The Gene: An Intimate History - Siddhartha Mukherjee Page 0,228

least in part, encoded in the human genome. And human history has, in turn, selected genomes that carry these impulses, ambitions, fantasies, and desires. This self-fulfilling circle of logic is responsible for some of the most magnificent and evocative qualities in our species, but also some of the most reprehensible. It is far too much to ask ourselves to escape the orbit of this logic, but recognizing its inherent circularity, and being skeptical of its overreach, might protect the weak from the will of the strong, and the “mutant” from being annihilated by the “normal.”

Perhaps even that skepticism exists somewhere in our twenty-one thousand genes. Perhaps the compassion that such skepticism enables is also encoded indelibly in the human genome.

Perhaps it is part of what makes us human.

* * *

I. Another system to deliver “programmable” cuts in specific genes using a DNA-cutting enzyme is also being developed. Termed a “TALEN,” this enzyme can also be used for genome editing.

II. One important technical detail is that since individual ES cells can be cloned and expanded, cells with unintended mutations can be identified and discarded. Only prescreened ES cells, carrying the intended mutation, are transformed into sperm or egg.

Epilogue: Bheda, Abheda

Sura-na Bheda Pramaana Sunaavo;

Bheda, Abheda, Pratham kara Jaano.

Show me that you can divide the notes of a song;

But first, show me that you can discern

Between what can be divided

And what cannot.

—An anonymous musical composition inspired by a classical Sanskrit poem

Abhed, my father had called genes—“indivisible.” Bhed, the opposite, is its own kaleidoscope of a word: “to discriminate” (in its verb form), “to excise, to determine, to discern, to divide, to cure.” It shares linguistic roots with vidya, “knowledge,” and with ved, “medicine.” The Hindu scriptures, the Vedas, acquired their name from the same root. It arises from the ancient Indo-European word uied, “to know” or “to discern meaning.”

Scientists divide. We discriminate. It is the inevitable occupational hazard of our profession that we must break the world into its constituent parts—genes, atoms, bytes—before making it whole again. We know of no other mechanism to understand the world: to create the sum of the parts, we must begin by dividing it into the parts of the sum.

But there is a hazard implicit in this method. Once we perceive organisms—humans—as assemblages built from genes, environments, and gene-environment interactions, our view of humans is fundamentally changed. “No sane biologist believes that we are entirely the product of their genes,” Berg told me, “but once you bring genes into the picture, then our perception of ourselves can no longer be the same.” A whole assembled from the sum of the parts is different from the whole before it was broken into the parts.

As the poem in Sanskrit goes:

Show me that you can divide the notes of a song;

But first, show me that you can discern

Between what can be divided

And what cannot.

Three enormous projects lie ahead for human genetics. All three concern discrimination, division, and eventual reconstruction. The first is to discern the exact nature of information coded in the human genome. The Human Genome Project provided the starting point for this inquiry, but it raised a series of intriguing questions about what, precisely, is “encoded” by the 3 billion nucleotides of human DNA. What are the functional elements in the genome? There are protein-coding genes, of course—about twenty-one to twenty-four thousand in all—but also regulatory sequences of genes, and stretches of DNA (introns) that split genes into modules. There is information to build tens of thousands of RNA molecules that do not get translated into proteins but still seem to perform diverse roles in cellular physiology. There are long highways of “junk” DNA that are unlikely to be junk after all and may encode hundreds of yet-unknown functions. There are kinks and folds that allow one part of the chromosome to associate with another part in three-dimensional space.

To understand the role of each of these elements, a vast international project, launched in 2013, hopes to create a compendium of every functional element in the human genome—i.e., any part of any sequence in any chromosome that has a coding or instructional function. Ingeniously termed the Encyclopedia of DNA Elements (ENC-O-DE), this project will cross-annotate the sequence of the human genome against all the information contained within it.

Once these functional “elements” have been identified, biologists can move to the second challenge: understanding how the elements can be combined in time and space to enable human embryology and physiology, the specification of anatomical parts, and the development of an organism’s