A First Draft of the Book

So after a year and a half of writing, a first draft of the book is ready.

Why a book, you might ask? And why another book on Genomics? What is special about this one? So here goes..

Imagine a physician trying to diagnose a patient’s condition. The patient’s symptoms appear mysterious, leaving the doctor stumped and the patient helpless. How can this doctor dig deeper to obtain a diagnosis?

Doctors use various tools to dig deeper. They use X-Rays, MRI scans, CT Scans and Ultrasound to view our internal organs. They even view individual cells from these organs under a microscope by drawing a few drops of body fluid or by conducting surgical biopsies. But none of these help when the cause of disease lurks deeper – at a molecular level.

In and around each of our 100 trillion cells are a large number of molecules. Reactions between these molecules keep us going. And some of our health problems are consequences of these molecules not behaving as we expect them to. But probing these molecules for abnormal behavior is not easy, for two simple reasons: (1) they are really tiny, and (2), there are way too many of them. In this soup of molecules, the pride of place is occupied by the Genome. So a few minutes on the genome before we return to the plight of our doctor and his/her patient.

The genome is our parents’ gift to us. Many other molecules in our body are derived from the genome indirectly, making it the master molecule. As a molecule (or actually a collection of molecules), it has its own distinctive form and function. Nevertheless, in our simple-minded view, it is just a book of characters – 6 billion characters that allow us to resemble our parents among a vast array of other functions. The specific characters in your genomic book may be different from those in mine. And therein lies a fundamental question. What do these 6 billion characters tell us about ourselves? Can they predict the future trajectory of our health? Can they predict if we will grow up to be good athletes, scientists or orators?

The answer is less dramatic than we might hope. For instance, identical twins are born with supposedly identical genomes. Yet, one twin may develop autism, schizophrenia, diabetes or cancer while the other does not. This serves as a reminder that genomic characters are not the sole determiners of our fate. Rather, they act in concert with various environmental factors and with sheer random chance.

Yet, there are a few genomic characters which drive home their agenda almost single-handedly. A few actually means a few hundred thousand – but nevertheless a small fraction of the entire pool of 6 billion characters. The root cause of our patient’s illness may well lie in the abnormality of one of these characters. How would our doctor ever pinpoint this character from among 6 billion choices?

For that, we have some remarkable technological advancements in recent years to thank. These make it possible for us to read the tiny genomic book of our patient, at modest costs. Indeed, even 5 years ago, this wouldn’t have been possible, and this book couldn’t have been written.

Returning to the plight of our doctor and his or her patient: today, the doctor can simply order a genome sequencing test if he or she suspects that the cause of illness is an abnormal genomic character. A request for this test, accompanied with some saliva or blood or biopsy tissue from the patient, arrives at a specialized genomics laboratory. After a couple of weeks or so, the doctor receives a report from this laboratory describing any abnormal genomic characters found. Simple, isn’t it?

Well, what happens in the laboratory in the interim is anything but simple. A very elaborate quest for the offending genomic character is conducted. Since requests from hundreds of patients might arrive at the laboratory in any given month, several such quests run simultaneously. The complexity and gravity of these quests then makes the laboratory seem very much like a war room.

In this genomics war room, molecular biologists in lab-coats scurry around transferring samples from one receptacle to another until the genome sequence comes out at the other end in the form of gigabytes of data, after 3 or 4 days. During this process, genomic molecules are extracted from the patient’s sample, chopped into small fragments, and subjected to a multitude of manipulations. Attention is then focussed upon some specific fragments that are relevant to the patient’s condition, for scanning the genome in its entirety is often too expensive. High-performance computers then set about piecing these fragments back together like a jigsaw puzzle. Differences between this assembled jigsaw and that from a normal person are compiled subsequently, yielding a long list of variants, i.e., likely suspects. Computers then scour vast amounts of biomedical literature for information that helps zoom-in on the relevant suspects. This still leaves a handful of variants in play. Finally, trained geneticists rack their brains to identify the ones that hold a clue to the patient’s condition. If all goes well, one or two clear candidates emerge and are reported back to the doctor. But things don’t always go well.

Many parts of the genomic jigsaw puzzle look very similar, posing hurdles in piecing the puzzle together. Bioinformaticians then disambiguate by studying subtle differences between these parts. Variants that have never ever been seen previously are found sometimes. Geneticists then have to extrapolate and make guesses to establish culpability. No variants are found sometimes, leaving everyone scratching their heads and prompting a relook at the gigabytes of data at hand. Some variants are hidden more subtly under these mounds of data and need new algorithms to extract. Inconsistencies on account of noisy data arise occasionally and have to be reconciled. Anxious doctors and patients call in the meantime enquiring for results. These results sometime require that difficult decisions be made. All in all, a recipe for frequent huddles, frustrating roadblocks and ecstatic aha moments.

The 9 stories in this book provide glimpses into this genomics war room. Each story deals with a distinct patient suffering from a distinct illness – whose root cause lies in a distinct genomic abnormality and often requires a distinct algorithm to unravel. I believe that the story of these detective quests in a  genomic war-room setting has never been told before, and that makes this book unique.

The intended audience for this book is just about anyone with scientific curiosity.  An introduction to the genome is woven into the stories themselves, as are forays into biology, medicine and computer algorithms, sparing any laboured inventory of boring facts before the action begins. That said, this first draft is surely more technical than the final product will be as I incorporate comments from early readers.

I hope you will at least give the book a quick browse if not a careful read. Critical comments are welcome.  Ideas to make the writing more interesting, entertaining and accessible would be most useful.  Of course, a book project is always a prolonged labour of love, so words of encouragement would be nice as well.