E.
coli bacteria have different solutions to cope with different types of nutrient
deprivation, including an 'optimistic' response to carbon limitations,
according to a team of researchers. Carbon-limited cells generate a large
number of inactive assembly lines (ribosomes), nitrogen-limited cells turn out
proteins more slowly, and phosphorous-limited cells use only half as many
assembly lines to generate the same number of proteins.
They
were surprised to find that the bacteria had different strategies for dealing
with each of the nutrient restrictions. Even more surprisingly, when carbon was
limited, E. coli responded by building up its protein-production
infrastructure, essentially preparing for a day when carbon would again be
abundant.
It
can help to think of the cell as a toy factory filled with individual assembly
lines (ribosomes) producing toys (proteins), Gitai said. Carbon and nitrogen
are key components of the toys, and phosphorus is vital to the assembly lines.
"When
resources get tight, the cell has a decision to make," Gitai said.
"What's the right usage of materials -- of its available resources? 'Am I
going to devote resources into making more assembly lines or more toys?'"
The
"toys," proteins, are the fundamental building blocks that allow
cells to grow, divide or increase in mass. The faster a cell produces proteins,
the faster it grows. Scientists have known for decades that there is a
straightforward, linear relationship between the number of ribosomes (assembly
lines) and the rate of protein (toy) production in E. coli. This has led to the
widely accepted theory that each of these assembly lines is
"optimized," operating constantly at its peak efficiency to produce
proteins as fast as possible.
"Surprisingly,
the current study radically changes this perspective," said Ned Wingreen,
the Howard A. Prior Professor in the Life Sciences and a professor of molecular
biology and the Lewis-Sigler Institute for Integrative Genomics (LSI) who was
also a corresponding author on the paper.
The
research team discovered that when they limited access to carbon and nitrogen,
key ingredients in the toys, the cells grew slowly but steadily while also
producing more and more assembly lines that sat idle.
"Under
extreme carbon limitation, about half the ribosomes -- half the assembly lines
-- are not even working," said Gitai. "That seems counterintuitive,
right? That seems wasteful. Why build your factory so you have twice as many
assembly lines as you need, and then not run half your assembly lines? We
posited that that might be good for ramping up production when times change,
and sure enough, that's what we saw."
These
bacteria live in feast-or-famine environments like the human gut, where a long
hungry period can end with the sudden arrival of a cheeseburger. "When all
these new nutrients come in, you have the ability to produce faster,"
Gitai said. "You already made all those assembly lines -- they're ready,
and now they can take off, now you can beat your competitors to the punch,
because you don't have to invest in all this infrastructure, making all these
new assembly lines. You have them set up."
This
has interesting implications for E. coli competition strategies, said graduate
student Hsin-Jung (Sophia) Li, who is the first author on the paper.
"Maybe the goal of the bacteria is not to maximize the current
growth," she said. "They might be preparing for better times -- more
forward-looking."
"Overall,
this work gives a new perspective on bacteria, and potentially other organisms,
suggesting they evolved not only to deal with current conditions but also for
life in a changing world," said Wingreen.
"It
has been an exciting journey," said Junyoung Park, a 2016 Ph.D. graduate
in chemical and biological engineering who is now a professor of chemical and
biomolecular engineering at the University of California-Los Angeles. "We
started with a simple observation -- nutrient-specific RNA-to-protein ratios --
but ended up with fascinating insights into the cell's competition
strategies."
E.
coli uses different strategies when different nutrients are limited, the
researchers found. "Carbon-limited cells generate a large number of
inactive assembly lines," Li said. "Nitrogen-limited cells turn out
products more slowly. But phosphorus-limited cells -- this was the exciting
part -- use only half as many assembly lines to generate the same number of
toys."
The
ribosome assembly lines depend on RNA, which is phosphorus-rich, so by limiting
its availability, the researchers essentially made toy ingredients cheap but
assembly lines very expensive.
"The
first surprise was that there's a nutrient-specific story here, that we
achieved the same growth rate three different ways," said Gitai. "But
the real surprise was the phosphorus. We found that if we make the assembly
lines more expensive, suddenly the same assembly lines can pump out toys at the
same rate, using half as many assembly lines. That tells us that under the
carbon- and nitrogen-limited conditions, those assembly lines were actually not
working as fast as they possibly could."
This
overturned the long-held model of the optimized ribosome and prompted
the researchers to investigate the mechanisms at work in the ribosomes, using a
combination of quantitative experiments, led by Li, buttressed by the modeling
and theory work of Wingreen and Zhiyuan Li, an associate research scholar in
the Princeton Center for Theoretical Science. They also collaborated with
Christopher King, who graduated in 2017 with a physics concentration, and
Joshua Rabinowitz, a professor of chemistry and LSI.
Converting
the enormous quantities of biological data into a clear theory illustrates the
"charm" of data science, said Zhiyuan Li, from processing the
measurements into "individual pearls, and then stringing them together
into a beautiful necklace by mathematical modeling that reveals the underlying
connections."
"This
paper is a great contribution to the community," said Ron Milo, principal
investigator of the Department of Plant and Environmental Sciences at the
Weizmann Institute of Science, who was not involved in this research. "It
gives us better insight into how cells make decisions regarding their
allocation of resources, which can be relevant for biotechnological production
of value-added chemicals."
The
research also raises a new question, said Gitai: "Do many bacterial
species use this strategy? You could imagine that in a community of bacteria,
there are some species that are optimists, some that are pessimists. ... It's
kind of an appealing idea that it's this 'eternal optimism' of E. coli that
allows it to trade off, if you will, between immediate benefit and the longer
term. When times are bad, it's going to say, 'Okay, I'm not going to worry
about doing as well as I possibly can right now, but I'll prepare for when
times get better.'"
One
of the biggest surprises of the research was that such a thoroughly studied
bacteria still has tricks up its microscopic sleeves, said Sophia Li.
"Even E. coli, arguably the most well-understood organism, can still give
us new surprises and interesting biology to learn."
See:
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
