The Seven Stones - Details

Research highlight by Pedro Beltrao, University of California, San Francisco

In a recent opinion piece, Andreas Wagner tries to reconcile the tension between proponents of neutral evolution and selectionism (Wagner 2008). He argues that “neutral mutations prepare the ground for later evolutionary innovation”. Wagner illustrates this point using a network model of genotype-phenotype relationships (Wagner 2005). In a so-called ‘neutral network’, nodes correspond to distinct genotypes associated with the same phenotype and are connected by an edge if the respective genotypes differ only by a single mutation event (eg point mutation). Examples of neutral networks include different genotypes coding for RNA or protein structures. In this representation, highly connected networks correspond to robust phenotypes that are not very sensitive to changes in genotype. Wagner notes the zinc finger fold as an impressive example of a highly connected neutral network as its structure remains essentially the same even after mutating all but seven of its 26 residues to alanine.

Using this model, Wagner describes how highly robust phenotypes can lead to faster exploration of the genotype space. He further proposes that evolution of innovation occurs via cycles of exploration of nearly neutral spaces (dubbed neutralist regime) followed by a reduction in diversity once a new phenotype of higher fitness is discovered (selectionist regime).

Although these models and ideas were mostly developed using models of sequence to structure relationships, Wagner cites several examples suggesting that these concepts are equally valid for cellular phenotypes that depend on molecular interactions (ex. gene expression patterns).

As Wagner points out, in order to understand the evolution of innovation we must fully understand the mapping between genotypes to phenotypes. This is why it is important to continue to develop richer evolutionary models to link changes at the DNA level with changes in molecular structures, interactions and ultimately phenotypes with a quantifiable impact on fitness. This is an area where systems biology should play an important role.

Models of RNA and protein structure stability upon mutation have existed now for some time (Hofacker et al. 1994, Guerois et al. 2002). More recently the study of large amounts of genomic information and/or systematic interactions studies are providing us with accurate models for different types of molecular interactions (Berger et al. 2008, Burger & van Nimwegen 2008, Chen et al. 2008). In parallel to these, theoretical analysis has been use to aid in the understanding of cellular phenotypes (i.e. cell-cycle, signaling pathways etc) (Tyson et al. 2003). Connecting these different layers of abstraction is an important challenge that will allow us to better understand the origins of biological innovation.

Berger MF et al. (2008). Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133:1266-76

Burger L & van Nimwegen E (2008). Accurate prediction of protein-protein interactions from sequence alignments using a Bayesian method. Mol Syst Biol 4:165

Chen JR et al. (2008). Predicting PDZ domain-peptide interactions from primary sequences. Nat Biotechnol 26:1041-5

Guerois R, Nielsen JE & Serrano L (2002). Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320:369-87

Hofacker IL et al. (1994). Fast folding and comparison of RNA secondary structures. Monatshefte für Chemie / Chemical Monthly 125:167-188

Tyson JJ, Chen KC & Novak B (2003). Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15:221-31

Wagner A (2005). Robustness and Evolvability in Living Systems. Princeton University Press

Wagner A (2008). Neutralism and selectionism: a network-based reconciliation. Nat Rev Genet 9:965-974

The RECOMB Satellite on Regulatory Genomics, RECOMB Satellite on Systems Biology, and DREAM reverse engineering conferences are currently held jointly at the MIT, in Boston.

Some of the talks are currently 'live-blogged' on FriendFeed and can be followed below or in the "Recomb-Sat/DREAM 08" room.

In his list of eight 'generative' values (Better Than Free), Kevin Kelly includes 'embodiment'–the actual physical realization of an item or event which could be otherwise freely distributed over the web. While we are all 'hyperlinked' on the Internet, the value of those unique qualities that cannot be generated or "copied" on the web is dramatically increased. The type of intense emulation and shared excitement sparked at the recent Science Foo Camp (SciFoo 2008), organized by Nature, Google and O'Reilly, gave a wonderful example of the unique value of direct human exchange during an exclusive event bringing together roughly 200 top scientists, 'geeks' and other technologists at the Googleplex in Mountain View, California.

