When typhus and smallpox, bubonic plague and cholera periodically swept through Europe during the Middle Ages, society despaired at these “acts of God”. The philosophical changes of the Enlightenment presaged the scientific, industrial and technological advances of the seventeenth and eighteenth centuries, and engendered confidence among practitioners that humankind's problems were ultimately tractable. With the careful application of reason, close observation and experimentation, underlying scientific principles were discovered that revealed laws of physics, physiology and chemistry.
These principles provided the bases for new social policies and industrial advances as the public gradually began to look to science for solutions. By the mid-nineteenth century, for example, improvements in sanitation were implemented to lessen the spread of infectious agents. The search for preventative measures against the common scourges that had begun with Jenner's inoculation of a young boy with cowpox in 1796 ultimately led to the intensive vaccination efforts of our own times. Thus from the throes of disease and pestilence arose several new disciplines, among them public health and immunology.
Early emphasis in immunology was intrinsically practical, such as the discovery by Behring of antitoxins, which were then used to prevent and treat diphtheria. Meanwhile other scientists made inroads into understanding what antitoxins were and what made them effective in the prevention of specific infections. However, as time went on, the study of how host organisms recognize and deal with microbial threats became increasingly divorced from disease prevention. By the last quarter of the twentieth century, enamored of the new molecular technologies and hungry to attain some data to verify or puncture the many speculative paradigms at large, many immunologists became estranged from practical application and biological processes as they dissected the system. Plentiful immune cell types, factors secreted by cells, internal signaling pathways and gene recombination of antigen receptors held us in their thrall and distracted us from the bigger picture. In spite of the plethora of data that we had amassed, it was difficult to integrate the data so that it could be utilized effectively by medicine. Constructs were made, but were often not borne out by practical experience. It seemed that we still didn't know what we thought we did (see Zinkernagel's Commentary on page 181 of this issue).
Why was this? Apart from not having all of the facts, it may be that we weren't asking our questions in an appropriate framework. The brilliant minds that are tackling molecular mechanisms would do well to consider the roots of immunology with a renewed emphasis on the interrelationship between the host and the pathogen. Studies of mechanisms where the ultimate goal is not an understanding of immunity are of lower priority. Comparisons and characterizations that merely add to our already enormous archive of data need redirection. This summer three of four multimillion dollar grants by the Bill and Melinda Gates Foundation went to tuberculosis, HIV and malaria. Once again this brought into sharp focus the plain fact that with all of our newly acquired knowledge we are still far from a routine understanding of major infections and their eradication. Physiology-based basic research is what best refines our immunology edifice so that we can effectively generalize from the particulars gleaned by studying individual pathogens.
Work in other disciplines complements that of immunologists in the effort to outsmart our modern scourges. The human genome sequencing efforts along with the sequencing of pathogen genomes such as Vibrio cholera, when coupled with other approaches, helps in the identification of virulence and survival factors of microbes and in improved treatment approaches for the afflicted. And at a meeting in June of the Society for Economic Botany over 45% of more than a thousand extracts of medicinal plants from Peru were reported to be surprisingly successful in laboratory assays at killing Mycobacterium tuberculosis.
Thus, approaches based on the most modern fruits of biotechnology and on the ancient art of herbal healing can converge in the pursuit of information about infectious disease. This new data, though, will not be put to its best use unless it can be considered in an accurate framework of immune biology. Problems with development of an HIV vaccine or effective immunotherapy for tumors are at least partly due to faulty extrapolations. We need to continually focus our basic research efforts on obtaining physiologic solid that provide a trustworthy foundation for future applications. To test the validity of our paradigms, the endpoints we assess need to be, as Rolf Zinkernagel would probably agree, more about immunity and less about immunology.
It is time for immunologists' delight in the details to be redirected. The molecular mechanisms uncovered must now be harnessed. We need to step back and consider once again how our chosen paths of investigation are leading to a better understanding of our response to infection. The time has come to return to our roots and recognize that only by pursuing the fundamentals of immunity in the context of infectious disease will we be able to routinely apply that knowledge in a systematic and successful fashion. Let's go back to the road less traveled by.
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Looking back to move ahead. Nat Immunol 1, 177 (2000). https://doi.org/10.1038/79706