Review of “The Gene: An Intimate History” by Siddhartha Mukherjee

I’ve been looking forward to reading Siddhartha Mukherjee’s latest book, “The Gene: An Intimate History”, since it was published in 2016.

His Pulitzer prize-winning “The Emperor of All Maladies” is one of the most interesting and informative books about cancer that I’ve read.

The implications of what has been learned about the gene and what it means for future generations are very personal for Mukherjee, as he reveals in this new book as he shares the stories of several family members who have been affected by mental illness.

What Is The Gene?

Like “Emperor,” “The Gene” beings with a history of sorts of how our knowledge of heredity and the way in which genetic traits are passed from generation to generation has evolved over time. This part of the book reads almost like a detective story, as Mukherjee describes how the mysteries of the gene–what exactly it is, where it is in the body, and how it works–were unraveled by researchers one step at a time.

A century of learning about the gene started with Gregor Mendel and his experiments with pea plants in the 1860s, and culminated in the 1950s when James Watson, Francis Crick, Rosalind Franklin and others finally identified the molecular structure of DNA–the famous double helix.

From the late 1950s into the 1970s, scientists deepened their understanding of how genes function, learning for example that genes could be turned “on” or “off” by particular cues. This in turn led to greater understanding of the linkages between genes, human physiology and a variety of diseases.

Using Genes to Treat Disease

The 70s and 80s became a major turning point, Mukherjee tells us, as researchers moved from describing the gene to learning how to manipulate it to create medicines to treat diseases–something that researchers up to that point hadn’t even really contemplated.

Researchers began to identify genes that produce essential proteins in the human body, and to use that knowledge to develop synthetic proteins to treat diseases.  For example, by isolating and identifying the composition of the gene that codes for the production of insulin in the human body, scientists were able to produce a synthetic version of insulin.

Scientists also began to identify individual genes linked to diseases such as cystic fibrosis and Huntington’s disease.

But looking for individual disease-responsible genes was only going to be of limited help in tackling disease. Mukherjee says:

But most common human diseases do not arise from single-gene mutations. These are not genetic illnesses as much as genomic illnesses: multiple genes, spread diffusely throughout the human genome, determine the risk for illness. These diseases cannot be understood through the action of a single gene. They can only be understood, diagnosed, or predicted by understanding the interrelationships between several independent genes.

Scientists realized that the one gene at a time approach was never going to be sufficient to understand complex diseases like cancer, Mukherjee tells us. Before we could understand what goes wrong in cancer, we needed to understand the complete “normal” human genome. The rush was on to sequence the human genome, an enormous feat that was finally accomplished in 2000.

Using Genes to Predict Risk for Disease

Although the human genome has now been sequenced, there is much more we don’t know about how genetic mutations interact with the environment and other triggers to lead to disease.

Mukherjee discusses the BRCA1 gene mutation to illustrate this. Although the mutation is rare, when the gene is mutated, the result is that the individual has an 80 percent lifetime risk of breast cancer. Yet, the variation among women with this mutation is very significant. The age at which a woman might be diagnosed and the type of breast cancer vary. And some with the mutation won’t develop breast cancer at all.

These variations across individuals happen because, even when the BRCA1 mutation is present, breast cancer requires multiple triggers. The environment–such as X-rays or DNA-damaging agents–plays a role. Chance plays a role in that the mutations that accumulate are random. In addition, other genes may either accelerate or mitigate the effects of the BRCA1 mutation.

In some diseases, where there are many types of inherited mutations that may be involved, along with an array of possible external triggers, the possible variations across individuals become enormous.

The mental illnesses schizophrenia and bipolar disorder are genetically linked. And, like breast cancer, they come in familial and non-familial (or “sporadic”) varieties. But that is where the similarity ends. The risk for familial schizophrenia/bipolar disorder, Mukherjee explains, involves more than 100 different genes. Beyond that, there are the influences of the environment, etc., making the questions of how either of these mental illnesses may or may not become a factor in any individual’s life–even if they’ve inherited some of the relevant mutations–an extremely complicated question.

What Does the Future Hold?

Even with all these uncertainties and complexities, with increased computational power, we should soon be able to “read” the genome more comprehensively–at least in the sense of determining probabilities for many diseases or conditions. Mukherjee says:

By the end of this decade, permutations and combinations of genetic variants will be used to predict variations in human phenotype, illness, and destiny. Some diseases might never be amenable to such a genetic test, but perhaps the severest variants of schizophrenia or heart disease, or the most penetrant forms of familial cancer, say, will be predictable by the combined effect of a handful of mutations.

In the next decade or so, we’re likely to know much more about probabilities of having certain diseases or conditions based on our genomes. But what do we do with that information? Can we intervene to lower risk? Can “gene therapy” become reality?

In the late 1990s, a time of great enthusiasm in the emerging field of gene therapy, a teenaged boy tragically died in a clinical trial of a form of gene therapy in which a modified gene to correct a deficiency in his metabolism was injected directly into the boy’s bloodstream via a virus.

There were many things that went wrong in that case, including a failure to follow what would, at least in today’s world, be appropriate clinical trial protocols as well as an underestimation of how the boy’s immune system would react to the treatment. But Mukherjee says that the basic concept behind the trial was sound. “In principle,” he says, “the capacity to deliver genes into cells using viruses or other gene vectors should have led to powerful new medical technologies, had the scientific and financial ambitions of the early proponents of gene therapy not gotten in the way.”

After a “lost decade” when gene therapy trials were halted as a result of the tragedy, second- and third-generation technologies are now being tested in clinical trials. In 2014, in a landmark study, gene therapy was used successfully to treat hemophilia.

In the final chapter of the book, Mukherjee discusses what he refers to as “the perennial fantasy of human genetics”–efforts to alter genes in reproductive cells and thus change the genetic makeup of a human embryo to prevent disease. Such research is of course fraught with ethical and other issues, and currently is subject to significant constraints.

Overall, I really enjoyed this book. It’s full of insights on what we know and don’t know about the gene and genetics. Mukherjee certainly suggests that there is much potential to use our understanding of genetics to help individuals, especially in treating disease.

But he is also saying we need to be careful. Technology is developing rapidly and allowing us to push the boundaries of what is possible all the time. There may be incentives to try to do more than we can safely and ethically do. These are issues we need to consider carefully as a society now and in the years ahead as new research findings are likely to continue to open up both new opportunities and new controversies in the use of our knowledge about genes.