Building Brick By Brick

YOU MIGHT MISTAKE Kelly Chibale for a graduate student as, on a sunny day, he crosses the University of Cape Town's (UCT's) picturesque campus to reach the chemistry labs. Sporting cargo pants and a short-sleeved polo shirt and greeting students with a warm smile and a handshake, you would never guess that the medicinal chemist is shouldering the weight of South Africa's drug discovery ambitions.

Chibale, a native of Zambia who after humble beginnings trained at Cambridge University, Scripps Research Institute, and Pfizer, is one of several key people across South Africa who are trying to build momentum for a viable biotech industry in the country.

It's a daunting task. When Chibale arrived in South Africa in 1996, fresh from a two-year fellowship at Scripps, drug discovery research was nonexistent. The pool of chemistry students was small, and although the country had a long history of natural products research, the chemistry culture was ruled by publishing, not patenting. "The typical paradigm was for people to isolate compounds from a plant, determine the chemical structure, and if it wasn't new, they gave up on it," he recalls. If a compound was new, they simply published their results with no consideration for protecting the valuable intellectual property.

Chibale has worked hard to help change that culture. Now chair of drug discovery at UCT's chemistry department, he has over the past decade cobbled together an impressive assortment of grants and partnerships with big pharma firms and nonprofit groups. The relationships have enabled him to bring critical equipment into his labs, to accommodate a large group of students and postdocs, and to gain access to parts of the drug discovery chain not found in South Africa. The result is active research programs in malaria, tuberculosis, HIV, hypertension, and oncology.

But Chibale's students don't necessarily have good career options once they've completed their studies, which means their training may never benefit the country. Indeed, many go abroad to find jobs. Although some of his projects could eventually be spun out into companies, the country has few, if any, experienced biotech entrepreneurs who can take on the task.

Chibale's challenges demonstrate what South Africa is up against as it seeks to create a biotech industry. The country is trying to assemble, piece by piece, the links of the drug development chain. In the process, South African scientists are finding they must overhaul how they think and work.

After a few years of indecisiveness, the key stakeholders—universities, government officials, national labs, and a network of partners—are learning how to collaborate on building the intellectual capacity and infrastructure to move ideas from the lab to the marketplace. They are starting to see the first fruits of their labor: The first viable drug discovery companies are on the ground, and several long-term partnerships have been established.

South Africa's first real push for a biotech industry began in 2001, when the government laid out a plan to shift from a resource-based economy—the country still relies on gold, diamonds, and other metals and minerals—to one based on knowledge.

Biotechnology was one area earmarked for growth. It was a sensible choice for several reasons: The country has traditionally had solid basic science, with academic researchers publishing regularly in international journals. South Africa boasts the third-highest level of biodiversity in the world, and at least a third of its plant life is unique to the country. Given that natural products or their derivatives account for some 60% of marketed drugs, those abundant natural resources could easily be mined for promising molecules. Furthermore, South Africa has a high-quality medical system—women from wealthy nations routinely fly in for a face-lift and safari—and is excellently equipped for clinical trials. Many drug companies are already conducting clinical studies here.

The government also strongly believes that South Africa needs to act against the scourge of infectious diseases afflicting its population. South Africa has more people living with HIV than any other country—about 5.4 million people in 2007, according to World Health Organization estimates. Doctors recently became alarmed at a rapidly growing health threat: people coinfected with HIV and tuberculosis. Yet the country depends on others to discover better and cheaper drugs to treat those diseases.

And South Africans are aware that their country's success—whether measured by the health of its population or by its ability to create a globally competitive industry—is also a success for the continent. Although half of the population of South Africa lives in poverty, its economy still dwarfs that of other sub-Saharan African countries. Progress on the continent tends to start in South Africa and trickle upward.

Given the coincidence of problem and opportunity, the government has made a serious financial commitment to grow a biotech industry that could develop new drugs and diagnostics. Since 2002, South Africa has invested roughly $90 million through Biotechnology Regional Innovation Centers (BRICs), according to Mosibudi Mangena, the country's minister of science and technology. And government-supported organizations, such as the Council for Scientific & Industrial Research (CSIR) and the Medical Research Council, are channeling some of their resources into drug discovery.

