A superb writer, Siddhartha Mukherjee’s books are easy to read.
Six years ago I reviewed Siddhartha Mukherjee’s book The Emperor of All Maladies: A Biography of Cancer. It was hands-down one of the best books I have ever read on a medical topic. Now he’s done it again. His new book is titled The Gene: An Intimate History.
Mukherjee is a superb writer. Much of what I said about his first book applies equally to his second, so I will quote myself:
It is a unique combination of insightful history, cutting edge science reporting, and vivid stories about the individuals involved: the scientists, the activists, the doctors, and the patients. It is also the story of science itself: how the scientific method works…
Beautifully written and informative
Reads like a detective story with an exciting plot.
He links this second book to his first by pointing out that cancer is an ultimate perversion of genetics, and that studying cancer means also studying its obverse: normalcy. He gives the subject a human face by interspersing anecdotes from his own family’s struggles with mental illness and its connection to inherited genes. He sets out to tell the story of the birth, growth, and future of one of the most powerful and dangerous ideas in the history of science: the gene. He says it is one of three destabilizing ideas that have transformed science: the concept that irreducible units underlie matter (the atom), digitized information (the byte or bit), and biological information (the gene). He explains how the consequences of these ideas have transformed our thinking, our language, our culture, politics, and society.
History
He delves into the fascinating history of our early gropings towards understanding inheritance. Pythagoras believed that information was carried only in the sperm, and the uterus only provided nourishment. The preformation theory held that sperm contained a miniature human. Lamarck believed that acquired characteristics could be inherited. Mendel was the first to discover dominant and recessive inheritance of traits, which meant that there must be inheritable units. His published research was ignored for decades, and only much later did those units come to be called genes.
The history of genetics was stained by the eugenic movement, which had dire consequences. In America, there were involuntary sterilizations of people who were thought to be defective but often weren’t, like Carrie Buck. In Nazi Germany, eugenic arguments were used to justify the murder of children, gypsies, Jews, and other politically undesirable groups.
The research of Mendel and others convinced scientists that there must be such a thing as a gene. Around 1900 they figured out that genes must be carried in the cell’s nucleus and narrowed it down to the chromosomes. Studies of fruit fly mutants and variants found that some traits were linked, so their genetic information must be located close to each other on the chromosome. But how was the information carried?
When DNA was first proposed, it was dismissed as a “stupid molecule” that couldn’t carry clever messages. It took a long series of ingenious experiments to reveal that DNA was the carrier of genetic information, and it was decades before the amino acid triplet code was discovered and the structure of the DNA molecule was revealed by Watson and Crick. Mukherjee tells the story step by step, experiment by experiment, with all the suspense and excitement of a detective story where the gradual accumulation of clues finally reveals the culprit. His use of language is delicious; for instance he says, “Bread molds are scrappy, fierce creatures.”
As he relates discovery after discovery, the story gradually educates the reader about all the important concepts in genetics: introns, “junk” DNA, the function of RNA, how genes direct the embryo to form a human, recombinant DNA, gene sequencing, how proteins are manufactured, genotype vs. phenotype, transcription and reverse transcription, alleles, and epigenetics. He explains the “central dogma” that information moves from genes in DNA to messenger RNA to proteins, and then explains why that overly simplistic theory has required several modifications.
He tells the complicated story of political restrictions on genetic experimentation and of the conflicts that troubled the Human Genome Project. He explains how genes carry a molecular clock that tells our evolutionary history and how gene analysis can reconstruct the movements of early human populations. He explains why the Mitochondrial Eve is the mother of us all. He tries to explain why men have a Y chromosome. He throws a monkey wrench into racial discrimination by showing that there is more diversity within races than between races. He talks about genetic factors in homosexuality and transgender identity. He explains why epigenetics is on the verge of transforming into a dangerous idea that is being used to justify junk science and a new Lamarckism. He even speculates about how life itself began.
