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Can an Engineer Fix an Immune System?–Rethinking theoretical biology

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Abstract

In an instant classic paper (Lazebnik, in Cancer Cell 2(3); 2002: 179–182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and “fix” biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik’s analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and “troubleshooting”, aimed at the identification of a “fix” for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model—the danger model with regulatory cells— and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper.

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Notes

  1. Despite the presence of a few circuit schematics no knowledge of electronics is required to understand the gist of the argument developed in the paper.

  2. I propose the term “modeling envelope” for the range of conditions where the correspondence rules hold with the stipulated accuracy, taking inspiration from the term “operational envelope” used in electronic engineering to refer to the range of conditions where a circuit complies with the stipulated specifications.

  3. Some linguists consider language as a cognitive artifact that, by imposing sequentiality, fosters the appearance of a more articulate, analytic, and hierarchical form of thought relatively to non-linguistic forms. For example, taking inspiration form the 18th century philosopher Condillac, linguist Raffaele Simone distinguishes a simultaneous and a sequential form of intelligence. In his words, “signs are responsible for a real cognitive revolution in man, for they permit the transition from a merely simultaneous thinking to a sequential representation of ideas. ⋯ The thus gained successivity of ideas enhances the development of all the operations of mind and introduces a quite new principle of thinking” (Simone 1987, p.68)

  4. The physical transfer (rather than, say, simple inactivation or resorption) of the pMHC from APC to Treg is essential only to realize the second advantage described in the text.

  5. Tissue-restricted rather than the equally plausible tissue-specific to avoid a conflict of acronyms with “tumor-specific antigen”.

  6. Unless this capacity has been disabled by the mutations that led to uncontrolled proliferation.

  7. This little provocation was inspired by the following statement by Russo (Russo 2004, p. 18): “A simple criterion to verify whether a theory is “scientific” is to check whether one can compile an exercise manual; if that is not possible, it’s certainly not a scientific theory.”

  8. Note that if the sites where SMM are located are also sites of ectopic expression of host TRA, the corresponding tissues must be protected from inflammation during the therapy.

  9. In this description I am not considering the role of humoral immune response, whose model the DMR inherits from the DM. Taking it into account would lead to the possible production of antibodies for the TSA, which might opsonize the cells of the SMM and lead to their demise even without prior inflammation.

  10. Typically, molecular mimicry is considered as possible source of autoimmune attack rather than as a protective element (Fasano and Shea-Donohue 2005).

  11. Of course, and most importantly, the choice of the problem must remain a primary ethical concern of the scientist.

  12. “The qualitative study of phenomena [must] necessarily precede their quantitative study.”

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Acknowledgments

Many thanks to Daniel Marbach for bringing to my attention Lazebnik’s paper, to Enrica Cantamessa and to Maurizio and Raffaele Persello for their help in reconstructing the history of the braking circuit, and to Delia Giallonardo, Roberta Maestri, Marco Palombi, Maurizio Persello, Markus Waibel, and to an anonymous reviewer for their precious feedback on the manuscript.

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    Claudio Mattiussi

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Mattiussi, C. Can an Engineer Fix an Immune System?–Rethinking theoretical biology. Acta Biotheor 61, 223–258 (2013). https://doi.org/10.1007/s10441-013-9180-x

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