Cancerland

by David Scadden

  Having lab work move from discovery to application is the dream for virtually all the scientists with whom I work. I have the good fortune of other recent work moving in that direction. It involves a lengthy project in which we decided to test whether our understanding of normal stem cell biology could give us novel insight into cancer. One of the young geniuses who came to train in my lab came up with the method to do just that. David Sykes is a physician-scientist in the group who reasoned that leukemic cells likely fail to shut off genes that must turn off for a stem cell to move through the steps of maturation necessary to make a functioning blood cell. He found such a gene and created a system that allowed us to test hundreds of thousands of chemicals to find any that might overcome the blockade in differentiation that cancer imposes. He found just a handful and then discovered that most of them targeted the same unexpected enzyme (an enzyme is a protein that modifies its neighbors and so is usually involved in turning things on or off in cells). That enzyme is one previously targeted by a drug company for other indications. It was safe but wasn’t active as tested so it was abandoned. We wanted to resurrect it so we could quickly get it to people to see if we could improve their leukemia. We had strong motivation because a rare subset of myeloid leukemias (AML), in which drugs could be used to overcome a differentiation blockade, had shown remarkable results. This type of leukemia (acute promyelocytic leukemia) was the worst form to get and I recall taking care of patients who died miserable deaths from this rapidly lethal disease when I was in training. It didn’t respond to standard cancer drugs that are basically cell poisons. When drugs were found that induced differentiation (one was an acne drug), it flipped the situation entirely and now 98 percent of patients are cured without ever receiving a standard cancer chemotherapy drug. We wanted to do the same for the rest of the leukemias and thought we might have identified a drug that could do it. Safe enough for acne, strong enough for leukemia was our goal.

  When doing research, partners are needed because the path is long and the resources needed are enormous. We eventually teamed up with colleagues at the Broad Institute and with Bayer Pharmaceuticals. We had all agreed that our greatest goal was to find something that could help people with leukemia. We soon learned that meant different things to different parties. If we took the old drug and revitalized it, it would be faster to patients, but less lucrative since the patent was expired. David and I were confident that we could get the drug, and we did all we could to convince our partners that we could do this together and find a creative business model so that all could be rewarded. We just did not think it right to waste time waiting for new, previously untested drugs when we could re-employ an old, well-understood and well-tolerated one. People would die in the interim. For over eighteen months, we repeatedly made our case and were met with silence or worse, even by our academic colleagues. We parted ways. Patients first, as long as money really came first, was not the way we wanted to live. Fortunately, we found some inspired funders and a passionate CEO and are making the drug and finalizing the clinical study as I write. Also, the paper announcing our findings also inspired four other companies to move forward and we hope that at least one will find the right medicine to flip the outcome for patients with leukemia. That is the dream and all that went into it will fade away if it can be realized. If so, we hope it will pave the way for thinking about other cancers in similar ways: as rogues that have gotten stuck in development. Rather than bludgeoning them to death, maybe we can find drugs that encourage their arrested development, allowing them to mature to the point where they no longer invade and destroy, but quietly reside as good neighbors.

  As of 2017, it seems clear that we are advancing cell biology at a pace that will dramatically improve our approaches to malignancies and diseases that have long defied science and medicine. The changes are happening now. There were twenty-five new drugs in 2015 in my field and twenty this year. I have finally hung up my stethoscope because of it. I seemed to always be catching up on new medicines to simply keep up. The residents and medical students I taught needed to know vast amounts of information on these emerging therapies and when I was on call, I spent hour upon hour poring over journals to make sure I was ready to handle any emergency that might arise. I always knew I had the backup of superb physicians at the MGH. One, David Kuter, who is head of hematology at Mass General, was always available to discuss particularly gnarly cases with me. (I would find is reassuring, were I a patient, to know that doctors do this.) But, I felt a little like the ballplayer who has reached the end of his athletic career and has begun to fear that he’s not carrying his weight for the team. I called Kuter and said, “I need to talk to you about stepping away from the clinic.” He answered, “What took so long?” He knew before I did—or at least before I could accept the fact that I might not be a clinical doctor.

  The decision wasn’t easy. The greatest rewards in my professional life have involved caring for patients who, every day, reminded me of what truly matters in life. But I didn’t want to put patients at risk for selfish reasons. I dropped clinical care, but will never drop being a doctor at heart. I am now a lab director, a department chair, an institute coleader, and a professor. I have to be a manager of diverse teams, but the skills of clinical medicine transfer well.

