Grand Challenges project ready to enter its next phase

6 May 2009

Tatum Anderson

Source: TropIKA.net

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Michael Gottlieb.

The Grand Challenges in Global Health project, a research funding initiative that is worth almost half a billion dollars – is at a crossroads as the Bill & Melinda Gates Foundation decides its future.

Next year, funding for 43 projects that received US$436m in grants back in 2005, will finish. The grants were awarded to projects seeking to solve 14 of the greatest scientific hurdles in global health – dubbed the Grand Challenges – that might lead to advances in combating diseases of the developing world.

The Foundation has remained tight-lipped about whether it plans to renew all 43 projects, award new ones, and even whether the Grand Challenges themselves will be revised. It is understood that meetings to discuss the next steps took place in Seattle at the end of April. What the future strategy will mean for a key partner in the Grand Challenges initiative – the Foundation for the National Institutes for Health (FNIH) – is also unclear.

One of FNIH’s core roles is to link with commercial, philanthropic and other academic institutions. It has been at the heart of the Grand Challenges project since the start and was responsible for managing the process that led to the whittling down of 1000 proposals from scientists around the world to a wish list of 14 specific problems. These include goals to improve childhood vaccines (so that they do not require refrigeration, needles or administering in multiple doses) prevention of drug resistance and improved vector control.

The Foundation was also responsible for managing detailed grant applications, in conjunction with a scientific panel made up of the great and good of the scientific establishment including: Julio Frenk, then Mexico’s health minister, Nirmal Kumar Ganguly of the Indian Council for Medical Research, and several NIH experts. Over 400 applications led eventually to 43 funded projects.

Michael Gottlieb: “Translating innovative discoveries into public health strategies”

The challenges require scientists to change the way they approach their work says Michael Gottlieb, who heads the Grand Challenges project at the Foundation for the NIH. Most generally work towards milestones such as ratifying a hypothesis. The Grand Challenges process has been about different milestones – products: “The projects required that the research was on a path towards translating the innovative discoveries into developing public health strategies for the developing world”.

Today, FNIH oversees 21 of the projects that were eventually chosen. The Gates Foundation looks after most of the rest, with the Wellcome Trust and the Canadian Institutes of Health Research (CIHR) also jointly monitoring a few.

The projects are wide-ranging. Some are basic research, such as understanding the mechanisms underlying latent tuberculosis. Others are more product-development based. One team is developing insect repellents that work by disrupting the mosquito’s ability to detect human victims by ‘smelling’ human sweat and the carbon dioxide present in breath. Another is creating a credit-card-sized diagnostic kit that can test blood for several infections, nutritional status and HIV illnesses in one go.

Several of the funded projects are highly contentious because they look at genetically-modifying food or vectors. Researchers in Australia plan to infect dengue mosquitoes with a bacterial parasite that kills them before they are old enough to transmit the virus. The parasite is then inherited and passed down to subsequent generations.

The most advanced of the projects overseen by Gottlieb’s team is a dry-powder version of a measles vaccine that can be inhaled through a disposable plastic device. Phase I clinical trials are scheduled to start this year.

Addressing neglected areas

Dr Javier Guzman, a director of research at the George Institute which has studied gaps in R&D, says that the Grand Challenges – and another Gates funding initiative in which the Foundation for the NIH is not involved, Grand Challenges Explorations – is seen to be addressing many areas that have long been neglected.

They are massive projects and run on a huge scale. When Bill Gates first announced the main Grand Challenges project, it was a $200-million fund. But by the time the awards were made in June 2005, this had swelled to $450 million, and the Wellcome Trust and CIHR added $27.1 million and $4.5 million respectively. Applications were so good, the money available to fund them was doubled says Gottlieb.

Michael Gottlieb is undaunted about the enormous sums involved; he is used to managing large-scale, big-ticket projects, especially for developing world diseases. He joined the Foundation from another part of NIH, the National Institute of Allergy and Infectious Diseases (NIAID), where he was chief of the Parasitology and International Programs Branch. There he had managed research grants that led to major collaborations in sequencing the genomes of protozoan parasites, including Plasmodium falciparum.

