A Cell Makes Decisions — How?

Editor’s note: For more on the “immaterial” aspect of the cell’s blueprint, see the new book describing the thought of biologist Richard Sternberg, Plato’s Revenge: The New Science of the Immaterial Genome (Discovery Institute Press), by David Klinghoffer. To be published on April 28, it is available for preorder now.

Watch an entertaining video in a press release from the University of Massachusetts (UMass) called “Rules of Engagement,” set to the Strauss waltz “Voices of Spring.” We see four varieties of enzymes deciding what to do when traveling along DNA strands and running into each other. We sympathize with these molecular actors, envisioning construction workers trying to work past each other in a narrow corridor. Somehow, they figure out the challenge and carry on. 

Later in the video, we zoom out and see that all these interactions blend into a magnificent ballet, resulting in precise folding of DNA into the familiar X-shaped chromosomes. If a cell is merely a “fortuitous concourse of atoms,” how is this possible?

Abiotic matter can self-organize in some circumstances. Tornadoes and hurricanes form spirals. Cooling lava forms hexagonal columns. Elements combine into geometric crystals. In those cases, though, the atoms simply follow physical laws without regard to consequences or function. Life is different. It solves problems for a purpose. It makes decisions.

Decisions to Cooperate

The condensins and cohesins in the video are not drawn into their interactions by gravity or electrostatics. Multiple levels of programming are involved, including: (1) genetic instructions to build the molecular machines, (2) “rules of engagement” to govern their interactions, (3) an overarching design plan to compact DNA into chromosomes, and (4) a need to separate the chromosome pairs into daughter cells in mitosis. To these programs could be added monitoring systems, repair mechanisms, and the astonishingly complex DNA replication process.

Programming makes the difference. Crystals, lava, and tornadoes do not follow a code telling them what to do. Philosophers and theologians may argue about whether the laws are designed and finely tuned for life, but once established, the laws generate predictable outcomes that can be described mathematically. The actions of molecules in the cell are not predictable from the laws, nor are the paths that electrons take in a silicon chip unless directed by a mind with a plan. 

The press release from UMass highlights a new paper in Science by Samejima et al., explaining that the plan for chromosome construction succeeds despite stochastic interactions at lower levels:

Given the dynamic interactions and stochastic nature of binding and loop extrusion processes, mitotic chromosomes do not adopt a single, fixed three-dimensional structure. Instead, they are disorderly structures with a common defined architecture. [Emphasis added.]

By analogy, construction workers at a building project, each with their specialties and skills, have leeway in the exact locations where they hammer nails or string wires, as long as they follow the overarching site plan shown in the blueprint.

Here are additional examples of decision-making by cells to reinforce the point that material cells can only make decisions if specifically structured to follow a blueprint with rules of engagement.

Decisions to Organize: Another “-ome”

A paper in Science by Waltz et al. adds to the growing vocabulary of “-omes” (genome, proteome, lipidome, etc.) with the term “respirasome” — a supercomplex that enables respiration in mitochondria. The individual complexes comprising oxidative phosphorylation, culminating in the wondrous rotary engine ATP synthase, are organized in a way that maximizes function. The authors note how precise the arrangement appears under cryo-electron microscopy:

Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo–electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo–electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.

The authors advance some hypotheses about why the complexes organize into these supercomplexes, noting that not all respirasomes have identical stoichiometry in different species. They speculate that “evolution appears to have repeatedly selected for respirasomes,” which is the Darwinian way of admitting that the patterns are functionally important (otherwise they wouldn’t exist now, would they?).

As visualized by in situ cryo-ET, this membrane architecture creates a narrow luminal space and lateral heterogeneity with the cristae, thereby enabling proton flux from respirasome source to ATP synthase sink…. In such a manner, respirasomes would enable efficient respiration through the indirect mechanism of establishing crista architecture and molecular organization. The native respirasome structure presented in our study provides a blueprint to specifically disrupt supercomplex formation in vivo and mechanistically dissect the physiological relevance of these enigmatic molecular machines.

The respirasome, therefore, appears as another decision-making structure that solves the problem of how best to organize machines in a factory for efficiency. Solutions like this are not predictable from the laws of nature alone.

