Abstract
Hypotheses and theories are essential constituents of the scientific method. Many vaccinologists are unaware that the problems they try to solve are mostly inverse problems that consist in imagining what could bring about a desired outcome. An inverse problem starts with the result and tries to guess what are the multiple causes that could have produced it. Compared to the usual direct scientific problems that start with the causes and derive or calculate the results using deductive reasoning and known mechanisms, solving an inverse problem uses a less reliable inductive approach and requires the development of a theoretical model that may have different solutions or none at all. Unsuccessful attempts to solve inverse problems in HIV vaccinology by reductionist methods, systems biology and structure-based reverse vaccinology are described. The popular strategy known as rational vaccine design is unable to solve the multiple inverse problems faced by HIV vaccine developers. The term “rational” is derived from “rational drug design” which uses the 3D structure of a biological target for designing molecules that will selectively bind to it and inhibit its biological activity. In vaccine design, however, the word “rational” simply means that the investigator is concentrating on parts of the system for which molecular information is available. The economist and Nobel laureate Herbert Simon introduced the concept of “bounded rationality” to explain why the complexity of the world economic system makes it impossible, for instance, to predict an event like the financial crash of 2007–2008. Humans always operate under unavoidable constraints such as insufficient information, a limited capacity to process huge amounts of data and a limited amount of time available to reach a decision. Such limitations always prevent us from achieving the complete understanding and optimization of a complex system that would be needed to achieve a truly rational design process. This is why the complexity of the human immune system prevents us from rationally designing an HIV vaccine by solving inverse problems.
Highlights
Most scientists have heard of the scientific method but usually have rather vague ideas about what it might be
Methodological reductionism has guided the development of molecular biology for half a century and was widely accepted because it was able to describe biological systems in terms of its physicochemical properties, giving rise to the belief that biology could be reduced to chemistry and physics [11, 12, 34]
Such metaphoric language seems to attribute to HIV a goal directed capacity to defeat the host immune system (IS), it is only the highly error-prone activity of the viral reverse transcriptase (RT) that is responsible for the enormous structural plasticity and antigenic variability of the Env glycoprotein, allowing the virus to evade immune control [71, 122]
Summary
Most scientists have heard of the scientific method but usually have rather vague ideas about what it might be. A major difficulty for explaining the success of the scientific method is due to the fact that scientific experiments in biology, for instance, produce results that regularly require continual self-correction because the data that are obtained are always approximations consisting of mixtures of “real” meaningful signals (relevant to what is being investigated) together with spurious “noise” due to random errors [7]. This prevents absolutely certain and reliable knowledge to be obtained and explains why the scientific method has frequently failed to solve problems in the past. It appears that the widespread expectation that the rational design of an HIV vaccine is likely to be more successful than tentative, small scale trial-and-error vaccine experimentation may have made it more difficult for vaccinologists to solve the inverse problems they are faced with
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