ONE |
OMAR |
The Nobleness of Life Is to Do Thus |
There’s a special providence in the fall of a sparrow. If it be now, ’tis not to come; if it be not to come, it will be now; if it be not now, yet it will come: the readiness is all.
—SHAKESPEARE, HAMLET, ACT 5, SCENE 2
I ONLY SAW OMAR TWO OR THREE TIMES WITHOUT NAHEED, HIS mother, in the roughly sixteen months of our acquaintance in New York. It is hard for me to think of them separately. From the first message I received from Omar in the summer of 2007 to my last glimpse of him as he lay dying with his mother curled up next to him in bed, I was exquisitely aware of the unique privilege it was to be witnessing this sublime relationship. Of course, love is never quantifiable. The friendship alone that existed between Omar and Naheed would require new heavens and new earths to accommodate it.
The sky and all the planets could not comprehend your expanse
Only my heart has the largeness to embrace the anguish
Naheed brought her two sons to meet me in September of 2007, shortly after I had moved to New York. Omar, the thirty-eight-year-old elder son, a graduate of Oxford and Columbia, had been diagnosed with a highly malignant osteogenic sarcoma of the left shoulder.
They had come for dinner. Omar had received a round of aggressive chemotherapy a few days before, and his mouth was a battlefield of raw ulcers, abraded mucosa, bleeding gums. As we sat down to an elaborate meal with family and a few close friends, Omar calmly produced a bottle containing some sort of a bland, soothing drink and sipped away as if it were an exclusively prepared gourmet meal, all the while entertaining us with his signature brilliant quips and observations. Such was his class, such his chic.
I can divide my association with Omar into three distinct phases. The first phase starting long-distance in the early summer of 2007 was all business: we were preoccupied with questions of what hospital he should choose, which surgeon; whether he should seek a second opinion in Boston; whether he should receive one combination of chemotherapy or another.
The second phase came when he started the dreaded but inevitable slash-poison-burn cycles. Omar underwent radical surgery first, where surgeons tried to remove the tumor in its entirety. Reports from the excised mass unfortunately showed that cancer had already spilled into the veins. This was essentially a death sentence. In an attempt to eradicate the microscopic tumor cells, aggressive rounds of chemotherapies and radiation therapies were initiated. He settled more or less into a routine of sorts, punctuated by periods of pancytopenia, or a decrease in the number of blood cells; an intense susceptibility to infections; excoriated mouth; an occasional hospitalization due to sepsis; and finally, a brief period of respite, only to be followed by more of the same.
He suffered horrible toxicities from each treatment and derived little benefit. The tumor continued to grow. One week, a nodule sprouted in the lung, where it appeared surreptitiously on the CT scan. Another morning, a tender, red lump appeared on the wrist.
Once during this time, I asked Naheed in front of Omar why she did not go back to Karachi for a few days. Her mother was ailing, and Naheed needed to fetch her own things, as she was now planning to stay for the long haul, at least until Omar’s chemotherapy ended. “He will not let me go,” she simply said. I looked at Omar. It was true. He could not bear to let her out of his sight. “Azra apa, [apa and aps are terms of respect accorded an older woman],” he said, “if a mother is around, nothing bad can happen to her child.” So Naheed, who had come for a few days to New York, ended up staying for eighteen months, spending practically 90 percent of her waking time either with Omar or working on something related to him.
Surprisingly, this second phase, perhaps the most exhausting for any normal individual, proved to be the most productive for Omar. He was teaching at John Jay College; he was analyzing current events; he was teeming with original ideas; he was writing profusely. Above all, he was confident and optimistic. He was newly married.
He never lost the life of the mind. He came to dinner at my place in May 2008, when Richard Dawkins was visiting. Naheed had brought her fabulous book, Kashmiri Shawl, as a present for Richard, who was thrilled to take it home to his wife, a fellow aficionado. Omar had prepared a series of questions to ask and had a long chat with Richard. In early June, Omar called me one evening to say that, as opposed to someone who has come up with a list of the hundred books one must read before dying, he had compiled a list of a hundred books that one must read in order to live. Would I be interested in going over the list with him? My friend Sara Suleri Goodyear, professor in the English department at Yale, was staying with me at the time. We were both delighted at this idea and arranged for Omar to come over for dinner with his list. That evening turned out to be exceptionally stimulating. Sara and I offered our remarks on the titles that Omar rolled out with a twinkle in his eyes. Most of our own personal favorites appeared on his list—from Homer, Plato, Aristotle, Herodotus, Thucydides, and Virgil to the Old and New Testaments, the Bhagavad Gita, and the Quran to Machiavelli, Omar Khayyam, and Aesop’s Fables. He listed Augustine, Cervantes, Dostoevsky, Tolstoy, Ibsen, Flaubert, Proust, Lampedusa, Ishiguro, Rushdie, Adam Smith, Darwin, Hawking, Stilgitz, Pinker, and Bertrand Russell to Feynman, Kuhn, and Diamond. The entire list can be seen in the article I wrote about him for 3 Quarks Daily. After he left, Sara and I talked late into the night about Omar. We marveled that someone so captivated by life, so engaged, so erudite, so young, could demonstrate such equanimity in the face of almost certain death.
