MOSES, A SCIENTIST from West Africa, is visiting a research laboratory in Brisbane. He has come to gather ideas on molecular approaches to developing a malaria vaccine and to encourage more collaboration with his own laboratory. In his village it is not uncommon for one in five children to die of malaria before their fifth birthday. Other diseases, in particular HIV/AIDS and tuberculosis, are rife. The average life expectancy in his country is 40 years. On his first visit to the West he is amazed at how healthy the general population appears to be. Few people look old. Things are very different from his village, half a world away, but several light years distant in terms of health and economic development.
This could be a scene from today’s world. But cast it forward to 2044 and the differences will be even more striking. The world will have segregated much further, along the lines of good health and poor health, economic development and stagnation, opportunity and despair.
In the next 40 years, it is likely that major health gains will be made against degenerative diseases and diseases of ageing. For every year over the past century, the average life expectancy for most of those born in Australia has increased by 73 days each year. This is showing no signs of slowing. Improved health and longevity over the past 100 years have been due to medical breakthroughs against different classes of disease – starting with infectious diseases. For the first 60 years of last century great gains in health resulted from the discovery of antibiotics (penicillin in 1928) and the commercial development of vaccines: diphtheria (1914), tetanus (1938), whooping cough (1945), polio (1955), measles (1963). The greatest international vaccine triumph was achieved in 1977 when the last case of smallpox was notified, on October 26, at Merka, Somalia. The smallpox vaccine, developed 200 years earlier by English physician Edward Jenner, ultimately led to the eradication of the disease (the only disease to be wiped out) which at its peak caused 10-15 million cases a year with a fatality rate of between 10 and 40 per cent. The success of the smallpox vaccine and, later, the polio vaccine campaigns has inspired many scientists and doctors to try to replicate that success with vaccines for HIV, malaria and other diseases.
In the final four decades of last century, the major gains in health in Western countries came from the continuing benefits of vaccines and antibiotics and from improvements in cardiovascular health and injury prevention. Research identifying the risk factors of smoking, elevated blood pressure, high cholesterol and physical inactivity, combined with public education and awareness campaigns, has resulted in improvements in cardiovascular health directly responsible for nearly a third of the increases in life span since 1960. It is sobering that despite improvements in cardiovascular health, we are still aware of only half of the risk factors for heart disease. It is also sobering that, in spite of what we know, obesity, physical inactivity and smoking are epidemic. In the same period, only six percent of the additional life years gained has been due to improvements in diagnosis and treatment of cancer, underscoring the huge impact that a dramatic cancer breakthrough would have.
HOW WILL HEALTH gains in the next 40 years come about? With a far greater investment in health research worldwide, new vaccines and new drugs will be developed. Their use, however, will be restricted largely to wealthy countries.
Many of the genes that regulate orderly cell growth and division, and the mutations that can result in a normal cell becoming a malignant tumour, have been identified. The remainder will soon be identified. This information is leading to the development of specific drugs capable of interrupting the tumour pathway. An example of this is Glivec which is showing great success in the treatment of one type of leukaemia. It is possible that each class of tumour will require its own drug. With the realisation that a failure of immune surveillance can lead to tumours escaping the “net”, there is enormous interest in developing cancer vaccines as therapeutic agents. Therapeutic vaccines generate an immune response to cure a condition that is already established. Prophylactic vaccines prevent the disease from occurring in the first place. At the same time more tumours have been linked to or proven to be caused by infectious agents (such as hepatitis B and liver cancer; human papillomavirus and cervical cancer, and Helicobacter pylori and stomach cancer). This may open the way for prophylactic cancer vaccines.
Degenerative diseases are a feature of ageing. Joints erode, blood vessels become clogged, neurons disappear, tissues become less sensitive to insulin and pancreatic islet cells that make insulin disappear. There are three approaches to counter the impact of degenerative disease: one of the most cost-effective is prevention based on avoidance of risk factors. Some of the best examples are the importance of smoking and excess sun exposure on various cancers. There is an epidemic of skin cancer in Australia, particularly in the sun-drenched states. Although familial and genetic risk factors have been identified (including genes linked to red hair and fair skin), UV exposure is a major environmental risk. People with fair complexions who live in cooler climes have a low incidence of skin cancer, but their risk increases dramatically if they live in sunny Queensland.