We have mapped the human genome and we understand a lot about the genetic code, but we know virtually nothing about the genomic code, which governs how multiple genes at various sites on the human genome coordinate gene expression in space and time to build, maintain and repair a human organism. We don’t understand the functions of noncoding tracts of DNA between the genes.
Tinkering with genes
Understanding the genome was the first goal. It inevitably led to a second goal: altering the genome. The hope was that we could outwit nature and take control of our own destiny, changing the course of human evolution. If we could identify genes that caused diseases, we ought to be able to fix the genes and eliminate diseases. We had eliminated smallpox from the world; now genetics offered the hope of eliminating everything from nearsightedness to cancer. We are still far from that goal and it is looking more and more unrealistic, but some progress has been made.
Genetic analysis can identify couples that might want to avoid pregnancy because of a high likelihood of transmitting a serious genetic condition like Huntington disease. Prenatal diagnosis can be used to guide selective abortion of fetuses with genetic diseases (and sometimes fetuses of the wrong sex!). Gene therapy is already possible, although some of the early experiments have gone awry due to incompetence, blunders, neglect, and gaps in knowledge. It is now possible to biopsy a human embryo and extract cells for preimplantation genetic diagnosis without affecting the viability of the embryo. In 2014 a landmark study was published in The New England Journal of Medicine reporting the successful use of gene therapy to treat hemophilia. Thanks to CRISPR, we have the ability to cut out a defective gene and replace it with a normal one.
The new technologies offer exciting promises but give rise to ethical dilemmas. Should society allow the creation of “designer babies”? Who is to determine what is normal and what is not: what if a defective gene causes mental illness but also causes genius and creativity? Genes affect the expression of other genes: modifying genes could have unforeseen consequences.
Something for everyone
The book is a cornucopia of delights that offers something for everyone. You can read it for its detective story and literary value. You can read it to get a basic education in genetics. You can read it to finally understand what epigenetics is really all about. You can read it for its explanation of cutting-edge science, for its tantalizing clues about where science is headed, and for a challenging view of the ethical dilemmas we will have to face as a society.
Mukherjee is a rare combination of scientist, storyteller, and educator. He is a truly gifted writer. I highly recommend both of his books, and I look forward to reading whatever he may choose to write about in the future.
Note: In the comments, several people have claimed that the book was scientifically inaccurate and have cited unfavorable reviews elsewhere. The criticisms were based on a New Yorker article which unfortunately was edited in a way that misrepresented the book. Those criticisms do not apply to the book itself. I want to clarify:
1) To those who questioned the size of the genome, be advised that different sources give different numbers, some including mitochondrial DNA and some not. And there are repeats that vary. And it makes a difference whether you count the Y chromosome or the larger X chromosome. The precise number is still unknown. The number Mukherjee gave was as reliable as any other.
2) To those who have read the book: please get out your copy and check again. The chapter on epigenetics BEGINS with transcription factors (page 391-2) and contains the following note on page 403: “The permanence of epigenetic marks, and the nature of memory recorded by these marks, has been questioned by the geneticist Mark Ptashne. In Ptashne’s view, shared by several other geneticists, master-regulatory proteins—[i.e. transcription factors] previously described as molecular “on” and “off ” switches—orchestrate the activation or repression of genes. Epigenetic marks are laid down as a consequence of gene activation or repression, and may play an accompanying role in regulating gene activation and repression, but the main orchestration of gene expression occurs by virtue of these master-regulatory proteins.” Also please note that histones occupy less than half a page in the whole book.
3) So Mukherjee’s critics are wrong, and it is obvious that the article did not represent the book well, since the New Yorker editors chose to use only a short excerpt that focused on histones, and they omitted the footnote which would have clarified Mukherjee’s information. There was an omission, yes, but it was terribly overblown by geneticists who work on transcription factors.
4) In short, the criticisms of Mukherjee’s book based on the flaws in the New Yorker article are misguided, and the book is scientifically accurate.
This article was originally published in the Science-Based Medicine Blog. It later appeared in Skeptical Inquirer under the title The Story of the Gene.
