Posted on 03/15/2005 2:41:19 PM PST by Michael_Michaelangelo
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 (see 01/26/2005 entry). 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.
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.
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.
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 (see 03/11/2005 commentary). 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.
I can't resist attaching the "newbie" label to our friend Patrick.....
People who are disconnected from others are called autistic. Interestingly, when they excel at something it is usually math or pure logic.
Most knowledge of the world requires trusting the word of others.
????
All of us except Patrick joined FR in '98....
Of course, what is “knowledge” and one’s valuation of “certainty” of said knowledge can be very personal. So this list ought to be taken only as input for personal reflection.
I would very much appreciate any further suggestions and would especially like to hear others’ views on valuation of the “certainty” of knowledge!
Coffee deprived placemarker.
True, but from my comparatively limited experience around here, any sign-up date where the year starts with "19" is by this time no longer a newbie. But gloat if you must.
Well, it was somewhat irresistable....
Two or three seem capable of being combined, somehow, especially these two:
4. Evidence/Historical fact, uninterpreted: I have verifiable evidence Reagan was once President.In each case, the "knowledge" comes from examining the evidence (presumably it's objectively verifiable) and then arriving at a conclusion. The conclusion may be virtually self-evident (Reagan) or it may be controversial. Such controversy could be due to a number of factors, such as limited evidence, or dubious reliability of the evidence, or questionable thinking about the evidence, etc. All of which leads us to:
10. Evidence/Historical fact, interpreted: I have an interpretation of the fossil evidence in the geologic record.
11. Determined facts: I accept this as fact because of a consensus or veto determination by others, i.e. I trust that these experts know what they are talking about.On this type of "knowledge," (accepted consensus) back in 1,050, I said this:
We often say that "the consensus of astronomers is that [blah blah]." And we routinely cite that as the reason for our acceptance of that opinion. I do this frequently. When I do, what I mean is: (a) the existence of the consensus is itself a fact; (b) the experts have reviewed the matter far more thoroughly than I could, and I respect the quality of their work generally; (c) I have no reason to doubt their thinking in this matter; and (d) I personally don't know, which is why I'm relying on experts.
Since this is a compilation so that we can understand one another better, I’ve taken the liberty of interpreting your last post (and a few earlier) into what I believe is a “Patrick Henry” list of types of knowledge and valuations of certainty. I’ve included mine below for comparison and to encourage others to submit their own.
Please let me know where I have misinterpreted your posts!
PatrickHenry’s types of “knowledge” and valuation of certainties:
1. Theological knowledge, direct revelation: I have Spiritual understanding directly from God concerning this issue, it didn't come from me.
2. Theological knowledge, indirect revelation: I believe in a revelation experienced by another, i.e. Scripture, etc.
3. Theological knowledge, Imaginings: I have personally surmised my own understanding of this spiritual issue.
3. Evidence/Historical fact, whether uninterpreted or interpreted: I have verifiable evidence Reagan was once President and I have an interpretation of the fossil evidence in the geologic recordwith your #4
4. Evidence/Historical fact, uninterpreted: I have verifiable evidence Reagan was once President.and your #10
10. Evidence/Historical fact, interpreted: I have an interpretation of the fossil evidence in the geologic recordinto one item:
Conclusion from evidence: I conclude from the verifiable evidence that ...This would cover a multitude of conclusions, some being obvious (Reagan was president) and some being controversial. The conclusion itself (and the underlying data) is that person's "knowledge." The conclusion's accuracy is always going to be an open question, as most reasonable people will admit. It depends on the quality and sufficiency of the evidence, and the validity of the reasoning that leads to the conclusion.
5. Trust in a Mentor: I trust this particular person to always tell me the truth, therefore I know …with my #6
6. Determined facts: I accept this as fact because (a) the existence of the consensus is itself a fact; (b) the experts have reviewed the matter far more thoroughly than I could, and I respect the quality of their work generally; (c) I have no reason to doubt their thinking in this matter; and (d) I personally don't know, which is why I'm relying on experts.into one form of provisional "knowledge" as follows:
Acceptance of another's opinion: I provisionally accept the opinion of X (an individual or group) as knowledge because (a) I haven't worked it out for myself; and (b) I have what I regard as good reason for confidence in X.This leaves the matter open, depending on whether confidence in X was justified, and whether X really knows what's going on. Thus, as with most knowledge, the acceptance is provisional.
