Largely forgotten today, Dr Yellapragada SubbaRow
was greatly admired as the 'Wizard of Wonder Drugs' such as Aureomycin,
DEC, folic acid, and methotrexate. Born an Indian, Dr SubbaRow remained
an Indian throughout his life and died in 1948 at the age of 53.
He could not be honoured appropriately in his lifetime, but “because
he lived you may be alive and are well today. Because he lived you
may live longer". I sincerely feel that the only way we can
honour this great Indian is to emulate his work that ensured equitable
and affordable healthcare for over half a century to the poor and
the rich alike all over the world.
In the value system of human society, the priorities are health
followed by wealth followed by wisdom. This quest for good health
and the urge to avoid or get over illness has driven mankind over
millennia to flock towards medicine men. Modern medicine based on
systematic scientific studies about the causalities of various disease
processes is, however, only a little over 100 years old. Modern
medical practices combining improved sanitation, immunization and
the use of medicinal substances of natural or synthetic origins
has drastically reduced morbidity and mortality from infectious
agents. However, emergence of drug resistant pathogens and new diseases
such as AIDS in recent years rudely reminds us that the war against
microbes is hardly over.
Healthcare in the 21st Century crucially depends on our proficiency
in the sunrise technology of molecular medicine. The edifice of
molecular medicine can only be built on a firm bedrock of competent
and innovative new biology research. I would like to pay homage
to Dr SubbaRow by citing some examples of our humble efforts in
this direction to break new grounds.
Ours has been the best of times globally because this is the first
century in which mankind had some respite from the constant fear
of premature death from diseases. Life expectancy has risen from
about 30 years at the end of the 19th century to about 80 years
in most developed countries. Even an Indian can expect to live to
be about 64 today whereas it was about 33 only fifty years ago.
Ours could also turn out to be the worst of times. The deluge of
new and re-emerging diseases, drug-resistant microbes and the epidemic
surge of AIDS pose hazards of calamitous dimension to public health.
At development costs of over $500 million and 10-15 gestation
years per new drug, even chemotherapy is fast becoming unaffordable.
Public trust in modern medicine is fast eroding with the spiralling
rise in healthcare costs and the resultant inequity in healthcare
delivery is aggravating social discord. We are living in dubious
and dangerous times indeed.
Shifting Paradigms in Health Care in Century 21. As the lifestyles
in the poor nations improve, a demographic transition in the disease
pattern is sure to happen in our parts of the world as well. With
the increased life span and an ageing population, the major goals
of medicine in the 21st century are control of cancer, cardiovascular
ailments, autoimmune diseases, and behavioural disorders. As the
molecular defects underlying pathological conditions are elucidated,
medicine in the new century will shift to an informational paradigm
that will emphasise diagnosis and prevention rather than expensive
therapy. An era of "predictive medicine" will emerge that
will permit assessment of the risk of an individual to contract
a specific disease so that many of such risks would be countered
by preventive measures, counselling, lifestyle changes, and so on.
There is robust optimism that new technologies for equitable healthcare
will emerge in Century 21 from the profound molecular insights into
life processes that new biology provides.
New biology is the outcome of the convergence since the 1940's
of the three major streams of biology: biochernistry concerned with
the isolation and chemical characterization of cell substances,
cell biology exploring the subcellular components of the cell, how
they relate to each other and to the intact cell, and genetics dealing
with the inheritance of characters by whole animals or plants. New
biology seeks molecular explanations for the many splendoured
beauty and aberrations of life, how it perpetuates and evolves,
and how it originated.
The powerful molecular approaches of new biology for studying disease
processes has spawned a new biopharmaceutical industry that specializes
in studying mechanisms of diseases and applies that knowledge to
their diagnosis, prevention and treatment. The triumphant march
of the biopharmaceutical industry is reflected in the large number
of new products that are approved or are in trial.
Chimeric toxin. Some of the proteins under development have no
precedent in nature: they are engineered as combinations of certain
domains from several proteins. For instance, Dr J.K Batra and his
colleagues at NII are using gene fusion techniques to develop a
molecule in which the EGF receptor-recognizing domain of the TGF
molecule is fused to a fungal toxin called restrictocin that inhibits
protein synthesis in animal cells. This hybrid protein selectively
destroys breast and lung cancer cells that overexpress EGF receptors.
For killing other types of tumour cells, which overexpress transferrin
receptors, they have engineered a molecule containing the transferrin-receptor-binding
domain of an antibody and a potent fungal toxin.
