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