The Gene: An Intimate History
“The author is a wonderful writer. . . . extraordinarily skilled at explaining complex scientific ideas to the general reader.”
In the autumn of 1944, toward the end of the Nazi occupation of Holland, the transport of food and coal to Amsterdam, Rotterdam, Utrecht, and Leiden was shut down completely. Civilians suffered the “Dutch Famine” or Hongerwinter. Those who survived continued to suffer chronic health problems. The children of mothers who had been pregnant that winter also suffered from chronic obesity and heart disease. This did not surprise geneticists, because it is obvious that the health of pregnant women affects their babies well into adulthood.
The surprise was that the grandchildren of those survivors also suffered higher rates of obesity and heart disease. It may be that survivors create an environment that leads to such health issues. But scientists found that there was a heritable factor at work. Somehow, human reaction to the environment had created a genetic memory.
French biologist Jean-Baptiste Lamarck proposed in the 18th century that animals evolved by interacting with the environment and passing acquired traits to their offspring. Antelopes that foraged in tall trees would stretch their necks by “use and disuse,” and pass the lengthened necks to the next generation. Eventually they would become giraffes. By reacting to the environment, thought Lamarck, they created a genetic memory and eventually a species.
Many of us learned in school of the opposing viewpoint developed in the mid-19th century by Gregor Mendel. A priest who twice failed the exam in biology necessary to be certified as a teacher, he spent his life in a monastery in the Moravian city of Brno. Mendel conducted what are now famous experiments growing peas, and he demonstrated that certain traits were hereditary and not acquired. Further, certain recessive traits would reappear in later generations. Although the one paper he published in an obscure journal was not widely read during his lifetime, and modern analysis of his journals suggest that his methods were not to today’s standards of scientific experimentation, by the turn of the century his views had overtaken Lamarck’s theory of acquired traits.
And as many of us also learned, science eventually discovered genes, DNA, and (in 1953) the double helix structure of DNA. So how does genetic replication react to an environment such as the Hongerwinter to enable traits acquired and passed to future generations? This is but one of the puzzles explained by Siddhartha Mukherjee, who won a Pulitzer Prize for his study of cancer (The Emperor of All Maladies), in his new volume The Gene. The answer comes from epigenetics, which is how genes are activated and expressed in reaction to their environment.
Epigenetic processes determine the cell’s individuality. In the case of the Dutch Famine, it appears that methylation chemically alters DNA, and this process is heritable. Other forms of epigenetics involve the packaging of DNA by proteins that bind the genetic material.
Every single cell in an organism’s body contains identical DNA, so there must be some mechanism by which cells with the same genes differentiate to form an embryo and then organs and then an organism that can reproduce with other organisms. At molecular level, proteins in the early embryo are deposited preferentially in different places by the mother. Those proteins activate and silence genes, thereby defining which part of the embryo is which.
“These genes, in turn, activate ‘mapmaker’ genes that make segments and split the body into broad domains. The mapmaker genes activate and silence genes that make organs and structures. Finally, organ-formation and segment-identity genes activate and silence subroutines that result in the creation of organs, structures, and parts.”
Genetic information is not so much activated as it is silenced. If most of the genome were not silenced, we would be inundated and overwhelmed by genetic instructions to the point of incapacitation (and indeed that may be part of the problem with cancer cells). Our genetic code is silenced much of the time, and only bits and pieces escape this biologic gag order in reaction to extreme environments.
The Gene is a comprehensive work that explains these complicated scientific theories in comprehensible detail. Dr. Mukherjee presents us with several engaging puzzles to structure the explanations. He tells of his uncles who suffered from schizophrenia and attempts to uncover the hereditary roots of their illness (and perhaps also to explain why he was fortunate enough not to inherit it). He covers the history of heritability from ancient Greek times to the present. He describes the history of scientific discovery and the biographies of the scientists involved. And best of all he gives us clear and simple explanations of the complex science of genetics.
That science, from early on, suggested the possibility of curing disease and creating heritable traits in future generations. Much of this field of eugenics was abused by the Nazis (the extreme of negative eugenics was their genocidal attempt to wipe out entire groups of people). It was also abused in the United States, where the courts allowed government sterilization of women deemed to be feebleminded. In retrospect, they were simply poor and disadvantaged. Fortunately, these horrific policies were imposed on relatively few.
It is not clear that we can select for most of the traits that social Darwinists would want. Mutations, as Dr. Mukherjee points out, are something of a social construct. We define what is “normal” by the environments we create, rather than by some objective set of criteria. Just a few hundred years ago Europeans created cities in which cholera bacteria thrived and spread from person to person. It caused such severe gastrointestinal distress that many died.
About 1 in 25 people of European descent carry a gene that enables retention of salt and water, and thus provides a comparative advantage during cholera epidemics. Though it is a “mutation” it clearly became more prevalent because it helped people to survive an illness that was widespread. But when a child inherits two copies of this gene, she develops cystic fibrosis. Similar advantages against malaria are provided by the genes that express in sickle cell anemia. What we call disease may prolong life in some environments.
The author points out that Herbert Spencer, “the philosopher who had coined the phrase survival of the fittest—had spent much of his life bedridden with various illnesses, struggling with his own fitness for survival.” How genes produce people is in large part due to interactions with the environment, and in large part subject to either random chance or a system of such enormous complexity that it appears to be random. Society is often better off selecting for the environment that interacts with genes, rather than the genes that interact with the environment.
In some instances a single gene mutation can be associated with the very high probability of suffering from a disease or syndrome—hemophilia is an example—and one would hope that our understanding of genetics will eventually allow us to cure the problem.
In 1969 if a gene linked to a disease was discovered, scientists had no way to understand the nature of the mutation, no way to compare it to compare it to a normal gene, and no way to reconstruct the mutation in another organism to study its function. “By 1979, that same gene could be shuttled into bacteria, spliced into a viral vector, delivered into the genome of a mammalian cell, cloned, sequenced, and compared to the normal form.” Science is able to create genetically modified crops, and genetically produced drugs. Altering the genes of individuals is around the corner.
Our unfortunate history with eugenics has put brakes on such research and so has fear that genetic alterations might have unintended consequences. We do not want some carcinogenic virus to escape the lab and become a part of our genome. And although scientists seem aware of the dangers, they also minimize what they do not know. Discussing the potential dangers of a virus used to transport DNA, called SV 40, Dr. Mukherjee says with no irony: “Indeed many virologists had become infected with SV 40, and no one had acquired any cancers.” But of course, if virologists had become infected with a virus that was supposed to be carefully contained in their labs, one begins to have doubts about the safety of such research.
The Gene covers many aspects of genetics, from science to history to philosophy to public policy. That is both an advantage and a disadvantage. It is a long book, and the organizing principals are not always obvious. The book is not a collection of essays, but at times it reads as if it is. It tries to be everything to everyone, which means that most people will find aspects that are extremely interesting, but they may also wonder why other aspects receive exhaustive attention.
The author is a wonderful writer. He is one of the prominent writers in the New Yorker magazine on medical topics. While he may not yet measure up to his predecessors at the New Yorker, which published Oliver Sachs and Atul Gawande, he is extraordinarily skilled at explaining complex scientific ideas to the general reader.