Scientific Clearing House

New paper on steroid-mediated gene induction

Carson Chow — Mon, 23 Jan 2012 17:25:37 +0000

A follow-up to our PNAS paper on a new theory of steroid-mediated gene induction is now available on PLoS One here. The title and abstract is below. In the first paper, we proposed a general mathematical framework to compute how much protein will be produced from a steroid-mediated gene. It had been noted in the past that the dose response curve of product given steroid amount follows a Michaelis-Menten curve or first order Hill function (e.g. Product = Amax [S]/(EC50+[S], where [S] is the added steroid concentration).. In our previous work, we exploited this fact and showed that a complete closed form expression for the dose response curve could be written down for an arbitrary number of linked reactions. The formula also indicates how added cofactors could increase or decrease the Amax or EC50. What we do in this paper is to show how this expression can be used to predict the mechanism and order in the sequence of reactions a given cofactor will act by analyzing how two cofactors affect the Amax and EC50.

Deducing the Temporal Order of Cofactor Function in Ligand-Regulated Gene Transcription: Theory and Experimental Verification

Edward J. Dougherty, Chunhua Guo, S. Stoney Simons Jr, Carson C. Chow

Abstract: Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available.

Are Strads overrated?

Carson Chow — Tue, 17 Jan 2012 18:05:33 +0000

In classical music, there is a mystique surrounding Seventeenth Century violins made in Cremona, Italy and especially the Stradivarius. These violins can cost millions of dollars and are supposed to be unmatched in sound quality by any violin made since. People have speculated that it is the wood, the glue, the varnish or some mysterious unknown quantity that makes them so much better although nothing has ever been pinpointed. Now, a study recently published in PNAS (see here) finds that the superiority of the Stradivarius may be more myth than substance. The study found that top-level violinists preferred modern violins to the classic Cremonese ones. It was the first every study that was double blinded so that neither the violinist nor tester knew which violin was being played. It is well-known in psychology that people’s preferences are strongly influenced by context. An example, is that wines perform better in taste tests when they are believed to be more expensive. The study has been criticized in that it was done in a hotel room and not on a concert stage. I’m sure a followup is in the works.

Talk at UAB

Carson Chow — Fri, 13 Jan 2012 15:42:31 +0000

I’m currently at the University of Alabama, Birmingham. I’ll be giving a talk this afternoon on obesity. This is a version of previous ones I’ve given before although I have updated the slides, which can be obtained here. (Note, my talks seem to have lots of slides because the animations are reproduced in PDF by recreating the slide).

Metaphysics as mathematics

Carson Chow — Mon, 09 Jan 2012 18:08:26 +0000

One of the branches of western philosophy is metaphysics, which asks about the nature of being and the world. It is the extension of what was once known as natural philosophy. Modern science is empirical natural philosophy. Instead of trying to answer questions about how the world is the way it is by thinking about it, it makes hypotheses and tests them experimentally or observationally. The late twentieth century was a time when physics, specifically string theory, drifted back towards metaphysics. String theorists attempt to answer questions about our reality by constructing theories that are mostly grounded on mathematically aesthetic principles. I have no real problem with string theory per se, except in its claim to be more “fundamental” than other branches of physics. As I have argued before (e.g. here), there are fundamental concepts at all energy and length scales.

What I will argue here is that we have been misguided in trying to reunite metaphysics with science. As I have argued before (e.g. here and here), it is not even simple to define what is meant by “fundamental laws” or a “theory of everything”. If our universe can be approximated arbitrarily accurately by a computable one (yes I know some of you disagree with this assertion), then what constitutes the underlying theory? Is it the program that generates the universe? Is it the most simple description (in which case it is not computable)? Or is it something else?

While metaphysics as science is a dead-end for me, metaphysics as mathematics is ripe for very interesting insights. Instead of asking directly about “our” reality, we should be asking about hypothetical realities. We should be doing philosophy of science and metaphysics on artificial worlds. This would then be a controlled situation. Instead of speculating about the underlying laws of our universe, we can simply specify a given set of properties in some hypothetical or simulated universe and probe the consequences. We can do this at arbitrary levels as well – universe, multiverse, meta-multiverse and so forth.

I think ironically that doing such a thing would give more insights into our universe than what we are doing now. For example, if we started to investigate what types of simulated worlds would generate life, it may inform us more about how probable life exists in our universe ( as well as force us to come up with some quantitative definitions for life) then sending out space probes (e.g. see here). It could also give us an idea of how variable life can be. We seem to be stuck on looking for biochemical life. Well maybe there are electromagnetic plasma life forms out there. If all it took to generate complex life-like objects was a nonlinear rule that didn’t blow up, then the answer to why our universe seems so well-tuned for us would be that any old rule would have worked although it would give entirely different looking life forms. Also, if we thought more about how we could generate or detect any type of consciousness in a simulation, that may help us better understand the consciousness we have.

