Epistolution Musing №2: The Role of Genes
Dear Friends,
This letter is part of a weekly series of brief thoughts I would like to share with you, either because I’ve come across your related work in biology or because you’re a person I like. I discovered an interesting problem in 2019, a problem I can’t forget. Epistolution is the unknown biological mechanism necessary to explain purposive activity that can’t be accounted for by genetic influences.
Recap: Twin studies are deceptively simple. Everything twins have in common is a result of heritable material, and everything they do not share is a result of something else. What causes two identical twins to diverge from one another at all? They share all the influences that evolution has provided for them…DNA, methyl groups, cytoplasm, cell membrane, mitochondria, etc.. The only thing they don’t share is how they put the tools together, the actual process of life. If twins diverged in random ways, then we could confidently say that all their functions are a result of their material inheritance. But if twins diverge in functional ways, then functions are not entirely controlled by inherited material. They are taken instead directly from the environment by some undiscovered process inherent in life forms. This is a staggering thought; it should ring alarm bells. All cells can learn! This week we explore the consequences of this shocking idea.
Every somatic cell is, essentially, a twin that has diverged from another genetically identical cell. Asexual organisms are clones of their sisters, but our bodies, too, are swarms of twins, or rather, trillionuplets. When we see cells creating a multicellular organism, we could be forgiven for thinking that the plan for what to create was in the genes. But the Anna/Amanda example shows that this is the wrong interpretation. The genes support a landscape of possible patterns the cells can choose, but the choice of what to become is a result of cellular learning. Each cell decides on its own what to turn into, based on epistolution. The fact that the cells are obliged to to use a certain genome to make their choices just makes it more likely than not that a certain morphology will emerge in the end.
My mother has an odd way of sneezing. She squinches up her face, holds her nose, and sneezes very quickly, exactly four times in a row. When she was a girl in a small town in south Mississippi, she attended a big Methodist church downtown with her family every Sunday. In the hushed atmosphere of the sanctuary during the prayers and sermons, her sneezes must have stood out. One day after church an older lady took her aside and declared, “Ginny, I haven’t heard that sneeze in this church since your grandmother died.” Apparently my great-grandmother, who died before my mother was born, sneezed in just the same peculiar way.
Genes are templates for RNAs and proteins. There is no doubt that genes underlie organisms’ behavior because cells need specific proteins and RNAs to function and all organisms are made of cells. Editing genes causes changes in development and behavior; if you replace a particular nucleotide sequence with another, often the organism shows a different trait. But does this mean that the genetic code alone controls behavior?
Genes must be expressed to have an effect, and not all genes are expressed all the time. In fact the different ways that a set of 25,000 or so genes could theoretically be uniquely expressed is a number far, far larger than the number of particles in the observable universe. And yet the genome is tapped in a remarkably reliable way as an organism develops; just the right genes are expressed at just the right times to support orderly function. This would seem to require that genes were expressed based on a precisely evolved blueprint, but instead at a local level gene expression is very chaotic. The expression of a given protein can often differ by three orders of magnitude in adjacent cells in the same tissue.
If organisms can learn, this means they can change the way their genomes are expressed in response to their environments. If this is true, then it means the genome is not a list of explicit detailed instructions like a computer code; such instructions cannot be changed freely. At a low level, computer codes have no plasticity; even one bit out of place causes a computer program to crash. What is it then? What causes the reliability of these patterns of gene expression?
Suppose we think of a genome not as a list of instructions but a list of tools. Anna and Amanda share the same tools throughout life, but their way of using them begins to differ over time. Genes are not the score that specifies the music, but the keys of the piano. Epistolution is occurring in cells that are choosing their own unique patterns of gene expression, but due to the physical and chemical propensities inside the nucleus some patterns of gene expression are much more likely to occur than other ones. They are “stickier,” for some reason. It’s like how it’s easy to blow a B flat on a trumpet but harder to blow a C. The biologist Conrad Waddington (more about him later) imagined the space of possible gene expression patterns as a dented plane, with some local basins representing “attractors” that tend to pull cells into them.
For example, stem cells in the human body tend to follow about 200 possible paths to adulthood, one for each cell type, blood cell, bone cell, neuron, etc. There are no intermediate neuron-bone cell hybrids, for example, the cell chooses an attractor and sticks to it. Epistolution still controls whether it chooses one attractor or another, but the attractors themselves are the result of the genes that underlie the development process.
These attractors can exist not only on the level of the individual developing cell but on the level of the organism as a whole. An entire organism can be nudged into a different form by the conditions in its surroundings. For example, a set of experiments by Mike Levin showed that without any genetic manipulation, a pointy-headed sort of planarian could be treated with bioelectricity in a way that triggered its head to develop into the shape of another, round-headed variety. This new form was then stably inherited by the offspring, which in the case of planaria arise through fission (planaria cut in two develop into two individuals.)
To me this recalls the way an individual human genetically predisposed to, say, alcoholism, can either become a heavy drinker or not depending on factors like his upbringing or marital status. Genes influence traits by setting the landscape of possible expression patterns, but in order to get an organism out of them we have to add another, function-finding process that decides which attractors to select. Homer Simpson once said, “Beer is both the cause of and the solution to all my problems.” An attractor can sometimes be like that.
Next week we discuss the problem that epistolution poses for the role of natural selection, and in so doing we ask a forbidden question, what is the aim of life?
Be Kind, and Be Brave,
Love, Charlie Sent 12/13/23
