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Cell Cognition and Cell Decision-Making

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Recent postings have provoked numerous questions about my application of the term "cognitive" to cell regulatory processes. I base this usage on the notion that cognitive actions are knowledge-based and involve decisions appropriate to acquired information. It is common today for molecular, cell and developmental biologists to speak of cells "knowing" and "choosing" what to do under various conditions. While most scientists using these terms would insist they are just handy metaphors, I argue here that we should take these instinctive words more literally. Cell cognition may well prove itself a fruitful scientific concept.

Choosing the right sugar to eat: Jacques Monod and bacterial control regimes

We can trace the origins of molecular understanding of how cells control reading DNA sequence information to Monod's pioneering studies (in 1942 Nazi-occupied Paris!) on how bacteria respond to a choice of sugars. They completely consume the sugar that provides the most rapid growth (typically glucose) before switching to the less efficiently digested one.

Unrelated bacteria use the same transport system to sense the presence or absence of glucose in their environment, but they employ different molecular components to transmit that information to the genome. So this important sensory mechanism evolved at least twice in bacterial history. In E. coli, the signal that glucose is absent is an intracellular "second messenger" molecule that is purely symbolic; it has no structural connection to the glucose transport process.

Recognition and metabolism of the less-preferred sugar is a sophisticated process. It involves transport components, metabolic enzymes and specialized regulatory proteins. Together, they function as microprocessors controlling expression from the corresponding DNA regions in response to each sugar and the second messenger. This integration ensures that proteins needed for digestion only appear when appropriate.

While many assert that the bacterial control system is purely mechanical, not enough experiments have been done to show whether cells respond in a deterministic way. What we know for sure is that even these smallest cells use sophisticated sensory and intracellular communication processes to discriminate between alternative nutrients.

Passing through the cell cycle successfully: the checkpoint concept

Complex cells with a nucleus (eukaryotes) display a tightly controlled multistage cell division cycle. Each stage involves intricate processes such as cell growth, DNA replication, and accurate transmission of genome copies to daughter cells. Elaborate biochemical reactions regulate passage from one stage to the next.

On top of the stage-to-stage control circuitry, a self-monitoring system makes sure everything comes out right. If the different biochemical and biomechanical processes fall out of synch, or if there is either a mistake or damage, sensory molecules detect the problem. They activate a "checkpoint" to hold up the entire cycle until everything has been set right for renewed progress.

Cells set distinct checkpoint systems for growth and division. The easiest to appreciate is the "spindle checkpoint." This makes sure that each daughter cell gets one and only one copy of each duplicated chromosome. The reliability of cell division depends on this sensory process. Left to random chromosome distribution, less than one in a billion divisions of our own cells would be successful. If any pair of chromosomes is not correctly aligned on the spindle apparatus to ensure equal transmission of the copies, the checkpoint apparatus senses the misalignment and emits a signal to halt cell division. Once all chromosomes are properly aligned, the checkpoint is released and division follows quickly.

Although each checkpoint could be deemed just another intricate mechanism, it is hard to consider the entire integrated cell cycle-checkpoint system purely mechanical. This is because the network is capable of responding to completely unpredictable events, such as external damage or experimental interventions. It displays reliability enviable in any complex human manufacturing process. Note that a dividing cell has far more components than any man-made device.

"To be, or not to be. That is the question."

There is widespread agreement in the molecular cell biology community that programmed cell death following trauma is the result of a cell decision-making process. When eukaryotic cells suffer injury (particularly well studied in the case of DNA damage), there are at least two different outcomes:

(1) a checkpoint, repair of the damage, and then resumption of the cell cycle,
(2) or cell suicide following an organized cascade of events, labelled "apoptosis." The dying cell disintegrates in an orderly way.

The cell chooses between repair and survival, on the one hand, and apoptosis, on the other, based on its environment. The key environmental features for human cells are nutrition and the presence of intercellular signaling molecules, called cytokines.

Some signals favor cell death, like Tumor Necrosis Factors (TNFs). A damaged cell detects them by means of so-called "death receptors" on the outer surface of its membrane. Other signals favor survival and proliferation, and are generally called "growth factors." Each type of growth factor has one or more specific receptors used to sense its presence.

A cell's response to a particular source of damage, such as X-rays, depends dramatically on the cytokines present in the environment. The response to trauma, where a cell decides either to adjust its activities and survive or undergo an orderly cell death, is an excellent candidate for empirical investigation as a cognitive process.

Interestingly, even so-called "simple" cells like bacteria have programmed cell death routines subject to control by signals from other cells.

In all cases, the cell suicide routine may be interpreted as a benefit to the multicellular community. This is also true of bacteria, which spend the majority of their active existence as multicellular organisms, not isolated single cells.

Although controversial as a general feature of bacterial life when first suggested, we now know that most bacteria display various multicellular behaviors. They involve emitting, receiving and processing a large vocabulary of chemical symbols.

Based on all the above, I think it can reasonably be argued that cell cognition and intercellular communication are central to all levels of life. They deserve detailed empirical and theoretical analysis.