That children share traits with their parents, grandparents, and siblings has been recognized since antiquity. How these traits were transmitted remained a mystery for more than two millennia. Unmasking this process has been the greatest scientific discovery since man discovered fire.
Siddhartha Mukherjee has written a history of this entire process – The Gene: An Intimate History. The intimate part relates to the interlacing of his family’s propensity to mental illness as a background to his story of the emergence of and development of modern genetics. Dr Mukherjee is an oncologist who is an assistant professor of medicine at Columbia University Medical Center. His gift appears to be the lucid explanation of science rather than as a producer of original research. His previous book The Emperor of All Maladies: A Biography of Cancer won the 2011 Pulitzer Prize for General Nonfiction.
The two most important works of 19th century biology were published within a few years of each other. The first, Darwin’s On the Origin of Species by Means of Natural Selection (1859), was an immediate sensation. Gregor Mendel’s Experiments on Plant Hybridization (1865), on the other hand, was ignored for 40 years. The two works are inextricably linked.
Darwin correctly surmised that that species evolved from earlier species, but had no idea of the means of inheritance. Darwin missed Mendel’s seminal work – Mukherjee describes how he almost found it. What Darwin lacked was the gene. Though Mendel didn’t know what a gene was, his work clearly denmonstrated that such an entity existed. Mukherjee amusingly describes Mendel’s repeated failure to pass his teaching exams. The founder of genetics, the most important botanist ever, even flunked botany.
How the gene was postulated, discovered, and worked is the subject of Mukherjee’s fine volume. His prose is lucid and he makes a complex subject accessible to the interested reader. His audience is just about anyone who is not fluent in the subject.
Before the gene was defined, chromosomes had to be identified. Thomas Hunt Morgan won the Nobel Prize for placing the gene on chromosomes. Alfred Sturtevant, Morgan’s student, working with fruit flies made the first genetic map of a chromosome. In 1944 Avery, MacLeod, and McCarty identified DNA as the mechanism for biological inheritance. In 1953 Watson and Crick delineated the structure of DNA – the now ubiquitous double helix. All this and much more is clearly described in The Gene.
The genetic code turned out to use four symbols rather than the two that a computer employs. A gene is a segment of DNA along the double helix consisting of base pairs. There are only four nucleotides which encode information: adenine (A), cytosine (C), guanine (G), and thymine (T). A pairs with T and C with G. There are spaces within a gene that do not encode the instructions of the gene – introns. The are segments along the DNA molecule that do not contain encoding information, they were initially called junk DNA as they seemed to have no function. The term was dropped as functions for these DNA sequences were discovered. They are now called Nonencoding DNA. It is possible that some of theses stretches of the DNA molecule actually may be junk. There are about 24,000 genes and 3 billion base pairs in the human genome.
There is more to genetics than genes. And it is here that Mukherjee may be a little weak. A gene exerts its effect by first producing a strand of RNA molecule that matches the DNA sequence. This process is called transcription. In RNA thymine is replaced by uracil (U replaces T). This messenger RNA molecule is then used to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence; this correspondence is called the genetic code.
The final effect on the organism of the gene or genes in question is influenced by what happens after translation (post-translational events), these events may have enormous effects on the eventual outcome initiated by the gene on the organism. The genotype is the set of instructions to which an organism is subject. The phenotype is the result of all the influences that end in the expression of a trait or combination of traits, ie the sum of nature and nurture. The post-translational effects are difficult to define and to predict, which is why identical twins are not completely identical.
Some of the examples that Mukherjee uses need further explanation. He says that the genes for color in cats are on the X chromosome. This is true for red-orange and black, but not for white which is on an autosomal chromosome. A tortoiseshell cat is a mixture of red-orange and black. These cats are always female as two XX chromosomes are needed. The only exception is the feline equivalent of Klinefelter’s Syndrome -XXY in which there is an extra X chromosome. A calico cat, also female, has a red-orange gene on one chromosome and a black one on the other. But it also has a white gene. The reason that red-orange and black are randomly expressed is that one X chromosome of every female cell is randomly inactivated. Whether the X chromosome is from the father or mother makes no difference.
Mukherjee says that only the sheep among higher mammals has been cloned, but many other mammals have also been cloned. CC the cat was cloned in 2001. She is brown and white, while her genetic donor (Rainbow) was a calico. CC has had normal kittens conceived the old fashioned way. She has an outgoing personality while Rainbow was introverted. Numerous labs have verified that the two animals are genetically identical. Yet another example of how there’s more to genetics (or genomics) than genes.
The genetics of sex could use a little more information. Mukherjee completely explains the X-Y chromosomes that determine gender in insects and mammals, but ignores the W-Z system which performs the same function in most reptiles and all birds. In the this system it is the female which is W-Z and thus determines the sex of its offspring.
His depiction of the SRY gene as the determinant of gender and gender identification completely ignores the Androgen Insensitivity Syndrome (AIS). In its complete form genetically male subjects are phenotypically female. All human fetuses are female in form until about the 7th week of gestation when under the influence of androgens produced by the testes (in X-Y fetuses) they develop male genitalia. In subjects with AIS a mutation of the androgen receptor gene (on the long arm of the X chromosome) renders them insensitive to androgens and they develop into phenotypically female babies and adults. They look like females and identify as such despite having X-Y chromosomes. Of course they are infertile and do not have menses. But otherwise they are normal females. Gender is a much more complex business than our currently deranged societal discourse on the subject realizes.
Mukherjee also says species cannot interbreed, a common but completely mistaken idea. Dog and wolves easily interbreed and give rise to fertile offspring. Even lions and tigers can interbreed. Sometimes the results of this cross are fertile.
But these objections are small gruel in a fine work. This is an outstanding explanation of the current state of genetics. The last part of the book is a compelling account of the complex ethical issues that confront molecular biologists as their power to manipulate the human genome becomes ever stronger. Replacing single genes that cause deadly human disease offers a simple choice. But changing the genome to alter more complex human characteristics is not only ethically challenged, it’s fraught with the almost certainty of unintended consequences. I think that manipulating the genome will prove more complex than Mukherjee does and he thinks it complex. He is also very aware of how complex the interaction of genes with the environment is and how hard it is to tease each component of human development from all the others.
Because of the hazard of manipulating the human genome, geneticists from all over the world, China excepted, are currently refraining from altering the genome of human embryos. This concern is appropriate and warranted, but seems paradoxical as there is no moral qualm among many geneticists about killing human embryos and fetuses. Mukerjee goes no where near this issue. Nevertheless, anyone interested in the proper study of mankind will read this book from cover to cover.