The First Cell

by Azra Raza

  For the next quantum leap, fundamentally different strategies have to be developed. The two immediate steps should be a shift from studying animals to studying humans and a shift from chasing after the last cancer cell to developing the means to detect the first cancer cell. Develop the technology, invent, create, collaborate, reach out across disciplines, harness all your intellectual and emotional faculties, and keep reminding yourself that your first and last duty is to the cancer patients.

  Scientists continue to perpetuate various incarnations of the mouse model, changing the seed or the soil, tinkering with the immune system, knocking genes in and out to refine the mouse’s ability to recapitulate the human disease for the same reason why oncologists cannot give up on trying one barely effective drug after another in patients. Each is a captive of the system that demands great exactitude in details while bypassing the fidelity of the fundamental proposition. Scientists are busy questioning the number of controls or drug doses in an experiment rather than looking to see why there is a 5 percent success rate for drugs developed through their preclinical platform. Oncologists spend most of their time balancing electrolytes rather than balancing the patient’s unrealistic expectations. Both suspend judgment faced by a system that prescribes algorithms and demands algorithms; scientists cannot expect grant funding unless their experimental design includes an animal model, and oncologists follow guidelines provided by key opinion leaders or they are opening themselves to legal challenges. Oncologists let the key opinion leaders decide how they treat patients, and scientists let their mentors set the agenda. Oncologists have no better options to offer their patients, and scientists have no alternative to a mouse model for the kind of experiments they must perform to gain any detailed understanding of biologic phenomena. Both fail to question the basic premise, whether it relates to scientists using a profoundly flawed mouse model to develop drugs with a negligible chance of producing benefit, or oncologists administering costly and invariably toxic drugs expected at best to prolong survival of their patients by a few weeks. Both do what they do because this is all that is available for them to do. Both are looking for car keys not where they dropped them at night but under the lamppost because it is light there.

  When I gave grand rounds at Columbia University recently, pointing out some of these issues, Ed Gelmann, my colleague and previous director of the division, said, “Azra, before the young people in the room slit their wrists, please tell them what they should be doing with their careers until a better cancer treatment is discovered.”

  My message to the young oncologists is that until you find a cure, make sure you are upholding the fundamental rule of medicine: primum non nocere—first, do no harm. Each physician evolves a unique clinical style of dealing with patients, but the one that never fails is spending more time with them. A surprising amount of success, as someone once said, comes from just showing up, and as Yogi Berra famously pronounced, “You can observe a lot by just watching.”

  Medicine is the most social of sciences, demanding heightened communication skills. Patients are anxious, distracted, knowing they have a fixed allotted time with their doctors. Disease, pain, and fear are disorienting. Often, patients cannot verbalize their deep anxieties without a prompt. Facing a “doorknob” doctor, whose one hand is always on the handle, they have no time to communicate their worries and expectations, their preferences. They are sensitive to the body language of their physicians, but their own bodies speak through a far more eloquent language. Instead of always reaching into the medicine shelves, doctors need to start reaching into the shelves containing books written in this corporeal language. They should consult their own libraries where the great works of fiction will teach them to link semiotics with the scientific, to interpret the human experience of disease, the illness part, written in the patients’ notational system of nonverbal communication complete with its own unique syntax, semantics, and pragmatics.

  Finding a new molecular signaling pathway in the cancer cell is great, of course, and it will earn you awards, acknowledgment in the field, and the respect of your peers. Trying to heal patients when they are dying from lack of treatment will not earn you gold medals or appear on your CV, but it will make you a better doctor and a finer human being, bring more peace to your own inner life, help you accept your own set of afflictions that life will inevitably hurl your way. Engaging in a narrative of humility; decoding the signs and symptoms of illness with empathy; and understanding that despite varied nationalities, each one of us has only one unique home—our bodies—will enrich interaction and help both sides accept and deal with the elusive, paradoxical, pernicious disease. The widely accepted 1964 version of the Hippocratic Oath succinctly encapsulates these practices: “I will apply, for the benefit of the sick, all measures [that] are required, avoiding those twin traps of overtreatment and therapeutic nihilism. I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon’s knife or the chemist’s drug.”

