[2005/03/14] The Future of Biology: Reverse Engineering
The Future of Biology: Reverse Engineering 03/14/2005 Just as an
engineer can model the feedback controls required in an autopilot system
for an aircraft, the biologist can construct models of cellular networks
to try to understand how they work. “The hallmark of a good
feedback control design is a resulting closed loop system that is
stable and robust to modeling errors and parameter variation
in the plant”, [i.e., the system], “and achieves a desired output value
quickly without unduly large actuation signals at the plant input,”
explain Claire J. Tomlin and Jeffrey D. Axelrod of Stanford in a
Commentary in PNAS.1 (Emphasis added in all
quotes.) But are the analytical principles of reverse engineering
relevant to biological systems? Yes, they continue: “Some insightful
recent papers advocate a similar modular decomposition of
biological systems according to the well defined functional parts used
in engineering and, specifically, engineering control
theory.” One example they focus on is the bacterial
heat shock response recently modeled by El-Samad et al.2
. These commentators seem quite amazed at the technology of
this biological system:
In a recent issue of PNAS, El-Samad et
al. showed that the mechanism used in Escherichia coli to
combat heat shock is just what a well trained control engineer would
design, given the signals and the functions available. Living cells defend themselves from a vast array of
environmental insults. One such environmental stress is exposure
to temperatures significantly above the range in which an organism
normally lives. Heat unfolds proteins by introducing thermal
energy that is sufficient to overcome the noncovalent molecular
interactions that maintain their tertiary structures. Evidently,
this threat has been ubiquitous throughout the evolution
[sic] of most life forms. Organisms respond with a
highly conserved response that involves the induced expression of
heat shock proteins. These proteins include molecular
chaperones that ordinarily help to fold newly synthesized
proteins and in this context help to refold denatured
proteins. They also include proteases [enzymes that
disassemble damaged proteins] and, in eukaryotes, a proteolytic
multiprotein complex called the proteasome, which serve to degrade
denatured proteins that are otherwise harmful or even lethal to the
cell. Sufficient production of chaperones and proteases can
rescue the cell from death by repairing or ridding the cell
of damaged proteins.
This is no simple trick.
“The challenge to the cell is that the task is gargantuan,” they
exclaim. Thousands of protein parts – up to a quarter of the cell’s
protein inventory – must be generated rapidly in times of heat
stress. But like an army with nothing to do, a large heat-shock
response force is too expensive to maintain all the time. Instead,
the rescuers are drafted into action when needed by an elaborate system of
sensors, feedback and feed-forward loops, and protein networks.
The interesting thing about this Commentary, however, is not just
the bacterial system, amazing as it is. It’s the way the scientists
approached the system to understand it. “Viewing the heat shock
response as a control engineer would,” they continue, El-Samad
et al. treated it like a robust system and reverse-engineered it
into a mathematical model, then ran simulations to see if it reacted like
the biological system. They found that two feedback loops were
finely tuned to each other to provide robustness against single-parameter
fluctuations. By altering the parameters in their model, they could
detect influences on the response time and the number of proteins
generated. This approach gave them a handle on what was going on in
the cell.
The analysis in El-Samad et
al. is important not just because it captures the behavior of
the system, but because it decomposes the mechanism into intuitively
comprehensible parts. If the heat shock mechanism can be
described and understood in terms of engineering
control principles, it will surely be informative to apply
these principles to a broad array of cellular regulatory
mechanisms and thereby reveal the control architecture under
which they operate.
With the flood of data hitting
molecular biologists in the post-genomic era, they explain, this
reverse-engineering approach is much more promising than identifying the
function of each protein part, because:
...the physiologically relevant
functions of the majority of proteins encoded in most genomes are
either poorly understood or not understood at all. One can
imagine that, by combining these data with measurements of response
profiles, it may be possible to deduce the presence of modular
control features, such as feedforward or feedback
paths, and the kind of control function that the system
uses. It may even be possible to examine the response
characteristics of a given system, for example, a rapid and sustained
output, as seen here, or an oscillation, and to draw inferences about
the conditions under which a mechanism is built to
function. This, in turn, could help in deducing what other
signals are participating in the system behavior.
The
commentators clearly see this example as a positive step forward toward
the ultimate goal, “to predict, from the response characteristics, the
overall function of the biological network.” They hope
other biologists will follow the lead of El-Samad et al. Such
reverse engineering may be “the most effective means” of modeling unknown
cellular systems, they end: “Certainly, these kinds of analyses promise
to raise the bar for understanding biological processes.”
1Tomlin and Axelrod, “Understanding biology by
reverse engineering the control,” Proceedings
of the National Academy of Sciences USA, 10.1073/pnas.0500276102,
published online before print March 14, 2005. 2El-Samad,
Kurata, Doyle, Gross and Khammash, “Surviving heat shock: Control
strategies for robustness and performance,” Proceedings
of the National Academy of Sciences USA, 10.1073/pnas.0403510102,
published online before print January 24, 2005.
Reader, please understand the
significance of this commentary. Not only did El-Samad et
al. demonstrate that the design approach works, but these
commentators praised it as the best way to understand biology
(notice their title). That implies all of biology, not just
the heat shock response in bacteria, would be better served with the
design approach. This is a powerful affirmation of intelligent
design theory from scientists outside the I.D. camp.
Sure, they referred to evolution a couple of times, but the statements
were incidental and worthless. Reverse engineering needs Darwinism
like teenagers need a pack of cigarettes. Evolutionary theory
contributes nothing to this approach; it is just a habit, full of poison
and hot air. Design theory breaks out of the habit and provides a
fresh new beginning. These commentators started their piece with a
long paragraph about how engineers design models of aircraft autopilot
systems; then they drew clear, unambiguous parallels to biological
systems. If we need to become design engineers to understand
biology, then attributing the origin of the systems to chance,
undirected processes is foolish. Darwinistas, your revolution has
failed. Get out of the way, or get with the program. We
don’t need your tall tales and unworkable utopian dreams any more.
The future of biology belongs to the engineers who appreciate good
design when they see it. It’s amazing to ponder that a
cell is programmed to deal with heat shock better than a well-trained
civil defense system can deal with a regional heat wave. How does
a cell, without eyes and brains, manage to recruit thousands of
highly-specialized workers to help their brethren in need? (Did
you notice some of the rescuers are called chaperones? Evidently,
the same nurses who bring newborn proteins into the world also know how
to treat heat stroke.) And to think this is just one of many such
systems working simultaneously in the cell to respond to a host of
contingencies is truly staggering. Notice also how the
commentators described the heat shock response system as “just what a
well trained control engineer would design.” Wonder Who that could
be? Tinkerbell? Not with her method of designing. No matter; leaders in the I.D. movement emphasize
that it is not necessary to identify the Designer to detect
design. But they also teach that good science requires following
the evidence wherever it leads.
[2005/03/14] The Future of Biology: Reverse Engineering
