Siddartha Mukherjee’s first book, “The Emperor of All Maladies: A Biography of Cancer”, is the third of his I’ve read. My interest earlier, and still, remains in understanding the biology of the organism, so I read his books on genetics and the cell first, trying to improve my understanding of the complex actions and structures of life before attempting to understand a disease that ravages and destroys so many lives. His effort to write this book led to Mukherjee receiving the Pulitzer Prize. It is a gargantuan endeavor, artfully constructed. It contains several stories in an overlapping, although, natural style beginning with man’s earliest recorded conception of the disease(s). It becomes clearer and clearer as you read through it that cancer is more a ‘family’ of diseases, linked by their pattens and effects as they progress within the cell and from there, into the collective structures of our body, than it is a singular disease. But that gets way ahead.

Cancer is not a ‘new’. The ancient Greeks wrote of it and there are scattered records of it much earlier from other civilizations. Galen, wrote of it almost 2,000 years ago, attributing it to an imbalance in ‘black bile’, one of the four humors, which when out of balance, he claimed, lead to various diseases (This was the justification for the practice of ‘bleeding’ a patient that continued on into 18th and early 19th centuries, not that long ago). Such ‘humors’ were thought for centuries to be at the root of many diseases and infections across Europe until scientists, through the use of microscopes, began to understand that the cell was the basic building block of all life, and that there was a microbial world beneath and within the world readily observable to us. Galen’s views continued to hold sway until anatomists, through their careful dissections, realized that ‘black bile’ was a fabrication, an attempted explanation for something unseen at work within the body. Cancer then, along with our understanding of the body and disease, began its slow, lurching, advancement through the practice of science. What actually is cancer?

Cancers are, in a sense, a ‘family’ of diseases, that we understand today to work through mutated genes, a modern concept that we are still grappling with. Cancers are different from one another, requiring unique treatments. They occur in different cell types, in different tissues and organs, progressing at varying rates, with differing virulence, sharing a pattern of unchecked growth. What cures or even slows one cancer is commonly entirely ineffective on another. The cancers themselves can even vary widely in their expression and behavior within a group, such as leukemia. It is not a fixed ‘thing’. And each varies in its onset, its progression, differing in its appearance as it ‘develops’ and moves throughout the body. What it shares, however, is its overall pattern of growth. Cancer, in all of its forms, is the rapid and uncontrolled proliferation of cancer cells, cells transformed into something no longer in service to the health of the whole. It is growth run amuck, intent only on its own increase as it seizes control of a body’s metabolism. Life, in cancer, is transformed to serve the cancer. Mukherjee takes you through all of the steps we’re aware of, that are continuing to unfold, from the beginnings of an individual cancer to its eventual overwhelming manifestation in a stricken patient. This is a story of our changing understanding of what cancer actually is, the people who’ve studied it and our still evolving medical approach to its ‘cure’. 

Cancer has ‘always’ been with us. Its increasing role as a major ‘cause’ of death is due to both our ability to see and understand what it is and the fact that we as a species tend to live long enough now that it has the time to manifest more fully in us. What goes with this is that we live in a world exposed to ever more mutagens and oncagens, than in times past. The chemistry of the world around us is increasingly being filled with novel molecules, many of which are toxic, effecting the conditions under which we live. While not being particularly toxic on their own in their collective effects and our increasingly continuous exposure our bodies come under stress, stress which can damage cells, which calls on the body to replace them. It has been observed that particular physical and chemical stressors, radiation, can lead to a variety of cancers. Time and exposure to these work their destructive ‘magics’ on our cells. Time itself results in mutations. It is not simply a matter of toxic exposures. 

We contain trillions of cells that are over time replaced multiple times and in each case, even given a process that continues with high fidelity such as this, mutations can accumulate gradually, the vast majority of which will not result in cancer. Understand that these replacements and consequent mutations occur to our body’s physical, somatic, cells not the ‘germ cells’ which are egg and sperm. Those are more closely protected and conserved. ’Cancer cells’ are not some kind of foreign invader. They are of us, altered cells that once served essential roles in our metabolism and growth, cells, however, that over time have been compromised by their exposures and the chance mutations that have occurred in such a way to alter their internal regulation. You and I possess unique genetics and our genetics set a baseline for our susceptibility to disease. On their ‘own’, in an organism not possessing the requisite mutations, cancer does not occur. We ‘require’ that our cells receive a ‘push’ into a cancerous state of growth.

We do not one day suddenly acquire cancer. It is not an infection in the commonly understood way of infectious diseases, but infection, may create the opportunity for its beginning as can other very particular stressors, toxins or even injuries. Time itself affords the opportunity for cell mutations which could tilt the balance toward cancer. It is a disease that itself ‘evolves’, changes over time, as key cells, or more specifically, their chromosomes, their genes, take on mutations of a particular sort. (Under the microscope cancer cells, blasts in leukemia, once they enter the ‘acute’ phase, are visually distinct from healthy cells. In earlier stages, their genes mutated, distinct physical changes in the cell’s appearance won’t have manifested, but it is there. Cancer is a progressive disease and as such can be very difficult to detect visually, even under microscope, in its earliest stages, not just because it may be forming deep within the body. This explains why ‘patients’ once seemingly cancer free, seem to suddenly burst forth with full blown cases. Cancer forms out of once healthily functioning and entirely necessary cells. This particular characteristic adds to the difficulty of ‘curing’ it, as very often, what kills the cancer cell, also kills the healthy unmutated cells.

‘Normal’ cells are periodically replaced on a ‘schedule’ unique to that cell and tissue. Normally, cells are regularly switched off and die, through the process of apoptosis, ‘silent cell death’ and then replaced. This process occurs in the cells of almost all animal cells, most frequently in blood and the epithelial cells of our skin and those that line our guts. New, replacement cells are created through the process of mitosis in which the chromosome are ‘unzipped’, then doubled, so that the cell when divided into two ‘daughter’ cells, each daughter contains a complete set of chromosomes tiny failures accumulating. Over time mutations and other damages may occur to particular genes in the chromosome. Researchers have been identifying these genes which produce or stop producing specific proteins which in turn act as switches within the cell, switches that determine the operation and growth of the cell. Cancers tend to be limited until specific genes are mutated, usually more than one, before their behavior becomes supportive of cancer. Essentially the more of these cellular switches thrown, or closed, the more likely a cancer can develop and the faster it may progress.

Cancer, simply stated, is the unchecked growth of cells. The first switch that must be ‘thrown’ is the one that permits unrestricted cell growth/division. Normally, a cell ‘waits’ until it receives a message to divide. In these cells the proto-oncagenes, necessary for normal metabolism, repair and cell growth, are always in the ‘on’ position. If this is the only mutation, the organism is in a ‘pre-cancer’ state. Its cells are not normal, but for a few rare conditions paired with similarly rare genetic conditions. There are a few cancers, that tend to commonly occur in families, increasing the likelihood of that form of cancer, but not others. They require less ‘redirection’ to switch those cancers ‘on’.

There are secondly, genetic switches within cells which act as growth suppressors, which for cancers can be interpreted as tumor suppressor genes. When activated, these shut down a cell’s capacity to divide. When the genes of both of these are mutated, a relatively rare occurrence because of the incredible ‘fidelity’ with which cell division and chromosome duplication normally occur, cancers begin in the tissues and organs of which those cells are a part of. There are so far found to be some 20,000 different human genes, these two mutations occur and tumors can begin to form.

There is a third mutation which adds to the process and that is the gene which creates the proteins which regulate apoptosis, the systematic death of the cell and the process by which it is essential absorbed back into the body without causing infection, an effective recycling system, which helps maintain the organism in an optimum state of health. With this switched ‘off’ the cancerous cells proliferate even more and deform, the tissue/organ. Unchecked growth is unleashed and the ‘body plan’ as it were, is abandoned. Normal cells and tissues maintain the structures which permit metabolic balance, homeostasis, within the individual organism. The organism, at this stage of cancer is on a path in which it is being subsumed by the demands of the cancer. What once served the individual organism now serves the cancer.

Mutations may continue. A fourth must effect another gene which gives even more dominance to the cancer through a process doctors call ‘angiogenesis’. Angiogenesis is the vital process by which new blood vessels form from existing ones, essential for healing, growth, and reproduction, but also key in diseases like cancer, where tumors hijack it for nutrients. It involves endothelial cell migration, proliferation, and tube formation. This complex process normally balances pro-angiogenic factors with inhibitors. The cancer, at this point, overrides this process, giving the tumor preferential service, and in so doing, denying, blood, oxygen and nutrients needed by healthy cells and tissues. This insures the tumor’s blood supply, supporting its unregulated growth, while also providing the cancer a means by which it can now move through the body.

Yet another mutation often allows the cancer to effectively mask itself, enabling it to metastasize, allowing one’s lung cancer, for example, to move into the lymph system, the brain and bone. Normally such growths would be identified by the invaded tissue or organ and vigorously attacked. Once this mutation has occurred the body has surrendered many of its defenses against the cancer’s spread.

It is especially important to note that these particular mutations are of absolutely essential functions and have perverted them in such a way that sets them ‘against’ the health of the individual organism. Health is not obtainable without the proper function of these processes. Homeostasis depends on the balance between growth and the many metabolic processes which work, energize and maintain the body in a high state of health. A mature organism requires that the majority of its metabolic activity serve the needs of its existing cells and tissues. We do not keep growing through out our lives. We require that these energies be directed toward maintenance and activity. A mature organism’s ‘growth’ must be limited to cell replacement. Cancer effectively highjacks the body’s ability to do this and does so progressively as the cancer develops and metastasizes. The healthy cells in an individual with cancer, continue, as best they can, but it becomes increasingly difficult to do so as the cancer progresses, its tumors enlarging while it metastasizes throughout the body. I used to wonder why doctors would refer to a cancerous tumor growing in a person’s brain could be a lung cancer? Cancer, just like an organism adapts and alters its strategy as it spreads, but it remains at its core that cancerous growth that ‘birthed’ it. Unchecked those cancerous liver, blood, lung, or whatever other cells, can and often do lead to the death of the individual its healthy self unable to maintain the ‘whole’ within the margins of homeostasis. The trick for doctors is in utilizing highly nuanced strategies to disrupt these disruptions and rid the body of the cancerous cells, while preserving the health of the whole.

Cancer is itself a dynamic, evolving series of processes, just as is any organism or infectious disease for that matter. Not only is cancer’s expression within an individual unique so is its treatment as the disease transforms, adapting to its circumstances. One chemotherapy regime, successful at one point, may not be later as the mutated genes and their proteins adapt to the treatment often becoming inured to it. Mutations can tip the scale toward an accelerating rate of mutation, some of which will be cancerous. Even the drugs designed with great specificity for a particular cancer, once amazingly effective, may later be rendered entirely ineffective. This happens because cancers are often not ‘cured’, but are forced into remission, which can be considered a sort of dormant state, from which it may reemerge. Life evolves and cancer, as a condition of life itself evolves towards what we can never know. If the principle drive of any organism, virus or apparently, any oncogene, is to replicate itself and continue its line, cancer will stay, in some way, with us. We are of the same material.

Mukherjee doesn’t dedicate much space to describing the biochemical and energetic processes going on within living cells. Other authors have taken that on. He does address some of this in his other books. There are several books that delve into it including another recent read of mine: “Transformer: The Deep Chemistry of Life and Death”, by evolutionary biochemist, Nick Lane. These processes are non-linear and collective. He writes of the energetic ‘flux’ within the healthy cell and organism, an organized ‘chaos’, which within an individual, tends toward what doctors refer to as homeostasis, or dynamic balance. Everything might appear to be going on at once in self reinforcing processes, switches opening and closing as that which is needed is provided, which can also serve as a signal to the whole that too much will soon be provided and the process decelerated while another steps up simultaneously, the existence of the individual advancing over time as if a wave, continually reforming, energizing and leaving the past and previous self, behind. 

Mukherjee presents the idea of ‘six degrees of separation’ in his exposition and what that means within the functioning individual organism, how if you take virtually every process that collectively makes and defines an individual, they are all connected through a myriad of biochemical processes and switches within six steps of the switches described above. It speaks to the centrality of these controlling mechanisms to the life of an individual human, any organism, and the cancers a mutation may produce. These are not distant or incidental functions. They are essential to health…and the success of a cancer. Health then, in all of its necessary dynamism, its contained cellular flux, is essential to the organism and the cancer that can derail it. These oncogenes and supporting genetic changes are slight perversions of necessity. How does one separate and remove such intricately interwoven functions? Their extrication, their elimination, in toto, could easily spell death for a healthy individual. Cancer treatment then, must be an act of rebalancing, of minute corrections and, historically, medicine has not done this with the necessary finesse required. In our relative ignorance we often attacked it with the equivalent of a medical sledgehammer and the patient, even when surviving, bore the wounds of the ‘cure’. Medicine has largely been working to eliminate a scourge and that would appear to be a misidentification of the problem.