NEW THERAPIES WILL be developed to replace diseased tissues. Therapies used today are symptom-oriented, but we will see the emergence of tissue engineering to replace diseased organs and tissues. Stem-cell therapy will be critical. Current tissue “engineering” relies on transplantation. Engineered tissues of the future will be developed from the patient’s own stem cells and thus will be free of problems of graft rejection. Elimination of rejection, however, would not be a feature of any tissues engineered from embryonic stem cells. Stem-cell therapy using the patient’s own cells to generate new tissues in vitro is likely to give way to even more exciting approaches whereby one’s own stem cells are activated in vivo and repair the damaged organ or tissue from within. Defining the chemical messengers that orchestrate this process – and thus the drugs to hasten the process – is already well underway.
Stem cells have the capacity for unlimited regeneration. They do not undertake the metabolic functions of normal tissues, but they have the capacity to replace those cells as needed. Stem cells come in two main types. There are cells that are derived from embryos, referred to as embryonic stem cells or ES cells. These cells can give rise to every single tissue (of more than 200) in the body. Clearly the embryo requires them if its small cluster of cells is to divide and differentiate into the multiplicity of organs and tissues of the mature human being.
The second type of stem cell is the adult stem cell or AS cell. These are found in the tissues and can replace the cells of that tissue. When skin is damaged, skin stem cells get to work to replace the missing cells. If a patient loses part of their liver as a result of surgery or injury, the liver can regenerate, thanks to resident stem cells in the liver. Bone marrow stem cells from related or matched donors are used to replace the bone marrow in patients with leukaemia whose own bone marrow is destroyed by the disease and the chemotherapy used to treat it. Bone marrow stem cells derived from a different person are, however, foreign to the patient. Unless the donor and the patient are closely matched for tissue type (akin to blood typing, but more complex) the donated stem cells and tissues to which they give rise will be rejected by the recipient’s immune system. It can be exceedingly difficult or impossible to find a willing donor who is correctly matched. There is a registered bank of several million donors and the chances of finding a correctly matched unrelated donor are about 50 per cent for Caucasians and significantly less for other racial groups. As the size of the donor bank increases, the chances of finding a match will increase.
For some serious but rare blood disorders, such as some of the severe hereditary immunodeficiencies, it is possible to combine stem-cell therapy with gene therapy. Gene therapy involves the delivery to the patient of the correct copy of a gene that has mutated and is not functioning in the patient. This therapy is at its earliest stages of development. A gene coding for a protein called the “common gamma chain” has mutated or is deficient in some patients with these disorders. It can be replaced in the patients own stem cells which can then be used to treat the patient. The advantage of this process, compared with using stem cells from a relative or the donor bank, is that the stem cells are not foreign and will not be rejected. A downside to this procedure so far is that some of the gene-manipulated stem cells have become leukaemic in a few patients as a result of the genetic engineering process (the process by which the gene is inserted into the stem cells). More work needs to be done.
A recent revelation with implications for tissue therapy is that AS cells can give rise to tissues other than the tissue in which they are located. This process, called “transdifferentiation”, means that it will be possible, for example, to prepare an enriched population of stem cells from the bone marrow or some other tissue and use it to repair injured heart tissue. This has already occurred in animals and humans, though clinical trials must be undertaken. Scientists in Brisbane, led by Professor Alan Mackay-Sim of Griffith University, have demonstrated that AS cells can be isolated from the olfactory mucosa of the human nose and can give rise to multiple cell types. This provides another source, apart from bone marrow, of easily procured cells for tissue engineering, facilitating the use of stem-cell therapy in the clinic.