Decisions to Prevent Problems

Another kind of decision-making seen in cells involves not just solving puzzles but preventing foreseeable problems. A paper in the EMBO Journal by Fagunloye et al. provides a case in point. The Shu complex is an “evolutionarily conserved” (unevolved) “heterotetramer composed of three Rad51 paralogs, Csm2, Psy3, Shu1, and a SWIM-domain containing protein, Shu2.”

Homologous recombination (HR) is important for DNA damage tolerance during replication. The yeast Shu complex, a conserved homologous recombination factor, prevents replication-associated mutagenesis. Here we examine how yeast cells require the Shu complex for coping with MMS-induced lesions during DNA replication. We find that Csm2, a subunit of the Shu complex, binds to autonomous-replicating sequences (ARS) in yeast…. Lastly, we show interactions between the Shu complex and the replication initiation complexes are essential for resistance to DNA damage, to prevent mutations and aberrant recombination events. In our model, the Shu complex interacts with the replication machinery to enable error-free bypass of DNA damage.

Note the irreducible complexity in this complex that they attribute to evolution. They claim this wonder of the cell evolved on the basis of finding differences between the Shu complexes in yeast and humans. They should instead ask on what basis they could expect material processes to sense, repair, and prevent damage: to go from mindless atoms to decision-making machines.

The Shu complex, they say, can repair “bulky DNA damage” and even bypass lesions, yielding a thousand-fold increase in replication accuracy (see the endnote for the impressive details¹). Aren’t mutations thought to be the seed-plot of progress in Darwinism? Without the proofreading accuracy of the Shu complex, a cell would likely suffer error catastrophe long before it could emerge.

Moreover, the Shu complex interacts with other complexes — facts that the authors call “intriguing” and “interesting.”²

Skinner’s Constant 

Material entities can make decisions, but only when they are guided to do so by an intelligent cause capable of foresight. Attributing decision-making to matter by invoking a nebulous concept of “selection pressure” — a synonym for Skinner’s Constant, the factor which, “when multiplied by, divided by, added to, or subtracted from the answer you got, gives you the answer you should have gotten” — requires magical thinking under the spell of an overactive imagination. The credibility of the Darwinian mechanism is inversely proportional to the details observed operating in living cells.

Notes

1. “During DNA replication, DNA damage can be bypassed using a template switching mechanism that is facilitated by the recombinase, Rad51. The yeast Shu complex facilitates the formation of Rad51 filaments in this replicative context where its function is restricted. This is unique to other HR factors that repair direct DSBs [double-stranded breaks] outside of DNA replication. How the Shu complex function is limited to facilitatebypass of replicative DNA damage is enigmatic. However, hints come from its DNA damage sensitivity, where the loss of any Shu complex members results in sensitivity to the alkylating agent, methyl methanesulfonate (MMS). Partially explaining this specificity for replicative repair, the Shu complex DNA binding subunits, the Rad51 paralogs Csm2-Psy3, preferentially bind to double-flap substrates and have increased affinity for a double-flap containing an abasic site, which forms during repair of alkylation damage. Loss of Shu complex function results in translesion synthesis-induced mutations and the mutation rate increases over 1000-fold when abasic sites accumulate.” (External citations omitted.)
2. “Importantly, these physical interactions with the replication initiation complexes occur independently of other HR machinery, including the recombinase Rad51 and the canonical Rad51 paralog, Rad55. Intriguingly, Csm2 enrichment at ARS sites is largely dependent on its interaction with Rad55. Interestingly, Rad55 is neededfor Csm2 enrichment at ARS sites while being dispensable for Shu complex interaction with Mcm4. These results are consistent with those from the Prado laboratory showing that Mcm4 interaction with Rad51 or Rad52 is also DNA-independent. Furthermore, we show that Csm2 and Psy3 DNA binding is largely dispensable for its interaction with members of the MCM or ORC complexes. Therefore, it is possible that Rad55 helps to stabilize or enrich the Shu complex to ARS sites but that the Shu complex alone is needed to interact with the replisome. Overall, our results delineate a model wherein the Shu complex interacts with the replication machinery to ensure an error-free bypass of DNA damage.”