The third phase of my acquaintance with Omar began around September 2008. He was now on a slippery slope and knew it. Despite multiple surgeries to remove metastatic lesions, including parts of both lungs, he continued to experience recurrences at distant sites. On the day we came together to celebrate his fortieth birthday, he was diagnosed with a large mass on the arm even while receiving chemotherapy. This was not good news.
Omar’s family responded. Naheed, his best friend, Noor, and his devoted, inspiring, and lovely wife, Mursi, brought him to see Dr. Gerald Rosen, a well-known bone and soft-tissue sarcoma expert at St. Vincent’s Comprehensive Cancer Center. Gerry advised a second round of radical surgery to remove practically half his shoulder, arm, and chest, hoping that would excise a wide margin around the primary tumor, which Gerry felt strongly was the principle origin of the malignant cells. Gerry offered to arrange with surgeons he knew to undertake the risky and extensive surgery, insisting that this was absolutely essential. With Omar’s tumor, as with most solid tumors, Gerry felt that if it couldn’t be cut out, the battle was already lost. The surgical team at the treating hospital was not in favor of this, and Omar was torn. The four came to my office after their visit with Gerry. Omar pointedly asked my opinion, and I was blunt with him. “The radical surgery Gerry is recommending is an enormous risk, but it is the only lifesaving measure. You are young, and the odds are high that you will get through it fine. Give yourself a chance and go for the surgery.” The alternative was an experimental trial. Under the best of circumstances, as I told Omar, trial drugs would prolong his life by a few months. Surgery represented the only possibility of a cure, even if it was fraught with potential catastrophes. But if he wanted to pursue an experimental trial, I told him, I promised to get him any drug he wanted. Omar listened calmly and finally said he would think about what I had said.
Informing Omar’s thinking were his two siblings, who had been working valiantly throughout to save their brother’s life. They searched incessantly for news of any novel approaches to therapy or announcements of clinical trials. Sara, Omar’s sister, came to see him with her adorable little boy, and Omar was immensely cheered up by their visit. (One of the loveliest things about Omar was that while he was interested in big things, he knew how to be genuinely happy in small ways.) He brought Sara over for dinner one evening. I was astounded by the detailed questions Sara asked me about Omar’s situation, the choices available to him, his immediate and long-term prognosis. His brother, Farid, was completing his doctoral dissertation at Brown, but he nonetheless spent every moment he could spare with Omar. Farid accompanied Omar to his medical appointments whenever he was in town and stayed with him at the hospital when Omar was an inpatient. One evening as they were leaving my home, I was greatly touched to see Farid quietly adjust the sling on Omar’s arm and help him into his coat without a word from Omar, who continued talking to me the entire time.
Although deeply involved, Omar’s family as well as his friends completely respected Omar’s independence and supported him unconditionally whether they agreed with his decisions or not. They stood resolutely by him and faced the tragic choices with a fortitude that reminded me on more than one occasion of the famous line from Faiz Sahib: “Jo aye aye ke hum dil kushada rakhtay hain” (Let whatever is in store come; our hearts are capacious).
In the end, Omar decided against the radical surgery that Dr. Rosen had recommended. He called me a couple of days later to ask my help in getting him enrolled in an experimental trial. He subsequently began one at Montefiore Medical Center and seemed in an unusually good mood when he and Mursi came for lunch at my place in November. By early January, however, the trial had failed, and he was exploring other possibilities with his usual vigor and velocity. We were all frantically searching. He became fixated on a drug called dasatinib, which was being tried in his type of sarcoma, although he was reluctant to participate in another experimental trial because it would restrict his ability to try other therapies. I promised to obtain a compassionate exemption for him from the makers of the drug and wrote a single subject protocol requesting the drug for him.
Omar had now lived through seven major surgeries—removal of practically half the shoulder followed by removal of parts of the right lung and then the left. He had received round after round of toxic chemotherapies with bouts of radiation treatments in between. He then enrolled in experimental trials with zero benefit. Meanwhile, the tumors kept popping up in new parts of his body.
OMAR’S PREDICAMENT HIGHLIGHTS how spectacularly we are failing to treat cancer.
His treating oncologists and I knew that the chemotherapy or experimental drugs he received following the failure of the original surgery had zero chance of curing him. If palliation was all we could offer postoperatively, what was a better option—to treat or not to treat? Was it cruel to Omar and his family to keep suggesting new drugs, which would give him a few additional weeks at best, when the writing was on the wall? It’s not clear they ever registered how short term any benefits would be. Omar and his family fully believed that, if a drug were FDA approved or at least in FDA-approved trials, there would be lifesaving benefits to offset the pain of any side effects. Did they really comprehend the fact that any survival benefit would be measurable in weeks?
The expectations of patients are compounded by the action of regulators. It takes ten to twelve years to bring a new cancer drug into the market at a prohibitive cost of anywhere from $500 million to $2.6 billion. Extensive intellectual and financial resources as well as time are invested in conducting preclinical research to identify potential new therapies for cancer, but these rarely translate into any real benefit for the patients. Only 3–5 percent of cancer patients participate in experimental trials; of these, only 3.8 percent of the participants in phase 1 trials between 1991 and 2002 achieved an objective clinical response. The results for phase 2 and 3 trials are not much better.
