What does it mean to develop an HIV vaccine by rational design?
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REVIEW
What does it mean to develop an HIV vaccine by rational design? Marc H. V. van Regenmortel1 Received: 18 July 2020 / Accepted: 3 September 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goaldirected intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.
Design A scientist’s ability to design something extremely complex finds its conceptual origin in the intention of the designer to achieve a certain goal, although the design procedure itself is highly tentative and mostly devoid of any logical or methodological rules that will necessarily lead to success. Metaphoric language is extremely widespread in molecular biology, and the “Book of Life” metaphor was described by Kay [1, p. 296] as producing information without meaning, codes with no language, messages with no sender, and writing devoid of authorship. The metaphors of molecular recognition, attraction and repulsion are widely used in biology for describing the stereocomplementarity between molecules that selectively bind to each other, and the term “design” is itself a useful metaphor for analyzing the many useful biological functions that seem to arise from the activity of a designer [2, p. 271]. Design is thus a metaphor for referring to attempts made to achieve a particular intentional Handling Editor: Tim Skern.
goal by the use of certain procedures but without necessarily achieving it. Although it used to be commonly accepted that, in biology, structure causes function, it seems more relevant to say that it is actually binding that causes function. The belief that the structure of a protein causes a biological function arises from a misunderstanding of the notion of causality, which is
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