A new model for publishing

Carson Chow — Mon, 02 Jan 2012 18:41:25 +0000

Two months ago in a guest editorial for DSWeb (see here), I expressed some dismay that while we have had great inovation in many aspects of our work lives, the current (broken) publication model has remained relatively unchanged. Now my colleagues at NIH – Dwight Kravitz and Chris Baker have published a stimulating and provocative article (see here) highlighting the many problems with the current situation, especially with the wasteful treadmill of trying to get something into a “high impact” journal, and propose a new model. Although this will mostly have salience for people in fields that try to publish in journals like Nature and Science, I recommend that anyone who publishes should read the paper and form their own opinion. Here is mathematician Kreso Josic’s take on the paper.

From my view as a physicist cum mathematician cum biologist, I’ve seen publishing from several perspectives. The theoretical physics/applied math world seems to have a good system already in place where everyone posts their papers on the arXiv and then publish in an “obvious” physics or math journal like one of the Physical Review or SIAM ones. These journals are fairly low cost for the authors, if you don’t want colour figures or physical preprints (but not cheap), and they have a nice system of transferring to sister journals if you are rejected automatically so the review process is efficient. However, publishing in the biology world is more of a nightmare that is well documented by Dwight and Chris in their paper. Here, getting into a high impact journal like Nature or Science can make or break your career and the chances of getting in are slim. Authors spend a lot of their time and energy trying to get their work published and if you have little name recognition in a field it is extremely difficult just to get your paper reviewed by the more prestigious journals. Dwight and Chris have some excellent ideas of how to fix this system, which I think have a lot of merit. The one thing I would like to see is to make the cost for authors be as low as possible so that it doesn’t impede low funded labs.

The Scientific Worldview

Carson Chow — Fri, 30 Dec 2011 19:43:46 +0000

An article that has been making the rounds on the twitter/blogosphere is The Science of Why We Don’t Believe Science by Chris Mooney in Mother Jones. The article asks why it is that people cling to old beliefs even in the face of overwhelming data against them. It argues that we basically use values to evaluate scientific facts. Thus if the facts go against a value system that was built over a lifetime, we will find ways to rationalize away the facts. This is particularly true for climate change and vaccines causing autism. The scientific evidence is pretty strong that our climate is changing and vaccines don’t cause autism but adherents to these beliefs simply will not change their minds.

I mostly agree with the article but I would add that the idea that the scientific belief system is somehow more compelling than an alternative belief system may not be on as solid ground as scientists think. The concept of rationality and the scientific method was a great invention that has improved the human condition dramatically. However, I think one of the things that people trained in science forget is how much we trust the scientific process and other scientists. Often when I watch a science show like NOVA on paleontology, I am simple amazed that archeologists can determine that a piece of bone that looks like some random rock to me, is a fragment of a finger bone of a primate that lived two million years ago. However, I trust them because they are scientists and I presume that they have received the same rigorous training and constant scrutiny I have received. I know that their conclusions are based on empirical evidence and a line of thought that I could follow if I took the time. But if I grew up in a tradition where a community elder prescribed truths from a pulpit, why would I take the word of a scientist over someone I know and trust? To someone not trained or exposed to science, it would just be the word of one person over another.

Thus, I think it would be prudent for scientists to realize that they possess a belief system that in many ways is no more self-evident than any other system. Sure, our system has proven to be more useful over the years but ancient cultures managed to build massive architectural structures like the pyramids and invented agriculture without the help of modern science and engineering. What science prizes is parsimony of explanation but at the risk of being called a post-modern relativist, this is mostly an aesthetic judgement. The worldview that everything is the way it is because a creator insisted on it is as self-consistent as the scientific view. The rational scientific worldview takes a lot of hard work and time to master. Some (many?) people are just not willing to put in the effort it takes to learn it. We may need to accept that a scientific worldview may not be palatable to everyone. Understanding this truth may help us devise better strategies for conveying scientific ideas.

Does the cosmos know you exist?

Carson Chow — Sat, 17 Dec 2011 06:15:09 +0000

After a year-long public battle with cancer, the writer and cultural critic Christopher Hitchens died this Thursday. Commenting on his early death, Hitchens reportedly told NPR that he was ”dealt a pretty good hand by the cosmos, which doesn’t know I’m here and won’t know when I’m gone.” Hitchens made this comment because he was a fervid atheist. However, the statement could be valid even if the universe has a creator. It all depends on whether you think the universe is computable or not. (By all accounts, it is at least well approximated by a computable universe.) If the universe is computable, then in principle it is equivalent to one (or many) of the countably infinite number of possible computer programs. This implies that it is possible that someone wrote the program that generated our universe and this person would in fact be the Creator. However, depending on the cardinality of the Creator (by cardinality I mean the size of a set and not a reference to Catholicism), the Creator may or may not know that you or any thing at all exists in her universe.

