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HIV,
TB and Malaria kill well over 6 million human beings each year. That
is a nation the size of Switzerland. Unfortunately those 6 million
deaths have little economic impact on deciders in the rich world for
whom the threat of bioterrorism (perhaps 6 dead!), easily
unlocks multi-billion dollar defense allocations. Other infections
probably kill or contribute to the death of 100s of millions of human
beings each year.
The 20th century was a period of
great revolutions in medicine, none more impressive than the
remarkable victories scored against infectious disease. The discovery
of antibiotics in the first half of the century gave hope to those
who died of bacterial infections related to childbirth, or wounds or
simply ambient microbes. Concurrently novel vaccines were offering
long-term protection from both viral and bacterial illnesses. In the
latter half of the century smallpox was eradicated and as we enter
the 21st century polio may soon join smallpox as just a
terrible memory for older people.
Despite the successes against bacteria and
viruses, the battle against fungal and parasitic disease never did
more than maintain an uneasy state of war.
Today the hard-won victories against
bacteria and viruses are being threatened by the increasing number of
microbes able to resist the current range of antibiotics. As many as
30% of people who enter hospitals in the developing world acquire
antibiotic-resistant infections, while being treated for something
else.
Vaccines seem to be maintaining their
usefulness, but despite our vast recent progress in understanding
life, very few new vaccines have been authorized for use. The problem
here is that the regulatory agencies have no clear protocols in place
with which to determine the safety and efficacy of vaccines. Unlike
old fashioned chemical agents, complex biological molecules are
effective only in their target species ‚ man. Tests in animals
have almost no relevance to the human condition or likely therapeutic
outcome. Some progress has been made in generating transgenic animals
as surrogates for human beings. However, these present terribly
limited models of human immunity, and do not take into account the
wider range of human-specific metabolic activities.
HIV, TB and Malaria are a trio of nasty
agents that illustrate the opportunities and difficulties faced by
the panoply of anti-infective strategies.
•
HIV is a virus causing AIDS
•
Tuberculosis is a disease caused by bacterium
•
And Malaria is a disease caused by a protozoan parasite transmitted
by mosquito bites
HIV is a group of viruses belonging to the
family of retroviruses. These retroviruses carry their genetic
information in the form of double stranded RNA. The RNA of
retroviruses is associated with an enzyme known as Reverse
Transcriptase. The RNA and reverse transcriptase are surrounded by a
cone-shaped protein shell or capsid. The capsid itself is surrounded
by another shell, the virus envelope, which is a complex of lipids
and proteins.
Once inside a target cell, a retrovirus
makes a DNA copy of the RNA using the reverse transcriptase enzyme
(so called because it works in a manner which is the reverse of the
normal DNA goes to RNA copying - or transcription). Inside the cell
most of the virus's genome exists as DNA. This will then intercalate
itself into the hosts chromosomal DNA.
In the case of HIV, the virus recognizes,
and specifically attacks, cells containing a certain marker on the
surface. This marker, known as an antigen, is called for convenience
CD4. HIV infects cells which carry the CD4 antigen. In man among the
cells carrying the CD4 antigen are key cells of the immune system;
lymphocytes and other white blood cells. HIV infection thus causes
damage to the immune system and stops the infected person from
eliminating that infection. The body tries hard however, but in the
mid or long term (2-15 years), HIV infection left untreated is
usually fatal.
Tuberculosis is caused by the bacterium,
Mycobacterium tuberculosis
(M. tuberculosis).
It is quite closely related to the agent of leprosy, Mycobacterium
leprae (M.leprae). Most mycobacteria are harmless soil
organisms, but several have become pathogens of man and animals. The
mycobacteria share several antigens and an attenuated form of the
agent causing tuberculosis of cattle, M. bovis, is used to vaccinate
against M. tuberculosis. This is the well-known BCG
vaccine. A TB infection can also be treated with appropriate
antibiotics, but increasingly resistance to these drugs is becoming
encountered.