Mukherjee traces the development of our treatment of cancer over roughly the last 150 years. He lays out medicine’s use of surgery, radiation and chemotherapy over this period and the rationale, the science, behind it. He covers the common lag between science and medical practice, as doctors struggle between the known and unknown to find informed and effective treatments.

This is also a human story, a story of the doctors and researchers themselves, the advances, the false leads, the brilliance, the insights, the doggedness too often turned into intransigence and denial, that has at times blinded us and impeded progress; as well as, sadly, led to even more suffering. He highlights the endurance of patients, the trust they place in their doctors and too often the doctor’s incapacity to fully consider the humanity of their patients.

Along the way he addresses the social and economic issues, of regulators insisting on meticulously conducted trials, ostensibly to protect the public from the untested and unproven drugs and therapies. These could result in patient deaths, which could lead to the erosion of the public trust. Doctor’s occasional ‘recklessness’, has set bonafide medical advances back in several cases. Desperate patients are particularly vulnerable, especially when patients have essentially surrendered themselves to the knowing doctors. In many cases patients have been left without alternatives, with death not far off, their cancers ‘refactory’, the designation of a condition created when a patient’s cancer no longer responds to available standard treatments, their prognosis fatal and urgent. He discusses several examples, including the handling of AIDS patients early on (not a cancer although Karposi’s sarcoma often presented secondarily with it.) and the case of several persistent cancer’s that the experimental use of new drugs had shown early promise treating, with high and rapid fatality rates. The FDA and/or HMO’s had not infrequently strongly resisted exceptions in the face of heavy patient demand and the inconsistencies of ‘compassionate use’ programs that allow such use. The lengthy process of methodical drug trials and their evaluation, clashing up against the life and death needs of patients, of ‘process’ over patient.

I found this to be an informed and fascinating read. Accessible to many. But like any other technical and complex topic, a fuller understanding requires some level of biological knowledge which is why my particular path to this book is relatively long. It’s a big book, 608 pages, 21 hours in its audio form, which I chose, and that alone requires commitment from the reader. Cancer is not a simple disease. There will be no single cure. No silver bullet. 

Cancer is itself a product of our own complexity, a system whose complexity acts in such a way as to maintain and regulate itself through and between all of its layers, feedback loops, even redundancies. We are organisms of walking, self-controlled, chaos and necessarily so. That we can fail in this way, does not surprise me, and that it can happen catastrophically as we balance on the energetic ‘knife edge’, between life and death, shouldn’t surprise any of us. We are fragile beings, born out of what Nassim Nicholas Taleb has labelled, an ‘anti-fragile’ process. Health and vitality arise out of complex and chaotic processes. Death is born out of narrowness, rigidity, fixity and limits, the elimination of the possibility of a creative response. Life is a product of the class of processes Darwin once named collectively as those of natural selection, in which an unending production of opportunities continuously replenish a population, a strategy of of many paths, a process which will always generate a variety of ‘answers’ many of which will fail in one way or another while ‘better’ answers will tend to succeed, to proliferate.

Is there an ‘answer’ to cancer? I don’t know. But our quest for one should put us on a path to health with less focus on disease. Death will come either way. Should we not do everything we can along the way to support that which we know to be ‘true’ about life? The fact that we permit carcinogens, those known toxic compounds that poison and mutate our genes, our capacity to live most fully; that we reinforce an economy that consistently places profit above the health of persons and place no matter what? Such compromises eat away at our bodies and the world, in ways that lessen us, and in this case, increasing the likelihood for debilitating mutations. Cancer, as are so many other diseases, are directly linked to our state of health, our cellular health, our ability to adapt and accommodate that beyond our control. We are in the habit of surrendering the health of the world as if it makes little difference. We permit these failures in our lives, even expect them, and so do little that we can to stave them off, settling for our chance to profit from an economic abstraction. Only later do we consider the pain of those who suffer it, while at the same time we consistently fail to recognize the resultant suffering sure to come our own way.