Let’s take a specific example to make this more concrete. It has been shown that simple cellular automata (CA) like Rule 110 are universal computers. A CA is a discrete dynamical system on a grid where each grid point can be either 1 or 0 (i.e. bits) and there is an update rule where the bits stay the same or flip on the next time step depending on the current state of the bits. (Rule 110 is a one-dimensional CA where a bit is updated depending on the state of its two nearest neighbours and itself.) Thus every single possible computation can be generated by simply using every bit string as an initial state of Rule 110. So the entire history of our universe is encoded by a single string of binary digits together with the bits that encode Rule 110. Note that it doesn’t matter if our universe is quantum mechanical since any quantum mechanical system can be simulated on a classical computer. Thus, all the Creator needed to do was to write down some string of digits and let the CA run.

Now, what constitutes “you” and any macroscopic thing in the universe is a collection of bits. These bits need not be contiguous since nothing says that you have to be local at the level of the bits. Thus you would be one of all the possible subsets of the bits of a binary string. The set of all these subsets is called the power set. Since, any bit can either be in a subset or not, there are sets in the power set. Thus, you are one of an exponential number of possible bit combinations for a finite universe and if the universe is infinitely large then you are one of an uncountably infinite number of possible combinations. Hence, in order for the Creator to know you exist she has to a) know which subset corresponds to you and be able to find you and b) know when that subset will appear in the universe. Thanks to the brilliance of Georg Cantor and Alan Turing, we can prove that even if a Creator can solve a) (which is no easy task), she cannot solve b) unless she is more powerful than a classical computer. The reason is because in order to solve b), she has to predict when a given set of symbols will appear in the computation and this is equivalent to solving the Halting Problem (see here for a recent post I wrote introducing the concepts of computability). Hence, knowing if “you” will exist, is undecidable. In a completely self-consistent world where every being is computable, no being can systematically determine if another being exists in their own creation. In such a universe, Hitchens’s is right. However, the converse is also true so that if there is a universe where there is a Creator that knows about “you”, then that Creator must also be computationally more powerful than you.

Two talks

Carson Chow — Thu, 08 Dec 2011 17:28:16 +0000

Last week I gave a talk on obesity at Georgia State University in Atlanta, GA. Tomorrow, I will be giving a talk on the kinetic theory of coupled oscillators at George Mason University in Fairfax, VA. Both of these talks are variations of ones I have given before so instead of uploading my slides, I’ll just point to links to previous talks, papers, and posts on the topics. For obesity, see here and for kinetic theory, see here, here and here.

In the Times

Carson Chow — Tue, 06 Dec 2011 17:16:24 +0000

The New York Times has some interesting articles online right now. There is a series of interesting essays on the Future of Computing in the Science section and the philosophy blog The Stone has a very nice post by Alva Noe on Art and Neuroscience. I think Noe’s piece eloquently phrases several ideas that I have tried to get across recently, which is that while mind may arise exclusively from brain this doesn’t mean that looking at the brain alone will explain everything that the mind does. Neuroscience will not make psychology or art history obsolete. The reason is simply a matter of computational complexity or even more simply combinatorics. It goes back to Phillip Anderson’s famous article More is Different (e.g. see here), where he argued that each field has its own set of fundamental laws and rules and thinking at a lower level isn’t always useful.

For example, suppose that what makes me enjoy or like a piece of art is set by a hundred or so on-off neural switches. Then there are different ways I could appreciate art. Now, I have no idea if a hundred is correct but suffice it to say that anything above 50 or so makes the number of combinations so large that it will take Moore’s law a long time to catch up and anything above 300 makes it virtually impossible to handle computationally in our universe with a classical computer. Thus, if art appreciation is sufficiently complex, meaning that it involves a few hundred or more neural parameters, then Big Data on the brain alone will not be sufficient to obtain insight into what makes a piece of art special. Some sort of reduced description would be necessary and that already exists in the form of art history. That is not to say that data mining how people respond to art may not provide some statistical information on what would constitute a masterpiece. After all, Netflix is pretty successful in predicting what movies you will like based on what you have liked before and what other people like. However, there will always be room for the art critic.

New paper on GPCRs

Carson Chow — Mon, 28 Nov 2011 18:58:16 +0000

New paper in PloS One:

Fatakia SN, Costanzi S, Chow CC (2011) Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors. PLoS ONE 6(11): e27813. doi:10.1371/journal.pone.0027813

Abstract

G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection.