In April of 2014, Kerstin Andrae-Marobela stood in a forest along the border of northern Botswana, watching as Sundana Simonambanga, clad in blue jeans and a loose plaid shirt, scraped a piece of light gray bark off the so-called 'fever berry' tree. The bark was a key ingredient in a three-step herbal treatment for HIV that Simonambanga, a local healer, told her he had been administering to infected men and women.
The first step of the process involves taking what's known as mororwe, derived from the roots of the African laburnum tree, which grows drooping branches decked out with bright yellow flowers. Simonambanga makes a powder from the dried roots and advises patients to prepare a bitter tea with it each morning for three weeks. The second three-week phase of the process involves an even more bitter infusion, known as mofofo, made from the black plum tree, or _Vitex doniana. _Both the mororwe and mofofo stages are designed to improve the physical stamina of patients and strengthen them for the third and riskiest part of the treatment: a single dose of what's called mukungulu.
Andrae-Marobela, a native of Germany with blue eyes and a short crop of salt-and-pepper hair, is a researcher with a background in human biology. She had driven more than eight hours to meet with Simonambanga. She'd come to observe, and later analyze the effectiveness of this three-step treatment in her lab 500 miles south at the University of Botswana, in the capitol of Gaborone.
When she'd made it back to her lab, she dried the bark and then ground it into a fine gray powder. Simonambanga told her that before administering it he stirs this powder into a bubbling porridge made from ground corn, and serves it in a teacup. Simonambanga, who originally hails from a small village in Zambia, also told Andrae-Marobela that patients stay in a tent in his yard while he observes any symptoms of nausea, diarrhea, or severe sweating. Beforehand, he consults with patients to learn more about their HIV status, and counsels them to continue visiting clinics where doctors can track immune-cell counts, and which antiretroviral medications they're receiving.
Mukungulu—the third and riskiest step in this process—is intended to help patients lower levels of the HIV virus in the body. It's just one of many herbal remedies used without government oversight in traditional healing in Botswana. It's also one of few that have shown hints of potency in recent cell experiments. One study at the University of Botswana, published last summer, highlights how these traditional methods could be scrutinized to develop new, medically condoned components of HIV treatment, both in Africa and elsewhere.
Inklings of mukungulu's antiretroviral potential emerged recently when Andrae-Marobela began testing the medicinal plants that healers brought her. The study, which she and her collaborators published over the summer in the Journal of Ethnopharmacology_, _describes the anti-HIV activity of mukungulu in preliminary tests of human cells. Four years ago, the team also studied the antiretroviral activity of mororwe.
So far, Andrae-Marobela's team has only examined the treatment in a preliminary test using a subset of human T-cells that have been manipulated to stay alive outside of the body for lab experiments and produce fluorescent proteins when infected by HIV. Exposing the cells to mororwe and mofofo caused a drop in HIV replication, but it's unclear whether the doses they used would be tenable in humans. Mukungulu, however, has seemed more promising: Low concentrations of the remedy caused a 45 percent inhibition of HIV replication in the cells examined.
The decades-long quest to identify real and truly beneficial medicines that thwart the HIV virus has relied heavily on synthesizing drugs in the lab with complicated chemistry, and testing them there. But a small subset of scientists, with the backing of venerable funders such as the US National Institutes of Health, are taking a wider look at the potential of natural compounds as future HIV drugs. Even fewer study traditional medicines actually used to treat HIV/AIDS, which makes Andrae-Marobela's work in Botswana particularly remarkable.
Andrae-Marobela's efforts to understand the medicines used by Simonambanga began almost a decade ago, when his mentor, Amos Namushe, a stout man fond of wearing white ankle-length tunics, attended a science workshop that she offered to local healers.
It was only a couple years earlier that Andrae-Marobela had arrived in Botswana. Until then, she'd spent most of her career working on genetically engineering mice to help scientists study muscle disorders and diseases such as Alzheimer's. Not long after moving to Botswana, she read a report from the World Health Organization about the need to study traditional medicines and reached out to local healers.
Although she hadn't grown up in Botswana, she was no stranger to scouring the local environment for herbal remedies. While growing up in Germany, she'd often go on walks in the region near the Rhine River with her grandfather, who pointed out many of the curative plants along the path. "That knowledge is not common anymore," she says, adding that the herbs he showed her are "mostly forgotten about these days."
