Chapter 4 – Effects of daily voluntary wheel running on visceral adipose tissue mitochondrial content in Otsuka Long-Evans Tokushima Fatty rats

Well I have finished Chapter 4 on schedule.  Now it is on to a completely different topic for chapter 5.  The effect of exercise on epigenetic changes in skeletal muscle of mice.  This project was a high impact, high reward, high risk project that the funding agencies loved.  I received an American Heart Fellowship and 5K of research money from the American College of sports medicine to help with research.  The funny thing is, this is an on going project and I will not be done with it by the time I turn my dissertation in.  As long as chapter 4 gets accepted into a journal then I will be fine.  Alright, I have 10 days to finish this chapter.  Time to get to work.

Do you Know an Exercise Molecular Biologist?

Well, most people have heard of an exercise physiologist, but not so many people have heard of an exercise molecular biologist.  Since exercise is undoubtedly an important (maybe the defining) physiological stress it makes sense for a lot of physiologist to attach that moniker to their title and use exercise in their research.  Molecular biology on the other hand, not so much.  Defined by wikapedia as

Molecular biology is the study of biology at a molecular level. The field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry. Molecular biology chiefly concerns itself with understanding the interactions between the various systems of a cell, including the interactions between DNA, RNA and protein bio-synthesis as well as learning how these interactions are regulated.

While physiologist are looking for interactions between organs in a whole organism, molecular biologist step it down a notch to looking for interactions within single cells.  For molecular biologist the idea of studying exercise is a foreign as the idea of studying protein 3D structure is to an exercise physiologist.  They just don’t overlap…or do they.  It is my belief that exercise, being the quintessential organismal stress, must have genetically conserved and molecular pathways that are activated within each cell.  One major problem to using exercise in molecular biology is the lack of good models.  Apparently its hard to get cells to exercise.

Although it might be hard to get cells to exercise the principles of exercise are applied to the most basic of molecular biology on a regular basis.  With such a small and easily manipulated genome the yeast became the standard organism to study the most basic principles of biology such as protein trafficking, cell signaling, and organelle interactions.  One of the most common ways to manipulate the yeast environment is by switching the energy source in the media around the cell.  That simple switch from glucose to fatty acids is not unlike what occurs with an extended bout of exercise, and the interesting thing is that yeast respond in a similar manner as we do, ramping up the metabolic processes necessary to use fatty acids for energy.

Another example is one that I heard recently by a senior investigator in the Life Science center concerning knockout mouse models and exercise.  It is common practice to knock a gene out of mouse and just look at how the phenotype differs from that of a wild type mouse.  Sometimes dramatic changes occur, and sometimes nothing.  Several mouse models where a gene beilieved to be involved in skeletal or cardiac muscle function have shown no adverse phenotype initially…that is until they exercised the animals.  Sometimes a paper claiming that no phenotype exists is even published before the animal is exercised and the phenotype revealed.  The fact is that exercise invokes a fundemental stress response in the animal, which can bring out the function of a gene previously unknown.  In this case exercise is more than science that is good for you, but good science as well.

Dissertation Time

In months I will be handing in my dissertation to my committee.  Two weeks after that will be my oral defense, and the day after that I close on my house.  So much happening in so little time and yet now I chose to update the blog.  I hope to continue to use this blog as an outlet for the struggles that I will undoubtedly have over the next two months.  So for my dissertation I have the 2nd, and 3rd chapter written, but will need to spend a day or so editing the format so that it works in the dissertation document.  That really leaves the following writing:

Chapter 1 – Introduction – probably 25-30 pages

Chapter 4 – Adipose tissue mitochondria in response to obesity and physical activity (15-20 pages)

Chapter 5 – Epigenetic changes during voluntary running on a high fat diet in mice (15 – 20 pages), although I have a pretty good intro written already

Chapter 6 – Discussion – probably 15-20 pages.  This is really going to be a bitch to try and organize such a wide range of topics into a cohesive intelligent and thought provoking chapter.  A challenge my committee wants me to do.

Appendix(s) – lots of unpublished data going in to the pad the the thickness.  Probably an extra 15-20 pages depending on the depth of discussions, methods, and intros.

So in summary I need to write about 85 – 105 pages (while citing over 200 papers for sure) in 2 months while continuing to do research for the month of February.   At least it is double spaced.

to be continued….

Systems Biology…I Think You Mean Physiology

So this past week there have been several really interesting and opposing articles related to the term systems biology. Just last week my mentor, who frequently get excited, was talking to me about how reductionist (ie the molecular biologist interested who continually put out papers in the one gene – one disease frame of mind) have attempted to hijack the disciple of physiology by calling it systems biology.