In addition to antibiotic resistance HIV is giving a new stimulus to
tuberculosis, for it is in patients with a damaged immune system that
M. tuberculosis becomes an opportunistic infection. Thus TB is a
further complication of the current AIDS epidemic.
Malaria is a disease caused by a protozoan
parasite of the genus Plasmodium.
Four principal parasites are recognized: P. vivax, P. malariae, P. ovale and P. falciparum. All four Plasmodium species have a two-host life cycle,
alternating between man and mosquitoes of the genus Anopheles. There has as yet been no
successful vaccine against Malaria. Quinine derived chemicals have
shown to be very effective at preventing Malaria infection, but
increasingly Plasmodium species are showing resistance
to these and other drugs. Successful treatment of Malaria can take
several forms. The cycle of transmission can be broken by destroying
Anopheles mosquitoes, the insect host of
Plasmodium. New drugs can be developed
which interfere with the complicated reproductive cycle of
Plasmodium. Finally a vaccine can be
developed, allowing the human host to recognize and eliminate new
Plasmodium infections. There has been
progress in vaccine development, but the consensus today is that an
effective vaccine is still far from reality.
All three of these agents can illustrate
the unfortunate division of society into rich world and poor world.
And this too is unfortunate, for the lessons to be learned from poor
world disease could be applied to the very many illnesses affecting
man in the rich world‚ which might be caused by infectious
agents.
HIV first came to prominence in the
homosexual community of the rich world in the early 1980s. Poor
hygiene in the rich-world drug abusing community further encouraged
the spread of HIV viruses. Now over twenty years later it has been
recognized that HIV comes in at least two viral forms and is not just
a scourge of homosexuals and drug addicts. The threat to the economy
of the rich world generated solutions ‚ of a sort ‚ for HIV
infection. Unfortunately these solutions, based on agents which
inhibit viral replication (nucleotide analogues and viral protease
inhibitors) are in themselves dangerous, and furthermore only control
the infection. Recipients of famous triple therapy will relapse if
the therapeutic regime is interrupted. In the developing world, and
particularly in Africa, promiscuous heterosexual sex is the primary
cause of the spread of HIV. Over 40 million persons have been
infected according to the World Health Organization (twice that
number according to some estimates). It is not clear to what extent
malnutrition and other infections enhance the transmission of HIV.
Tuberculosis was more or less eliminated
from the rich world by about 1970. It continued to exist only in the
poorest communities and as a disease caught on exotic holidays in
foreign places. It was treatable. No longer! The drugs no longer work
well and HIV has helped TB recapture much or all the ground lost in
the first half of the 20th century. In the rich world we
ignore the fact that, in much of the poor world, TB continued
unabated throughout the last century. That fact was brought home to
me when I lived in Hong Kong in the 1960s.
During the years of colonial occupation,
the major colonizing powers all came face to face with the threat of
Malaria. By draining swamps and controlling mosquitoes, significant
progress was made. Quinine derivatives became available and palatable
(to this we owe the gin and tonic) preventive agents. Simple physical
barriers such as mosquito nets and well built houses could reduce the
threat.
All the above and the many other infectious
and parasitic diseases compromised economic growth. Such was the
importance of our colonies that we developed solutions, if not cures,
for the problems presented. With the independence of the colonies
these concerns ceased to worry the former masters. And the diseases
came back, until the global community under the auspices of the
United Nations and specifically the World Health Organization
recognized that pools of disease were but a short flight away from
our rich economies. Action was needed.
In the above lines we identified three
specific agents of disease, representing viral, bacterial and
parasitic infections.
However there are many more disease states
for which no specific agent has been recognized. In some cases this
is because the disease state is congenital, due to a genetic or
environmental stress that resulted in abnormal development. Other
diseases can be due to environmental agents such as pollutants or
toxins. Accidents are in some respects a simple physical interaction
with the environment.
