by Azra Raza
A comprehensive exploration of these complex issues requires more than sequencing the genome of tumors to identify causative mutations. Cancer can only be transplanted artificially into healthy animals whose immune system is destroyed. As a result, all the accompanying reactions of the body, the counterpunch resulting in a misdirected immune response, the system-wide reaction to the presence of malignancy, the whole array of paraneoplastic syndromes are entirely absent in animal models. Who has cataloged the B-symptoms of joint pains and night sweats in mice?
CANCER INCIDENCE INCREASES with age, although the two processes—aging and cancer—are biologically almost the opposite of each other. As cells age, they don’t necessarily die; they enter a state of suspended animation called senescence, where they halt proliferation, minimize metabolic activity and energy consumption, and no longer perform any useful function, but continue to produce waste products as a natural consequence of being alive.
When cells hit the Hayflick limit, they go into senescence or die. The clock that keeps track of the number of divisions are stretches of DNA on the ends of each chromosome known as telomeres, which shorten every time a cell divides. Most cancers avoid senescence or death by producing an enzyme called telomerase, which can rebuild the lost DNA. Three scientists—Elizabeth Blackburn, Carol Greider, and Jack Szostak—shared the 2009 Nobel Prize in Medicine and Physiology for their discovery of how chromosomes are protected by telomeres and how telomere DNA is restored by telomerase.
Older age is associated with shortened telomeres and accumulating senescent cells. The problem with these senescent cells is that by maintaining minimal biologic activity to stay alive, they continue to produce waste products without performing any useful function. The “trash” removal system of the body works overtime to remove the debris of not just functioning, dividing cells vital for the body but also these freeloaders. In addition, the senescent cells produce proteins that cause chronic inflammation. The resulting toxic environment is perfect for hosting and promoting growth of mutated cells and is a significant contributor to both cancer and other age-related diseases. The mutated seed finds a hospitable soil in an aging body.
Aging causes inflammation. Cancer cells thrive in an inflammatory soil. And of course, as we’ve seen, with aging also comes a collection of DNA mutations, their number increasing exponentially with age.
Surprisingly, there are otherwise healthy individuals—over the age of sixty, usually—with no sign of any disease, walking around with anywhere from 2 to 20 percent of their blood cells derived from a clone carrying mutations in genes associated with highly malignant diseases like MDS and AML. This situation where there is no clinically apparent abnormality in the blood counts or identifiable marrow disease but in which disease-related mutations are nonetheless present in blood and marrow cells is called clonal hematopoiesis of indeterminate potential, or CHIP. The long name suggests that there is a group or clone of cells carrying a mutation known to be associated with serious pathology, but in the absence of low blood counts, its potential to cause disease is indeterminate. Incidence of CHIP increases by every decade of life. Up to 20 percent of individuals in their sixties and 50 percent of individuals in their eighties have CHIP. CHIP turned out to have a very low incidence of progressing to MDS (about 1 percent) but is associated with other illnesses like cardiovascular disease and strokes, especially in those cases where no apparent risk factor for cerebrovascular disease was easily identifiable. Few centenarians show CHIP. If you dream of hitting a hundred, make sure you don’t have CHIP.
In addition to senescent cells, accumulation of mutated DNA segments, increasing debris, and a pro-inflammatory microenvironment in the elderly, a spatial reorganization of the bone marrow with increasing age may also disturb the normal physiologically graded cell-cell signaling. Activities of cells are, at least partially, under the control of their microenvironment or the stromal cells through chemical and neural signals. The dose of the signal is critical, and, to some extent, depends on the physical distance between the two cells. With increasing age, a great deal of actual tissue is lost as cells reach their proliferative limit and die. In a healthy adult, roughly half the marrow is occupied by blood-producing cells, and the other half is empty space filled with fat. With increasing age, this fifty-fifty fat-to-cells ratio changes so that it is common to find a seventy-year-old individual with 70 percent of the space in the marrow filled with fat. Such fat increases the distance between effector and target cells. Even a slight decrease in the inhibitory signal dosage would result in a proliferative advantage for the target, distanced from its controlling stromal cell. If such a target cell also has accumulated mutations, it would gradually lead to an unchecked expansion of the clone. As this abnormal situation continues unchecked, the marrow can eventually become predominantly “monoclonal” or populated by the daughters of one cell. This monoclonal population could also be marked by specific and identifiable genetic mutations, the most common CHIP-associated ones affecting TET2, DNMT3A, and ASXL1 genes.
Monoclonality, however, does not mean that a malignant transformation in one of the daughter cells is imminent. Rather, monoclonality may predispose the cells to the development of malignancy. As the clone continues to expand rapidly, the number of monoclonal cells grows, and the system may begin to move away from equilibrium and toward self-organization and a critical state. Could the reorganization of cells residing under an abnormal architecture in the marrow be governed by the same rules as self-organization in sandpiles? Once a critical state has been achieved, the system would be prone to sudden and cataclysmic changes. Support for this comes from several observations. For example, practically every malignant cell in patients with chronic myeloid leukemia is marked by a translocation between chromosomes 9 and 22, which is known as the Philadelphia chromosome in honor of the city where the discovery was made. Some years ago, it was demonstrated that clonal expansion and a monoclonal state preceded the appearance of the Philadelphia chromosome.
