onsdag, august 20, 2008

Dogmaomics-kurs: A systems critique to systems biology


Dei siste dagane har Kwest vore ivrig deltakar på eit kurs i molekykærbiologi og filosofi på vakre Hardangervidda. Her tok ein sikte på å diskutere konsept, føresetnader og historie i molekykærbiologien, i naturskjønne omgivnadar. Kan det bli betre? Nei.


Kurset var arrangert av Senter for Vitenskapsteori, som stillte mannstungt og diskusjonsvillig, samt Molekykærbiologisk Institutt, begge ved Universitetet i Bergen. Eit dusin interesserte frå Oslo, Bergen og Trondheim sine miljø for Molekykærbiologi, vitskapsfilosofi/etikk og informatikk hadde latt seg lure med.

Det som gjorde det heile ekstra spennande, var at Hans-Jörg Rheinberger frå Max Planck i Berlin, var med på turen. Han er ein ledande skikkelse innan molekykærbiologi/filosofi-miljøet, og han har tidligare vorte omstendelig omtalt på denne bloggen i serien "Kunnskap i det små".

Underteikna fekk også den gleda å halde eit lite innlegg, og med Hardangerjøkulen som bakteppe, og eg bestemte meg for å prøve meg på ein type systemkritikk på det som er den nye vinen innan livsvitskapane nett no: systembiologi.

blog-sida til kurset vil de kunne finne liste over dei tekstane som var bakgrunnen for kurset, og som innlegget vart basert på.

Her kjem innlegget, som er på språket engelsk. Håper det går bra for våre lesarar.



A systems critique of systems biology.
As the topic of today is systems biology, I will have this as the theme of this talk. And as the article of O’Malley and Duprè (1) was for me an interesting introduction to the field, I will use this as the main reference for my talk.

When I read about systems biology, it strikes me as interesting that, as I know of, only few, if any at all, studies in applied systems biology have been published. When reading the article of O’Malley, and others alike, one gets the impression of watching a brainstorming-process: how are we going to do this? Thus, the field of systems biology consists largely of visions, concepts and ideas. Trough conceptual thinking and technological development one hopes to put these into application in the near future.

The goal of systems biology, as stated by O’Malley and Dupré, is “…to obtain a fundamental, comprehensive and systematic understanding of life”. The view that organisms are built up of systems in various levels, and that these systems are very complex, is not new one. Neither is the interest in studying these systems. But how to do this has been a more difficult question to answer, as methods largely have been qualitative and low-throughput.

As I see it, there are two main reasons why systems biology is emerging right now:
1. High-throughput methods as genome sequencing, micro-array analysis and mass spectrometry analysis has produced large datasets, and has allowed a more global way of studying organisms at a molecular level.
2. The development of bioinformatics tools enables analysis of large data sets, and modelling of complex scenarios with multiple variables.

What one hope to gain from this are: more quantitative studies of molecular mechanisms, where the effects of several variables are taken into account. The systems biologist wishes to keep his eyes on more than one thing at the time. In the longer run, he would like to make a model of the biological organism or organisms, so that he can simulate for example the effects of adding a drug to the system, in silico. Maybe one could say that the systems biologist is bringing molecular biology from a data-collecting science to a predictive science?

So, what are the assumptions that systems biology builds upon? The most obvious one is that biology is, or can be described, as a system. Systems biologists study “the organization of life itself”. O’Malley and Dupré asks three questions related to this assumption:
1. What is a system?
2. What biological units map onto those systems?
3. How are individual biological units and their behaviours altered, controlled or constrained by becoming components of the system?
They say further on: “understanding this causation (or how causality operates at different levels of organization) (…) is the true cause of systems biology”. So, if we want to go from a descriptive to a predicative science, we must assume that life is organized; it has a system. We have used the last 60 years to figure out the parts of the system. Now we have to figure out how they work together. The systems-theorist describes a new conceptual framework, where the components of the systems are fine tuned and adapted to fill a role in the system. They see a possibility for biology to “become a search for laws rather than the investigation of historical outcomes of unknown generality”. The teleological turn is obvious.

So, to test the assumption that life is organized, I will try to investigate the antithesis of this, namely:
If H1 is “life is organized and systematic”, then
H0: Life is not systematic, but chaotic.
Can we argue for this? Yes, to a certain degree one can, and old Charles Darwin have something to do with it.

As an example I will take the HIV virus. Lets imagine that the perfect systems-biologist developed a modelling-tool of the entire human cell, where he can change the phenotype by varying the epigenetic modelling etc. The ultimate goal for a systems biologist: all the knowledge we have of the constituents of the system integrated into a functional model. He has used this tool to model how the cell responds to for example different drugs that works as inhibitors for different proteins, thus being able to design a drug with fewest possible side effects. He now wants to use the model for developing drugs against HIV infection. But the virus mutates very fast, and there are many different strains of virus. The virus will mutate to new forms, in a random manner, and in random speed, and the driving force behind the change is that the variant that is not picked up by the defence-system is the one that survives and dominates. How can the systems biologist deal with this?

As we see, the random aspect of evolution, and the effects this have on organisms, both on a macro and micro-scale represents an epistemological problem to systems biology: organisms change as a function of time and selection pressure, and the changes have a certain degree of randomness. In many cases this is mainly a theoretical problem. The temporal effect of evolution does not create problems in general studies of for example signalling pathways. But, many problems connected to medicine have to deal with evolution. One can mention vaccines, cancer-development, and as we have mentioned, virus-infection.

So, can one say that organisms are organized systems? We cannot say so per se, but one can say that the systems-concept is a fruitful framework of thinking, a concept of understanding, just as the “central dogma” once was.

To deal with the element of randomness, I propose that one would have to add an evolution-and-time-variable to the systems-approac. In doing that, one could also gain more insight into how evolutionary mechanisms drives the system-development. Maybe one could end up saying that system-robustness and circuit-design are participating forces in the evolutionary development. From this, one can state that organisms is in a constant flux of change, that this change is largely random. In this flux, local systems and equilibriums are created with various spatial and temporal sizes. Understanding the dynamics of more or less local systems is an important step when investigating the dynamics of biology.

(1) O'Malley & Dupré: Fundamental issues in systems biology, Problems and paradigms 2005.

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