Recognizing the unmet need in oncology and pressured by advocacy groups and cancer patients, the FDA is willing to approve an agent if it can prolong survival by a mere 2.5 months over existing treatments. Even with this low bar for approval, only 5 percent of drugs make it to market. Cancer has the lowest success rate among twenty-one disease indications. Those few drugs that are approved might as well have failed; once they are administered in non-trial settings, the results are no better than those that were not approved. This is partly because of how trials are conducted. Subjects participating in experimental protocols are handpicked and generally in reasonable physical shape. They have to pass strict eligibility criteria, including a good performance status, normally functioning heart, lungs, liver, and kidneys, and be free of any serious comorbid condition. Most cancer patients are more decrepit, suffering from additional comorbidities. Whatever little advantage is achieved in prolonging survival under the rigorously supervised clinical trial settings is lost once the drug is approved and used freely by practicing oncologists to treat unselected patients.
Over the twelve-year period from 2002 to 2014, seventy-two new anticancer drugs gained FDA approval; they prolonged survival by 2.1 months. Of eighty-six cancer therapies for solid tumors approved between 2006 and 2017, the median gain in overall survival was 2.45 months. Of the cancer drugs approved during the past two decades, 70 percent of them were at best useless, showing no measurable survival benefit. Between 30 and 70 percent of the drugs may actually be harmful to patients. A study published in the British Medical Journal showed that thirty-nine of sixty-eight cancer drugs approved by the European regulators between 2009 and 2013 showed no improvement in survival or quality of life over existing treatment, placebo, or in combinations with other agents. My own specialty, MDS, is a case in point. There are two approved strategies to treat MDS. One drug, lenalidomide (Revlimid), is restricted for a subset of patients, roughly 10 percent, whose MDS cells have a deletion in the long arm of chromosome 5. For the remaining 90 percent, one of two approved drugs, azacitidine (Vidaza) or decitabine (Dacogen), are recommended. With either drug, the chance of improving anemia in low-risk MDS, to the point at which transfusions would no longer be needed, is approximately 20 percent. There is currently no way to preselect the 20 percent of patients likely to respond. This means 80 percent will receive chemotherapy for five to seven days every month for a minimum of six months with little or no benefit but with all attendant toxicities and at prohibitive financial expense. In responding patients, the drug administration must continue for as long as there is no progression in the disease. Responders are not cured; the median duration of response is ten months, and an occasional patient continues in remission for years.
So what advice should an oncologist give to a patient faced with these options? In a larger sense, the choices we make for our patients are made by people we never meet. Even if I felt differently, I could not make a truly independent decision. Other experts have devised formal criteria for best practices, and any nonconformity could leave the deviant open to legal challenges. Driven by internal forces, we seek refuge in emulation. Responsibility is assumed collectively by a group of key opinion leaders, or KOLs, in the field. The group takes into account all the existing scientific literature and a fair summary of innumerable clinical trials to eventually distill the experience into a broad set of principles. The guidelines that emerge are at the heart of evidence-based medicine, and the wider community of oncologists subsequently uses these to classify, stage, and treat their cancer patients, evaluating the results of their treatment in a uniform and universally interpretable language.
This is a good thing. Indeed, evidence-based medicine is essential. But it is not sufficient by itself when caring for individual patients. No matter how large or statistically significant the data are from which the universal rules are derived, application of population-based insights to specific patients remains very challenging. The typical experimental trial with a 30 percent response rate is really telling us that if a hundred patients with similar clinical and biologic characteristics were treated with the drug, thirty will likely respond. For an individual patient today, we have no way of knowing whether they are one of the 30 percent who respond or the 70 percent who don’t. Besides, how meaningful is the response? If the median duration of response is, say, ten months, then of the thirty patients who responded, fifteen will lose the response before ten months, and fifteen will continue to benefit beyond that. A few of those will be long-term responders. The disease will come back. This rule applies to even the most successful targeted therapies today with only rare exceptions. They offer improvement in survival by a few months over supportive care. Nevertheless, when I’m faced with an elderly patient with lower-risk MDS without deletion of chromosome 5, receiving two units of blood every two to three weeks, the KOLs say I should give the FDA-approved treatment, despite its 20 percent chance of a limited-duration response. And when faced with a patient like Omar, should experimental trials be offered if the treatment is of no survival benefit? Again, the KOLs say yes.
Imagine now, with these data in hand, you are sitting across the desk from Omar. It is impossible to use the best evidence-based medicine derived from large populations to make decisions about him as an individual. There is embarrassingly little information to predict the most likely outcome for Omar. If he were one of the fortunate ones, then we hoped he would be that rare long-term responder. We had to give it a shot. Nothing ventured, nothing gained.
The oncologists believed that by treating Omar with experimental drugs and chemoradiation therapy, they at least offered him a chance of response, no matter what the odds. But the problem isn’t simply that the drugs he was given ultimately didn’t help him—the problem was with the advice he got, too. It’s possible the advice we gave him wasn’t realistic or explicit enough—perhaps we should have suggested he spend whatever time he had left enjoying life rather than vomiting his guts out after each round of chemotherapy and living on revolting, tasteless liquids because of the raw carbuncles that studded his throat. He could have spent at least a little time traveling with his new wife, visiting friends in England and his family in Pakistan and Bangladesh. Instead, Omar was a perpetual captive; either he was receiving one kind of therapy or another or suffering their side effects, which, beside the vomiting and the ravaged mouth, included very low blood counts and a highly suppressed immune system, landing him in the hospital regularly with bouts of infections.