The incidence of monoclonality increases in direct proportion to advancing age; as many as 40 percent of females over age sixty show monoclonal-born marrow function. Not only are almost all cancers monoclonal, but their precursor state, called dysplasia, is also monoclonal. Normal cells start to look dysplastic in abnormal environments. Thus, dysplastic states affecting the bone marrow, cervix, liver, esophagus, and stomach are all monoclonal, and the dysplastic morphology suggests an abnormal soil or microenvironment. Once a system follows critical-state universality, it is impossible to predict the course it is going to have.
AGING IS THE most potent carcinogen because it creates encounters between all the phenomena that cause cancer. Nora Ephron, with her wry wit and laser-sharp observations, famously advised women to start hiding their necks once they turned forty-three. “Our faces are lies and our necks are the truth. You have to cut open a redwood tree to see how old it is, but you wouldn’t if it had a neck.” When I look in the mirror these days, I often wonder, if these are the changes on the outside, what havoc is being wreaked by aging inside my body? A lot, it seems. At least four major areas of profound biologic alterations turn the aged body into a hotbed where malignant cells can thrive. I call it the MIST of aging. First are mutations. In addition to heredity and exposure to toxic environments, each new round of DNA replication as a cell divides causes fresh copying errors. Cellular metabolism also causes DNA damage. Mutations from these sources add up over time. The second is the immune system’s increasing inefficiency. All bodily processes become more decrepit with age, causing the immune system to falter and miss eliminating a cancer cell at its very inception. Third is an increase in the number of senescent cells with age. Senescence by itself is anticancer because the cell stops dividing. However, it is carcinogenic for other cells because it is still metabolically active, producing waste material that accumulates, causing the natural habitat of cells to turn toxic. This inflammatory microenvironment provides the ideal soil for the abnormal cancer seed. Finally,
there is the problem of tissue loss with age, dramatically visible on the face and neck but equally disfiguring internally. Tissue depletion leads to geographic reorganization in organs such as the bone marrow with resulting spatial renegotiation between cells whose activity depends upon precise physiologic gradations of chemical signaling. These four factors descend like a mist that cloaks the elderly in the possibility of cancer. Where in Per’s model, a grain of sand is eventually enough to tip the system into an avalanche, the bodies of the elderly are engulfed in a swarm of them.
Every carcinogen—whether the inheritance of a genetic predisposition, or changes due to aging, or exposure to toxic agents or pathogens—gives rise to mutations in oncogenes and/or tumor suppressor genes. Theoretically, this should simplify the search for solutions aimed at targeting the genetic mutations. The problem is the nonstatic nature of the changes. With each division cycle, the cancer cells sustain new mutations. The emergent complexity of cancer in adults is because of this constellation of hundreds of small cuts acting together and is the reason why cancer in the elderly is harder to treat than in children. In the elderly, the assortment of mutations is not the same even in subsequent generations of cancer cells within the same individual, let alone in two different individuals. In the young, there is no time to have accumulated DNA replication errors; cancer arises from the malfunctioning of a major gene- or nodal-signaling pathway, which immortalizes the cell into a perpetual cycle of proliferation at the expense of maturation. Attacking a single target has a higher chance of being effective than trying to overcome the cumulative dysfunction of many proteins operating in a toxic, pro-inflammatory microenvironment. This happened in the case of chronic myeloid leukemia, but even there, the drugs proved effective only during the stable, chronic phase of the disease, not when the acute, blastic phase evolves. Finally, the interaction of cancer cells with the immune system results in a panoply of disparate, painful, and life-threatening signs and symptoms grouped under the broad term of paraneoplastic syndromes. Biologic studies spanning half a century should be sufficient to illustrate the unsolvable nature of carcinogenesis for a long time to come. In the next chapter, application of this knowledge to design individualized approaches to treatment will be examined and results of such precision medicine initiatives discussed.
PER BAK’S TRAGIC story evolved a continent away, at a great remove from me—I only learned the details through phone calls and e-mails. And yet, it acquired a great significance for me. I was advising him about handling some of the exact same issues related to end-of-life decisions that Harvey and I were facing. The parallels were surreal: two brilliant, energetic, driven, focused men at the peak of their productive careers with megaplans for the ensuing decades, abruptly shown the finish line. Both had young children who they would not live to see become adults, graduate from college, marry, give them grandchildren.
