31 January 2013

Africa: Ancient Remedies for Modern Diseases

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SABINA graduate Justin Omolo was the first RISE student to earn his PhD, which he completed in December 2011.

In doing so he has traveled an original and creative path, exploring surprising links between the knowledge of traditional healers and the techniques of modern bioinformatics and synthetic chemistry. This journey may have brought him to the threshold of a treatment for HIV/AIDS that is both ancient and brand new.

His scientific education began at the bachelor's level in the early 2000s, when he enrolled in a triple program of chemistry, biology, and education at the University of Dar es Salaam (UDSM) in Tanzania.

After earning his B.S. in 2004, he won a DAAD-NAPRECA Regional Scholarship from Germany in 2005, which allowed him to continue his studies at the chemistry department of University of Botswana in Gaborone, Botswana.

His main interest was in phytochemistry, analyzing plant extracts and looking for active compounds in medicines - especially those used by traditional healers. He began by focusing on a small tree called Ziziphus mucronata, or buffalo thorn, which commonly grows on termite mounds in Tanzania.

Because of its thorns it is often used as a fence; it also bears nutritious, grape-sized fruits, and like other members of the Ziziphus genus, is used by traditional healers to reduce fever, kill pain, and treat various other symptoms.

Traditional healers in Tanzania have been identifying, experimenting with, and using natural products to treat patients for millennia. While modern medicine came to regard the use of such crude extracts as unscientific a century or so ago, patients continued to trust their local healers, both because there were few medical doctors available and because they could not afford the cost of a modern clinic.

In fact, the work of healers is based on a large and enduring truth: Virtually all plants have medicinal qualities because they must produce chemical defenses against pathogens. Early healers learned to "borrow" these defenses to treat the viral, fungal, and bacterial infections of humans, often with great success.

Many plant medicines are extracted from the roots, root bark, and stem bark, the zones where invading pathogens first attack. In these regions, plants can begin excreting their chemical defense within seconds of an attack. So sophisticated is this armamentarium that individual plants may be able to produce hundreds of unique chemicals in their defense, offering curious humans a vast selection of potential medicines we have only begun to analyze.

While Justin was eager to get to the chemical core of Z. mucronata, he also had to do a year of coursework for his masters, leaving him only a year for lab research.

During that year he succeeded in isolating the plant's terpenoids, some of which showed moderate activity against HIV, and found them relatively easy to identify. He also demonstrated strong anti-microbial activity in a group of alkaloids, but when he began the complex task of identifying the specific alkaloid compounds responsible for the activity, progress slowed.

"These alkaloids are much more complex than the terpenoids," he said, "and I didn't have the time to identify them. There were four alkaloids, but if you're not experienced in that area, you can spend a year guessing which the active fractions are. At other times you may be lucky and get it right away." Despite this difficulty, his work was judged favorably and he finished his MSc degree in December 2006.

At that point Justin could not find support for further studies, and instead joined the staff of UDSM in June 2007 as an assistant lecturer. After supporting himself there for several years, in 2009 he heard about the RISE program and was able to secure a SABINA scholarship with the help of Quintino Mgani, a UDSM lecturer and RISE advisor.

Together they developed a plan that would enhance Justin's skills not only in phytochemistry, but also in synthetic chemistry. There were several reasons for pursuing both activities. First, phytochemistry is essential to identify pure compounds that have a desired medical activity.

This begins with harvesting the plant itself, isolating the most active crude fractions, and, through repeated purification steps, isolating the single chemical responsible for the desired activity.

This compound is then examined with an NMR instrument to identify the chemical properties of the molecules. Once the chemical structure is identified it can be produced synthetically and, in theory, developed into a drug that is sold commercially.

Purifying a chemical from whole plants, however, is a cumbersome process. The number of tons of raw plants required to obtain useful amounts of pure chemical can be so large as to jeopardize entire plant populations in the wild. Through the techniques of synthetic chemistry, however, producing an active compound can be done quickly and efficiently from commercially available raw materials.