Well-versed in the needs of developing countries, he had been responsible for helping to establish the Malaria Research and Reference Reagent Resource Center (MR4) when at the NIAID. MR4 provides vital reagents including parasites and antibiotics to hundreds of researchers working on malaria in developing countries and elsewhere. MR4 is part of the Multilateral Initiative on Malaria (MIM), the federation of agencies involved in malaria research, control, and development assistance which Gottlieb currently chairs. (Gottlieb is now also involved in a project with similar aims to MR4. This time it is related to bioinformatics. NIAID’s PlasmoDB.org website hosts genomic and proteomic data for different species of malaria parasite).

Critics

But even though big money is involved, critics say that the Grand Challenges project risks having a limited effect.

Firstly, there are concerns that biomedical and technological solutions are being viewed as silver bullets. Anne-Emmanuelle Birn, an associate professor, Canada Research Chair in International Health at the University of Toronto reckons global health problems will only be fixed if there are accompanying social and economic measures too. “I would certainly reiterate the importance of integrating social, political and technical approaches to enhancing overall human health and diminishing inequities within and across populations,” she told TropIKA.net.

Focusing on vaccines is great, says Birn, but not if the health systems that deliver them are absent. Similarly, single-dose, needle-free vaccines might be cost-effective, but risk reducing the number of times mothers bring their babies to clinics that monitor healthy growth and development, she explains. And effective vaccines against diarrhoeal disease could perhaps delay the provision of clean water and sanitation to then half the world’s population without access. (Activists say goals related to clean water and sanitation are already more than 10 years off target). Addressing HIV and multiple drug-resistant tuberculosis is also commendable, but not if the improvements in the conditions that exacerbate them persist; social conditions, poor nutrition, overcrowding and unsanitary housing, economic insecurity and inadequate healthcare services.

And relying on new GM crops is not enough to solve the problem of malnutrition, which often happens in some of the most fertile areas on earth. Amartya Sen, the Nobel-prize-winning economist, who has demonstrated that malnutrition and famine are not caused by technical roadblocks but rather by political and economic factors, she adds.

Secondly, the solutions may end up being too expensive for the people at whom they are aimed. Some tools might require immense marketing spend, as well as development costs. Considerable resources might be needed to allay public fears before genetically modified insects can be set free, for instance.

And finally, focusing on new technologies rather than making sure existing cheap ones are more widely available could also be a mistake. One team, led by Jef L Leroy at the Mexican National Institute of Public Health (Instituto Nacional de Salud Publica) in 2007, looked at what proportion of research on childhood mortality was directed towards better medical technology – including Grand Challenges grants. Their study (1) found that a staggering 97% of the grants were for developing new technologies, which might end up reducing child mortality by over a fifth. However, the team suggested if existing technologies were fully used, that reduction might be as much as three times larger.

Pragmatism

Gottlieb agrees that the Grand Challenges ideas could end up being expensive but hopes that Gates funding will get over the more expensive hurdles and make the new tools attractive to private companies that could eventually bring them to market.

And, several products might feed into future or existing product development partnerships, he adds. Today such non-profit organisations – including Aeras, FIND and MMV – share the cost and expertise in bringing drugs, diagnostics and vaccines to market with the private sector.

Those who do set some store by new biomedical solutions point out that the Grand Challenges is funding areas that were previously in desperate need of funds. However, there are many other areas that have not yet received help under the initiative and it is not yet clear whether the Foundation will take account of areas the initiative missed last time around. For example, diseases such as lymphatic filariasis and river blindness (onchocerciasis) have yet to receive attention. Non-communicable diseases are also missing from the Grand Challenges list.

It is particularly surprising that kinetoplastid infections, which cause the three diseases sleeping sickness, Chagas disease and leishmaniasis, are missing from the Grand Challenges list of projects, given Gottlieb’s background as an associate professor in the Department of Immunology and Infectious Diseases at Johns Hopkins University School of Hygiene and Public Health, where he focused on the biology and biochemistry of these diseases.