BUT TO START an industry from scratch will take more than money to get things up and running. The country faces a steep learning curve.

In the U.S. or Europe, cities and countries that attempt to establish biotech hubs already operate in a scientific, regulatory, and financing environment attuned to the industry. Talent and experience are abundant; their primary hurdle tends to be achieving a critical mass of companies or attracting sufficient funding. Meanwhile, places with rapidly developing pharmaceutical industries, such as India and China, have a long history in drug manufacturing to build from. South Africa, and the African continent more generally, doesn't have a drug industry legacy to serve as the foundation for growth.

"It is challenging because essentially biotechnology is new in South Africa," says Theresa Smit, general manager for biotechnology and health for the country's Department of Science & Technology (DST). "The tendency has always been toward academic-based research. Now, we're trying to drive the innovation side to link that to industry."

To complicate matters, South Africa has a young government that is navigating uncharted waters. Just 15 years past the end of apartheid, the abhorrent system of institutionalized racial segregation, the country itself is quickly evolving. As the government tries to develop the best plan for starting an entire industry, officials are cautious about taking advice from outsiders—even if it is desperately needed.

"Because of our past, there is a strong drive to create things where there is a real cultural identity and feeling of ownership," says Richard Doyle, chief executive officer of the investment firm Vertical Capital Partners. "After what the Europeans have done to us for decades, you can understand we're a little sensitive."

One of the government's first steps was to establish three BRICs—Durban's LifeLab, Cape Town's Cape Biotech Trust, and Pretoria's BioPad. Each is akin to a government-funded venture capital group that pulls ideas from the private sector, academia, and government labs to create companies.

Officials also pushed to create centers of competence, pooling talent from universities and government labs to encourage collaboration and sharing of expertise. Chibale, for example, runs a drug discovery center that aims to train students in synthetic medicinal chemistry and to build in silico, in vitro, and in vivo capabilities. The idea is that "from there, you start forming the links to create a value chain that can lead to an industry," Smit explains.

Seven years after the initial push, the biotech industry is still fragmented. In that time, a few companies have started with investments from the BRICs, but nearly all are focused on medical devices, nutraceuticals, or other areas outside of small-molecule drug discovery. Many have struggled because they lack follow-up resources or a sustainable business plan. Furthermore, the pockets of knowledge along the drug discovery chain generally rest with a single scientist. "We lack critical mass in a lot of areas," Smit acknowledges. "We need to create that succession"—from the skilled academic base to younger scientists.

DST IS STARTING to acknowledge that it will take outside help to build capacity in South Africa. To establish viable companies—the kind that attract investors beyond the government—the country will first need to develop a strong base of scientists skilled in the art of drug discovery. And indeed, the culture of researching in isolation is slowly starting to shift. Cross-continental partnerships with experienced academic and industry scientists are forming, and South African institutions are creating informal partnerships to share expertise.

One of the first collaborations of scale that specifically targets drug discovery is with Atlanta's Emory University. Chemistry professor Dennis C. Liotta, who invented several key HIV drugs, saw that South African postdocs coming through his lab were good organic chemists but lacked experience in translating basic science into potential products. With the help of the South African government, he formed the Drug Discovery Training Program, which brings South African scientists to Emory (C&EN, Sept. 15, 2008, page 23).

Liotta and his partners are evolving the training program, now in its second year, to match the needs of the South African scientists. In 2010, the incoming fellows will likely have the option of spending some or all of their time in industry. Two new partners—pharma giant GlaxoSmithKline and contract research organization Scynexis—are both interested in hosting scientists.

Exchanges like the one with Emory and its partners are important for expanding students' knowledge, but they have serious limitations: When students who train abroad come back to South Africa, they cannot practice what they've learned, Chibale says. More often than not they leave the country again because well-paying jobs in their field don't exist.

