by Azra Raza
All these advances occurred because patients agreed to donate their blood and marrow cells to the repository. In these thirty years, I have met maybe a handful of patients at most who refused. The rest, 99.99 percent, instantly agreed. Of course, pulling extra marrow causes some extra pain. Introducing the large needle through an electric drill or brute physical force is not too uncomfortable because we numb the entry site thoroughly, but once we start pulling through a syringe, marrow starts moving inside the bone, waking up thousands of nerves per millimeter, causing a profoundly uncomfortable sensation. It is not exactly pain, but unpleasant. I have performed thousands of bone marrow biopsies on patients and continue to perform a dozen or so every week even today. Yet I am humbled each time a patient acquiesces. “Dr. Raza, even if it does not help me, it could help someone else. I trust you. Do what you have to do.” Some patients have donated samples dozens of times; they know what’s in store for them. They do it so it may help us find better solutions for future patients. How is it possible not to hang our heads in deep gratitude in front of such unparalleled grace?
How, too, is it possible to not try to do more? The repository constitutes an invaluable resource, holding the key to addressing fundamental questions, some common to all cancers, not just MDS and AML. Over the past several decades, in every instance that we have studied samples from the repository for research purposes, we have uncovered exciting biologic information and published our results in the highest-profile peer-reviewed scientific journals. However, these small-scale research projects, many in collaboration with scientists around the country, are limited in scope. They have answered important, but specific, basic questions about one or another aspect of the disease. These have been performed on a limited number of samples, a few hundred at best. Once the human genome was sequenced and technologies were brought up to economies of scale, I was anxious to undertake a careful, systematic study of thousands of samples sequentially obtained on patients as their diseases evolved. Grants I applied for received regular rejections. I was faulted for not using a system that could be manipulated, such as animal models.
While in vitro testing and animal models are good for studying basic aspects of understanding gene functions and interactions, defining signaling pathways, and observing effects of knocking genes out in controllable, well-defined, simplified systems, I am interested in therapy-driven research. How can I develop better treatment options for my patients? Mouse models are practically worthless for cancer drug development, but funding agencies and the current scientific culture are so heavily invested in the system that nothing can make them accept the folly of their failing models. Hundreds of scientific studies have already shown that there is close to zero relationship between efficacy in animals and what happens in humans. What more evidence is needed than a greater than 90 percent failure rate of drugs brought to the bedside through such inappropriate, irrelevant preclinical platforms? Yet grants are not funded in general without animal models. What accounts for this deliberate blindness? The only reasonable explanation is that the survival of these grants depends upon remaining blind. The oncologist equivalent of this insanity is on daily display when hours are spent upon obsessively balancing electrolytes while the entire body succumbs to cancer.
No grants are available even to support the maintenance of the tissue repository. What has allowed my biobanking attempts to continue are philanthropy and generous patients. If it were not for fund-raisers to which our benefactors, friends, patients, and their families contribute wholeheartedly, I would have to pour the samples down lab sinks and call it a day. I have seen this happen once. As a well-known cardiologist shifted her laboratory program to a new hospital, her old employers refused to let her move her repository, and out of spite, the institution trashed each one of her samples with glee.
FRUSTRATED BY THE limited availability of resources, I had to become more creative. Why should my patients and I be hostage to rules devised by a few individuals who have little idea about what cancer is in real humans? For God’s sake, we are living in the most affluent country in the world in the most affluent time in the history of mankind. Surely, there are other resources to be tapped, alternate ways of funding the tissue repository project. I decided to go public. I spoke out at every opportunity I had, in grand rounds and tumor boards, dinner lectures and national meetings; I wrote opinion pieces, gave interviews, harassed private foundations and industry moguls to do the right thing. Everyone politely listened, agreed, and went home to continue doing whatever they were doing. Nothing happened.
During the Christmas break of 2014, I woke up one morning, particularly distressed. Lady N. had died. I was struggling to find a new option for Kitty C. I would see twice the usual number of patients in clinic the week following Christmas because of the holidays. The jolly good cheer of the season brings impractical hopefulness to patients. They yearn for better solutions. I wanted to offer them better solutions. I was feeling the pressure. I was feeling even more frustrated by my helplessness. I was confident I could find many answers if only I was able to conduct a thorough, systematic study of samples stored in the tissue repository.
Half-heartedly, I opened a stray magazine and read that a sportsman was rewarded with a record seven-year, $126 million contract.
That did it.
What kind of a society are we living in where a sportsman is compensated with hundreds of millions of dollars for ball games, and I have to beg and borrow, grovel and plead, for paltry sums of money to find better treatments for cancer? Cancer is no longer a disease that happens to others. Most of us have one degree of separation from it at best. So why such grotesque disparity? Such heartless indifference? Samples of bone marrow and blood obtained over three decades from thousands of patients through unbearably painful procedures, drilling into bones, stabbing at collapsing veins, remained frozen, languishing in liquid nitrogen, for lack of funds. The entire budget for cancer research through the National Cancer Institute is $5 billion, accounting for less than 0.1 percent of US federal spending. What I needed for my work would constitute a fraction of that athlete’s obscene compensation package. It was and is unconscionable.