Fortunately, one of the SABINA faculty advisors, Prof. Charles de Koning of the University of the Witwatersrand in South Africa, is a synthetic chemist who agreed to supervise Justin's work. And Prof. de Koning, in turn, introduced him to a colleague, Dr. Vinesh Maharaj of South Africa's Council on Scientific and Industrial Research (CSIR), who was working closely with traditional healers. These healers lived in the region around Tanga, a city in northeastern Tanzania, where the humid coastal environment supports a treasure trove of biological diversity.

An exciting aspect of Dr. Maharaj's project was that he had found a willingness among both healers and modern doctors to pool their knowledge. This had already given rise to the Tanga AIDS Working Group (TAWG), formed at the height of the Tanzanian AIDS/HIV epidemic around 1990.

The TAWG partnership had grown out of an observation by a German physician, Dr. Elmar Ulrich, who had noticed that many HIV/AIDS patients were visiting both hospitals and traditional healers in their search for help. He decided to try to bring the two groups closer together and perhaps create a mutual referral network.

Dr. Ulrich succeeded in hosting a meeting that was highlighted by the leadership of an 84-year-old healer named Waziri Mrisho. At one point, Mrisho slowly stood up and said he would like to volunteer to treat HIV/AIDS patients with three traditional extracts - within the hospital.

He said that his own grandfather had taught him the value and use of these plant extracts, and that they could alleviate many of the symptoms characteristic of AIDS.

The group agreed, and Mrisho brought the extracts and administered them to in-patients according to his family's guidelines. According to an American scientist who was present, David Scheinman of the University of Texas at Austin, the patients generally experienced improved appetites, weight gain, fewer and less severe opportunistic infections, and better health and well-being. The plant remedies became the hospital's standard HIV/AIDS treatment for patients who preferred herbal medicine, and the success of the program brought support from OXFAM, the World Bank, and USAID.

By the time Justin came into contact with the TAWG, Mrisho had died, a fourth extract had been added, and an additional project had begun - the Tanzania National Medical Group (TNMG).

This group had the goals of identifying the active compounds in the four herbal remedies and then assessing the feasibility of synthesizing them and scaling up production to a commercial level.

Justin began working with the plant extracts at the Council for Scientific and Industrial Research (CSIR) in Pretoria, with support from the Global Research Alliance, of which CSIR is a member. At first he worked on phytochemistry using dried plant samples that were purchased from the healers around Tanga.

As his work became more specialized, he was able to prepare 17 separate fractions that showed antimicrobial activity. He took the most promising of these to the University of Basel in Switzerland, where he tested them for activity against HIV/AIDS, and then to an institute in the Netherlands for further antimicrobial testing.

He then concentrated on those fractions showing highest activity, and continued to purify them until he had isolated the chemical compounds.

When scientists from the lab in Switzerland came to South Africa, they brought some encouraging news. It was already known that the HIV replication cycle begins with the fusion of the virus to the surface of the host cell, and continues with entry into the cell and multiplication of the viruses.

They told Justin that the plant extract operated by inhibiting the HIV virus from fusion with the cell surface. They promised him support in Basel to do a postdoc after completing his PhD studies.

While Justin was doing the second part of his studies at the University of the Witwatersrand with Prof. de Koning, the Swiss emailed him again - but this time the news was disappointing.

His fraction was indeed very active against HIV, they said, but it was also toxic to humans. Justin and his colleagues were puzzled to hear this. In the 2000s, Mr. Scheinman had tested the extract from which the compound was isolated, and found that it is active and not toxic.

The next step for Justin and his advisors is to finalize their testing to resolve any such questions. Then they plan to take the results to the Gates Foundation and other funders for support in synthesizing the compounds.

He is also working with National Institute for Medical Research (NIMR) in Tanzania, attempting to isolate about five grams of each of the three compounds for further testing by a U.S. pharmaceutical firm; as of early 2013, the firm had not been identified. Justin estimates that the phytochemistry for that project alone will require half a ton of plant materials.

He also continues to work with Mr. Scheinman of Texas, a long-time member of TAWG, on all of the complex activities that make up a researcher's life: writing proposals, editing papers, raising funds.

"The hardest part," he confesses, "is to wait for funding. We are ready to synthesize the compounds at the School of Chemistry, University of the Witwatersrand, which will allow production at larger scale than we can do by phytochemistry. But it is expensive, and we need more support."

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