TSRI Training Program in Molecular Evolution

An Introduction to Molecular Evolution

The term “molecular evolution” is sometimes used to refer to the study and contemplation of the origin of life. We propose a more general definition here, more attuned to the experimental scientist: molecular evolution is the development of new molecular function by evolutionary processes. Next to the scientific method, evolution is the most powerful scientific principle that defines the modern age. It is time that biomedical science follows the lead of evolutionary biology and educates our students to appreciate the significance of natural selection and make use of its potential.

Our training program emphasizes three major topics: the principles of evolution, the central relevance of evolutionary processes at the molecular level to problems of disease, and the use of molecular evolution as a laboratory tool. Here you will find information about the program and about the subject of molecular evolution, and contact information for the scientists involved.

Conceptual boundaries

Evolutionary techniques all rely in some manner on the repeated process of   generating a diverse population of individuals/molecules, selecting members of the population that meet some fitness criterion, and amplifying those selected individuals while introducing new variation to provide a new population of candidates. While one could therefore regard almost any iterative cycle of discovery and development as conforming to this formula, some limits must be drawn. For example, we do not place standard “combinatorial chemistry” (such as for drug discovery) in the category of molecular evolution, nor are we concerned in this program with evolution as the origin of life, or with evolutionary biology at the species level.

Molecular evolution as a discipline

Four ideas compel us to regard molecular evolution as a discrete discipline worthy of study and development:

(1) As best illustrated by the processes of life, evolution is the most powerful method yet discovered or imagined for the creation of function (molecules and systems of molecules that do something).

(2) Through the discoveries of modern biochemistry, molecular biology, structural biology, and chemistry, the molecular mechanisms of biological evolution are now becoming understood. Furthermore, components of the biological evolutionary process can now be extracted for use in the laboratory, so the power of evolution is becoming available to the non-specialist.

(3) Most scientists are not trained in the latest of these techniques, and new developments are emerging rapidly. The tools of molecular evolution are sure to become ever more available throughout the development and application of biotechnology. Most importantly, many do not yet think to use evolution when tackling problems of molecular science, or have an incomplete understanding of its power and pitfalls when they do so.

(4) Evolution is at the heart of two of the most important areas in human health and therapeutic medicine: the immune response and the emergence of therapeutic resistance in pathogenic organisms. It is therefore of crucial and immediate practical importance to biomedical science.

The opportunities we face are perhaps best captured by analogy. By the 1940’s, the term “biochemistry” had been in use for perhaps 30 years, and a well-established set of ideas concerning the processes of living things had been developed. However, new methods of biochemical analysis such as electrophoresis, protein sequencing, and X-ray crystallography were being developed, allowing living systems to be probed and understood as molecular in nature. The full consequences, enabled by both technology and new ways of thinking, could only be guessed at then, but it was clear that big changes were afoot. We stand today at the threshold of a revolution of similar magnitude. The understanding of evolution contributes to a reversal of the reductionist trend of the last century of molecular science, allowing us to manipulate interacting systems as units of function, and comprehend how such systems operate in biology. Our students will lead the development of this emerging field in the years to come.

The practice of molecular evolution is distinct from traditional molecular science in the following ways.

• Reliance on hypothesis-driven experimentation is relaxed (but not abandoned). Evolving systems are often asked to solve multivariate problems in which hypotheses about individual steps cannot profitably be posed. Instead, one constructs an evolution experiment to select the desired answer, and then investigates what individual steps were taken by the system to arrive at that answer. Hypothesis-driven design is often useful in setting up the most efficient such experiments, but room must be allowed for the evolution engine to probe unanticipated solutions.

• Evolution can be “directed” but not “controlled.” Even though we are in the early days of molecular evolution, it is abundantly clear that evolving systems will usually solve problems in ways that the experimenter does not anticipate and may, indeed, sometimes not find useful. For example, unless one is careful, one may evolve an RNA aptamer that binds to the alkylamide linker that connects the intended target to a solid support, rather than to the target itself. In cases in which the generation of candidates is routine (such as by polymerase chain reaction for aptamers), much of the intellectual energy in an evolution experiment is transferred to the design of the selections. How to select for what you want and eliminate what you don’t want requires creativity, attention to detail, and an abiding commitment to perform control experiments.

More generally, it is to be appreciated that evolutionary experiments can run a continuous gamut from true evolution that occurs among self-replicating, mutating, and interacting units (the signature phenomenon here is unregulated feedback) to a stepwise series of selection/amplification/mutation transformations performed entirely by the laboratory worker. The greater the control imposed on the system, the less evolution can occur: evolution cannot be directed from the top down. In a real sense, the field of molecular evolution consists of learning how to operate between these two extremes: how to let molecular systems adapt to challenge in ways that will be informative for the practical problem at hand without imposing too much design, which would unduly restrict the potential space of possible solutions.

• More information comes out of evolving systems than goes in. It is often said, accurately, that evolution is the best way to provide “emergent properties” – loosely defined as systems in which the whole is greater than the sum of the parts. A more general analysis leads to the conclusion that the coin of the evolution realm is information: not only is the evolved function generated during the experiment, but, in many cases, a record of how that function came to be developed can be reconstructed. Lasting lessons that extend beyond the particular experiment frequently emerge. For example, in vitro evolution of enzymes is a popular technique in certain laboratories and biotechnology companies. In many instances, it is shown that efficacious enzyme mutations often occur far away from the active site of the protein, an insight that pays dividends in other fields such as drug development. The affinity maturation of antibodies provides an analogous natural system where the actual process of evolution may be recovered and analyzed in detail. And, of course, the how of pathogen resistance to treatment is the key information needed to devise new ways to attack the evolved organism. The most sophisticated of such insights are providing us with ways to direct pathogen evolution in manageable ways.

Our Mission

Evolution is nature’s most powerful tool for the creation of new function, but is usually discussed only in the context of organisms and species. Practitioners of the molecular sciences – chemistry, molecular biology, chemical biology, biochemistry – are seldom taught to appreciate how evolution shapes molecular function in biology or how evolution can shape molecular function in the laboratory.

Our goal is to enable our students to understand how nature evolves molecules, and to take inspiration from these lessons to understand and use molecular evolution for biomedical science. Many of the most exciting emerging technologies and breakthroughs in the treatment of disease have evolution at their core. In the Scripps tradition, we aim to train a new generation of interdisciplinary scientists to lead this revolution.

The program mentors are organized into three sub-groups, as described here. Two of these groups focus on biomedical areas in which evolution plays a central role, and the third focuses on molecular evolution as a laboratory tool with applications in many fields. With vigorous interactions that already exist among mentors, an instructional framework to provide a common intellectual foundation for the students, activities to foster communication throughout the year, and a strong common commitment to the enterprise, this program will make lasting contributions to biotechnology and basic science.

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