Was it really the best solution to do nothing? If we had withheld treatment, the tumors would have grown rapidly and caused tremendous pain as well. Which would be less excruciating? Subjecting patients to painful toxicities of futile treatments with their enormous attendant physical, financial, emotional, and psychological burdens is challenging. Would palliation of the pain with local control of growing tumor masses have been any less painful? Did we ever give Omar the choice of no treatment at all? And should we have? The past is some guide. The toxicities of chemotherapy and radiation therapy are well recognized today, whereas it has become rare to see the ravages of unconstrained cancer. Stephen Hall, in his excellent book A Commotion in the Blood, describes the last stages of a highly malignant sarcoma in a young girl at the end of the nineteenth century:
The endgame in cancer is never pretty, less so in an era where doctors chased rather than managed the less ghastly symptoms. The breast tumors had become the size of goose eggs, the abdominal tumor even larger; the length of her body from head to toe was stippled by small tumors that Coley likened to buckshot or split peas. Last came the vomiting, several times a day, though she had no solid food; soon, she was regurgitating copious amounts of blood. “The attacks occurred almost hourly,” Coley noted, “and were very exhausting to the patient in her extremely weak condition.” Elizabeth Dashiell remained conscious of this horrific piracy of her eighteen-year-old body until very nearly the end, when finally, mercifully, she died at home in New Jersey at 7:00 a.m. on January 23, 1891.
Not only is such an uncontrolled death horrible, hopes are squandered on chasing cures that can’t be found. But then, unexpected benefit can also occur, even after ten years of repeated failures, if the right drug is given. The challenge is how to match the right drug to the right patient from the start.
One patient of mine, Philip Kolman, suffering from a lower-risk MDS, was essentially giving himself up for dead. In his own telling, “One day in early 2017, my Florida doctor told me that he had nothing left to give me. My transfusions were becoming very frequent, two or three units of blood a week. He said that I should contact everyone I knew to see if there was a [research] program available for me.” In stark contrast to Omar and his siblings, Kolman says, “I accepted the news with the understanding that I didn’t have much time left, and I started to make final arrangements.” Among them was to write to me. Although he was prepared to lie down, I was not; I told him to fly to New York for tests for a new research program. Once he was in, his need for transfusions quickly dropped from every week to every four to five weeks; his condition worsened a bit before stabilizing at a transfusion every two to three weeks. “I’m now waiting for the next drug to come along with its promise of a new beginning and hope.”
WEEKS BEFORE HIS death, I visited Omar at home on his fortieth birthday. He was quite the dandy, and that evening, he had taken care to dress up. He wore a formal black jacket and beautifully fitting trousers. With an impossible innocence, he took me aside. He had something to show me: a rock-hard reddish growth that had appeared out of nowhere on his arm in the preceding forty-eight hours. With an indefatigable will to live, the exceptionally intelligent young man stared intently at his arm and asked me whether I thought it meant the return of the sarcoma. He hoped I would say no, that it was an infection. It was the one time during the course of my time with Omar that I felt physically ill—and I was not even his family. It wounded me to think of how Mursi and Kamal, Sara and Farid, and most of all Naheed would take the cancer’s resurgence. I could not bear to stay at the party. Despite Naheed’s remonstrations, I left within minutes, and before I could reach the subway, I was retching on the sidewalk.
My husband, Harvey Preisler, was directing the Rush University Cancer Center in Chicago when, at fifty-seven years of age, he received the diagnosis of cancer. He had personally supervised my training in oncology. One rule he emphasized was not to become too close to patients. I am not certain that I have followed his advice as faithfully as he wanted me to. He appalled me when he said, “You are going to take care of me.”
“But, Harvey,” I objected, “all my life, you are the one who insisted that I could no longer remain objective if my feelings clouded my clinical decisions.”
He simply said, “Sorry, I only trust your judgment.”
In the subsequent five years, we looked at countless blood reports, MRIs, and CAT scans together, staring at the growing masses in his abdomen, the persistent fungal infection spreading menacingly in the lungs. Harvey knew precisely what those images meant. He was not someone looking for false hope. He was not a man easily duped. Yet he would invariably turn to me and ask, “So what do you think, Az?” He needed to suspend his judgment and looked to me to decide how he should feel. I took infinite care never to break his spirit.
Julie Yip-Williams, who blogged about her colon cancer and died on March 19, 2018, at age forty-two, said, “Cancer crushes hope, leaving a wasteland of grief, depression, despair and a sense of unending futility. Hope is a funny thing, though. It seems to have a life and will of its own that I cannot control through the sheer force of my mind. It is irrepressible, its very existence inextricably tied to our very spirit, its flame, no matter how weak, not extinguishable.”