THE THIRD APPROACH to counteract aging will be more effective and have a dramatic effect on society. It is likely that within the next three decades we will have developed technologies and drugs to slow the ageing process. The cells that make up our bodies have a finite life span based on the number of times they can divide (referred to as Hayflick’s limit). Cells placed in culture can normally divide only 50-60 times. One factor that limits the extent of cell division is that the chromosomes shorten fractionally with each division. Some tumour cells, however, can preserve chromosome length – in part through the action of an enzyme called “telomerase'”. As a result they can – and divide without limit. A study published last year inThe Lancet (Vol 361, pages 393-395, 2003) found that individuals with longer telomeres lived longer because they suffered from fewer diseases. Learning how to preserve chromosome length in normal cells could lead to approaches that simply block the ageing process.
The effect of such therapy would be dramatic. There would be a quantum leap in life expectancy, but at a price. Drugs or therapies could be expected to attract a premium price, based on what individuals could afford to pay for five, 10, 20 or even 40 years of additional life. Based on current willingness to pay for items that prolong life (such as airbags for cars), or additional payments made to individuals in high risk professions, economists estimate that we value our own life at more than $100,000 a year. Individuals who could afford it might thus be expected to pay thousands of dollars a year for a pill that prevents ageing. What about the majority who could not afford the price tag? Would government pay? Unlikely, given it would have to raise the same amount from additional taxes. The situation could arise where the richest people in the wealthiest countries could live for significantly extended lives.
While that might seem far-fetched to some, it is not too different from what happens today. In Australia, the average life expectancy for women born today is 82 years. For Aboriginal women it is 62 years. For some African nations ravaged by HIV/AIDS it is under 40 years. It is likely that in the next four decades the average life expectancy of Australians will rise to more than 100 years (maybe much more), whereas for inhabitants of the world’s poorest countries it will remain about 40 years.
In Australia and other wealthy countries, cohesive family and social structures will be further tested. People will stay in the workforce for longer. Pressure will continue to mount for people to limit their family size. The widening divergence between rich and poor countries will also result in social division and further destabilisation of world order. We may well ask whether our improved lifestyle is worth the price. It is a question to which many would like to answer “No”, but they won’t be able to. Life is precious.
OUR VISITING AFRICAN scientist in 2004 will be awe-struck by the advantages of the West. In Brisbane he will work in some of the best laboratories in the world, alongside some of the world’s leading scientists. Though many will be old in years and experience, they will generally have good health and appear young. It is likely that a vaccine for malaria will have been developed, but won’t be affordable in his country. His research will focus on alternative vaccine strategies that could reduce the vaccine cost from $200 to $1. Even a dollar is a lot in a country with an annual expenditure on health of about a dollar per person. Developing an affordable vaccine will be a difficult project. Vaccines are estimated to cost $US500 million to develop. To recoup these costs and to fund new vaccine research, manufacturers put a price on vaccines that wealthy countries can afford but that poorer countries cannot. This has had dramatic consequences.
In the past 25 years the number of vaccines used routinely in developing countries has risen from six to seven. Over the same period the number of vaccines used routinely in Australia has almost doubled to 12. Vaccines can improve world health only if they are used. Smallpox and polio vaccines have been dramatically successful throughout the world because they were simple and cheap – relying on a modified non-pathogenic virus to induce immunity. Current approaches to vaccine development are neither simple nor cheap. Most vaccine programs are based on “subunit” platform technology. Subunits – typically, recombinant proteins – are preferred by regulatory agencies, such as the Therapeutic Goods Administration in Australia and the Federal Drug Agency in the United States, because they are well defined and unlikely to contain extraneous material which could potentially induce side effects. Subunits are, however, poor at stimulating the immune system (the key role of a vaccine); and difficult to identify, to produce with the correct molecular shape (required for maximum immune function) and to administer. Expensive technology is required to overcome these weaknesses. They are, however, very safe. Safety standards and tolerability limits are set to satisfy Western consumers. Vaccines with some side effects, perhaps even severe side effects which occurred only occasionally, might have a considerable net impact on public health in a developing country, but will never be developed.