To build connections and trust with healers in Botswana, Andrae-Marobela started hosting workshops, inviting them to bring their favorite medicinal plants. In these sessions, she guided them on how grind up the plants and make extracts to test whether or not the plants had antioxidant proprieties or acted against bacteria or fungi. Namushe attended such a workshop in December 2007, but didn't bring any mukungulu that day. It was only three years later that he revealed mukungulu to her as the third and final step in the HIV treatment that he had already given to at least 60 men and women, she says.
Botswana has one of the highest rates of HIV prevalence in Sub-Saharan Africa, the region of the world hardest hit by the HIV/AIDS epidemic. More than 22 percent of adults in the country are infected with the virus, according to 2016 estimates published by UNAIDS. Although HIV transmission is in decline in Botswana and the availability of effective antiretrovirals (ARVs) has generally improved, certain challenges linger. Access to such drugs is uneven, and although no doctor would question their necessity, some of these life-saving medicines carry possible long-term side effects such as heart disease and nerve pain. There's also worry over the emergence of drug-resistant HIV strains. Andrae-Marobela sees a need to find new compounds that could be added to the cocktails of drugs used to fight the virus.
That's where local healers like Namushe come in. They were treating symptoms such as fatigue, loss of appetite, and skin infections in patients with HIV long before the cause of illness was identified, or researchers had discovered antiretrovirals that worked against the disease. Traditional medicines typically target fungal or bacterial infections, which in the case of HIV can take hold because of the way the virus compromises the immune system, Andrae-Marobela explains. But it might be that some of these medicines also help the immune system fight HIV. This is something she is trying to figure out.
The challenge that scientists like Andrae-Marobela face is persuading the larger scientific community to study some of the natural remedies used by healers. "We have the tools to characterize and investigate phenomena," she says. "And the healers have data that is based on decades-long observations of patients. For us, that's valuable."
Efforts by researchers in Botswana to work with healers are part of a long history to tap into indigenous knowledge to help in the battle against AIDS, which has been linked to the deaths of 35 million people since the pandemic began. As far back as 1989—well before a working arsenal of antiretrovirals for HIV was developed—the World Health Organization called on researchers to assess the usefulness of traditional medicines against the virus. In the intervening years, scientists have studied a range of natural remedies, including a substance called cortistatin A, isolated from marine sponges, as well as the somewhat toxic compound coumarin, found in high concentrations of the tonka bean and in other natural sources.
It's rare for these compounds to reach the stage of human testing against HIV. Researchers at the University of California, San Francisco, for example, had planned a pilot study in nine HIV-infected individuals to analyze the activity of a tea made from the traditional Chinese medicinal herb known as kansui. However, the trial was recently put on hold—before they had even enrolled participants—so that the scientists could first perform a trial of kansui in macaque monkeys to assess its safety.
The general lack of evidence to support the benefits of herbal remedies has not dissuaded people in Botswana from seeking them out. A seminal report published in 2001 from the World Health Organization noted that the the country's traditional healers, known locally as the 'dingaka,' were seen as performing a significant role, especially in rural areas. The same report from the agency estimated that there were around 3,100 traditional medicine practitioners in Botswana. This type of medicine, in fact, is the primary form of health care that up to 80 percent of people in Africa seek out.
But medicines that are popular are not necessarily effective. The reality is that homespun and traditional HIV treatments have a checkered history, particularly in regions of Africa where high rates of infection exist alongside strong faith in folk remedies. The vitamin campaigner Matthias Rath created waves in South Africa when he asserted that vitamins treat AIDS and that antiretrovirals were toxic. In another example, Zeblon Gwala, who worked many years as a long-haul truck driver before opening a clinic, claimed that his secret concoction called ubhejane could treat the disease. The promotion of ideas unsupported by the scientific consensus "did huge damage," says Nathan Geffen, author of _Debunking Delusions: The Inside Story of the Treatment Action Campaig_n, a book about the fight against AIDS denialism.
Geffen notes that these peddlers of alternative treatments "had the support of some senior people in government" in South Africa during the presidency of Thabo Mbeki around a decade ago: "Thank goodness this is for the most part behind us and has no serious political support anymore," he says. The Mbeki government's resistance to facilitating the distribution of antiretroviral drugs caused 330,000 people to die unnecessarily in South Africa between 2000 and 2005, according to estimates by public health researchers.
South Africa has tried to formalize the role of traditional healers by creating a pathway by which they can be licensed, passing a Traditional Health Practitioners Act in 2007, although the legislation is not yet fully implemented. In contrast, traditional medicine is not formally sanctioned in Botswana, making it legally risky to perform there. If a patient dies under the care of a healer in Botswana, the practitioner lacks the protection of a professional license and can be accused of murder.
