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Book Club: “The Emperor of All Maladies” by Siddhartha Mukherjee

Posted on : Jul-17-2015 | By : John | In : Book Club

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The Emperor of All Maladies

The Emperor of All Maladies

This month’s book is The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee, an oncologist at the CU/NYU Presbytarian Hospital and a wonderful writer. He is also assistant professor of medicine at Columbia University A former Rhodes scholar, he graduated from Stanford University, University of Oxford (where he received a PhD studying cancer-causing viruses) and from Harvard Medical School.[*]

This is quite a long and deep book, as it must be for such a vast subject. Cancer is not one disease, but hundreds of related diseases, with disparate causes, and the story of how it afflicts humanity and the long search for prevention, treatment and cures requires in depth discussion. Fortunately, we’ve had two months to read it, but if you’re just starting it now, you’re really going to have to cram for the examdiscussion! Still more fortunately, Dr. Mukherjee is a wonderful writer, able to explain complicated scientific concepts with great facility, explore history without getting bogged down in tedious lists of names and dates, and always keeping his deep sympathy for the doctors and researchers struggling to treat a disease that was once invariably fatal, and most especially their and his patients and their families.

The history of cancer treatment is long and often misdirected. Surgeons tried to extirpate it with increasing radical surgery. Chemotherapists tried to kill the cancer without killing the patient with increasingly lethal combinations of poisons. Radiotherapists attempted the same with X-rays, gamma rays, and radioactive isotopes. Palliative care specialists just tried to make the remaining days of the patients as comfortable and numerous as possible, without expecting a cure. Meanwhile, researchers attempt to find a unifying cause of cancer, in order to discover new ways to prevent or cure it. Some looked to the genes, innate properties of the cancer cells and of the people who are its victims. Maybe people are born with cancer genes, or maybe they acquire them by mutations. Other scientists looked to external causes, toxins, radiation, and viruses. Epidemiologists searched for clues in common factors shared by the victims. None of these methods or theories provided a magic bullet for treatment, nor was the evidence for any of them compelling.

Despite the lack of a single effective treatment or a uniform working theory, much progress was made. Childhood leukemia is no longer a death sentence. Hodgkin’s disease can usually be cured. Strides have been made in many other cancers. Still, the death rate from cancer has remained static. Fortunately, epidemiology reveals an important clue. The growth in lung cancer deaths in women exactly parallels the increase in smoking in women in the post-war years, and compensates for the declines in incidence and mortality of all other forms of cancer. Prevention doesn’t look promising for most forms of cancer, but the most common form, lung cancer, is almost entirely due to smoking and is entirely preventable. Don’t Smoke!

Many cancer researchers and much of the public (including my Dad, who insisted cigarettes didn’t cause cancer; he was a smoker) supported the virus theory, despite the fact that only one specific virus had only ever been linked to a single rare cancer in chickens[**]. Eventually, research into this virus would lead to important biochemical clues about how all cancers work, including those caused by toxins or radiation. In the 1970’s, using early gene sequencing techniques and a much deeper understanding of chromosomes, DNA, RNA, cell replication, and viruses, scientists discovered a unique gene in the chicken cancer virus, RSV. Splicing out the gene made the virus incapable of causing tumors. But how? Normally, when a virus infects a cell, it hijacks the cell’s machinery to make more viruses. Then, either the cell dies, releasing the accumulated store of new virus copies into its environment, or the viruses escape the cell and it reverts to its normal state. The RSV virus did something different. It left the cell alive but in a precancerous state. The only thing that made sense was the virus had somehow integrated itself with the cell’s genome. But RSV is in an RNA virus and Eukaryote cells store their genetic code in DNA, and a central dogma of biology, since even before the structure of DNA was discovered, was that DNA produced RNA which produces proteins. RSV did it backwards. Eventually, it was accepted that it represented a new class of viruses, retroviruses, which were capable of inserting themselves (or a DNA analogue of themselves) into the host cell’s chromosomes. Here, said the virologists, is the mechanism that explains how viruses give rise to cancer! Then, at last, a human retrovirus was discovered, but it didn’t cause cancer. Instead, it destroyed the immune system and resulted in AIDS.

Still, something interesting had to be going on with the src gene (so called because it produces sarcomas, a type of tumor) in RSV. src didn’t seem to be essential to RSV; it could still infect chickens and propagate normally with the gene excised, it just no longer caused cancer. Geneticists theorized that the virus had some how picked up a normal gene in a genetic accident somewhere along the line (or picked up a mutant form of the gene from infecting a cancer cell.) If this was the case, they should be able to discover a genetic 3rd or 5th cousin of src in chicken cells, so they went looking for it. The completely unexpected result was they didn’t find a distant relation, they found almost the exact same gene in ordinary chicken cells. Looking further, they found the gene in duck cells, quail cells and goose cells. And then in pheasants, turkeys, mice, rabbits and fish. And emus, sheep and cows. src was everywhere. But the src in RSV is slightly different from normal src. Its function is to produce a protein that activates other proteins by attaching a phosphate group to them. src is in turn strictly regulated by other genes. It only operates when it is supposed to, during cell division. RSV’s variant of src is literally out of control; it operates continuously resulting in out of control cell replication, the defining feature of cancer. Since RSV is a retrovirus, it has inserted itself into the host cell’s chromosomes and gets replicated along with the rest of the genes, meaning each generation of descendant cells contains the same out-of-control version of src. Other cancers might not be caused by mutant versions of src, but they are clearly caused by some breakdown of the normal process of cell division and replication.

Will this new insight into cancer’s biochemistry result in new preventions, treatments and cures? Has it already? I hope the last section of the book explains this, as I’ve just gotten to it. We will discuss it in depth at our next meeting, on Saturday, July 18, at 3PM, at our usual meeting place, Harvard’s Northwest Science Building, 52 Oxford St in Cambridge. You can RSVP on Facebook. Please bring your appetite and a treat to share (or just your appetite if you are treat-production challenged; we always have way more than enough). If you don’t have time to read the book, come anyway! Maybe you’ll be inspired to read it later.

As always, Mary will be leading an online discussion of the book the next day (Sunday July 19) at the Skepchick Book Club

[*] From the author’s biography on Amazon.com
[**] Eventually, a handful of other viruses linked to cancer were discovered, including Hep B and HPV (both vaccine-preventable.)

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