Extreme ailments require extreme cures. Desperate times call for desperate measures. Wrapped in water-resistant layers of stretchy, moisture-wicking fabric, gloved, monkey-capped, goggled, booted with thermal socks and light sneakers, I went for a long run along the Hudson in twenty-two-degree weather to clear my head. It was apparent that the strategies I had tried were not working. I obtained enough money every year to continue to fund the repository and my dedicated group of lab scientists and researchers, publishing important enough clinical and basic biologic studies to remain a credible voice in the field. But I needed a more serious investment in my research plans now. Who could help? This kind of support was beyond the scope of the usual suspects entrusted to fund scientific research, such as the NCI. The only option would be to somehow interest individuals with the bandwidth to undertake such a vital project. What I needed was an old-fashioned patron.
To begin, I pictured myself as a socially conscious, good-hearted, compassionate, and exceedingly rich person wanting to do something to help humanity. If I wanted to identify an authentic cause to support—preferably, one free of countless intermediaries, tax-exempt organizations, and professional fund-raising agencies—I would have to undertake a lot of research. It could be challenging. Maybe there is someone out there waiting to hear of so deserving a cause as accelerating cancer cure? Fueled by the ever-present faces of frantic patients desperate for respite, I decided to approach the rich of the land directly. I sincerely believed that if only they could see what a fantastic opportunity it was to help cancer research in a meaningful way, they would be falling over each other to come to my rescue. Only one problem remained: How do I reach them?
A light bulb flashed on in my brain. In the middle of my jog on that freezing morning, I made a sharp right onto West Eighty-Sixth Street toward Barnes & Noble on the corner of Br
oadway. I purchased a copy of the latest Forbes magazine with its list of the one hundred richest people and spent the entire day chasing down their mailing addresses. Most could only be reached through the respective philanthropic arms of their companies. Nonetheless, I addressed the actual billionaire by name and wrote a brief, personal letter to each. I described the miracle of the unique tissue repository. I explained the evolving panomics technology available to study these samples. I expressed high hopes of finding novel targets of early detection and therapy that could be identified through such studies, targets that would allow us to arrest the disease at its inception. I made the case that defining the molecular, genetic events as MDS progresses to AML could possibly help us understand a universal set of principles, algorithms all cells follow in the process of acquiring immortality: the genes activated, the pathways ignited, the proteins shut down, the immune checkpoints silenced as a premalignant cell becomes autonomous and frankly malignant. The studies on the MDS-AML tissue repository samples could help us understand prostate and breast cancers, lung and GI tumors. I told them that the implications were infinite and exciting. I requested their support to provide the resources to do it. On December 31, I carried a large cardboard box of envelopes, addressed by hand, and stuffed them into the corner mailbox.
Over the next few weeks, I waited with bated breath. I received ten responses. All were form letters, obviously, regularly mailed to supplicants like me by clerical staff. No billionaire had actually read my letter. I was sure of it, because if they had, why would they not have responded positively? Three months went by. I busied myself again with writing endless grant applications. I forgot all about the Billionaire Project. One March afternoon, I was working in my office when the phone rang. “Hello, Dr. Raza, this is Patrick Soon-Shiong. You wrote to me some time ago. Sorry, I am just physically opening my snail mail. Needless to say, I am calling you because I am very impressed by what you have done with banking the tissue samples for three decades. Congratulations. I think we should meet.”
HE WAS DIFFERENT from how I had imagined him to be. For one thing, Patrick has the softest voice. After knowing him for these past few years, I still cannot imagine him ever raising it; in fact, when he wants to make a point, he lowers it even more. For another, he has the sweetest relationship with Michele, his beautiful wife. Their comfortable, carefree exchanges are hugely reassuring, grounding them in a deeply human way. The day of our first meeting, Dr. Abdullah Ali, the brilliant director of our MDS Research Program at Columbia University, and I had arrived at their sprawling Bel Air mansion a half hour ahead of our appointment. The guard on duty refused to open the heavy iron gates and instructed us rudely through a slit to wait outside. We had crossed the street and were standing under a tree to avoid the blazing California sun when an SUV drove up. The young driver scrutinized us as the gates opened and the car slid in. Minutes later, the driver emerged from a side gate, introduced himself as Phil Yang, Patrick’s assistant, and apologized for the guard’s treatment of us. He escorted us in and invited us to make ourselves comfortable in the beautiful conference room, equipped with the latest audiovisual equipment with an open patio surrounded by gorgeously manicured plants and hedges. The warmth of Phil’s welcome relaxed us, and soon Shahrooz Rabizadeh, the director of Patrick’s scientific enterprise, arrived with laptop in hand. With Phil’s and Shahrooz’s assistance, we loaded my slides and waited for Patrick.
