Will the Real Walter Gilbert Please Stand Up?

Stephen L. Talbott

RSS Feed for Biology Worthy of Life:    

Posted: August 22, 2013   (Article 9)

In 1992 the preeminent geneticist, Walter Gilbert, memorably dramatized the significance of the Human Genome Project by telling audiences how in the future every individual’s genomic sequence will be inscribed on a digital disk. He then illustrated this future by pulling a CD out of his pocket, holding it up, and saying, “Here is a human being; it’s me”.

It now appears likely, however, that when such a future comes he will need to carry around many disks, each containing a unique digital sequence corresponding to one of the multiple genomes in his own body. His problem will then be to decide which disk holds the real Walter Gilbert.

The genetically variable human being

With the sequencing tools available to them, biologists are now in a position to explore the genomic details, not only of many species, and not only of many individuals, but also of different tissues within a single individual. A brief article in Science, written by James Lupski* of the Baylor College of Medicine in Houston, nicely summarizes in its title what they are discovering when they look at these tissues: “Genome Mosaicism — One Human, Multiple Genomes”.

It is becoming increasingly apparent [Lupski writes] that a human individual is made up of a population of cells, each with its own “personal” genome.

“Mosaicism” refers to the fact that if a DNA alteration, or mutation, occurs during the development of an organism, this mutation will be inherited by all the cells, or the entire tissue, generated from that parental cell. And if this happens a number of times during development, then the mature organism may turn out to be a mosaic of cell populations with different genomes.

A DNA alteration may consist of anything from a different “letter” (nucleotide base) at a particular position in the genomic sequence, to a different number of copies of a particular gene, to various rearrangements of genome segments, to the addition or subtraction of entire chromosomes or chromosome arms. “These mutational processes”, writes Lupski, “can occur at any stage of development; in stem cells, differentiating cells, and in terminally differentiated somatic cells”. But the earlier they occur in development, the more likely they will make a large contribution to the genomic mosaic that is the mature human being.

Genome alterations play a role in the genesis of various disease conditions — although (and this is a way of thinking about the matter too easily overlooked) we might also say in many cases that disease conditions can play a role in altering the genome. For example, there is a lively debate today about whether mutations should be regarded primarily as causes of cancer or results of it. In any case, changes in the genome should bring to mind much more than the possibility of disease. In Lupski’s words: “the extent of somatic mosaicism that is now being reported in a variety of healthy tissues and cell types suggests that it also has physiological functions”.

Take aneuploidy, a condition where a particular chromosome in a cell exists in an unusual number. In humans, this means there would not be two copies of the chromosome in a cell, but, say, one or three. According to a recent paper (Bushman and Chun*) aneuploidy occurs in 30–35% of cells in the developing human brain. And while the amount at maturity isn’t yet known, “a significant population of aneuploid cells is also present in the adult human brain” — about 10% of cells by some estimates.

Studies of aneuploidy in the non-diseased central nervous system question the assumption that aneuploidy is in fact ‘abnormal’ in the development of certain cell lineages, and that it is deleterious — views contradicted by the maintenance of aneuploid populations in the normal brain. ... The stable and seemingly permanent changes produced by genomic alterations in a single neuron could provide a mechanism for creating and stabilizing functional mosaic populations within the brain, such as those constituting a neural network.

Looking more generally at the many types of genomic variation (not only aneuploidy), one sees regional variations between the frontal cortex and cerebellum of the brain within a single individual, suggesting, according to Bushman and Chun, “non-random mechanisms in the generation and/or maintenance of this variability”.

It appears that the organism has its own plans for its genome, and that it is fully capable of re-designing what used to be called the “master plan for development”.

The embryo: unstable, or healthily adaptable?

Perhaps your interest was piqued by the indication above that the amount of aneuploidy in the mature brain appears to be less than that in the embryonic brain. There is good reason for curiosity here, since the question arises: how might the variation, once established, be reduced?