Why Did Modern Science Arise in the West?
There have been numerous great civilizations -- in India, China, Egypt, and Mesopotamia -- that flourished long before the modern Western civilization of Europe. They have all contributed unique arts and innovations. They have maintained long centuries of peace and relative prosperity for their citizens. But there is no other civilization that compares to the West in terms of its rapid growth of technology, its scientific knowledge of nature, and its economic power. Within a period of about 400 years, the West has moved from the 'Dark Ages' of feudalism and medieval superstition to the present age of science and technology. How did this happen? What philosophical ideas were behind it?
Alfred North Whitehead, the 20th century philosopher and historian, although not a religious man in any traditional sense, has offered an answer to this question that comes from an unlikely direction:
"I do not think, however, that I have even yet brought out the greatest contribution of medievalism to the formation of the scientific movement. I mean the inexpungable belief that every detailed occurrence can be correlated with its antecedents in a perfectly definite manner, exemplifying general principles (causality). Without this belief the incredible labours of scientists would be without hope. It is this instinctive conviction, vividly poised before the imagination, which is the motive power of research: -- that there is a secret, a secret which can be unveiled. How has this conviction been so vividly implanted on the European mind?
"When we compare this tone of thought in Europe with the attitude of other civilizations when left to themselves, there seems but one source for its origin. It must come from the medieval insistence on the rationality of God, conceived as with the personal energy of Jehovah and with the rationality of a Greek philosopher. Every detail was supervised and ordered: the search into nature could only result in the vindication of the faith in rationality. Remember that I am not talking of the explicit beliefs of a few individuals. What I mean is the impress on the European mind arising from the unquestioned faith of centuries. By this I mean the instinctive tone of thought and not a mere creed of words.
"In Asia, the conceptions of God were of a being who was either too arbitrary or too impersonal for such ideas to have much effect on instinctive habits of mind. Any definite occurrence might be due to the fiat of an irrational despot, or might issue from some impersonal, inscrutable origin of things. There was not the same confidence as in the intelligible rationality of a personal being. I am not arguing that the European trust in the scrutability of nature was logically justified even by its own theology. My only point is to understand how it arose. My explanation is that the faith in the possibility of science, generated antecedently to the development of modern scientific theory, is an unconscious derivative of medieval theology."
-- Alfred North Whitehead, Science and the Modern World, p. 18-19.
There are two ways acceptance is provisional. Whenever we place our trust in authority, concensus, or a majority opinion, we are obliged to accept views other than what our own knowledge is sufficient to see. And so you say. This kind of acceptance admits that Descartes' most-commonly- distributed-commodity-in-the-world-called-reason involves serious limitations and is not as common as was thought (especially in terms of capacity and capability).
The second way in which acceptance is provisional is in the recognition that in fact all knowledge is provisional insofar as we are ethical. That is what Socrates says on the matter. If we don't admit that all knowledge is provisional, we raise one of the kinds of knowledge to an absolute. Certainty is nice, but it is partial. Even the principles of mathematics that were so appealing to Plato are limited--just ask StJacques.
We take so much for granted, ckilmer, rather than try to understand how things actually came to be as they are. The civilizations of the East never produced any kind of systematic science; and Whitehead is correct to note that there was nothing in their otherwise brilliant cultures that could conduce to that end. The inconvenient fact (for many) is that science rose in a Christian culture, from classical and Christian roots.
Thank you ever so much, ckilmer, for posting this choice selection from Whitehead.
Then again, the Greeks didn't accomplish what the Europeans did; and perhaps that bolsters Whitehead's point. The intense theological pursuits of the Middle Ages perhaps put in place the sorts of thought processes necessary to assimilate those ideas into a wider system of knowledge.
I've also heard it claimed that the Black Death helped with the transition -- among other things, the surfeit of old clothes/rags enabled the production of cheap paper, and thus a means of distributing information.... But then again, the Chinese had paper, and didn't accomplish the same things.
If we understand Whitehead's point as being that Christianity "set the tone," not only for scientific progress, but also for the ideas of individual worth and individual rights, then it appears that he was right.
Today's youth just don't respect the Olympian gods. What's this world coming to?
Excellent insights, r9etb. Well said. Thank you so very much for writing!
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