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'Chasing Ehrlich's dream: the quest for magic bullets'

by Sandip K Basu,
National Institute of Immunology

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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 PAS.

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 and HIV.

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 us.

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 goals.

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.

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