Or they don't return at all. Christopher J. Parkinson, group leader for discovery chemistry at the government-run CSIR Biosciences, offers a recent example. A former graduate student who went to Yale University for a postdoc called him last month to say he planned to stay in the U.S. to work at an aroma chemical company. "It's one hell of a balancing act," Parkinson says. "You need to expose people to a few different scientific minds to broaden their perspective, but it's very difficult to compel somebody to come back."

The solution, many South African scientists say, is to create lasting partnerships that allow the research to continue after the fellowship ends.

Acknowledging the problem, Liotta has come up with a potential solution. Emory is now in advanced talks with DST to bring a modern high-throughput-screening center and the related chemistry labs to South Africa. Emory would provide scientific expertise and training, and the facility would fill a missing piece in South Africa's drug discovery capabilities, DST's Smit says. Available to anyone in the country, the center could encourage collaborations between South African institutions, as well as facilitate cross-Atlantic partnerships.

In time, a library of compounds derived from indigenous plants could be developed, creating a national asset that could be mined for internal drug discovery efforts or licensed to fund other projects.

Other organizations also recognize the need for partnerships to build drug development capacity in South Africa. In March, Howard Hughes Medical Institute and the University of KwaZulu-Natal (UKZN) unveiled a far-reaching collaboration that could provide the most substantial on-the-ground training to date.

The organizations are establishing the KwaZulu-Natal Research Institute for Tuberculosis & HIV (K-RITH), a research center dedicated to tackling the HIV/TB coepidemic. To be located at the Nelson R. Mandela School of Medicine, in Durban, the institute will also serve as a training ground for the next generation of South African scientists.

The $30 million facility, funded largely by HHMI but with a substantial contribution from LifeLab and UKZN, will mirror labs at the Albert Einstein School of Medicine, in New York City. Students will have mentors on both sides of the Atlantic and "can just fly in and out and hardly notice when they are in the laboratories whether they are in Durban or in New York," says A. Willem Sturm, dean of Mandela's medical school who will serve as interim director of K-RITH.

For LifeLab, K-RITH is an example of recent efforts to identify areas where an investment will have the greatest impact. The goal is to make the new labs accessible to any researcher in South Africa, including those at companies funded by the BRICs, says Carl Montague, deputy CEO of LifeLab.

The program expands an ongoing collaboration around HIV pathogenesis among three scientists: Harvard University's Bruce D. Walker, Albert Einstein's William R. Jacobs Jr., and UKZN's Salim S. Abdool Karim. HHMI and UKZN are bringing together state-of-the-art science in the U.S. with the real-life experiences in the heart of the HIV/TB epidemic, Karim says. KwaZulu-Natal has one of the highest rates of HIV/TB coinfection; roughly 70% of those infected with TB also suffer from HIV.

The six-floor building will boast two floors of high-level biosafety labs appropriate for TB research. In addition to the researchers already studying HIV and TB at UKZN, the partners expect to add 30 to 40 new scientists. They hope to start building the facility in September and complete it sometime in 2011.

Importantly, as research ramps up, scientists don't need to worry about where their next chunk of money is going to come from. HHMI took a long view of its investment in South Africa, agreeing to provide $4 million in annual funding over the next decade on top of its investment in the facility itself.

That level of funding promises to change scientists' approach, which traditionally has been dictated by whatever was in fashion and guaranteed to win funding, Karim says. "They want us to think long term and tackle the big problems—not be constrained by immediate results."

The HHMI program addresses sustainability, a key issue confronting research organizations across the country. UCT's Chibale has many collaborators, but every program has an expiration date. And even though CSIR is a government institution, its discovery chemistry group gets only about 25% of its funding directly from the government. The rest comes from competitive or contractual funding, which, as any academic researcher knows, can quickly dry up.

To build expertise in the country, others are adding their own twist to a traditional financial model. The Medical Research Council has established licensing agreements with a big pharma firm for several small-molecule diabetes drugs. On the surface, the deal looks typical—it divvies up duties and includes the standard milestone and royalty payments. But MRC also made sure provisions were embedded to help buttress South African science, says Petro Terblanche, executive director of MRC's technology and business development directorate.