To get a better understanding of the history of these terms lets use our good friend goggle. Founded in 2000 the Institute for Systems Biology is located in beautiful Seattle Washington. This is the definition of systems biology that they use on their website,

 

Systems biology is the study of an organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions which give rise to life. Instead of analyzing individual components or aspects of the organism, such as sugar metabolism or a cell nucleus, systems biologists focus on all the components and the interactions among them, all as part of one system. These interactions are ultimately responsible for an organism´s form and functions. For example, the immune system is not the result of a single mechanism or gene. Rather the interactions of numerous genes, proteins, mechanisms and the organism´s external environment, produce immune responses to fight infections and diseases.

Now lets move to a definition of physiology from the American Heritage dictionary.

phys·i·ol·o·gy play_w(“P0278400″)

 (fz-l-j)

n.

1. The biological study of the functions of living organisms and their parts.

2. All the functions of a living organism or any of its parts.

Alright so yes the definition of physiology is somewhat broader, but nevertheless it covers what is mentioned in the definition of systems biology.  Perhaps because it is not explicitly stated in the definition of physiology that the parts of organisms can be studied in an integrative manner.  Maybe this is why integrative physiology departments and meetings have popped up in recent years in concert with this idea of systems biology.  However, physiologist have been studying the multiple organ systems (in physiology we call systems organs) for as long as the field has been around.  In fact in 1964 C. Lad Prosser said the following,

…the net effect of the new knowledge now emerging in physiological genetics is to provide a cellular explanation for the adaptive interactions between the environment and the organism.”

To me this is unbelievable that he had the foresight to recognize the potential for examining the ways that genes can help explain adaptive changes in the organism (ie in systems).  The words physiological genomics only appeared on pubmed in 1998 a mere 34 years after Prosser’s insight.

Physiologist were interested in exploring how the gene-environment interaction affects the organism as a whole quite a bit earlier than systems biologists were.  Now just as my boss has been upset with the way former reductionist have attempted to take over physiology by a new name other have become upset as well.  In recent introduction to a series of reviews pertaining to performance in the Journal of Physiology Micheal Joyner and Bengt Saltin don’t hold back in their final paragraph stating

One general conclusion from all of the reviews and papers is that the main regulatory and adaptive responses to acute and chronic exercise defy simple reductionist explanations. A more provocative conclusion is that before the reductionist community naively concluded they needed to reinvent and rename physiology in the guise of ‘systems biology’, investigators interested in exercise were already committed to understanding the interactions of key biological responses at multiple levels of organization and integration. An even more provocative conclusion is that the systems biologists have much to learn from the successes of investigators interested in exercise and even more to learn from their continuing questions

 I very much agree with Joyner and Saltin.  It is true that they have much to learn from us and that many important and interesting questions remain to be solved.  Of course this was published in the Journal of Physiology where the main readership is, yep you guessed it, physiologist.  For this message to hold physiologist need high impact papers and commentary in journals with a high impact.  Of course this becomes more difficult when nature publishes a recent article discussing the advantages to using a systems biology approach rather than a physiological approach to study aging.   Of course aging is a physiological process, clearly without a single gene responsible for its pluripotent effects.  It is a question that physiologist have been attacking for decades using a variety of multiple system approaches (ie animals and humans).   What is really striking about this article is the great lengths that the author, Thomas B. L. Kirkwood, takes to avoid using the word physiology.  Is it such a bad idea to claim to that taking a physiological approach to studying aging is such a bad thing?  After all we accepted the role that genetics would play in physiology a long time ago.  Isn’t it about time that the reductionist recognized that they have much to learn by framing their studies in a physiological light?

Even for those not interested in exercise from a health standpoint it is still a useful physiological tool to study the gene-environment interaction.  Here is the example that I like to give about why using exercise in any phenotyping study is necessary.  Blood flow is capable of increasing 40 fold with exercise in working skeletal muscle.  An animal knockout model might display a phenotype where blood flow increases (or decreases) 5 fold.  While that is interesting in itself it still tells us nothing about the capacityof the system.   After all a few muscle contractions could normalize the blood flow, but you won’t know unless you test the system at max capacity, ie exercising.  All these genetic knockout models take a very narrow view of the gene-environment interaction and hardly ever attempt to use exercise to rescue the phenotype despite its pliotrophic effects. 

Hopefully systems biolgist will come to their senses and join physiologist in studying the complexity of how organisms adapt to their environment.