CDC-NII Malaria Vaccine. Tools of cell biology and genetic engineering
are being used for replacing existing vaccines, with safer and more
effective versions and are improving the prospects of new vaccines
against AIDS, cancer, malaria and other parasitic infections. For
instance, Dr Hasnain at NII has made a composite gene by stitching
together several gene fragments for proteins exprissed in various
stages of malaria parasite's development, and expressed this engineered
gene in baculoviruses. Studies at CDC with this artificial protein
look highly promising as a new lead towards a candidate vaccine
Towards the medicines of tomorrow: targeted drugs. Despite such
welcome developments, the fact is that effective treatments against
new and re-emerging diseases are proving ever harder to invent.
New drugs becoming increasingly difficult to come by, we Sought
alternative means so that molecules with desired curative potential
that are currently unusable due to toxic side effects can be made
therapeutically useful. Let me illustrate our approach towards such
medicines of tomorrow.
Advantages of Site specific drug delivery. Why drugs often produce
toxic reactions? Current pharmacological practice is based on the
central dogma that the .effect of a drug depends on its concentration
in the blood or other body fluids. Of about 1013 cells comprising
the human body, only a small fraction needs intervention with drugs
to cure or curb a specific disease, Having no special affinity for
the diseased target cells, most drugs in current use can access
normal cells as well. Since most drugs enter cells by passive diffusion,
a relativelyhigh dose of the drug needs to be administered to attain
therapeutically effective drug concentration inside. the cells,
which aggravates the problem of toxicity. Ever since Paul Ehrlich
introduced the concept of magic bullets in 1906, a common priority
goal of therapeutics has been the designing of vehicles containing
exclusive signals for recognizing the target cells, and delivering
drugs selectively to these cells.
Targets on cell surface. Two general targets on the surface of
mammalian cells are exploitable for such site-specific drug delivery:
1) antigens against which specific, non-cross-reactive antibodies
can be developed, and 2)receptor molecules capable of efficient
transport of macromolecular ligands. The carrier for targeting a
drug to specific cells thus can either be an antibody specific for
the target cell, or a ligand for the receptor molecules present
only on the target cells (Basu 1990). Ehrlich himself proposed the
use of a specific antibody as the carrier of the chemotherapeutic
Disadvantages of Anti body-med iated targeting: The antibody-mediated
targeting approachr raised great hopes after fine discovery of hybridorna
technology for production of highly specific monoclonal antibodies.
However, it has still not been possible to solve many of the problems
of this approach.
Receptor-tirtediated transport of LDL. The receptor-mediated approach
is of more recent vintage and derives from our work on the role
of low-density lipoprotein in atherosclerosis. This work delineated
how specific receptor molecules on the surface of rnammalian cells
bind macromolecules, leading to their internalisation and processing
in specific intracellular compartments. This process is now called
receptor-mediated endocytosis and is universally recognised as a
major transport mechanism utilised by mammalian cells for a variety
LDL receptor work established. We had great fun working out the
mysteries of this process during 1975-83 but the story is textbook
Characteristics of Receptor-mediated endocytosis important for
drug delivery. Twenty years ago, thanks to late Professor B.K Bachhawat,
I got a job in India. Not having much of a lab to begin with, I
had all the time to ponder over how to build a scientific career
in India. There was no point working on LDL as my seniors in the
LDL receptor adventure, Goldstein and Brown, were already on the
verge of a Nobel Prize which came in 1985. Eventually I realized
the potential of the process of receptor-mediated endocytosis for
the purposes of drug delivery.
Macrophages pivotal cells. I also understood that macrophages in
animals mount multipronged defensive responses that protect them
against a variety of invading microorganisms and developing cancers.
However, in many instances these defensive responses are overwhelmed,
circumvented or even misdirected so that these protective cells
become the focal points in a large number of diseases - infectious,
metabolic or neoplastic, which affect millions of people world wide.
Therefore, a generalised targeting regimen specific for macrophages
would be extremely useful.
Characteristics of Scavenger receptor system: To target macrophages
we needed a receptor restricted to these cells. In the course of
my earlier work on lipoprotein metabolism we discovered a receptor
system present primarily on cells of marophage lineage. It appears
that God created scavenger receptors for my career development in
Pathway of receptor-mediated drug delivery. We went about exploiting
the principles of receptor-mediated endocytosis for selective drug
delivery. We chemically attached the desired molecule to maleylated
albumin or polyguanylic acid so that the conjugate is specifically
recognized by the scavenger receptors present primarily on macrophages.