Gottlieb is pragmatic. Though large, the resources are limited, not all the teams that applied for funding could have been accepted. “I would have loved to have seen [inclusion of these diseases],” he says. “But, we at FNIH are pleased with the opportunity to be working with a group of dedicated investigators, mostly academics, who have really intended to change the way they conduct their approach to the project in order to solve the challenge and to have an impact for those most in need in the developing world.”

A key area that needs more attention in future is the intersection between vaccines and undernutrition he says. The fact is that many vaccines that work effectively in the developed world do not perform so well in developing countries. The belief is that some vaccines become ineffective if the children are malnourished. Gottlieb and NIH’s Fogarty International Center are therefore about to embark on the MAL-ED project (Interactions of Malnutrition & Enteric Infections) that will focus specifically on under-nutrition and bacterial and viral infections of the gastrointestinal tract. The project is separate from Grand Challenges initiative, although funded by Gates, and will follow 1600 children across several continents from birth for the next few years. “One of the goals of the project is to identify the factors, including nutritional and changes in gut physiology, that explain the observed difficulties in immunizing children in the developing world,” Gottlieb says.

Decisions made as a result of last week’s meeting Seattle will form the beginning of the next phase of the Grand Challenges for Global Health Initiative.

What is clear is that the person who first proposed the idea of grand challenges that a community can solve – the German mathematician David Hilbert (2) – has guided research in mathematics for a hundred years. Hopefully, solutions to the challenges for public health will not take so long to find.

Key questions

Briefly, what are the priority concerns of your organisation?

To fund the development of tools to prevent, treat and cure diseases of the developing world and improve nutrition.
And, more precisely, what goals have you set?

To improve childhood vaccines:
GC#1: Create effective single-dose vaccines that can be used soon after birth
GC#2: Prepare vaccines that do not require refrigeration
GC#3: Develop needle-free delivery systems for vaccines.

To create new vaccines:
GC#4: Devise reliable tests in model systems to evaluate live attenuated vaccines
GC#5: Solve how to design antigens for effective, protective immunity
GC#6: Learn which immunological responses provide protective immunity.

To control insects that transmit agents of disease:
GC#7: Develop a genetic strategy to deplete or incapacitate a disease-transmitting insect population;]
GC#8: Develop a chemical strategy to deplete or incapacitate a disease-transmitting insect population.

To improve nutrition to promote health:
GC#9: Create a full range of optimal bioavailable nutrients in a single staple plant species.

To improve drug treatment of infectious diseases:
GC#10: Discover drugs and delivery systems that minimize the likelihood of drug resistant micro-organisms.

To cure latent and chronic infections:
GC#11: Create therapies that can cure latent infections
GC#12: Create immunological methods that can cure latent infection.

To measure disease and health status accurately and economically in developing countries:
GC#13: Develop technologies that permit quantitative assessment of population health status
GC#14: Develop technologies that allow assessment of individuals for multiple conditions or pathogens at point-of-care.
What is it about your organisation’s approach to these issues that distinguishes you from others in this field?

[Its scale] US$436m.

What progress has been made so far?

Measles dry powder vaccine about to go into Phase I trials.

Which other organisations will you be working with most closely?

A selection of institutions funded by Grand Challenges:

Aktiv-Dry LLC, Colorado, United States
Serum Institute of India Ltd., Puna, India Beijing Hualton, Beijing, China
Indian Immunologicals, Ltd., Hyderabad, India
Tufts University, Massachusetts, United States
US Centers for Disease Control and Prevention, Georgia, United States
BD Technologies, North Carolina, United States
National Jewish Medical and Research Center, Colorado, United States
US Johns Hopkins University, Baltimore, Maryland
Centre International de Toxicologie, Evreux, France.

References

1. Leroy JL, Habicht JP, Pelto G, Bertozzi SM (2007). Current Priorities in Health Research Funding and Lack of Impact on the Number of Child Deaths per Year. Am J Public; 97(2): 219-223. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17194855

2. Hilbert, D (1901-1902). Mathematical Problems. Bull. Amer. Math. Soc. 8, 437-479.