What were Omar’s choices? Succumb to hopelessness and despair, face the terrified looks of his wife and mother who followed his every move, or pin his hopes on the oncologists pushing the limits of modern medical offerings? With cancer, it is rarely a matter of either-or; there is seldom a choice between hope and despair. Patients face both simultaneously, or serially. Omar did, too, with a stoic’s sobriety combined with an unflagging optimism of will.
OMAR’S EXPERIENCES, AND Philip’s, point to some devastating concerns about the state of cancer research today.
A common semantic distortion relates to the description of an ineffective therapy as “the patient failed the drug” instead of the other way around. The drugs, not the patients, arrive at the bedside for clinical trials when confidence in their success is 5 percent at best. The preclinical lab data used to identify the potential benefits of a drug cannot predict what will actually work in a clinical setting. We were forced to use trial and error both in Omar’s case and Philip’s, instead of being able to identify sooner what could or could not work for each, at great financial and personal cost. What are we doing wrong? Why have we failed to translate the scientific advances of high-profile publications into improved outcome for our patients?
It is high time to question the current paradigm of research. There are bright spots—many subsets of patients, even with aggressive tumors, have been successfully treated with drugs developed using the present approaches: chronic myeloid leukemia, most childhood malignancies, and some forms of adult bone marrow and lymphoid cancers. We shall see why. But we shall also see that the exceptions exist among a litany of failures. These failures are systemic. The vast majority of researchers are studying diseases they never see, in animals who don’t get them spontaneously, or in test tubes where the “cancer” must be artificially created and maintained. Such contrived data bear little resemblance to the actual tumors, yet these “models” are the ones turned over to industry for further clinical development. This approach to drug development, the exceptions notwithstanding, has been stupendously unhelpful. How did we get here?
IN JANUARY 1912, Alexis Carrel, soon to be a Nobel laureate for work in surgery, removed cells from the heart of a chicken embryo, plated them on a dish in his laboratory, and, to the great surprise of the scientific community, kept them alive and growing robustly for the next three decades. The cells thrived as long as they were fed the right cocktail of nutrients, and Carrel’s miraculous culture led to the conclusion that living cells have the potential for immortality. Unfortunately, no one else could replicate Carrel’s results—in general, investigators could maintain cells in culture, but no one could demonstrate the continuity of survival for weeks, let alone decades—nor explain what enabled them to survive in Carrel’s flasks.
The question whether cells possess the potential for immortality remained unresolved until 1960, when Leonard Hayflick provided the answer. Through a complex series of experiments, Hayflick succeeded in routinely growing cells in culture for long periods, but not forever. Cells are not immortal. They age and they die. If external forces do not kill them first, Hayflick found that, after roughly forty-five divisions—known today as the Hayflick limit—cells follow one of two paths. Either they eventually dial down their activities to the bare minimum necessary for viability, curl up, and enter a period of senescence, or they commit suicide. Carrel, Hayflick argued, could not have been culturing his original cells all those years. Instead, the nutrient solution Carrel used daily to feed the cultures most likely contained viable embryonic stem cells, which seeded and grew on their own.
The Hayflick limit, accepted as a golden rule of biology, has proved to be true for normal cells ever since. Cancer cells, however, are different. One tumor took off in the laboratory and achieved immortality. On February 8, 1951, a cervical cancer was removed from Henrietta Lacks and brought to the laboratory of George Otto Gey. HeLa cells, labeled using the first two letters of the patient’s first and last names, began to thrive in culture, giving rise to the first human tissue culture “cell line.” Acting almost as if they were a monstrous superorganism, HeLa cells have steamrollered their way from test tubes to animals, gulping cocktails of nutritious chemicals, floating in flasks and cutting jagged paths across methylcellulose-coated petri dishes, climbing, creeping, fanning, and expanding perpetually for six decades. They metamorphosed; compared to the normal human cell’s chromosome number of 46, their chromosome number varies between 70 and 164. HeLa cells are unique in their ability to survive under the most challenging environmental conditions, carving out a space for themselves with unmatched velocity, be it in inorganic flasks or in mice.
To date, some forty thousand pounds of HeLa cells have been grown, studied, molecularly dissected, genetically reprogrammed, used as teaching tools for graduate students, formed the backbone of elaborate, major grant proposals, and otherwise spread throughout science. This orgy has led to an embarrassment of riches for the researchers, earning for them thousands of patents covering diseases ranging from polio to cancer. Ironically, this unexpected gift, an enormous boon for researchers, exchanged hands and laboratories, crossed oceans and continents, all without the knowledge or consent of Ms. Lacks, who died eight months after the original tumor was plucked from her pelvis. (Rebecca Skloot skillfully recounts the scandalous drama of HeLa cells, involving interactions of race and research, greed, business, and bioethical issues, in her 2010 best-selling book, The Immortal Life of Henrietta Lacks.)
The consistent, predictable growth and behavior of HeLa cells provided researchers with an opportunity to experiment, including tests of the efficacy of a number of agents, on a reproducible in vitro model. The success with HeLa led to the broader discovery that, with practice, skill, and a little luck, malignant cells from a variety of tumors could be induced to grow continuously in the laboratory. This in turn gave birth to development of additional cell lines, and researchers flooded the field with a deluge of experiments conducted on all types of cancers.
