Grand Challenges

by Ian Magrath

Figure 1. Harrison’s chronometers; from left to right, above and below: H1, H2, H3, and H4. Reproduced with permission: © National Maritime Museum, London.

Prior to the ability to accurately estimate longitude, maritime navigation was a hit or miss affair—and each could bring equally devastating consequences. One foggy night in October 1707, Admiral Sir Clowdisley Shovell, returning home after successful skirmishes with the French navy in the Mediterranean, mistakenly thought his fleet to be further west than it was. As a consequence, four of his five ships were wrecked on the rocks of the Scilly isles and 2,000 men perished in the frigid waters. Over 30 years later, in September 1740, Commodore George Anson set off for the South Pacific. Rounding Cape Horn, and hampered by a crew hard hit by scurvy, his ship, the Centurion, encountered a violent storm—not uncommon in these treacherous waters. This one lasted for 58 days, but Anson managed to bring his ship through it, in spite of losing many men to scurvy and the storm. Turning north, he headed for the Island of Juan Fernandez where he knew he would find the fresh food and water his crew so desperately needed. After several days of sailing, land unexpectedly came into view. It was the western coast of Tierra del Fuego, indicating the ship to be at least 200 miles off course. Turning west, then north, the Centurion finally reached the 35th parallel on which Juan Fernando lay but again, Anson had no idea whether to sail east or west. Two weeks later, after two 180° turns and 80 more men dead from scurvy, the Centurion finally dropped anchor at Juan Fernandez, having lost half of its original crew of 500.

Figure 2. Incidence and mortality rates in more and less developed countries for the year 2000. The number of cases per 100,000 per year, age-standardized to the world population are shown. Data from Globocan (IARC).

Ironically, fully five years before its disastrous voyage to the Pacific, the Centurion had tested a highly accurate chronometer constructed by a little known clockmaker named John Harrison. This instrument allowed the calculation of longitude on the basis of the time difference from the home port, and had been highly effective in the course of a test voyage to Lisbon. Unfortunately, when the Centurion set sail for the Pacific the chronometer was in Harrison’s London house, where the clockmaker was already working on his third, more refined version of the instrument (Figure 1). It would be another 50 years or so before highly accurate, handmade timepieces, based on his design, began to be used routinely for navigation. Harrison had developed his chronometers in response to the Longitude Act of 1714 whereby the British Parliament, stimulated by the Shovell debacle in home waters, had offered a prize of 20,000 pounds sterling to anyone who could invent a “practical and useful means” of solving the longstanding “longitude problem.” This Grand Challenge led to the establishment of a distinguished panel (Sir Isaac Newton among them), not only to judge the submissions, but also to award grants to enable impecunious inventors to participate in the enterprise—so important was it to the military and economic success of the nation. This panel was possibly the world’s first research agency.

Figure 3: Ratio of mortality to incidence rate (age-corrected) for more and less developed countries in the year 2000. Blue: less developed countries. Yellow: more developed countries. Data provided by Max Parkin (IARC).

Today, there are many challenges in science and technology as important to economic growth and national security as the estimation of longitude became half a millennium ago. The High Performance Computing Act passed by the U.S. Congress in 1991, for example, recognizes the importance of information technology in navigating the complexities of scientific data. Some of the more urgent grand challenges, occasioned by rapid increases in human populations and economic/industrial development, are those in the environmental sciences. In the U.S. National Research Council’s list of eight, the fifth is to understand the ecological and evolutionary aspects of infectious diseases. Certainly, infections, with their devastating potential to result in the deaths of millions of people, precisely because of their ability to spread, must always remain high on the list of human challenges. Infectious diseases, however, as a cause of disease-related mortality, are much less of a problem in the affluent nations than are non-communicable diseases, particularly cardiovascular diseases and cancer, and the epidemiological transitions which occur in the course of socio-economic development include a reversal of the relative importance of infections versus non-communicable diseases as a cause of premature mortality. Nevertheless, the growing problem of AIDS, the recent outbreak of SARS and the justifiable fears relating to biological warfare emphasize the chilling potential of microbes to wreak havoc on human populations—as well as the fact that health is a global issue.

Health is a Global Problem

The importance of a global perspective on health was recently emphasized by another Grand Challenge, announced by Bill Gates at the recent meeting of the World Economic Forum at Davos, Switzerland, in which he pledged $200 million to support finding solutions to critical problems or “grand challenges” in global health. The determination of what these critical problems are will be made by a panel of experts, and based on proposals submitted by individuals and consortia from anywhere in the world. The funds will be jointly administered by the Bill and Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health. What is particularly novel about this initiative is the inherent expectation that it will stimulate research on diseases that particularly affect the developing world. This is greatly needed; the Global Forum on Health Research has estimated that 90% of the research in the world today addresses problems which cause only 10% of its health burden.

Developing countries have 60% of the world’s cancer, but only a third of the total radiation facilities (some 2,200 compared to 4,500 in affluent nations). Fifteen African nations and several Asian countries have no radiotherapy machines at all. —Source: International Atomic Energy Agency

The Grand Challenges in Global Health initiative is directed towards a broad array of health problems. Following the example of the National Cancer Act of 1971, Andrew von Eschenbach, the Director of the U.S. National Cancer Institute (NCI), has re-focused attention on cancer by announcing yet another challenge—to eliminate suffering and death from cancer by the year 2015. Whether this ambitious goal will be achieved will be dependent not only upon science and technology, in the context of the discovery, development and delivery of new products or approaches to cancer prevention, diagnosis and cure, but also upon human psychology—relating in part to the political will (e.g., to enacting and enforcing robust legislation pertaining to tobacco control) and in part to the ability to convince people to adopt healthier lifestyles. Whatever the year 2015 brings, there is no doubt that enough is presently known about the causation of cancer and its treatment to envisage a time when this goal will be largely achieved. This is a major step forward compared to the situation just a few decades ago. While Dr von Eschenbach concedes it is unlikely that cancer will be eliminated in the foreseeable future, the challenge increases the focus on reducing the cancer burden, which is presently growing rapidly—largely in the 85% of the world’s population that lives in the developing world.

The focus engendered by the Longitude Act resulted in a solution to an intractable problem within little more than 20 years, although it took an additional half century before it was widely applied. The problem of delivery is a particularly difficult one in the developing world, the more so because controlling cancer, which consists of over 100 diseases, is unlikely to be achieved by a single solution. With more than 60% of cancer occurring in developing countries in the year 2000—a figure expected to reach 70% in 2020 as a result of population expansion and aging, and the adoption of the unhealthy habits of the western world—prospects for slowing the increase in mortality and decreasing suffering from cancer in countries with limited resources appear to be gloomy indeed. One of the factors inhibiting progress is the lack of emphasis on cancer as a health problem in these countries—in part due to the high cost of cancer treatment and, in part, to the frequent, erroneous assumption that cancer is incurable. So how much of a problem is it, compared to other health problems, and what might realistically be done in the developing world to prolong life and reduce suffering from cancer? What, in other words, are the Grand Challenges that apply to cancer in developing countries?

Cancer in Context

Cancer is a significantly greater problem, in terms of incidence rates (cases per 100,000 of the population per year), in affluent nations than in developing countries. In developing countries, although cancer incidence is lower, mortality rates are proportionately higher (Figure 2). This is largely because a higher proportion of patients present with advanced disease. The International Agency for Research on Cancer (IARC) has estimated that there were approximately 6 million new cases of cancer in developing countries in the year 2000, 4 million of whom died of the disease. In terms of the burden of illness, this is much less than HIV/AIDS, which presently afflicts perhaps 40 million people in the world, some 95% of whom live in developing countries. Yet only half as many people (2 million) die from AIDS each year in developing countries as from cancer. Similarly, tuberculosis currently infects approximately 60 million people a year but also results in only 2 million annual deaths, while 300 million patients develop malaria annually, 90% of them in sub-Saharan Africa, resulting in about a million annual deaths. The enormous human and economic cost of ill-health caused by these three infectious diseases should not be underestimated, and indeed, a Global Fund was established in 2002 to fight them. But it is important to note that together they account for only some 25% more deaths each year (5 million) than cancer (4 million) in countries with limited resources. Many of the patients who die from cancer have no curative options since they present for treatment at a time when their cancer is too far advanced (estimates vary, but perhaps 60-80% of all cancer falls into this category in developing countries). Depressing though this fact is, it implies that the cost of care is rather less than might be expected on the basis of numbers of cancer patients alone, since palliative care is much less expensive than treatment with curative intent. It will be important to develop more accurate figures for the absolute and relative costs of cancer treatment in a range of developing countries. Such figures are largely lacking. Importantly, socioeconomic development results in a reduction in the mortality from infectious diseases but an increase in both incidence and mortality rates from cancer. Thus, greater efforts are needed now to improve cancer control in developing countries, with the dual goals of preventing incidence rates from reaching those in affluent countries and lowering present mortality rates.

Measures for controlling cancer must be adapted to both the regional pattern of cancer as well as to the level of development. Firstly, the pattern of cancer varies markedly throughout the world. The incidence of some cancers (e.g. lung cancer, breast cancer and colon cancer) is roughly proportional to the level of socioeconomic development, although other cancers (especially those associated with specific infectious disease such as hepatitis and schistosomiasis) are more dependent upon regional factors relating to lifestyle and environment. Secondly, access to care, whether for prevention, early detection, or treatment, also varies with the level of development. In designing strategies to control cancer, knowing about the pattern of cancer is not enough. It will also be important to know what resources are available to local populations to prevent or treat cancer. In this regard, it is of interest that data from IARC demonstrate that in cancers in which radiotherapy and surgery are primary treatment approaches (most cancers), mortality ratios (the ratio between annual age-adjusted incidence and mortality rates) differ on average by less than 10%, between more and less developed countries (Figure 3). Although these figures probably paint a somewhat optimistic picture, because information is both more readily available and more accurate from countries at higher levels of development, these figures suggest that major strides would be made by improving patient access to accurate diagnosis, to appropriate surgery and to radiotherapy. Unfortunately, there is a dearth of radiotherapy machines in developing countries—half as many as in affluent countries, although developing countries bear 50% more of the cancer burden. Fifteen countries in Africa and some in Asia presently have minimal or no pathology services, no radiotherapy facilities, and few surgeons capable of performing major cancer surgery. While all three involve highly skilled professionals, the number required is relatively small. Further, the delegation of more routine tasks to nurses and technicians, along with increased collaboration among existing centers, mediated, where possible, by telemedicine linkages, could greatly improve the efficiency of, and access to, consultative services. Whereas governments can often support the cost of surgery and radiotherapy once the facilities have been established (being largely the cost of staff salaries), chemotherapy costs, and the supportive care required by patients receiving it, can be very expensive (particularly if requiring imported drugs). Anti-cancer drugs are, therefore, generally out-of-pocket expenses, and thus less accessible to the average patient in developing countries. This may be a part of the explanation for the much worse results in developing countries in patients with cancers in which chemotherapy is a primary treatment modality, e.g., testicular cancer.

Grand Challenges for Cancer Control in Developing Countries

The quintessential feature of developing countries is, by definition, their lack of resources. In the field of cancer this translates into a lack of experts of all kinds (including cancer specialists, nurses and technicians), a lack of facilities (diagnostic, treatment, and laboratory), a lack of equipment and products (diagnostic reagents and machines, drugs, etc.) and a lack of institutions, professional societies and cooperative groups focused on education and research. This leads, in turn, to an inability to conduct high-quality research and hence a paucity of basic information about cancer, including population-based statistics on the patterns of cancer, data on the results of interventions, and simple tabulations of any research studies that may be ongoing. In addition to the lack of institutional and professional resources, there is also a lack of personal resources—illiteracy and poverty rates are high. It is this combination of professional limitations, poverty and illiteracy that results in late diagnosis, such that a high fraction of patients have disease too extensive to be cured. Many of these problems are outside the scope of scientific and medical organizations, but there is much that can be done to help educate professionals, politicians and the public, to maximize the use of enabling tools such as information technology, and to command additional resources. The central issues can be encapsulated in six interdependent Grand Challenges (Table 1). Controlling cancer might be compared to the basic requirements for a successful sea voyage—there must be a destination in mind, an accurate map of the route, a means of knowing whether the ship is on course, and an able crew. The lack of any of these will lead to failure. Anson lost half his crew to scurvy—much more delay and his ship would have become unsailable. Today, the limited human capacity of developing countries is similarly compounded by the high burden of disease. Sadly, the ability of the limited existing programs of education and training to increase capacity is all too often blunted by the flight of the best talent to countries able to offer better facilities and greater personal prosperity. Thus, training alone is insufficient. Attractive opportunities must be created for young professionals in their home countries.

The proposed challenges are stated in a sufficiently general way that each is comprised of challenges within challenges (like building a chronometer; Harrison’s third contained 753 parts). They will vary in their relative priorities and with respect to the cancers of primary focus in different countries, but they also apply to cancer in developing countries in general. Like many challenges seriously undertaken, they may also result in unexpected benefits. The longitude problem, for example, at first seemed most likely to be solved with reference to the positions of the heavenly bodies—the method used since ancient times to estimate latitude. This prompted the establishment of observatories in France and England, leading to a wealth of new astronomical data. Galileo’s method of assessing longitude, which was based on the timing of the eclipses of the moons of Jupiter, led unexpectedly to the measurement of the velocity of light—one of the foundations of modern physics. Harrison invented the bimetallic strip and caged ball bearings in creating his third chronometer. More relevant, perhaps, studying Burkitt’s lymphoma in Africa resulted in many advances in the understanding and treatment of cancer and to the discovery of an important human virus. What invaluable knowledge might come from more investment in cancer research in developing countries? But anticipated rather than serendipitous benefits are the primary reason to undertake these challenges, and meeting them, even in part, would slow the rapid increase in cancer incidence occurring in developing countries while improving the length and quality of life of cancer patients. Notably, none of the challenges requires the development of a new scientific method, technology or product. Ironically, they might be more readily overcome if that were all that were necessary!