Making a bet at a conference led to a Marsden Fund research grant for Canterbury University’s Dr Ren Dobson. His team are now looking into how nature – in, to our eyes, an apparently haphazard way – manages to evolve new enzyme functions in response to life in a novel environment. By investigating E. coli, the team are providing insight into both causes of antibiotic resistance and the nature evolution itself.
What is an enzyme exactly?
Enzymes are protein catalysts that nature uses to speed up the chemical processes of life. Enzymes
are the work horses of cells that give organisms the ability to perform a broad range of cellular chemistry—from breaking down food to breathing air. For example, the enzyme that we are
studying, pyruvate kinase, performs the last step in glycolysis, which breaks down glucose
molecules and turns them into cellular energy. Although we are studying the enzyme in E. coli, the
chemistry that pyruvate kinase catalyses is the same in humans (and most organisms).
How do you go about watching an enzyme evolve?
It is tricky to do this, since evolution happens on long time scales. However, Richard Lenski, from
Michigan State University, has been watching a bacterium (Escherichia coli) evolve by putting
12 identical populations on a starvation diet and seeing how they respond. Since 1988, he and his
lab have been diligently culturing the bacteria, day after day. Although the bacteria initially grew
poorly, over time random mutations in the genome were inherited in successive generations and the
E. coli increased in fitness—that is, because of the changes in their genomes, and therefore in their
proteins, they got better at growing quickly on the starvation diet.
Since E. coli have a fast generation time (more than six generations a day) Lenski and his
colleagues have “watched” evolution for more than 70,000 generations (more than 1 million human
years!). By sequencing the genomes of the 12 bacterial populations, he is able to track any changes
in the enzymes that the bacteria use in their daily functions. The key for us is that he found that
the enzyme pyruvate kinase was altered in all 12 populations, which was unusual. Importantly, we
could see this enzyme evolve not once, but 12 times!
And who won your bet?
Where we became involved in all this was to ask the question – what are these mutations in
pyruvate kinase doing to increase the fitness of the bacteria? Richard Lenski thought that the
mutations destroyed all function of pyruvate kinase, but we thought the opposite—they were
changing the function. It turns out that the mutations in pyruvate kinase only change the way that
it behaves and they don’t destroy the enzyme. In fact, several of the mutations made the enzyme
much better at doing its chemistry. But the most interesting change was that the evolved enzymes
were often regulated differently. This was a conundrum, since the mutations were not positioned
within the regulation domain of the protein. Very recent data we have collected suggests that the
change in enzyme function may be caused by the mutations altering the way the enzyme moves.
If mutations are changing the function of enzymes when you wouldn’t expect it, does that
mean Mother Nature is more deliberate than we think?
No, Mother Nature is making random mutations all of the time, but the vast majority of them don’t
stick around for very long. It’s quite lucky that there are some that are beneficial!
Should we be scared by E coli’s ability to evolve?
All organisms have the ability to evolve (E. coli, since it is a bacterium, has the ability to evolve
faster as it has a very short generation time), but we shouldn’t be scared of this phenomenon –
don’t expect a science-fiction mutant to take over the world any time soon! On a more serious note,
though, it is important to study how E. coli evolves so that we can understand how it develops
antibiotic resistance, for instance. The random mutations that benefit the cells can also thwart our
efforts to kill them. The more we learn about enzyme evolution, the better we can develop methods
to overcome their resistance.
These interviews showcase researchers supported by the Marsden Fund which, since 1994,
has been supporting fundamental, investigator-led research in New Zealand.