Many such experiments examined the effects of potential anticancer agents on these tissue culture cell lines with the hopes of developing reliable methods to predict responsiveness. The question was, how faithful are cell lines to their ancestry? Partially so. The success of a tumor in a human (or any other animal) depends on many factors, including how well it has managed to subvert the tissues in which it exists to support its growth at the expense of normal cells surrounding it. Cell lines are created by removing tumor cells from this natural habitat, forcing them to adapt to a new, and hostile, environment. The journey from an organ to plastic containers results in the creation of almost a new species of cells that diverge wildly from their parents in morphology, genotype, phenotype, and biologic behavior. The artificially grown cells can only replicate some but not all the characteristics of the cells from which they originated. As a rule, for example, they don’t grow in perpetuity. To survive for any length of time, however, additional transformative changes occur, affecting not just the raw material of genome but also the expression of genes, so that before long, cells in vitro bear little resemblance to the parent from which they originated. For one thing, the doubling time of cultured cells is much faster. In fact, they are selected for long-term passages in the lab precisely because of their ability to divide rapidly and grow furiously. Cultured cancer cells also have a very different relationship with oxygen. In the body, cancer cells exist with low levels of oxygen, whereas those in the lab come to require significantly higher oxygen levels—up to ten times as high.
In addition to acquired genetic mutations, another issue with cultured cells relates to expression of genes as messenger RNAs. The sum of all transcripts representing expression at the RNA level is called the transcriptome. When gene expression profiles of various cell lines derived from different cancers were studied, the transcriptomes of the cell lines resembled each other more than they did the cells of organs from which they were derived.
Compounding the issues was the discovery that some of the fastest-growing cultured cells regularly find their way into adjacent plates, even under the most stringent of lab protocols. The first hint of trouble came as early as the 1970s, when chromosomal studies of cell lines derived from a variety of cancers showed that all appeared contaminated with HeLa cells, which turned out to be the Mother of All Contaminants.
Drugs tested on these cell lines could reliably predict response in the cell lines. The in vitro test showed no predictive value when brought to the bedside. HeLa cells accurately predicted the efficacy of drugs for HeLa cells. Not humans. Despite their utility for genetic and scientific experiments, cells cultured in vitro could not be relied on for drug development.
At that point, it might have been logical to give up the idea of in vitro modeling attempts for drug development. Instead, more artificiality was introduced into the preclinical model. Although it appeared that cell lines grown in animal models instead of plastic dishes were more comparable to cancers thriving in humans, it was not clear what the precise in vivo requirements were for hospitable and—importantly—comparable growth. The infinite complexity of a human body was neither comprehensible nor reproducible. Instead, researchers sought to hijack the body of a surrogate to grow these tumor cell lines. Enter the mouse model.
ON THE MORNING of May 3, 1998, my husband, Harvey, having been diagnosed with cancer in March, looked over his coffee mug and handed me the New York Times. HOPE IN THE LAB, a headline shouted. A CAUTIOUS AWE GREETS DRUGS THAT ERADICATE TUMORS IN MICE. The gobsmacking opening line of the article read: “Within a year, if all goes well, the first cancer patient will be injected with two new drugs that can eradicate any type of cancer, with no obvious side effects and no drug resistance—in mice. Some cancer researchers say the drugs are the most exciting treatment that they have ever seen.” Richard D. Klausner, the director of the National Cancer Institute, was quoted calling the work “the single most exciting thing on the horizon.” Jim Watson, the Nobelist for discovering the structure of DNA, said, “Judah is going to cure cancer in two years.” Judah Folkman himself, the researcher at the heart of the story, was more cautious; as the article’s author, Gina Kolata, put it, “All he knows, Dr. Folkman said, is that ‘If you have cancer and you are a mouse, we can take good care of you.’”
Harvey and I had lived through many cycles of frenzy in our professional life caused by laboratory triumphs of drugs followed by dashed hopes in humans. Now our relationship was more personal. Harvey expressed skepticism, yet a cancer patient’s wistful anticipation had propelled him to ask me what I thought in the first place. The basic premise of the strategy was exciting and the animal data deeply compelling. Both drugs acted by cutting off the blood supply of tumors, causing starvation, growth arrest, and eventual regression without producing any toxicity. Thanks to the New York Times report, the sensational story leaped from the confines of a research laboratory in Boston to make headlines in newspapers and television broadcasts across the nation. Cancer patients pleaded with their oncologists, desperate to get the drugs, imploring to be selected for clinical trials, ready to travel anywhere needed. The stock price of the company EntreMed, which produced the drugs, shot up fivefold in one morning, soaring from twelve dollars to eighty-five dollars. I got in touch with Dr. Folkman, who was exceptionally responsive and kind. He invited me to a daylong scientific conference in Boston where all the data along with clinical trial plans were to be presented. I registered for the meeting and came back greatly encouraged about the possibility of rapid translational success. Within a short time, word got out: however spectacularly the drugs worked in mice, they failed spectacularly in humans.
Although mice and human lineages diverged about eighty-five million years ago, humans have been recording observations related to physiologic traits in mice since the dawn of civilization. The systematic practice to understand human ontogeny through a study of anatomy and physiology in animal models dates back to ancient Greece, and as Aristotelian methodology traveled along the ancient trade routes, animal models became the preferred research tool of Arab and later European physicians.