Many a night, I woke up to see Harvey sitting perfectly motionless at the edge of the bed with his back to me, deep in thought, for what felt like interminable hours. What does time mean to people who are running out of it? An inexplicable, intuitive reticence restrained me from interrupting the trafficking in his mind. How does a man hearing the footsteps of death approach closer every day negotiate the themes of dying, loss, pain, grief, the withering sense of waste, the unbearable, crushing sadness of things that will be left undone? How could it be otherwise? Cancer chipping away at the body relentlessly in slow, steady, excruciating blows; the lucid, sharp, coherent mind forced to reside in an aching, skeletal corpus, documenting each ignominy with sensorial precision. In those dark Chicago nights, we were two tormented souls caught in our own private hells, frozen into rigid postures; his vertical immobility matched by my horizontal stillness. Both were afraid to acknowledge that the other was awake because that would invite language to intrude. Verbalizing a fraction of what we were suffering, objectifying the pain in words, no matter how frugal the language, risked a diminishment of its caustic, dizzying, disorienting potency, his physical and mine emotional. Soon I would be speaking in rooms forever depleted of his voice, I would be breathing air that would no longer contain his breath. Even as I tried to control the pounding in my chest, my mind, hostage to surreptitious invasions of rationality, would coldly conduct a microscopic analysis of how to define my feelings precisely, to classify whether it was mourning for Harvey or anxiety for Sheherzad and myself having to live without him. Thoughts and emotions, conflicting and confusing, attacked simultaneously, smashing through any residual protective shield of hope, driving home the murky pathos of the coming emptiness in my life, the lonely days ahead, with a fierce, violent acuity that pierced with physical brutality, choking my parched throat, triggering waves of nausea.
Do other cancer patients experience variations on these themes, the vertigo of evanescent, soul-destroying, irreducible suffering? Do they run their weary fingers through serrated edges of anguish, say farewells in unspoken, unheard of languages in the silence of sleepless nights?
ONE OF THE saddest conversations I had with Per was several months after his bone marrow transplant. Just when everything appeared to be stabilizing, he developed one of the known and dreaded complications of the transplant procedure: severe pulmonary damage. After many rounds of therapies, some bordering on the heroic, Per finally knew that he was not going to make it.
BOTH HARVEY AND Per were dead within a few months of each other. Two lives lived with breakneck speed and intensity had abruptly exploded. They expanded, amplified, enlarged peculiarly in their stunning, outsized impact on those left behind precisely because they were snatched prematurely. I entered a fog-like space of my own, mechanically going through the motions, but all the time feeling riven, fragmented. Trying to be a reassuring mother, showing up at work, seeing patients, running a lab, winding up Harvey’s scientific program, finding placements for a dozen scientists whose jobs ended unceremoniously. Dealing with estate issues, social security applications, hospital bills, insurance companies, grieving relatives, and well-meaning friends. Dealing at the same time with my own cosmic turbulence, the melancholic thoughts in my mind.
I felt a cleavage in my mind
As if my brain had split;
I tried to match it, seam by seam,
But could not make them fit.
The thought behind I strove to join
Unto the thought before,
But sequence raveled out of reach
Like balls upon a floor
—EMILY DICKINSON
THREE
LADY N.
A Loaded Gun
MARCEL PROUST SAID THAT THE REAL VOYAGE OF DISCOVERY IS not in seeking new landscapes but in having new eyes. I experience a slightly different version of this dictum practically on a daily basis, developing new insights through my patients’ eyes. None could claim a vision more penetrating and acute than Lady N. She was high-spirited and boisterous, with a rowdy, uproarious personality that sparkled with wit and humor, possessing an uncanny habit of connecting seemingly unrelated things through common sense, extreme intelligence, inimitable humor, and pure and simple intuition. And most importantly, she had a blazing, sizzling passion for life writ large all over her massive five-foot, ten-inch frame.
Aged sixty-two, Lady N. swept into my clinic for her first visit in 2008 with this farcical, preposterous announcement: “FYI, I have been extremely anemic for at least twenty-five to thirty years, if not longer,” she told me. “I also believe strongly that there is a genetic component to my MDS.” She went on, “As you know, my father’s sister’s first child was born with no marrow in his bones.” Although she had been anemic for a long time, her MDS had not been diagnosed until just before I met her. The first few years were not too hard, as her diseased cells were marked by a deletion in the long arm of chromosome 5. This special subtype of MDS is associated with slow progression, a longer survival, and an especially good response to Revlimid, a derivative of the once-infamous drug thalidomide.
BACK IN 1999, I
had personally prescribed thalidomide for Harvey, one of the first lymphoma patients ever to receive the drug on a compassionate basis.
When Harvey’s cancer started manifesting a series of sudden, startling, painful paraneoplastic syndromes, we knew some form of therapy was now inevitable. Around this time, I heard data presented by an oncologist at a national meeting who had tried thalidomide in patients with lymphoma and had seen sporadic benefits. I immediately felt this could be a safer alternative for Harvey, who was still reluctant to start chemotherapy. I told Harvey I thought it was worth a try. What did we have to lose—a few weeks? Harvey listened to me and was willing to go along with my suggestion. Needing reinforcement for such an experimental use of the drug, we visited Harvey’s primary oncologist in Chicago, Steve Rosen, a charismatic, deeply empathetic, kind, caring physician, a great friend, and the cancer center director at Northwestern. We reviewed Harvey’s treatment options. Chemotherapy. A different kind of chemotherapy. Steve listened to my case for trying thalidomide. He agreed to prescribe the drug. Backed by Steve, as well as Owen O’Connor, chief of the lymphoma service at Memorial Sloan Kettering, I was able to get the drug on a compassionate, one-patient protocol basis for Harvey from Celgene, its manufacturer.