Leishmania mexicana-infected hamster footpad. The power of our
approach was first demonstrated in an experiment in which L. mexicana
were injected into hamster footpads which swelled to about 10 times
the normal size due to multiplication of the protozoa inside the
macrophages. When free methotrexate (MTX) was given no substantial
cure was achieved. Administering the drug in a form targeted to
macrophages as MBSA-MTX conjugate brought the footpad size back
to normal. All the animals remained healthy and no antibodies against
the drug conjugate could be detected in these animals (Mukhopadhyay
et al. 1989; Basu et al. 1994). The fact that the first paper in
this series of my first PhD student in India, Amitabha Mukhopadhyay,
was published in the journal Science reflects the novelty and importance
of these findings.
Improved survival of MTb infected guinea pigs with PAS-MBSA. The
conjugated drug improved the survival of guinea pigs infected with
Mycobacterium tuberculosis to 87% compared to only 13% with free
Effect of MBSA-DOX on C11F9 multidrug resistant tumours. The conjugated
doxorubicin had an antitumour effect.
Antisense strategy. Binding of oligonucleotides complementary to
a critical sequence in an mRNA can reduce or prevent production
of the target protein. Several such antisense molecules are about
to enter clinical trials as antiviral agents. Antisense therapy
is likely to be effective against viral infections, inflammatory
conditions and cancer. Selective and efficient intracellular delivery
of antisense molecules to the target cells is essential for success
of this approach and better methods are needed.
Antisense inhibition of VSV replication. We demonstrated that scavenger
receptor-mediated intracellular delivery of antisense molecules
to macrophages inhibits the replication of vesicular stomatitis
virus. We are now using this principle to design new antiviral agents
against macrophage-trophic viruses such as dengue, Japanese encephalitis
Scavenger receptor-mediated manipulations of macrophage metabolism.
Over the last 15 years or so, we have used scavenger receptor-mediated
endocytic process for manipulating macrophage metabolism for three
major purposes: combating intracellular infections such as leishmaniasis,
tuberculosis and vesicular stomatitis virus, controlling macrophage
cancer, and modulating immune responses.
Drs Rath/Bal and their colleagues at NII added an entire new dimension
to scavenger receptor-mediated modulations of macrophage metabolism.
They showed that targeting of antigens to scavenger receptors led
to enhanced immunogenicity, providing a novel lead for new generation
adjuvant less vaccines, generation of the Th1 type of immune response,
opening a new approach for immunoprophylaxis especially against
intracellular pathogens; diversion of an ongoing allergic immune
response to a nonallergic route, perhaps brightening the prospects
of mitigating the misery of millions; abrogation of T cell tolerance
to self antigens, providing a new, tool to dissect mechanisms of
immune tolerance and etiopathogenesis of autoimmunity (Abraham,
et al., 1995, 1997; Singh et al., 1998)
I hope I have presented some evidence to convince you that (a)
newer tools of cell biology such as monoclonal antibodies and/or
receptor-mediated endocytosis appears to be a rational approach
for site specific drug delivery; (b) this approach merits serious
consideration in designing new chemotherapeutic agents as well as
resurrecting otherwise effective but highly toxic molecules for
site-specific chemotherapy; and (c) the actual availability of drugs
based on the targeting principles mentioned above, however, have
many hurdles to cross before drugs based on these elegant principles
would find their way to the market place.
Thus, Paul Ehrlich's quest is still on, magic bullets still elude
The worrisome schism
Let me now draw your attention to a widely held misconception about
scientific progress and societal well being that threatens the entire
framework of science.
Harnessing new biology for healthcare has been the preserve so
far of the developed countries. Of late, these nations invoke stringent
property rights regimes with proprietary controls on knowledge bases
these efforts generate. Accordingly, the commercial interests of
both the developed countries and of the elite of the Third World
determine the priorities of biomedical research the world over,
rather than the urgency of the unmet needs of poor Third World citizens.
This has created a worrisome schism between expectations and realities
in the Third World.
Two factors aggravate this schism: 1) The lacunae in healthcare
delivery to the poor are due far more to resource constraints and
implementation failures than the lack of technologies. 2) Much of
new biomedical research agenda is based on hype as seen in the recent
fuss with genomics, which is unlikely to translate into real life
utility (other than boosting share prices) at least for the poor
any time soon.