Domestication of a variety of mice as pets occurred in China and Japan in the eighteenth century, eventually leading to the development and creation of modern laboratory mice. While Victorian England was busy trading in “fancy” mice, the use of animal models had become the established method to conduct biologic studies by the beginning of the twentieth century. Theories of Mendelian inheritance were investigated through mating programs in mice, and genetic mapping was well under way as early as 1915. A variety of approaches was pursued in developing mouse models for cancer research, and as is true for every model, each had its advantages and its limitations. Approximately 97 percent of human genes have homologues in the mouse genome, for example—a clear advantage versus other laboratory organisms. But the nucleotide sequences of mouse and human genomes are only about 50 percent identical.
Many of these differences are directly owed to the dissimilarities in the environment in which the two species evolved. The major dissimilarities between mice and humans relate to factors such as the life cycle of mice. They reach sexual maturity at six to eight weeks, gestate a litter of five to eight pups in less than three weeks, and live only about three years. Mice have a metabolic rate seven times greater than humans. Since drugs in mouse models are very rapidly metabolized, the amount used in mice and humans is very different. The dosage of drugs is reduced drastically when used in clinical trials. The immune system in mice evolved to combat earthborn pathogens, whereas most of our challenges come from airborne pathogens. This stark difference in the immune systems is reflected in the cell types circulating in the blood of the two species. Humans have 70 percent neutrophils and 30 percent lymphocytes, while mice have 10 percent neutrophils and 90 percent lymphocytes in the blood. Besides these glaring differences, one of the biggest challenges in using mice as the in vivo host to human tumor cells is that, unlike a human with cancer, the target lab mice are healthy. To accept transplanted human cells without having a mouse’s body reject them as foreign bodies, the immune system of the recipient mouse has to be destroyed first. Such immunocompromised mice could hardly represent the in vivo environment of the human body in which cancer cells thrive. Yet scientists fully expected the behavior of these cells to help them identify useful drugs for patients.
The idea of using an animal to provide the vital growth environment for tumor cells led to the birth of today’s most frequently used cell line–derived xenografts (CDX). Tissue culture cell lines were injected into mice with the intent of creating a more reliable model for cancer therapeutics. Use of animal models as preclinical platforms for cancer drug development began in earnest with the mouse-in-mouse grafted tumors during the 1960s. Such models produced by transplanting a given mouse tumor yielded early successes in that several cytotoxic chemotherapies like procarbazine and vincristine were identified and proved useful in the treatment of a host of cancers. That does not say much for the efficiency of the CDX model per se because cytotoxic drugs kill cells indiscriminately, be they normal or cancerous. This is why they are so toxic when administered to patients. The same results would likely be seen in less elaborately constructed, cheaper cell culture systems. Nevertheless, CDX became the model of choice for all kinds of drug development. Responses to cytotoxic drugs ranged between 25 and 70 percent among different cancer types. The NCI invested generously in producing between six and nine cell lines each, derived from a number of common tumor types, hoping that this would cover the variability seen in efficacy. This led to the creation of the NCI-60 panel, comprising sixty cell lines derived from nine types of cancers, which was then handed over to investigators for the development of CDX models.
They failed uniformly as far as drug development was concerned.
In reality, such models for drug development represent an irresponsible and serious waste of shrinking research resources, and not just in oncology. Sepsis, burns, and trauma in animals were all investigated as models for the inflammatory changes associated with those phenomena in humans. There was no correlation. Indeed, every one of the 150 treatments for sepsis brought to the bedside of acutely ill humans because of their success in treating mice was a staggering catastrophe.
Humans do not benefit but are harmed by misleading animal testing, especially when it comes to predicting the efficacy of targeted therapies. These are drugs developed to attack individual and specific cancer-driving proteins. The targeted therapies identified through CDX models have an abysmal success rate of 5–7 percent when brought into clinical practice. This includes the agents developed to target genetic mutations such as BRAF, EGFR, HER2, and a few others. When occasional drugs appear to work in both humans and the in vitro models, it is not because of similarities in the biology of the diseases but because the drugs happen to be general cytotoxic agents. Timothy Johnson, a physician, told the Boston Globe during the height of the enthusiasm for Folkman’s work that “my own medical perspective is that animal cancer research should be regarded as the scientific equivalent of gossip—with about the same chance of turning out to be true, i.e. truly effective in humans. Some gossip turns out to be true, but most of it does not… and gossip can cause great anguish for those affected, in this case millions of desperate cancer patients worldwide.” He was right.
As various in vitro and CDX efforts failed, focus then turned to improving quality of the cancerous seed rather than the soil in which it was planted. Instead of using cultured cell lines as starting points for creating a preclinical in vivo CDX model, freshly obtained human tumors were implanted in animals, at times, even matching organ to organ; cancer cells from human pancreas implanted in mouse pancreas. These patient-derived xenografts (PDX) models could serve as “avatars” for individual patients to test a variety of drugs against their tumor cells directly as they grew in vivo in a mouse. Once again, the NCI invested large sums of money in producing and handing out one hundred PDXs to investigators for research.