A sobering example of this is the vaccine for rotavirus. Rotavirus, discovered in 1972 by Australian bacteriologist Ruth Bishop and colleagues from the University of Melbourne, is responsible for about 800,000 deaths due to diarrhoea each year, mostly in poor countries and mostly among very young children. After many years of research, a vaccine was developed and tested in early phase trials in the US and shown to be safe. However, a large trial involving 1.5 million children (after the vaccine was released) demonstrated that a small percentage of recipients developed a condition known as intussusception, whereby the small intestine folds inside itself resulting in a blockage. A child died and the vaccine was potentially implicated in some of these cases. The vaccine program was halted and attempts to develop a safer vaccine were begun. In Western countries, rotavirus causes diarrhoea but few deaths, so it is easy to understand why a vaccine that might be responsible for a small number of deaths should not be licensed in Australia or the US. Developing countries are loath to adopt safety standards that are lower than those that operate in the West for many reasons, some more difficult to justify, but it is likely that widespread immunisation with rotavirus vaccine would cause many fewer deaths than would occur from rotavirus infection in unvaccinated children. It is to be hoped that efforts to develop a completely safe vaccine will be successful, but that is by no means certain.
MEDICAL RESEARCH IS the engine that drives improving health. In Australia (in 2000-2001; the latest year for which full data is available), health research and development absorbed $1.7 billion, primarily from public sources. Economists estimate that up to half of the gains in life expectancy and improved productivity are directly attributable to medical research; the remainder comes from public education and awareness campaigns. For example, medical research has demonstrated that smoking can cause heart disease and lung cancer (plus an awful lot more), but the efforts of the Heart Foundation and Anti-Cancer Councils, and government regulations banning cigarette advertising and smoking in public places, are just as important.
As mentioned earlier, average life expectancy at birth increases about 73 days per year and up to half of these gains are as a direct result of medical research worldwide. Does Australia’s contribution to medical research really matter? The answer is a definite “yes”. As a percentage of global GDP our medical research output is the highest in the world. Australians are good at biological and medical research. The research performed in Australia buys better health not only for Australians but for people of other countries. Some of the more notable achievements and discoveries by Australian scientists include: the production of penicillin; the discovery of lithium for the treatment of bipolar disease; the first cloning of malaria antigens, paving the way for the ultimate development of a subunit malaria vaccine; the discovery of Ross River virus and its role in arthritis; the discovery of the link between sleeping position and sudden infant death syndrome; the discovery of the bionic ear; the discovery of the link between helicobactor infection and stomach ulcers; the discovery of blood cell growth factors; and the development of a vaccine to prevent cervical cancer.
Are we spending enough? The non-profit independent organisation Research Australia (www.researchaustralia.com.au) recently conducted a survey and found that 65 per cent of respondents ranked government spending on health and medical research as very important – third behind expenditure on “hospitals and health care” and “schools and universities”, but well ahead of “defence” and “sports”. The poll also found that nearly a third wanted the government to spend more than six per cent of health-care dollars on research and 55 per cent wanted the government to spend between two and six per cent on research, compared with the current rate of between one and two per cent. All the available evidence suggests that if we spend more on health research, health, productivity and life expectancy will increase and the economy will grow more quickly. It is essential, however, to include the health priorities of poorer countries in our research agenda. Their health and our wellbeing depend on it.
For this to happen we need to maintain and accelerate excellence in education and to foster dedicated and motivated scientists. The factors that drive scientists are manifold. The quest for discovery is central – to be the first person in the world to discover something relevant to who we are, why we are as we are, and how we can improve our health and wellbeing. The discovery bug is infectious. Some of the best scientists seem a little out of place in general society because they are so focused on what they do. Many are motivated by a passion to make a difference to the world, particularly that of people in poor circumstances ravaged by disease. It is frustrating that the returns on medical research are always long term. Our health is improving today because of discoveries made 10 to 20 years ago. Research and research scientists require nurturing and strong community support. We have always enjoyed this support and, in recent years, funding for research has improved. This is welcome, but much more is needed if we are to achieve further gains.
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GR OnlineMore immediate, however, are disruptions to essential public health control measures such as the provision of insecticide-treated bed nets and seasonal malaria chemoprophylaxis campaigns. As a result, WHO fears the annual death toll from malaria could double.
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