There are various possible answers (which I will not explore here), but the first thing to realize is that the question applies not only to the brain, but to the developing embryo as a whole — and not only to aneuploidy, but to all sorts of genomic variation. In a 2009 study of early human embryogenesis, the researchers (Vanneste et al. 2009*) reported chromosomal changes in a “staggering 70%” of the embryos. They were looking at just the first several cell divisions after fertilization (known as “cleavage” divisions,) and they found “not only mosaicism for whole-chromosome aneuploidies” in most of the embryos, “but also frequent segmental deletions, duplications and amplifications”. They concluded that “chromosome instability is prevalent in human embryogenesis”.

The study was conducted using 23 embryos derived from healthy young women undergoing in vitro fertilization. This, of course, suggests the possibility that the chromosomal aberrations might have something to do with the in vitro procedure itself. But while there is some (debated) evidence that such procedures could yield a slight increase in mutations, this in no way accounts for the current research results. Only 2 (9%) of the 23 embryos in the study had the normal chromosome number in all cells, a figure that might be thought to reflect an upper limit on the possible success rate for in vitro fertilization. Yet the actual success rate is over 20%.

Other investigators have come up with similar results, and there is also supporting evidence from normal (in vivo) pregnancies:

Analyses of DNA samples that were obtained from postnatal tissues of normal individuals as well as individuals referred for clinical genetic diagnostic testing pinpoint the early human embryo as a cradle of chromosomal rearrangement. (Voet et al. 2011*)

It seems indisputable that mosaicism is common — if not the rule — during early embryonic cell divisions, and that mosaic embryos may develop into normal fetuses. “It is now clear that structural aberrations are a common occurrence in preimplantation embryos” (Mertzanidou et al. 2013*).

Given our current state of knowledge, the word “aberration” seems unnecessarily prejudicial. But it also reflects common usage. One typically speaks about chromosomal “abnormalities” as being the result of “errors” — for example, errors in DNA replication. It’s true that in humans a great percentage of fertilized eggs do not develop to birth. And we, like all organisms, are subject to disease and death at all stages of our physical existence. But shouldn’t we be alert to the possibility of a rather more complex story? The following facts seem particularly relevant:

First, “it has been suggested that embryos might ‘self-correct’ their chromosome complement as they develop”, and “several studies show that the proportion of aneuploid cells in embryos diminish as the embryos go through the cleavage, morula and blastocyst stage” (Mertzanidou et al.*).

Second, the prevalence of mosaicism now being described in the mature human being is powerfully suggestive, to say the least. Perhaps the organism knows what it is doing and has good reason to modify its genome in differing cellular contexts. After all, it modifies everything else. Might not chromosomal variation — “self-correcting” or otherwise — sometimes contribute importantly to the organism’s normal development?

Third, we are discovering more and more ways in which organisms do in fact manage their own genomes, not only early in development, but throughout their lives.

Fourth, we know that the earlier the stage of human development, the greater the plasticity we observe in the developing organism. Indeed, the plastic, formative powers of the embryo are apparently great enough to normalize cancer cells that have been transplanted from a tumor into the embryo. It would not go altogether against expectation to see the genome participating meaningfully in this plasticity.

Finally (and most challenging for the materialistically minded biologist) there is that peculiar “shall we or shall we not” conversation — first between egg and sperm, and then between embryo and mother — that embryologist Jaap van der Wal points to as characteristic of human conception and embryonic development. The conversation looks rather like a “negotiation” or mutual accommodation concerning the terms of a potential human life, and perhaps we shouldn’t be surprised to find a great deal, including parts of the genome, “on the table” for this negotiation, especially during the embryo’s earliest, most profoundly formative phases.

There is always a certain risk in betting against the wisdom of the organism when it is engaged with its own genome. We now have a long history of wrong bets. Given that the story of the genetically mosaic embryo is itself in its embryonic stages, we can expect an interesting narrative to emerge over the coming few years. And whatever the twists and turns in this story, we can be quite sure that the real Walter Gilbert needn’t worry about choosing among his (potentially) many genomes. He cannot be reduced to any one his genomes, or to all of them together. Who, after all, manages the transformations of his genome?

This document: https://bwo.life/org/comm/ar/2013/real-walter-gilbert_9.htm

Steve Talbott :: Will the Real Walter Gilbert Please Stand Up?