  An attentive bedside manner, which includes confidence and optimism, is essential if I’m to give young scientists the support as well as the structure they require. The same is true for the financial partners that make science possible. Governments and big pharmaceutical firms supply much of the funding to keep America’s labs running. However, every year private philanthropies, some of which are managed by individuals and families, also donate tens of billions of dollars to medical science. Many of our consistent donors have personal experiences with cancer, diabetes, and other diseases and they give in order to help spare future generations. Others, who have larger sums to give, are looking for a big breakthrough to give them the sense that they have done something substantial, for all of humanity, with their fortunes.

  Partnering with individuals of such means can be extremely exciting. No one accumulates an immense fortune without possessing real intelligence, and some of these philanthropists can ask extremely challenging and interesting questions. People want to have some confidence that their investment, even if it’s a charitable donation, has some chance of yielding a big return like, say, a new drug or a durable discovery. Some will even shop around for just the right institute or individual, as if they are studying the racing form to pick the winning thoroughbred. Meeting with these folks is not for the faint of heart, but just as we evaluate research proposals to find the ones with the best promise, philanthropists must get answers to their questions before they choose between a seemingly endless number of worthy proposals. The Harvard name (you could even call it a brand) might get us in the door, but no one will write a check on the basis of that alone. With this in mind, I worked to develop my ability to make the science understandable and discovered I enjoy it.

  I have also come to enjoy even the difficult aspects of managing scientists, which often means helping brilliant young people stay on track in the face of technical and personal challenges. Everyone who comes to our labs is hoping, in the end, to develop medicines that cure. The best people for this work are fiercely independent and feel a powerful drive to achieve. The problem is that fiercely independent people sometimes struggle to take advice, even when it’s in their best interest. In one recent case I spent a year counseling a truly brilliant person who cannot see he has reached a scientific dead end. In every conversation my advice has been met with a proposal to test one more compound, and then another. The trouble is that each test can take months to complete. Before you know it, a gifted mind has wasted a year chasing a chemical ghost. My task in these situations, which arise quite often, is to serve as mentor, parent, boss, and coach. In this instance a new teammate, added at my suggestion, has helped set the project on a new, Plan B course. In the process the original sc
ientist is developing a bit more emotional intelligence.

  This may be the moment to note that even with all the technical resources at our disposal, from instruments to artificial intelligence, science still needs the human touch. The best example may be in the hard-to-quantify but nevertheless significant force of intuition. What most of us experience as hunches can turn out to be signals from the brain, which is observing developments and making connections at a rate faster than we can comprehend. That nagging feeling about a hypothesis or an experiment can be an emotional prod, deployed by the subconscious. Studies of the brain done with FMRI (functional magnetic resonance imaging) machines have located parts of the brain that fire when intuition is sparked. The best theories suggest that the feelings produced in these moments of inspiration represent the brain’s effort to snap the conscious mind to attention to something that engages its computing capacity at its highest levels. This process was understood by Albert Einstein to represent the “leap in consciousness” that is more valuable to the process of discovery than the intellect.

  Although it’s not medicine, modern biology is a passionate pursuit that engages as much of you as you can give and requires an expansive and generous style. The idea of the isolated scientist alone with his or her thoughts and experiments has been eclipsed by the model demonstrated to me decades ago by Adel Mahmoud, who was as good with people as he was with ideas. I see this quality in many of the younger scientists affiliated with the stem cell institute. In addition to their scientific brilliance they are resilient and effective at leading team talents. However, there is plenty of room for improvement. Some of our young scientists have to be drawn out, encouraged to think big, and prodded along the path. Others must be mentored in the art of letting go. We have to kill projects, which is fine because there’s value in checking off the answer to any question, even if it’s disappointing.

  Fortunately, there is always the next idea. And in time you will see your work added to others to create a better and longer life for many. This is the result I hoped to realize when I first recognized the power of blood and bone. It seems to be coming faster every day.

  POSTSCRIPT: SCIENCE IN THE FUTURE TENSE

  In every generation, science and medicine are challenged to make genuine progress in a way that truly serves humanity. Success in medical science depends on a hierarchy of interests that starts with the physical and emotional suffering of individuals and their families who deserve compassionate care. Step higher and you encounter ways that communities can be served through sanitation, safe food supplies, immunizations, and other prevention strategies. Science should make all the baseline efforts of care and prevention better, and more effective, while limiting unintended negative outcomes.

  Unfortunately, the frontier quality of some research can make it impossible to see that a new medicine or technology comes with risks. Radiation used for the diagnosis and treatment of some diseases was not known to cause malignancies until they had already occurred. More commonly, as you’ve read in these pages, promising therapies turn out to be less useful than initially imagined. However, these disappointments should not discourage us entirely. In oncology, for example, some treatments that disappoint after appearing to be breakthroughs still work for just a small number of patients with specific genetic mutations. Patients who are diagnosed with the same general kind of cancer but fall outside this subgroup may feel devastated by this twist of fate. But those who occupy the thrilling sweet spot are certain that all the effort to develop the therapy was more than justified.