The reality is that improvements in healthcare over the short.
term do not need biomedical research as critically as they need
political will and administrative skill. But restraining biomedical
research with near-term expectations stands guaranteed to lose us
the real and enormous long-term benefits by way of unpredictable
futuristic technologies that rigorous, competent research has been
historically shown to bring. Conceptual insights for breaking new
grounds strike competent minds unfettered by short-term utilitarian
Antiscience in public policy. You might have noted how anti-science
and irrational viewpoints have exerted increasing influence on public
health policy matters of late. There are instances galore, both
in the First World and in the Third: The irrational edge that the
heated debate on genetically modified foodstuffs takes on, even
in otherwise technology-savvy societies such as Germany. Closer
to home is the fanatic zeal of an erstwhile influential Union Minister
in India for regulating animal experimentation with ill-informed
rules and their motivated implementation, which made serious real-life
biomedical research nearly impossible to pursue in India and drove
our fledgling drug discovery industry to Western countries for crucial
animal testing with obvious increase in costs.
No sober public debate on this critical issue has so far been possible
in India, given the tendency of the media to favour emotive or celebrity
reportage. The controversy thus simmers without being understood.
Why use animals for experimentation? Biomedical research aims to
work out how a human or animal body functions and looks for clues
for interventions to correct dysfunction for ensuring better health.
However in the 20th century, society at largeset the ethical norm
to treat human life with utmost dignity. Therefore no human application
is permitted until an intervention is proven to be safe as extrapolated
from experimental studies often involving animals. Animal experimentation
thus becomes necessary out of respect for human life.
Staunch animal-rights activists demand that animals, being living
creatures, must be accorded the same dignity as human beings, or
even more by virtue of being innocent.
Is such an anthropomorphic view of the animal world justified?
Is there ethical coherence to it? If their strident demands result
in a virtual ban on using animals for any kind of research, what
do we lose?
We do lose a lot. Most wonders of modern medicine that remarkably
improved human and animal health would not have been possible without
the use of animals for experimentation. There are examples galore:
surgical procedures for heart and kidney transplant, vaccines against
polio and whooping cough, miracle medicines from Aureomycin to Zantac.
The list goes on.
Infections pose a constant and evolving threat to human life. Since
1973 about 20 brand new disease entities have been identified against
which we have no effective vaccine or medicine.
Effective new ways are needed to cope with these and other diseases
ranging from cancers to cardiac disorders.. For such attempts to
be meaningful, the pathological processes involved need to be understood.
If animals cannot be used for mimicking such human conditions in
the laboratory and finding answers to problems, human beings will
have to be used for extensive experimentation with potential danger
to life and health in the process. Society has already rejected
this as unethical.
If neither animals nor human beings can be used, all future research
towards understanding the functioning of the human body and attempts
to keep it healthy would have to be stopped. Since this is hardly
agreeable, we must accept that there is nothing inherently 'morally
evil' about experimenting on animals, and the notion of 'animal
welfare' is far more tenable than any concept of 'animal rights'.
Since animal experimentation is indispensable, is regulation of
animal experimentation necessary? The answer is a definite 'yes’.
All social human activities must be regulated with pragmatic rules
set after democratic debate.
How do we then reconcile the conflict between the ethical perceptions
of a vocal fringe with an essential requirement of biomedical research?
What society must vehemently resist however is the subversion of
'human rights' by the so-called 'animal rights' activists who try
to introduce unworkable rules for animal experimentation in pursuit
of a covert, non-democratic 'anti-vivisectionist' agenda.
This one of the lesser-appreciated but critical examples of the
labyrinths of ethical considerations in science and technology.
Dawn or dusk? What is the image of a future for humanity that new
biology heralds for us? It could be the dawn of opportunity resplendent
in societal wisdom - our hopes for our children. It could also portend
the dusk of the long dark night -- a tired, spent-out generation
mired in indecision or foolish bequeaths - a generation that will
be cursed by our children. The decision is ours.
References: 1. J. Drews (1993). Into the 21st century: Biotechnology
and the pharmaceutical industry in the next ten years. Biotechnology
11: 416-420. 2. A. M. Thayer (1996). Market, investor attitudes
challenge developers of biopharmaceuticals. Chem. Eng. News, August
12. 3. D. E, Hassett & H. L. Whitton (1996) DNA immunization.
Trends Microbiol. 4: 307-312. 4. C. H. Hsu et at (1996). Immunoprophylaxis
of allergen induced immunoglobulin E synthesis and airway hyper
responsiveness in vivo by genetic immunization. Nature Med. 2: 540-544.
5. S. Brahmachari (1996). Human genome studies and intellectual
property rights: Whither national interest? Current Science 72:708-716.
6. G.Walsh (2000). Biopharmaceutical benchmarks Nature Biotech.
(Adapted from slide show notes)