The Gene: An Intimate History

Author: Siddhartha Mukherjee

My first taste of Siddhartha’s scholarship was reading his Pulitzer Prize winning “Emperor of Maladies”. Until I read that book, I did not believe that a single human being could both be an expert in his field and have the ability to impart this knowledge to a lay person in a clear and entertaining manner. So when he wrote another book, I was intrigued to see if he could do it again.

Within the first few pages, I discovered that this book is going to live up the high standard that Emperor of Maladies set. The brilliant part of Siddharth’s book is how he develops the narrative. He gets into the minds of the scientists and describes the environment, their interactions and finally their discoveries. It is scientific drama at its best and in many ways the book reads like a thriller.

Once the DNA chemical structure was identified, the scientific community embarked on a race to decode the genome and identify the locations of specific genes on individual chromosomes. Typically this is easier for genes that cause diseases and there are several like Huntington’s disease, breast cancer, etc. that have been clearly identified.

One  side benefit of decoding the human genome is that by analyzing the genes of a sample of diverse humans, we can make some interesting inferences on where man first evolved. Younger tribes have smaller variation in their gene pool while older tribes have a more diverse set of genes. The most diverse is found among the San Tribe in Southern Africa from where it is believed that humans first evolved around 200,000 years ago. After a 100,000 years or so they migrated to Asia, Europe and then America, where the native Americans have the least diverse set of genes.

Another interesting observation is gleaned from the very small amount of mitochondrial DNA that all of us have. This is fairly tiny — around 20 genes — and is passed on from the mother to her children. Since the sons cannot pass this forward, the mitochondrial genetic line of the mother ends if she does not have any daughters. It is not hard to see that assuming the size of the population remains constant, the diversity in the mitochondrial genes in the women keeps reducing with each passing generation and after a certain point, all of us would have descended from a common set of mitochondrial genes, which is the case today. Hence, we are all descended from one woman who lived around 200,000 years ago. We don’t know what she looked like, but the world has christened her Mitochondrial Eve.

Siddhartha has found a magical way to write about scientific history that really appeals to me. Rather than paint a chronological view of the historical discoveries, he organizes his thoughts around the basic questions that humans have wrestled with over the ages. He builds these up in a logical manner and answers each of them with the drama and flair that makes it so readable. Given that the questions build on one another, it is natural that it follows a roughly chronological order.

Here are the questions and the scientists who answered them [ Spoiler Alert ]

1. Is the unit of heredity discrete (like a 0 and 1) or is it a continuum (like paint). - Gregor Mendel and his famous experiment with tall and short pea plants (there were other contrasting traits too)
2. Once the notion of a “gene” was established, the question then is do they move separately or in packs on a “chromosome”? This was answered by Thomas Morgan through his famous experiment on the Drosophila fruit flies at Columbia University in the first decade of the twentieth century.
3. Once we knew about chromosomes, we wanted to know how the actual genes were spaced out on a chromosome? Which ones were close and which ones were farther apart? Sturtevant, a student of Morgan’s analyzed the data on fruit flies for traits that were inherited together and made some early determination of the distance between genes on a fruit fly chromosome.
4. Then you reach the question of how changeable is the chromosomal map of genes. Can some split and recombine ? Can they mutate ?
5. We now have the scientific basis for Darwin’s theory of natural selection and it is worth interpreting it again with all that we have learned so far.
6. With the basic hereditary mechanism under our belt, we would like to figure out the actual chemical composition of the carrier of this information. Could it be DNA, and what does it actually look like?  The last question took some creative genius from Watson and Crick who in 1953, proposed their now famous double helix model of DNA
7. How big is the genome and can we map an entire one. First we try some simple creatures but the holy grail is mapping the entire genome which was completed by the Human Genome Mapping project in 2003.
8. Can we now identify the exact amino acid sequences that constitute a gene and its related behavior. We know this for a few hereditary diseases like Huntington’s disease, Breast Cancer, Hemophilia, etc.  While we don’t know the function of all the genes in our genome, there will come a day when we have that mapped completely.
9. Can we selectively splice (and replace) a defective gene ? Initially this seems really hard to do but the CRISPR system has allowed us to perform exactly this function.

The last question leads to an ethical dilemma. While the CRISPR technique is used mainly to repair some “defective” genes, it is quite plausible that it will be used to inject some desired “enhancement” into our gene pool. These experiments can quickly go awry and lead us into all kinds of mess that will be very hard to escape from.

Contrary to what is on the jacket cover, Siddharth’s personal story seems like a veneer that is added to the book and is not tightly integrated into the narrative. It seemed a stretch to connect it to the book and seemed out of place to to me. The small smattering of pages that digress with Siddhartha’s personal story does little to detract from the well researched content that is so artfully narrated in the book.