The deal calls for technology transfer to South Africa and includes capital equipment provisions that have enabled MRC to build a facility in Cape Town for diabetes research. Scientists can now probe more deeply into the mechanism of action of the disease and then feed that information into MRC's drug discovery programs.

OTHER SCIENTISTS are working with South Africa's existing resources, scant as they may be, to pull drug candidates out of the lab. CSIR was restructured in late 2005 to better align its research activities to its mandate—improving the quality of life for South Africans.

"We decided to push a little bit harder in our human health focus, specifically with diseases that were problematic in South Africa," CSIR's Parkinson explains.

A drug discovery group was formed, but it took several years to overhaul its research approach, which previously focused primarily on process chemistry. Some scientists had to be retrained and others hired, but the effort has resulted in a team that uses multiple approaches to discover and design drug candidates.

In developing the discovery chemistry group, Parkinson found partners within South Africa to provide expertise that doesn't exist in CSIR. His group has a deal with the University of Pretoria Biomedical Research Center to gain access to in vivo studies, and the University of the North West's Potchefstroom campus provides formulation services.

With funding from LifeLab, CSIR has also helped spin off a company that intends to address the HIV epidemic in South Africa. Currently, no intermediates or active pharmaceutical ingredients for antiretroviral drugs are produced locally. Based on biocatalysis technology, Arvir Technologies was launched to enable low-cost production of β-thymidine, a key intermediate in several HIV molecules.

Financial backing from LifeLab and BioPad allowed Emory's Liotta and colleagues to start a company in hopes of creating jobs and building new skills in South Africa. iThemba Pharmaceuticals is a contract research firm offering medicinal chemistry, custom synthesis, and scale-up services. It expects that its contract work will eventually fund its own drug discovery projects on underserved diseases.

The company was launched in March with a staff of seven chemists and lab space for many more. iThemba's management includes two former drug industry executives who moved to South Africa for the opportunity. Rebanta Bandyopadhyay, the chief scientific officer, previously worked at Pfizer and Dr. Reddy's Laboratories, and Chris Edlin, the head of chemistry, had been at GlaxoSmithKline and Roche.

MANY HOPE that iThemba will be just the beginning for South Africa. "It only takes one or two noticeable successes, and it could all take off," CSIR's Parkinson says.

At the official launch of iThemba in Johannesburg, Science Minister Mangena was blunt about the need for some successes in South Africa. He reminded the audience that malaria, TB, and HIV have wreaked havoc across the continent and can be considered no less than "genocide by disease."

"We definitely need the help that iThemba seeks to provide," Mangena added. "South Africa is the most highly developed country in Africa, and most of the continent looks to us to show the way forward."

Although the challenges in South Africa are plentiful, most people involved with trying to develop a biotech industry stress that progress has been made. "Ten years ago, there were no BRICs, no innovation funds, no tech transfer offices at universities," Vertical's Doyle notes. "We're really a system that has come a long way."

That system continues to evolve. The government is now establishing the Technology Innovation Agency, which will bring all the BRICs under one roof. The one-stop shop will benefit entrepreneurs seeking funding and help the agency better focus its investment activities.

Government officials are also gaining a better understanding of what the most critical gaps are. As they formulate the next stage of the national biotechnology plan, DST and other agencies are conducting an audit of the capacity, equipment, and technology that exist in the country, DST's Smit says.

Once officials know where the real strengths are, they can start considering how best to bridge the gaps. "Do we try and build competence or create partnerships with other countries or institutes that can help us?" Smit asks. "We need to try to not do everything, but focus on the things where we can and should be successful."

And the culture of working in isolation is starting to change. The programs launched by Emory, HHMI, and other institutions are both encouraging long-term collaborations and building scientific skills across the drug development value chain.

"We are such a small scientific community, and yet if we continue working each one for themselves, it's not going to amount to anything," UCT's Chibale says. "But if we pool our resources together in partnership, I think we can make a difference. And this country has to succeed. This country cannot fail for the sake of the continent."