SciFoo is a so-called 'unconference': there is no program or more precisely, as Timo Hannay explained during the opening of the conference, the attendees are the 'program'. The actual schedule was defined only on the first evening in a purposefully chaotic process by anyone who wished to organize a session on any topic. For the next two days, in a festival of parallel sessions, astrophysicists, 'googlers', technologists, molecular biologists, taxonomists, game designers, flying car constructors, publishers, thinkers and (some) dreamers discussed and exchanged ideas with great enthusiasm and a rare intensity and openness.

Needless to say that deciding which session to attend was close to impossible... In any case, I ended up following three types of talks: a series on systems biology related topic (data integration, machine learning, personal genomics, baroque structure of the transcribed genome), several (of many) sessions focused on the theme of open data/science and finally some more eclectic sessions (only from my standpoint, of course) on diverse topics such as the foundations of the concept of time in physics, on some demonstration of very simple yet powerful Python scripting exercises to analyze text and the potential of game design to harness our 'cognitive surplus'. I cannot possibly summarize all the talks, interactions and impressions gathered at this meeting, but here are a few subjective excerpts:

• There were quite a few sessions on open science and open data. Ernst Hafen made a strong case for the need of a unique AuthorID that would help in tracking the multiple aspects of researchers' scientific activities. With regard to data, Google announced that a new service will soon be launched, Google Research Datasets, offering to host, for free, large datasets of any type. The service will allow inclusion of some minimal meta-data about the submitted datasets and will provide a mechanism to define a delay before the dataset is made publicly visible. This will probably become a very simple and convenient way for storing data (in particular if a useful API is developed), so convenient in fact, that we may have to be a little careful that it will not turn into a temptation to bypass the 'minimal information...' standards usually required by traditional public databases.
• George Church provided an overview of the Personal Genome Project (PGP) and described the type of biological data that will be integrated with the genomic and genetic information collected from consenting PGP volunteers: analysis of the transcriptome of pluripotent stem cells derived from the subjects; sequence of the repertoire of recombined V-D-J regions in immune cells ('VDJome') to exploit correlations between given V-D-J sequences and antigen-specific stimulations; characterization of the microbiome used as a tracer of the environmental and physiological conditions; record of phenotypic traits and disease conditions using controlled vocabularies. Finally, George also emphasized the exponentially decreasing cost of sequencing, which will not only make large scale sequencing of full personal genomes feasible but will also potentially open entire new fields of applications based on massive DNA sequencing.
• Lee Smolin talked about the nature of the concept of time in physics and investigated the question of whether our perception of time as the 'experience of successive present moments' is 'real' or, alternatively, an emergent property of the laws of physics. I cannot pretend I followed the entire argument, but I learned that the mathematical representation of the physical reality involves the geometrization of time (as one of the state space's dimensions), leading in fact to a representation devoid of temporal flow (somehow the clock has to be outside the system). To this geometrical representation, physical laws are associated and applied to initial conditions. If I did not misunderstand it, it appears that this approach used in physics might have to be considered as approximative because it may only be valid for subsystems of the universe whereas it might not be appropriate for a true cosmological theory of the entire universe, with possibly disturbing consequences on the nature of physical laws...
• Believe it or not but music can be 'geekified' as well: Chris diBona, later in the evening, brought his tenori-on for a fun demonstration. I want one of those!

The meeting ended with some final scientific fireworks, when some of the speakers gave a series of brilliant 2 min summary talks, providing a colorful overview of the many sessions we inevitably had missed. I have to admit that I like fireworks and I would certainly have enjoyed having a little more of this final kaleidoscopic view of science. Clearly, the authentic value of this conference lies in the unique and direct human interactions, but I wish there would be nevertheless some way–perhaps by using this last session in some form of outreach action–to disseminate this pure joy of scientific diversity and curiosity to a broader audience.

Credits: illustrations from Bob Lee, Flickr, some rights reserved