He appeared on the dot. He had just finished his morning exercise routine and was freshly showered and shaved, ready for another action-packed day. He greeted us with a kind smile and much curiosity. Soon after the pleasantries were over, we got down to business. I began my formal presentation. It was a marvelous experience. That Patrick is exceptionally intelligent goes without saying. The astonishing part was the lightning speed with which he grasped the import of what I was presenting. Despite being a surgeon who had probably not encountered the acronym MDS since his medical school days, Patrick instantly understood the underlying complexity involved in defining the natural history of this heterogeneous disease. He asked many relevant questions, summarized the issues at various points in my talk, debated intricate technical details with Abdullah, and directed thoughtful clinical, patient-related queries at me.
There was to be a big omics meeting the next day at his home-office complex to which cancer center directors and reputed scientists from around the country were invited. Patrick asked me to present my ideas, helped me choose the slides, framed the critical questions, and ended up with a series of proposed studies for collaborative work. I was really impressed by the breadth and depth of his knowledge. Michele floated in lightly, looking beautiful in a summer dress, trailed by assistants, to whom she was imparting instructions on placement of chairs, directing where lunch tables were to be laid, setting the agenda for the day, planning an evening excursion for the entire group. She came over to where we sat and gently inquired if we were ready for lunch. Patrick took me on a walk around the impeccably landscaped garden, showed me around, pointing out favorite trees and plants, eventually arriving at a gazebo with a breathtaking view of the picturesque lands around. We ate a light salad and talked. We took another walk, enjoying the pastoral splendor in the middle of a buzzing, hyperactive city, and continued our scientific discussion. By the end of five hours, we had developed an exceptional understanding of each other’s missions. The friendship with Patrick and Michele, started on that sunny morning in 2015, has only deepened with time.
What bonded the three of us inseparably was our shared mutual concern for patients. In one meeting, I sensed the profound empathy this couple has for human suffering and for their relentless, insistent, fearless commitment to alleviate it. It is Patrick’s and Michele’s respect for others that marks all their manners; one way in which they best show it is by thoughtfully listening to what others have to say. A scientist can become consumed by devotion to facts without caring about what their value is to humanity. Patrick and Michele have avoided that suffocating trap.
They were born in South Africa, where they were no strangers to prejudice and discrimination, but they never let it defeat them. Their journey from Port Elizabeth and Johannesburg through Patrick’s residency in Canada, to a UCLA professorship, performing the world’s first encapsulated human-to-human transplants of islet cells from the pancreas and the first full pancreas transplant on the West Coast, then as a NASA researcher, developer of Abraxane (a form of chemotherapy for breast, lung, and pancreatic cancer), and corporate CEO is the stuff of legend by now. But the man’s story is perhaps more worthy than the legend of it.
The first two pancreas transplant patients at UCLA did fabulously, except they both rejected their transplant. Pancreas transplant rejections are the most frightening thing, because you’ve hooked the pancreas to the bladder. When the organ rejects, port-wine blood pours out the ureteral catheter. I said to myself, “Wow, do I really believe this is the right thing to do to a patient?” Which led me to tell my chairman that I’m going to shut down the program of which I’m the director. I decided that I needed to understand regenerative medicine. I got interested in the immune system because I was trying to induce tolerance, and that is when I learnt that cancer cells have figured out how to induce tolerance, to tell your body “don’t eat me because I’m actually you.” So the irony is that the first part of my career was to induce tolerance for transplants, and the second part was to break tolerance to actually tell the body to kill cancer cells.
As physicians we’re trained to be reductionists. We rigidly follow protocol. But life is not that way. Cancer is not linear—it is completely non-linear. It lives in the science of chaos. There’s no single point of control. You need to attack it in a non-linear fashion across time and space, monitoring it and truly dancing with it. If you biopsy a patient with breast cancer twice in the same day, once in the breast and once in the lymph node, you can get cancer cells with different sequences. This heterogeneity breaks all these reductionist assumptio
ns, because which target are you hitting and what made you choose it? The only chance we have, in my opinion, is to do what I call micro killing and macro killing at the same time. Micro killing meaning you go after these little targets, maybe even using a little chemotherapy. And macro killing meaning either surgery, radiation, or immunotherapy.
Patrick is particularly allergic to the widely held dogma that DNA alone holds the key to a cancer cure. He has been advancing a more comprehensive study of cancer and its microenvironment that includes detailed DNA, RNA, and protein measurements. Patrick has also consistently pointed out the damage inflicted by the traditional high-dose chemotherapy regimens to the immune system, the very system we need most in the fight against cancer. He has initiated multiple, very exciting clinical protocols employing cellular therapies and vaccines combined with more conventional approaches of chemo and targeted therapies in cases of advanced cancers.