The rapid advance of the sequencing of the genome of humans and other species has revealed how little we actually understand about how our cells operate.
Accurate gene identification requires approaches that extract information from the inherently low signal-to-noise ratio of the human genome. We shall describe some of them in Chapter 8. Here we discuss only one general approach, which is based on the observation that sequences that have a function are relatively conserved during evolution, whereas those without a function are free to mutate randomly. The strategy is therefore to compare the human sequence with that of the corresponding regions of a related genome, such as that of the mouse. Humans and mice are thought to have diverged from a common mammalian ancestor about 80 x 106 years ago, which is long enough for the majority of nucleotides in their genomes to have been changed by random mutational events. Consequently the only regions that will have remained closely similar in the two genomes are those in which mutations would have impaired function and put the animals carrying them at a disadvantage, resulting in their elimination from the population by natural selection. Such closely similar regions are known as conserved regions. The conserved regions include both functionally important exons and regulatory DNA sequences. In contrast, nonconserved regions represent DNA whose sequence is unlikely to be critical for function.
The power of this method can be increased by comparing our genome with the genomes of additional animals whose genomes have been completely sequenced, including the rat, chicken, chimpanzee, and dog. By revealing in this way the results of a very long natural “experiment,” lasting for hundreds of millions of years, such comparative DNA sequencing studies have highlighted the most interesting regions in these genomes. The comparisons reveal that roughly 5% of the human genome consists of “multi-species conserved sequences,” as discussed in detail near the end of this chapter. Unexpectedly, only about one-third of these sequences code for proteins. Some of the conserved noncoding sequences correspond to clusters of protein-binding sites that are involved in gene regulation, while others produce RNA molecules that are not translated into protein. But the function of the majority of these sequences remains unknown. This unexpected discovery has led scientists to conclude that we understand much less about the cell biology of vertebrates than we had previously imagined. Certainly, there are enormous opportunities for new discoveries, and we should expect many surprises ahead.
Molecular Biology of the Cell
is referred to by many as the “Bible” of molecular biology. Its lead author, Bruce Alberts, served as President of the U.S. National Academy of Sciences for 12 years from 1993-2005. This is about as “mainstream science” as molecular biology gets.
Let us take for granted, for a moment, their summary dismissal of 95% of the genome as functionally unimportant, or at least unlikely to be critically important.
The unexpected realization in the last few years that “we understand much less about the cell biology of vertebrates than we had previously imagined” should lead us to wonder, if our knowledge is but a drop in an ocean, how did it come to pass that we understand this particular drop and not another? If it is but a grain of sand in a seashore, how did we come to understand this particular grain, and not another?
The reality is that while the scientific method is, under ideal conditions, an objective method of acquiring knowledge, it is always imperfect humans with biases, financial interests, and ambitions who wield it.
Even as many scientists may struggle to keep their personal interests and preferences in check, science over the course of the twentieth century has been patronized by for-profit, non-profit, and governmental institutions with more explicit social goals and interests.
While these interests may not generally stand in the way of the ideally objective operation of the scientific method, and thus rarely if ever dictate the answers to scientific questions, they certainly have their hand in which questions are asked, and to a lesser but nevertheless meaningful degree how scientists go about finding the answers.
The term “molecular biology,” in fact, was coined in 1938 by Warren Weaver, director of the Rokcefeller's natural sciences division, to rename for the third time the program originally known as “pscyhobiology,” the aim of which was “the rationalization of human behavior.”
Edward Allsworth Ross coined the term “social control” in 1894 in response to what he saw as the inevitable class conflict that engendered debates between socialism and capitalism. Ross's “social control” would nationalize not the means of production and distribution but rather the thoughts, feelings and desires that would drive the private sector. In 1925, F.E. Lumley defined it as “the practice of putting forth directive stimuli or wish-patterns, their accurate transmission to, and adoption by, others whether voluntarily or involuntarily.”
Scientists who followed Thomas Huxley's 1864 “protoplasmic theory of life” that attributed all physical and mental attributes of life to the physical substance within the cell and shared John B. Watson's 1913 theoretical goal of “the prediction and control of behavior” would see the elucidation of the physicochemical foundations of life as the preeminent means of developing a science of social control.
Eugenics offered the first means of making social control an exact science, and by 1940 over 30,000 forced sterilizations had been performed in the United States.
The scientific credibility of eugenics waxed and waned. The rediscovery of Mendel's laws of heredity around 1900 suggested all traits and behaviors were controlled by a single gene. But the eugenics movement suffered a number of setbacks when scientists began to realize that many traits are affected by more than one gene and many genes affect more than one trait. Arguments about race and other sensitive topics, and ultimately the Holocaust, tarnished the ethical reputations of the movement.
Nevertheless, even in the post-WWII era many scientists openly flirted with eugenics. For example, in the 1950s Linus Pauling stated the following:
It will not be enough just to develop ways of treating the hereditary defects. We shall have to find some way to purify the pool of human germ plasm so that there will not be so many seriously defective children born . . . We are going to have to institute birth control, population control.
Pauling even thought for a time during the 1960s that we should be marked on the forehead with our genetic defects:
There should be tattooed on the forehead of every young person a symbol showing possession of the sickle-cell gene or whatever other similar gene . . . It is my opinion that legislation along this line, compulsory testing for defective genes before marriage, and some form of semi-public display of this possession, should be adopted.
These types of attitudes shaped our initial understanding of genetics, where we came to see a gene as something that exerts fundamental deterministic control over an organism.
As time went on, however, a new eugenics founded not on sterilization of the unfit but rather on genetic modification of the less-than-perfect would take the stage. Under its patronage, we have learned about the extensive abilities of cells to modify their own genomes, a glimpse of a radically different view of genetics.
Joshua Lederberg, co-discoverer of genetic recombination in bacteria, saw this new eugenics as the popular view among scientists:
[T]he ultimate application of molecular biology would be the direct control of nucleotide sequences in human chromosomes, coupled with recognition, selection and integration of the desired genes, of which the existing population furnishes a considerable variety. These notions of a future eugenics are, I think, the popular view of the distant role of molecular biology in human evolution.
Caltech's Robert Sinsheimer suggested this new eugenics would be a more democratic one than the old:
The old eugenics was limited to a numerical enhancement of the best of our existing gene pool. The new eugenics would permit in principle the conversion of all the unfit to the highest genetic level.
We must then wonder, how would we have come to see genetics if we were asking radically different questions?
In the next post, I will discuss the fascinating ability of our B cells to create their own antibody genes, and then to edit these genes in direct response to their environment, honing the affinity of the antibodies they produce for the antigens encountered by their host.
Without doubt, genes do carry heritable information and genes do contribute to virtually all of our traits, and on occasion even determine them.
My purpose in this series is not to deny these facts, but simply to shed some light on what else we can say about genes and DNA, and to give a glimpse of some fascinating science out there that suggests our popular conception of what “genetic” means might be very different had our scientific establishment's initial foray into molecular biology been intended to understand how it is that we can generate high-affinity antibodies to virtually any pathogen we encounter, rather than to understand how to control human behavior.
We must remember that while objective science will always allow the facts to contribute to its discoveries, the questions we ask just as powerfully determine the answers we get.
Now, on to the series…
The New Genetics — Part I: How Our B Cells Create Their Own Antibody Genes
The New Genetics — Part II: Some Biological Heredity Is Neither Genetic Nor Epigenetic
The New Genetics — Part III: Genes Don't Express Themselves
The New Genetics Part IV: Who's In the Driver's Seat? How Cells Regulate the Expression of Their Genes
The New Genetics Part V: Is the Intestinal Microbiome Part of Our Genome?