Given the legal risk of being a healer in Botswana, Andrae-Marobela and her scientific collaborators had to build the trust of healers they ultimately teamed up with. One of her scientific collaborators, the molecular biologist Ian Tietjen of the Simon Fraser University in Burnaby, Canada, notes that healers in Botswana are wary of foreign scientists given the history of colonialism. "The feeling of traditional healers is, 'Are you taking me seriously?'" Tietjen says. "In the West, when we hear about a lot of holistic medicine or healers, there's this stereotype of people banging bones and yelling for rain. There are these stereotypes that healers feel are put on to them. They want to be taken seriously."
Tietjen sees a lot of value in building these relationships. His belief that a plant-derived medicine could work against a major global disease is anything but farfetched: To take one example, the widely used drug for malaria called artemisinin, which is derived from the sweet wormwood plant, was discovered by in the 1970s by the scientist Youyou Tu. She learned how to successfully extract this compound by studying ancient texts of traditional Chinese medicine, an achievement that earned her a Nobel Prize last year.
That said, the interactions between conventional and indigenous drugs remain unpredictable. And the early cell study from Andrae-Marobela and her group suggested that the traditional medicines don't necessarily act synergistically with approved drugs, as one might hope: When the team exposed human cells to antiretrovirals in tandem with mororwe, mofofo and mukungulu, these plant extracts didn't do anything to make the drugs more effective than they already are.
The unpredictability of herbal compounds could be the catch that dooms traditional medicines—at least until they're studied more closely. Stopping antiretrovirals is reckless and almost certainly fatal, and mixing them with indigenous remedies could cause toxic interactions between treatments.
That's what worries Ruth Brack-Werner, a virologist at the Helmholtz Zentrum München in Germany who is screening more than 10,000 natural compounds against HIV. "While they may not interfere with the antiviral activities of standard medicines, they don't appear to display antiviral activity in the presence of these medicines either," she says.
There's a long process ahead as science works to understand whether these compounds might be useful. The effects of herbal extracts still need to be examined in cells taken directly from patients, rather than just an engineered cell line, Brack-Werner says, adding that preliminary findings on the potential of natural extracts to treat HIV also spur misguided attempts to obtain such compounds. "I get a lot of calls," she says, regarding people's reaction to her own work on different natural compounds. "They ask, 'How much of this can I take?'"
Brack-Werner says that there is far from enough evidence, such as clinical trials, available to recommend the natural compounds used in the Botswana study. "Natural compounds are unfortunately always thought to be safe for some reason," she says. "Really that's only an assumption. My worry is that people will indiscriminately start taking herbal stuff because they perceive it to be safer, and this is not necessarily true. The most poisonous compounds we have are from nature." She adds that she is "much alarmed" by the healers' statement that an overdose of mukungulu can be potentially fatal.
Andrae-Marobela says the potentially lethal nature of mukungulu was information passed through the generations from Namushe's mentor to him. She stresses that this type of information transmitted this way: "Usually how they learn is from earlier generations, and maybe previously there was an incident when somebody overdosed and did die."
The goal for scientists such as Andrae-Marobela is to carefully evaluate natural compounds that might help complement or boost existing ARVs. But more cell experiments are needed to understand if mukungulu really has an effect, and if so, there are years of animal tests to determine its safety before it would ever be studied in humans in a clinical trial. "It's way too early to test this for a larger audience," Tietjen says. He echoes other scientists in saying that the herbal remedies are no replacement for ARVs: "Even the healers say to stay on your ARVs."
Tietjen and Andrae-Marobela know one thing for certain, though: They want the traditional healers they work with to get credit for their participation in the ongoing research. In the recent paper they published, they made sure that Simonambanga and his mentor, Amos Namushe, were listed as coauthors on the study.
In fact, when Andrae-Marobela had the results from the cell tests of mukungulu in hand, she drove ten hours north from her lab in Gaborone, Botswana, to the country's border with Zambia to tell Simonambanga about the findings in person. Simonambanga, who was spending time in his home village just across the border in Zambia, didn't have a visa at the time to enter Botswana. Instead, he took the ferry across so they could meet on a small strip of land by the river—just before the passport checkpoint. "We met in a no man's land," Andrae-Marobela says. "There was a tree. We sat under it, and then we went through the figures together."
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