Clearly there are diseases which have
nothing‚ or little‚ to do with infectious agents, but it
may be surprising just how many illnesses are due wholly or in part
to infectious agents. Any weakness or prolonged illness will
compromise the immune system, leaving the body vulnerable to
infection.
Some kinds of breast cancer may be caused
by viruses. Other types of cancer may be in part inherited, but an
environmental trigger‚ such an infectious agent‚ can
directly provoke the cancer (an example of this is Burkitt's
lymphoma, triggered by Epstein-Barr virus).
It seems possible that many inflammatory
illnesses may be due to infection with small bacteria or mycoplasmas.
These are not easily diagnosed and are so omnipresent that
differentiation of harmless and pathological species may be next to
impossible.
At school we all learned about parasites,
symbionts and commensals. Parasites live in or on us and harm us.
Symbionts live in or on us and pay for the ride by actively helping
us. Commensals appear to hitch a ride doing neither good nor harm.
Those are fairly simplistic definitions, but they are workable.
And they confuse the perception that all
bacteria and viruses are bad. Some bacteria are essential. Without
them humans could not absorb essential vitamins from the gut (which
contains kilogrammes of bacteria!). Viruses; surely they are all bad?
No! Some viruses may play a role in controlling bacteria which might
otherwise harm us. Others may even play a role in monitoring and
controlling cancer. But surely we all learned that viruses are
pathological agents. True in the 1950s, but now we know much more.
Ordinary cells may communicate in part through the exchange of virus
like particles. When does a virus-like particle become a virus?
Consider even the tapeworm (disgusting), but in some parts of the
world a tapeworm more than pays its way by preventing the
establishment of other parasites that could do real harm.
Vaccines are a cost-effective solution to
disease. One or a few treatments can secure life-long protection from
disease. Some vaccines may actively combat established infections or
disease states, by recognizing antigens on infected cells and killing
them and their pathological content or alerting the immune system.
Modern vaccines may be expensive to
develop, but even priced at ¤ 250 a treatment, this represents a
huge cost saving on days of productive work lost, not to mention the
cost of active medical interventions.
Although there seems little incentive to
develop a vaccine which helps poor people far away in irrelevant
countries, it is just those poor people that constitute a danger for
you and me in the rich world.
•
Firstly, they may harbour diseases which travel to infect us or which
we may catch on vacation in exotic destinations (and return home to
our families and friends).
•
Secondly, poor people constitute a reservoir of have-nots who eye our
wealth jealously. For those who have nothing violence is a sure way
to attract attention. America learned this lesson in September last
year.
•
Thirdly, health is the first pre-requisite of a competitive
workforce. The second is education, but that can only work if
children or adults are well enough to follow a course of learning.
Vaccines deliver health that allows them to study. Healthy workers
make a healthy economy and if we are to grow richer we must generate
new markets in the developing world. The developing world can only
become a market if its people can pay. Vaccines deliver the health
that allows them to pay the bills.
Population densities in many parts of the
world are higher than ever before. These high densities favor the
emergence of new infectious diseases, like HIV, or the re-emergence
of old diseases we have nearly forgotten - like TB. Malaria too is
re-emerging and this is due primarily to our neglect. Let us attempt
to stop this potential wave of destruction.
Yes disease affects poor people far away,
but it is terrifying how rapidly the spectre of endemic infection and
ill health could come to haunt us again.
Yes we should be concerned about biological
weapons. However, the only good thing to come out of the present
scares is the realization that we can all be struck down by
infection. A world prepared to fight infectious disease through heavy
investment in vaccine research and development is a world ready for
biological weapons. Remember last year biological weapons killed 6
people. HIV, TB and Malaria alone killed 6 million and the other
infections collectively killed perhaps 100 million. Let us get a grip
on reality! It is Mother Nature who controls the biological weapons,
not the terrorists!