental organizations are enthusiastic about Artemisia.

For one, the plant can easily be grown where malaria is prevalent. And the processes involved in transforming it into a drug can become local business. And without the high-end pharmaceutical manufacturing practices needed to extract, purify, and package artemisinin, the cost of DLA will be far less than ACT. In fact, it is a therapy tailormade for the poor populations who most need it.

Lucile Cornet-Vernet, founder of La Maison de l’Artemisia in Paris, goes a step further, promoting Artemisia, in the form of tea infusions, as a home-grown malaria remedy. An orthodontist, she first learned about Artemisia when a friend who contracted a near-fatal case of malaria on a trip to Africa used tea infusions to cure himself.

Today, Cornet-Vernet’s NGO works with agronomists to select Artemisia variants well suited to the local soils and climates, and sets up centers (42 in 20 countries, at last count) to teach people to grow the plant. “Everywhere, we start small,” she says, “with just one person, then it grows exponentially until we have hundreds.”

Like many advocates for Artemisia, she says she is frustrated with major global health organizations, particularly WHO, which continue to promote ACT over Artemisia. “We believe we will succeed, because we know it is effective,” she says, “but we still have a problem, and it is WHO. They have to be convinced.”

Convincing WHO will take good science, she says, and her interest in the science of Artemisia therapy led her to Weathers. Cornet-Vernet and Weathers agree that, as important and groundbreaking as Weathers’s research on DLA has been, it will take more than the accumulation of positive findings to sway the skeptics. “WHO wants to see good, well-controlled clinical trials in peer-reviewed journals before they are even going to think about Artemisia,” Weathers says. “That is our goal, to get those out.”

The results of one such trial was recently published in Phytomedicine, the leading journal on plant-based medicine. It was co-authored by Cornet-Vernet and Weathers, along with an international team that also included Melissa Towler, a postdoctoral researcher at WPI who has been studying Artemisia with Weathers for several years, and Chen Lu, a recent PhD graduate in mathematical sciences.

The study compared the efficacy of tea infusions of Artemisia annua and Artemisis afra to ACT in a group of over 950 malaria patients in the Democratic Republic of Congo. In a nutshell, the Artemisia teas (even those made with A. afra, which produces almost no artemisinin) were much more effective than the current drug in clearing parasites from the blood, and did so faster (and with no apparent side effects).

“The ACTs failed miserably,” Weathers says. “At the end of the treatment period, many of the patients treated with ACTs still had parasites, while virtually none of the patients who’d consumed the tea did. We don’t fully understand why the ACTs did so poorly, but it was very striking.”

Just as significant, unlike the patients who’d received ACT, those who’d consumed the Artemisia tea infusions had no detectable gametocytes in their blood after treatment. A mosquito biting these individuals could not ingest the parasites needed to continue the life cycle, effectively breaking the cycle of infection.

The clinical trial was a milestone, but will it be enough to erase WHO’s reservations? Weathers and Cornet-Vernet aren’t sure, but they want to see more clinical trials done, regardless. In particular, Weathers would like trials focused on DLA, which, she says, may work even better than tea.

But even as the scientific studies continue, support for Artemisia is growing. “A lot of countries in Africa are looking at Artemisia quite seriously,” Weathers says. “I think we may see ministers of health taking this up as an alternative treatment.”

At the same time, the advocacy of Cornet-Vernet and others is gaining notice. Malaria Business, a new Belgian documentary about Artemisia that also features Weathers’s research, was recently shown at the French National Assembly, and favorable articles have appeared in Le Monde and Paris Match, both focused, in part, on Weathers’s findings.

While the global conversation about Artemisia plays out, Weathers will keep her focus where it has always been, on advancing the science. She is particularly interested in exploring other applications for the plant and its collection of phytochemicals. “It’s bioavailable, it gets through to all the organs—it even crosses the blood-brain barrier—and it has antimicrobial activity,” she says. “It could be used to treat lots of things. And it can be grown just about anywhere. I think there could be huge demand for such an inexpensive and versatile therapeutic.”

First published in the WPI Journal, Spring 2019

This article was originally published in the WPI Journal. For the current issue, please visit the WPI Journal website.