  In the biological age, when genomic sequencing is becoming routine, we have reached a point where most cancers can be screened for mutations. This practice is now routine at major medical centers and is making its way to community hospitals and oncology clinics nationwide. Similar screening is now possible for a variety of diseases and has improved both diagnosis and treatment in dramatic ways. For example, in a recent positing on a popular website called The Mighty, a young woman who had lived for two decades with a diagnosis of cerebral palsy recounted how genetic screening determined she had a different disorder—dopa-responsive dystonia—that could be treated with a single medication. She took the pills and began to walk unassisted, a day later.

  Dramatic success stories are not the norm, but they become more possible with inexpensive gene sequencing and as we get better at processing huge amounts of data. The information I’m talking about is collected every day, in billions of bits, as people move through the health care system, track their fitness on wearable devices, manage their diabetes with finger-stick tests, and complete electronic health diaries.

  As of 2017, far too little of this data is being scooped up, organized, and used in an effective way. However, efforts are being made to correct this problem. In 2015 the government launched the Precision Medicine Initiative Cohort Program, which will enroll one million people in a program that will collect biological samples for genetic testing and medical histories. Individuals will, of course, be notified if something is discovered in their samples. However, the main purpose of the project will be to provide research fodder for scientists studying a huge range of health issues. Organizers believe they will discover relationships between environment and various conditions, and, perhaps, identify diseases that appear connected. They also expect the project will establish the basis for trials of targeted drugs by creating groups of people with relevant genomes and helping scientists locate and work with them

  Experts who collect and manage billions of pieces of information refer to it, generally, as Big Data. Big Data, and, to be more precise, the ability to process Big Data, causes excitement because it allows us to act with more knowledge and less guesswork. Genetic testing can determine which people will respond to a special drug and which will not. This is what it meant by the term “precision medicine.” Many tech companies are moving into this field with huge investments. IBM’s “Watson,” which is an advanced artificial-intelligence technology, has been adapted to provide information about treatment options to breast cancer patients who submit their genetic information.

  An aid and not a replacement for doctors, Watson was found to closely match so-called tumor board recommendations when tested by a big health care system in Bangalore. IBM is also using Watson to check medical imaging results and other test results to uncover diseases that have been overlooked. Beyond oncology, IBM is looking at using Watson to read imaging and consult medical records to find patients who may have early-stage heart disease or be vulnerable to stroke and certain types of eye disease or neurological conditions. Intel is working on a project called All in One Day, which will give cancer patients both a genetic profile of their malignancies and a plan of treatment within twenty-four hours of their diagnosis. The target price for the service is $1,000. Today this process can take weeks or even months, and costs much more.

  For high-level science, the next step in Big Data could involve liberating information to serve more purposes. Right now, academic scientists, private laboratories, pharmaceutical companies, and others feel enormous pressure to protect the information they collect in order to maximize the reward for all their hard work. To some extent the incentives to keep this work secret make sense. Who would invest all the time and money required by science if someone else can come along and capture the benefits? However, if there’s one thing that was learned from the human genome project it was that people working together, in an open-source way, can push science along very rapidly. The key to encouraging this pace will lie in maintaining the kind of incentives that drive people to create while opening up avenues of collaboration.

  In medicine, the challenge of information overload will grow greater every year. Managing may well involve technologies that allow us to monitor patience remotely, leaving much of the routine work to some form of artificial intelligence. I’m not saying that doctor robots will be taking over, although we will become more reliant on some forms of computing. Instead, we will depend on sophisticated algorithms, whi
ch will improve on their own as data grows. This technology will tell us how people respond to medications taken in different doses, at different points in their illness, and under varying conditions of stress. Inputs on diet and exercise could change our understanding of how drugs are metabolized.

  The great potential available to us with a rapidly expanding knowledge base and biologically precise therapies, many of which will leverage the power of the immune system, suggest a future rich in possibilities. The promise also calls upon us to embrace the guidance available, not in technology or biology, but in the humanities. Using what we are discovering is going to require an ethic that takes into consideration the value of each human being and the recognition that we all deserve care and cures. Recent research has turned up the fact that in America, one’s health can depend on where you live, right down to a particular neighborhood in a city or town. A recent decline in the life expectancy of middle-class whites in America, driven mainly by stress-related issues—substance abuse, mental health crises—tells us that it’s not enough to develop treatments to target organic illnesses. We must attend to the human spirit along with the body and this requires respect for the human experience.

  Science in the service of society will give us medicine that is also just. My experience in both communities—those of caregiving and research—give me hope in this regard. Almost no one takes up either without the desire to see suffering reduced and health increased across communities, nations, and the globe. This improvement, in all our lives, is the future we will realize. And it is coming fast.