Saturday, September 03, 2011

Lamarck wasn't entirely wrong

kw: book reviews, nonfiction, genetics, epigenetics

Many years ago I read an article about the results of some genetic programming experiments. Genetic programming is a means of designing using a computer method that is based on natural selection. The article was about the design of a low-pass electronic filter using electrical components such as resistors, capacitors and inductors (coils). Starting with a basic filter design having a few components, a program would make large numbers of small changes (like changing the value of a resistance), a few medium changes (such as move a wire connection), and rare larger changes (say, add a capacitor between two points), to generate a few hundred or a few thousand modified designs. Then a test program would calculate the performance of each and rate them. One or a few of the modified designs would perform the best, and the process would be repeated. At the end of several trials, the experimenters built some of the filters to see how they performed.

The process resulted in a number of surprises, but the one of interest here was a design with only a few components, and three of them comprised a resonant circuit "off to the side" of the main filter elements. When the filter was built it performed spectacularly well, but they could not figure out what the "off to the side" circuit was doing. They tried eliminating it, and the performance was very poor. There was nothing in electronics theory that could help them understand that odd circuit, but it was clearly essential to the total function of the filter. Somehow it regulated the overall operation.

With simple examples such as this to go by, it is no surprise that natural selection, operating for billions of years, has resulted in a genome for any given living thing, replete with surprises. Even bacteria, seemingly simple as they are, are the products of almost four billion years of evolution. Far from being a simple tank full of chemicals that interact in random ways, a bacterium is a sophisticated, surprisingly complex chemical machine. But we don't see them in everyday life. We do see larger things: plants, animals, and fungi in particular. These creatures, made of more complex eukaryotic cells, have biochemistry that is much more involved. The membranes within each cell, that segregate the nucleus and a number of "organelles", set up an environment that more resembles a colony of thousands of bacteria than a single cell. At the center of all this, we find the nucleus with its chromosomes, seemingly the seat of the genetically controlled "executive office" of the cell. Not so fast.

In his book Epigenetics: The Ultimate Mystery of Inheritance Richard C. Francis opens to us a different view, one in which this "executive" is a subject of cellular process, rather than a dictator. In his words, "…the executive function resides at the cellular level and the genes function more like cellular resources" (p xiii). The whole cell self-regulates, with the genes acting as a storehouse and consultant wrapped together.

The old view of "one gene, one protein" is on one hand 90% correct, and on the other wholly outmoded. Some genes code only for components of the ribosomes, which are composed of RNA. Some code for "microRNAs" that turn back and glomp onto certain proteins to regulate their rate of operation or even destroy some of them. Other sections, not specifically called genes, regulate the expression of other genes. But there are cellular processes, including methylation principally, that pervasively interfere with gene expression, and are largely responsible for the silencing of nearly all the genes in every cell, so that a liver cell only does liver cell stuff and a muscle cell busies itself with making things move, not making hormones or trying to digest food.

Such processes are called epigenetic, meaning "beside genetic". I think of them like the odd circuit that helped the filter work properly, but didn't seem to be a direct part of the filter. Epigenetics in particular, then, refers to the collection of processes that are not directly under the control of genes and their proteins, but instead operate upon them, creating a feedback mechanism. Feedback isn't so mysterious; it is what regulates all our technological devices. My dishwasher runs itself because of a feedback mechanism. Feedback controls the rate your heart beats. Certain stimuli cause the controlled rate to increase or decrease; if it were free-running it would be very unstable and prone to stopping without warning.

Where my title comes in, is that some changes in cell function that occur due to epigenetics are sufficiently permanent that they are inherited and affect the next generation. The simplest example is a child born to a mother who was subject to high levels of chronic stress during pregnancy. The high levels of stress hormones in her blood affect the development of the baby, who may be born earlier than usual, or weigh less, and is likely to experience certain maladies in later life. Even more, in what is called the Grandmother Effect, if this child is a girl, her children will similarly be more prone to the same maladies; the epigenetic changes she experienced while developing in her mother's womb affect her own egg cells and are passed on to her children. So be nice to your pregnant sister!

I don't pretend to understand methylation, but it takes place all the time, causing CH3- (methyl) groups to be attached all over the DNA. Usually, methyl attachments slow down gene expression, but in some cases they speed a gene up. A sufficient number of them will silence a gene altogether. The amount of methylation and its targets are at least partly controlled by the environment, and sometimes also by the choices an animal makes, or its emotional responses to the results of its choices. In this regard, Lamarck's contention that acquired characteristics are inherited was at least a tiny bit correct: Some of what happens during our life can be passed on to our offspring.

Now, most epigenetic changes are wiped clean when germ cells are produced, a kind of "epigenetic erasing". But not all. In my reading outside the book, I found that about a hundred things, such as certain forms of color blindness and a number of disease syndromes, are now linked to epigenetics.

The author states that this book is only a small window into the subject. It is vast, and requires much more study than just the "genome/proteome" studies we thought would result from DNA sequencing. For example, a particular "gene" (we need a new word now) doesn't create a protein, but a proto-protein. Even, the early stage of mRNA generation has an intermediate step or two of editing before the proto-protein is produced. Then nearby microRNAs set to work on the proto-protein, or other enzymes remove bits of it or rearrange it, and some methylation of the protein may occur also, until it is ready as the final, working protein, for whatever task it was prepared. Thus, the gene is not the unit of protein generation, but a template for some working parts from which a protein is produced. There is a lot of other cellular machinery involved.

Just like the nuts, bolts, wires and so forth in a hardware store can be assembled into many different devices, so I am coming to look on the products of some genes as standardized parts that can be cobbled together into quite a variety of products. That is how millions of proteins can be produced, when we have only about 22,000 genes in our DNA. It is the entire mechanism, as complex and unwieldy as it is, that has been the subject, and product, of gigayears of evolution by natural selection. The genes are an important part of it, but to say that only the genes evolve is like saying all houses are the same, except for the wiring. The genes have indeed evolved; the cell and its effects on how the genes work has also evolved. That is my take-away message from this fascinating book.

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