Unfortunately, the technique didn’t always work. In one instance, a laboratory company pursuing this research was able to culture tumors for only half of the 1,163 people who sought their help. The researchers ultimately found only 92 patients who received treatments based on testing in the PDX models, although they did find that the PDX predictions were accurate 87 percent of the time. How practical this approach would be is questionable since it can take six weeks or more for the tumor to grow in the mouse and be ready for appropriate testing against a series of drugs.
But, the above notwithstanding, there are strong signs that PDX is, generally, not going to be predictive, again owing to adaptations for the implanted tumor to its new environment. To study how the genome of the tumor changed through multiple rounds of transplantation in mice, more than one thousand PDXs representing twenty-four types of cancers were studied. Implanted tumors evolved differently from their parent cells. While glioblastomas gain extra copies of chromosome 7 in humans, the PDX model of the tumor lost them over time. The National Cancer Institute tested twelve anticancer drugs—that were already being successfully used to treat humans—on PDX mice growing forty-eight different kinds of human cancers. In 63 percent of cases, the drugs failed. Even worse, according to a report in Nature on the study, researchers at the NCI concluded that other compounds that might work in humans were never tested on the erroneous belief that if they couldn’t help PDX mice, they couldn’t help humans either. But from my perspective, even if the models worked as well as we had hoped they would, the fundamental problem would still remain—very few effective anticancer treatments exist, so the predictions made through these models are more likely to be useful in what to avoid rather than what to give the patient. I cannot stress this enough times; scientists need to stop making more and more artificial mouse models and tissue culture cell lines for cancer drug development. These resources can and should be invested in better pursuits.
No one, however, willingly surrenders their pet projects, no matter how far they have drifted from the original intent, as long as they can maintain their grip on grants and power. A repetitive triangular pattern characterizes the scientific culture, similar to the kyklos, the recurrent cycles of government, described by the Greeks, of democracy, aristocracy, and monarchy along with their degenerate forms—ochlocracy, oligarchy, and tyranny. What begins as a perfectly sensible democratic state of affairs transmutes into an oligarchy when a small group of privileged individuals exercising control over institutions and organizations handing out perquisites succeed in dominating the field. The democratic-to-oligarchic shift gives rise over time to a “hereditary aristocracy” in which newly minted key opinion leaders, with the blessing of their scientific mentors, inherit the exclusive power to define rules, monopolize grant-funding powers, and reward each other with perks the field has to offer. Adding a final insult to injury, these little arrogant cliques manage to hijack the entire narrative in a field.
I met a young male researcher recently whose ego was so dense, light would bend around him. He presented a seminar at Columbia University, where he described mouse models carrying a mutated gene associated with MDS. He also presented data that administering a drug that inhibited activity of the protein, not the mutated protein, was curing whatever disease he had inflicted upon the mice (it certainly was not anything even close to human MDS). When I asked him what gave him any confidence that the results of the drug therapy he showed in mice would have value for humans, he scoffed, “Sorry, Azra, mouse models are not going away.” That was already two years ago. I am sure he has cured a lot more mice since then. I am also sure he has received grants to continue this work. His coresearcher at the same institution started a recent lecture with a slide comparing survival curves of AML patients for each decade from 1970 to the present. The graph showed essentially zero improvement. He then used words I have been hearing for forty years describing how he was going to understand the intricate molecular mechanisms inside AML cells and then devise ways not to kill them but to modify their behavior so they no longer remained malignant. This is precisely the problem. It is as if the past forty years have not existed. Freshly minted brilliant young scientists arriving in waves, confidently proclaiming their plans to convert cancer into a chronic disease that patients can live with and not die from. On what basis? Indeed, there are unimagined novel technologies now that did not exist a few decades ago, but the complexity of cancer remains beyond their reach. To think otherwise is unrealistic and a victory of hope over experience.
Clinical researchers are busy trying to open new experimental trials, and basic researchers are worrying over the next grant they need to write. The only way to unmask the magnitude of bizarreness is to find a new and improved way of doing things, a way not just marginally better but quantum leaps better. This is precisely what oncology needs right now. If we’d kept trying to improve upon the typewriter, we would never have invented the word processor. Toying with or repairing old models of treating cancer will yield incremental advances at best. The cancer problem requires a radically different approach. We should not be aiming for weeks of improved survival. Our goals should be higher. The public needs to see how far we have drifted from the original aims as oncologists and researchers and at what cost to the patient.
Everyone needs to pause and think about what they are doing and why. Young researchers and all oncologists must think differently, to question dogma, to reject the deep-rooted archaic traditions, to discard the existing, inadequate research models and boldly use the emerging technologies to explore exciting new strategies to solve the cancer problem. Only a new way of thinking and doing will shift the paradigm and get the practitioners to discard their old ways. All researchers need to pay attention to technologic aspects emerging within and outside of their own disciplines, developing a broader strategy to address the complexity of cancer by using inclusive, pluralistic approaches rather than relying solely on reductionist strategies. Young researchers need to practice consilience, learning from and cooperating with experts in disparate fields to solve the biologic and technologic hurdles. The traditional strategy of treating cancer reached its maximum potential several decades ago. Dying for a Cure, a British advocacy group, bemoans that “at the current rate of progress it would take 1,778 years at least before we saw a 20-year survival improvement for all 200 types of cancer!”
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 today 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