  There is a very beautiful sher (couplet) by the great Urdu poet Ghalib:

  Taufeeq ba andaza e himmat hay azal se

  Aankhoun mein hay wu qatra jo gauhar na hua tha

  From infinity, accomplishment rests on endurance

  Rain’s triumph lies in becoming a tear and not a pearl

  The myth in Urdu poetry is that only the first few raindrops from the very first rains of the season have a chance of becoming a pearl if they land inside a clam. In this couplet, Ghalib provides consolation to raindrops that missed being the first of the season and therefore have no chance of becoming a pearl. He reminds them that they cannot become a pearl, but now they have the possibility of becoming a tear that comes out of the eyes of a lover. The cure part is the pearl; healing is the tear. You can do both.

  When Philip Kolman wrote me, so, too, did his wife, Marsha, complimenting me generously on being an exceptional doctor. I wish I felt like an exceptional oncologist. Most days, I feel like a complete failure. However, Marsha’s letter clearly points out what the patients and families need from their physicians. “I have sat in many doctors’ offices over the years with Philip. I can only think of you and one other doctor that did not make me feel I was invisible while discussing medical issues,” she wrote. “What is most impressive is not feeling you have to be a detached, unemotional doctor. You can be clear and professional but also show us your emotional human side.”

  Marsha’s letter made me think about how and why our medical culture has evolved in such an anomalous manner that patients are surprised by finding an emotionally engaged physician. That should be the rule rather than the exception. It reminded me of the time when my daughter was a premed undergraduate student, and a very successful physician friend, over for dinner, proceeded to compliment her rather obliquely, “Sheherzad, I am so happy to see that you are considering medicine for your future profession. A great choice! As a doctor, you will never be without a job, no matter what part of the world you are in, you will gain instant respect, even from strangers, and of course you can make as much money as you want.” To which Sheherzad sweetly replied, “But my parents always told me that the only reason to go into medicine is to reduce the suffering of fellow humans.”

  We have become a health-care system highly skilled in pursuing a cure but not healing, dealing with acute emergencies yet alarmingly lacking in simple acts of empathic communication. Today, physicians caring for hospitalized cases spend less than 20 percent of their time on direct interaction with patients and 80 percent or more on bureaucratic nightmares of dealing with electronic records, making chart rounds, checking test results, viewing x-rays and scans, and performing inane administrative duties. In the outpatient setting, there is intense pressure to see as many patients as possible within the allotted time. The crushing piles of nonmedical work crammed into too little time makes overworked, emotionally stressed, physically challenged doctors become physicians they themselves detest. Most physicians to
day feel dissatisfied with much of what they do, and they yearn for the chance to spend more time with their patients. Defined in the strictest Aristotelian manner, happiness is the pursuit of excellence, or living up to one’s potential. Our job as teachers and mentors is to facilitate compassionate interaction between the young physicians and those they are charged to care for, encouraging them to meditate thoughtfully upon the drama of human distress and sorrow they witness. The reality is far from this: ought is definitely not is. Caught in the deluge of morale-sapping, monotonous, demeaning, tedious, menial scut work, the pursuit of anything other than sleep is unthinkable for young physicians. Before pointing a finger at them, we need to ask ourselves as a society whether we have created the conditions so they have the opportunity to become the best versions of themselves or not.

