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Jack W. Szostak, Ph.D.

How did life begin? Scientists may never know exactly
how a swirl of chemicals came together to form the first
living organisms some 4 billion years ago, but Jack
Szostak is working to recreate a hypothetical model of
this process in the laboratory. By building simple
cell-like structures in a test tube, he and his
colleagues are attempting to establish a plausible path
that led primitive cells to emerge from simple
chemicals. Ultimately, Szostak hopes to answer
fundamental questions about evolution's earliest steps.

At the outset of his career, Szostak made pioneering
contributions to the field of genetics. His discoveries
helped clarify the events that lead to chromosomal
recombination—the reshuffling of genes that occurs
during meiosis—and the function of telomeres, the
specialized DNA sequences at the tips of chromosomes. He
is also credited with the construction of the world's
first yeast artificial chromosome. That feat helped
scientists to map the location of genes in mammals and
to develop techniques for manipulating genes.

But a Nobel Prize–winning discovery in the 1980s by
current HHMI President Tom Cech and Sidney Altman
propelled Szostak down a new research path. The pair
independently demonstrated that RNA, the sister molecule
of DNA, can catalyze certain chemical reactions inside
cells, a job previously thought to be the exclusive
domain of proteins. Until then, RNA was thought to have
just one function: storing the genetic information cells
need to build proteins. This new revelation about RNA's
dual role suggested to some scientists, including
Szostak, that RNA likely existed long before DNA or
proteins because it might be able to catalyze its own
reproduction. Their discovery made it easier to think
about the origin of life, Szostak says. "They inspired
me to try to think of ways to make RNAs in the lab that
could catalyze their own replication."

By 1991, Szostak had shifted the entire focus of his
lab to evolving new functional RNAs and other molecules
in a test tube. As the basis for his work, Szostak
developed a technique called in vitro selection to study
the evolution of biological molecules. This method
screens vast numbers of molecules for a predetermined
function, such as the ability to catalyze a specific
chemical reaction or bind a target molecule. Those that
don't fit the desired profile are filtered out and the
process is repeated over and over again until
researchers find the molecule that does a particular
job.

Using in vitro selection as a way to apply the forces
of natural selection in a laboratory setting, Szostak
and his colleagues evolved RNAs that bind to ATP, a
common biological substrate, from a massive library of
1,000 trillion random RNA sequences. Such artificially
evolved RNAs that bind to target molecules are now known
as aptamers, and they have many potential applications
in the diagnosis and treatment of diseases and as
biosensors. Szostak's team has also used in vitro
selection to evolve catalytic RNAs, called ribozymes,
from trillions of random-sequence RNA molecules. "Many
new ribozymes have now been evolved by in vitro
selection," Szostak says. "The range of chemistries
these artificially produced ribozymes can catalyze is
much greater than that carried out by ribozymes found in
living cells. It raises the interesting possibility that
in an earlier era, ribozymes might have played a wider
role than they do today." Szostak is also investigating
in vitro selection for its ability to identify small
molecules that bind specific target proteins. If
successful, the technique may provide a streamlined way
to pinpoint potentially useful drugs to fight disease.

Today, Szostak's main focus is the construction of a
simple, artificial cell that can grow and divide as well
as evolve in a Darwinian sense to adapt to its changing
environment. To do this, he is attempting to make and
then combine two self-replicating systems: a nucleic
acid (such as RNA or DNA) that can transmit genetic
information and a simple membrane-bound vesicle that
keeps the nucleic acid chains from drifting apart. A
major challenge is coordinating the growth and division
of the membrane-bound vesicle with the replication of
its contents. Szostak has found that the nucleic acids
themselves can drive the growth of the fatty acid
membrane; as they replicate, the internal osmotic
pressure increases, swelling the vesicle and stretching
the membrane so that it absorbs fatty acids from other
vesicles that are under less internal pressure. Cells
with faster nucleic acid replication should therefore
grow faster than cells with slower nucleic acid
replication. In this way, simple physical principles
coordinate the replication of the nucleic acid genome
and the replication of the rest of the cell structure,
leading to the emergence of natural selection and
Darwinian evolution based on competition between
cells.

Dr. Szostak is also Professor of Genetics at
Harvard Medical School and Alexander Rich Distinguished
Investigator at Massachusetts General Hospital,
Boston.

RESEARCH ABSTRACT
SUMMARY:

To increase understanding of the origin and early
evolution of life, Jack Szostak explores the origins of
functional biological macromolecules and membranes.
View
Research Abstract

Photo: Mark Wilson

HHMI INVESTIGATOR

1998–Present
Massachusetts General
Hospital

B.S., cell
biology, McGill University, Montreal,
Canada

Ph.D.,
biochemistry, Cornell
University

National
Academy of Sciences

American
Academy of Arts and
Sciences

New York
Academy of Sciences

National
Academy of Sciences Award in Molecular
Biology

Hans Sigrist
Prize, University of Bern,
Switzerland

Genetics
Society of America Medal

The 2006
Lasker Award

2008 H.P.
Heineken Prize for Biochemistry and Biophysics,
Royal Netherlands Academy of Arts and
Sciences

The
Origins of Function in Biological Nucleic Acids,
Proteins, and
Membranes

AT HHMI

Researchers
Build Model Protocell Capable of Copying
DNA
(06.04.08)

Simulating
Evolution: Artificial Enzymes Designed in the
Laboratory
(08.15.07)

Lasker
Award for Basic Medical Research
(09.16.06)

Evolution
Is Our Laboratory

Battle of
the Bubbles May Have Sparked Evolution
(09.02.04)

Clays May
Have Aided Formation of Primordial
Cells
(10.23.03)

A
World Apart

Evidence
that a Ribozyme Evolved Multiple Times
(10.31.01)

Researchers
Evolve New Proteins in the Test Tube
(04.04.01)

ON THE WEB

Exploring Life's
Origins
(exploringorigins.org)

The
2006 Lasker Award
(laskerfoundation.org)

The
Szostak Lab
(harvard.edu)

Search
PubMed

Back
to Top

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