  APPROXIMATELY 90 PERCENT of patients who die of cancer die because their disease is advanced—metastasized. This situation has changed little in the past fifty years as newer strategies have failed to benefit patients with metastatic disease. When novel treatments are tested on monotonous populations of biologically uniform cells, be they grown as cell lines in plates or in animal models, spectacular responses can be achieved regularly. They fail as spectacularly at the bedside because cancer is immeasurably heterogeneous, infinitely evolving, perpetually mutating in the human body. What accounts for this disastrous failure? First and foremost, it is a consistent denial on our part to appreciate the dense and profound complexity of our foe and our insistence that we can use a reductionist approach to break down the problem to a single culprit gene or signaling pathway that can be easily targeted. In this chapter, we have seen that this approach might work in all types of laboratory experiments but not in actual patients. In the next chapter, we will see why, by examining the root cause of cancer.

  THE DRUG DASATINIB that Omar so badly wanted was approved for him on a compassionate basis in record time. Before I could actually deliver it to him, however, I received the fateful call from Naheed. It was Tuesday night, January 20, 2009, and I was having dinner at home with my friend Mona Khalidi. “Omar is having difficulty breathing, so I thought I would let you know.” I could not swallow another bite after that call. Mona was very disturbed to see my state. “Is something wrong?” Yes indeed. Something is terribly wrong when a parent is watching her child die. “The response to a greeting from a younger person in Arabic is often, ‘May you live to bury me,’” Mona said. Alas, for my friend Naheed, this was not to be.

  I arrived at Omar’s place to find him propped up in bed, severely short of breath. Kamal, his beloved father, sat ashen-faced in the living room; Naheed and his friend Noor were fussing around Omar while Mursi, ever the most loving wife and efficient caregiver, was taking detailed instructions from the home health-care nurse at the dining table for the administration of sublingual morphine.

  Despite the shortness of breath, Omar was his usual self, wearing a pink Lacoste shirt. He never lost his sense of style. As soon as he saw me, he asked about the dasatinib. I told him we got it, and he gave the brightest smile, which lit up the room. He proceeded to recount the great time he had had watching the swearing-in ceremony of Mr. Obama. “Now,” he said to me, “please tell me a good joke.” I promptly recounted the apocryphal story going around. Mrs. Clinton, piqued by a snide remark about her husband’s administration, turned on the reporter and said through a steely grin, “So. Please remind me exactly what you did not like about my husband’s eight years in office? The peace or the prosperity?” Omar let out a hearty laugh at that and then wanted Mursi to come and change him into pajamas. He insisted on getting up to go to the bathroom even as Mursi tried to get him to stay in bed. That was the last time he would get out of bed. He was given more oral medications after that and sublingual morphine, and slowly he slipped into a sleep of sorts. His breathing became more and more labored.

  I thought he should be admitted for intravenous morphine, but Mursi said his wish was to meet the end at home. In that case, I wanted them to bring a morphine pump for him; the nurse said it could not be done until the next day, as such elaborate arrangements take time. This would prove the only time in the space of sixteen months that I saw Naheed lose her cool.

  “What kind of a system is this, Azra? We have paid for everything all along, and we are prepared to pay cash for whatever they want now. Why aren’t pharmacies, which are supposedly open twenty-four hours a day, able to provide him with morphine now? It’s money they always worry about in this country, isn’t it? Tell them I will give them all the cash they want. Azra, tell them! Get them to bring morphine for him now!”

  “Let us go for a little walk,” I suggested. I forced her to come down, and we stood outside the building on Riverside Drive in the freezing January night, and she smoked, her face impassive. Eventually, she turned and looked me in the eyes and asked me how long it would be now. I could not meet her gaze for long. “Do you want me to be brutally honest?”

  “Yes,” she said, staring blankly at the sidewalk.

  “It could take several days, but I don’t think he will last this night.”

  She looked away and kept smoking.

  We came upstairs silently. Half an hour later, she asked me to sit on the sofa with her in the living room. “Okay,” she said, “now describe to me in detail what to expect when the end comes.” I did. Slowly and deliberately. After a while, she went and lay down next to him. Thus I found them several hours later as I went in to say goodbye. A few hours later, around 5:30 a.m., I got her call. She simply said Omar had stopped breathing.

  I REMEMBERED THE first time he had come to my apartment in New York when Omar had shown such astonishing composure as we ate an elaborate meal and he calmly braced himself to swallow the tasteless protein shake. His lips puckered ever so slightly as the liquid painfully swirled its way through denuded mucosal gashes in his mouth. “The aesthetic is to reach poise,” as Mahmud Darwish quoted Edward Said. In that moment, with that one movement of his mouth, one innocuous sip, months before the end, I knew that Omar owned the aesthetic.

  MARK ANTONY IN Antony and Cleopatra, act, 1 scene 1, says, “Let Rome in Tiber melt, and the wide arch / Of the rang’d empire fall! Here is my space / Kingdoms are clay; our dungy earth alike / Feeds beast as man / The nobleness of life is to do thus.” Indeed, the nobleness of life is to do exactly what both Omar and Naheed did during the scoundrel times they faced together. I salute them both and feel the richer for knowing them.

  Maqam e shauq teray qudsiun kay bass ka naheen

  Unhee ka kaam hay yay jin kay hauslay hain ziyad

  —ALLAMA IQBAL

  Striving toward ultimate consummation is not the purview of angels

  Only those with vast reserves of valor dare venture

  TWO

  PER

  Sandpiles and Cancer

  IN 2001, I READ MARK BUCHANAN’S WONDERFUL BOOK UBIQUITY and became introduced to the “sandpile” game devised by physicists Per Bak, Chao Tang, and Kurt Wiesenfeld, and the concept of critical states. Bak, Tang, and Wiesenfeld created a computer model of grains of sand falling one at a time in a pile; as the pile grows and becomes unstable, a single grain of sand can set off an avalanche. The grain of sand that sets off the avalanche is no different from the other grains already in the pile. Rather, what changes is that the pile becomes increasingly hypersensitive and unstable as the grains fall, forming a peculiar self-organized system that gets pushed away from equilibrium, prone to sudden and cataclysmic changes. This state is called a critical state, and it seems to develop in the sandpile on its own, without the need for any external organizing force. This is not just true of sandpiles; self-organized criticality has been found to underlie events as disparate as earthquakes, forest fires, stock market crashes, and mass extinction of species.

  Not long after I read the book, I was thinking about the application of these universal laws to cancer—especially the parallels between self-organization in sandpiles and the initiation of leukemia t
hrough self-organization in bone marrow cells—when I received a call from a cancer patient who wanted to consult with me from London. His name was Per Bak, and he had been diagnosed with MDS.

  Since he was too sick to be transferred to the United States, I referred Per to my colleagues in London, where he underwent both chemotherapy and ultimately a bone marrow transplant. Following interminable and depressing weeks for Per in the hospital, I finally received the good news that he was improving.

  There were many days when Per would call me with his latest results or ask me to help interpret what the hematologists had told him. After our professional consultation was over, we frequently ended up discussing critical states and a related concept, known as power laws. Many things became clear to me for the first time during these trans-Atlantic conversations with Per. What if we imagined the grains of sand as cells and the pile as the body? With time, the body acquires many changes due to the unintended consequences of aging and becomes unstable, more prone to disastrous avalanches resulting from the same innocuous activities of the cells that in the past did nothing to disturb the pile. Exploration of the potential causes for initiation, expansion, spread, and lethal behavior of the disease from this perspective would require that more or at least equal attention be paid to the soil in which the seed of cancer thrives. This would represent a radical shift of our focus from concentrating on the properties of the diseased cells to examining the health of the entire body. A disheartening fact that nags me constantly is that despite spending more than $500 billion on cancer since 1971, which amounts to $50 billion per year or $20,000 per cancer patient who died in the past forty years, we were—and are still—uncertain about the roots of cancer. Perhaps involving brilliant minds like that of Per Bak, who belong to entirely different disciplines, would bring new insights into our field?