Life Science, a Life in Science and is Life Just a Science
January 12, 2014
I am most grateful to be bestowed this honor today by such a distinguished group of my compatriots. I gather that as a response to receiving the life-time achievement award, I should say a few words about my life. This I will do not with the view of training the focus of this talk on my life’s chronology but to touch on a few events which can be illustrative of what I consider to be important in my life.
Dr. Gerald Chan (file photo).
Let me begin by talking about my study of life science, or biology. I was raised in Hong Kong when it was a British colony. I attended a Christian school where I benefited from very high quality teachers. Some of them were university professors before they came to Hong Kong from Mainland China. I had a physics teacher who did his graduate work at MIT and a history teacher who was trained at Harvard. However, when I took biology, the teacher was a young man who had just graduated from university. He was a terribly boring teacher. I thought the subject matter was boring as the biology he taught was very descriptive. Drawing a leaf and labeling its parts did not excite me. I had never encountered a subject in school that I did not like until I took biology.
So when I began my university studies, I chose to study engineering. I did fluid mechanics and very much enjoyed the elegance of differential equations. One day, I wandered into a part of the engineering school where I had never set foot. It was a nuclear facility of sorts and there I met a professor who engaged me in conversation. He offered to teach me an independent study course which I liked because that meant I did not have to go to classes. I would meet with him once a week as he tutored me through my reading of the book Nuclear and Radiochemistry by Friedlander and Kennedy. That got me interested in radiation and I went on to Harvard to read medical radiological physics. As part of that program of study, I had to take a course in radiation biology. It was there that I met a professor who showed me that biology was intellectually stimulating. Rather than the descriptive biology which I had in high school, I encountered a field of inquiry which appeals to first principles of physics and chemistry to explain how life functions.
Being at Harvard and being newly interested in biology in the 1970s was a blast. Many of the first generation giants in the study of DNA were still teaching there, such as Jim Watson, Matt Meselson and Wally Gilbert. On top of that, we were free to cross- register at MIT where there was a whole other set of giants such as Salvador Luria, Har Gobind Khorana and David Baltimore. The sense of privilege was overwhelming when one would read about the double helix structure of DNA in the text books and was able to take a course from Watson himself, or the Meselson-Stahl experiment and have a course taught by Meselson, or the phage experiments of Luria and Delbruck and knew that Luria’s course would soon be open for registration. The accessibility of the giants was powerful in imbuing in the young students a sense of possibility.
Indeed, to have the opportunity to interact with great minds is the highest privilege of a student. In addition to my course work, I used to be a seminar junky. There were so many seminars each day of the week among the medical school departments, the Biolabs in Harvard’s Cambridge campus, MIT, the Mass General and the hospitals in the Longwood Medical Area. We saw before our eyes the unfolding of great chapters in science. We listened to great scientists speak and we watched them being challenged by equally prominent scientists in the audience. We watched the free exchange of cutting edge research findings and how scientists struggled to interpret them in the context of currently known science. We saw scientific postulates and paradigms formed, challenged, evolved, affirmed or fade into oblivion.
Science is about the pursuit of truth. The way science was organized in America in the 1970s was particularly conducive to fulfilling this objective. Each professor ran his own little kingdom where he and his followers were free to do whatever they saw fit in their pursuit of the truth. Funding was copious enough to allow diversity of opinion and autonomy to all. With the principal funding sources being third parties outside of one’s department, it meant that one did not have to kiss up to the big man in the department in order to get funded. My mentor Bill Haseltine was famous for being a brash young man who, as a newly minted assistant professor, said in public in a seminar that the science of the chairman of the department was wrong. It was a classic example of what the economist Milton Friedman called economic freedom as a pre-condition to true freedom. As well, there was freedom in exchanging research findings and forming collaborations. There were no lawyers, no invention disclosures, no material transfer agreements, no technology transfer office. It was the last of the innocent times before the financial profit motive infiltrated science.
If I were to look at the impact of my scientific training on my subsequent life in the investment business, equal in significance to the training of my mind was the experience of having lived in a community of idealistic free agents each pursuing the truth as he saw fit. There was a fearlessness that came with the idealism. For some, it even bordered on foolhardiness as they sought truth with abandon. There was an implicit faith that the truth would ultimately triumph and that everything would be all right. Debates were steps that we took towards the truth and they were conducted with respect. We took those steps with pleasure and we cheered others who did the same. We appreciated science because we were all peering into the sublimeness of life as it unfolded before our eyes.
The making of the scientist in me has meant that even in the investment business, making money has never been the primary motivation. It was always about doing something interesting, doing something which had intrinsic beauty in it. That was the motive force which kept me going. It also served as a litmus test by which I chose what projects to get into and what projects to weed out. To be sure, this approach to investment is a risky proposition. I struck out many times. My investment track record is a high beta one, in Modern Portfolio Theory terms, but I suppose that is all right as long as there is a good alpha to justify it.
Many of you have read my commencement speech given at Johns Hopkins Nanjing two years ago. I talked about our being pressed by this age into becoming mere economic beings with life in all other dimensions wilted. I would still say the same to you today. Being a mere economic being may make you a good investment professional, but it will not make you a good human being. My reminder to myself and advice to others is always to mind that core of humanity in you. One can be mindless about many things, but one cannot afford to be mindless about his own humanity without running the risk of deforming, damaging or destroying that which is most intrinsic to one’s being.
With that as a backdrop, let me turn now to talk about a few of the more interesting investments I have made in recent years. When I was a graduate student, I was taught that the modalities of cancer therapy were surgery, chemotherapy and radiation. Much like radiation therapy, chemotherapy has been for years an exercise in widening the therapeutic window for drugs which are basically promiscuous cytotoxic agents. The field of signal transduction pathways opened up the possibility of targeted therapy, namely the tyrosine kinase inhibitors. Because of overlapping nodes and pathways in biological networks, the targeted therapies are never quite as targeted as we would like them to be. Another downside is that the more targeted a drug is, the more it is prone to the cancer cells mutating around it. Still, the kinase inhibitors are a big improvement over promiscuous cytotoxic agents.
It was this fundamental dissatisfaction with the state of cancer therapy that predisposed me to consider radical alternatives. Five years ago, when I was presented with the opportunity to invest in an oncolytic virus company, it was a very bold proposition. Never has an oncolytic virus been approved by the FDA as a cancer therapy in spite of multiple attempts. Conventional wisdom would have it that investing in a better kinase inhibitor would have been a safer thing to do, but that was the kind of incrementalism that I simply could not make myself do. It is common for people to seek risk mitigation in company, in other words, finding comfort in the crowd. Regression to the mean has never been one of my aspirations.
I looked at the data of not one, but several oncolytic virus companies. The tumor selectivity engineered into the virus made sense based on biology. The safety of the virus also seemed to be adequately addressed. The limited clinical data looked compelling. To make a long story short, I invested in Biovex and the company was sold two years later to Amgen with Phase 2 data for about a billion dollars with much of that paid upfront.
The financial outcome aside, it intrigued me that the oncolytic viral therapy worked not only because of direct oncolysis by the virus, but that the efficacy was mediated by the host immune system as evidenced by the abscopal effect away from the site of intra-tumoral administration of the virus. This was in early 2011, slightly over a year before the anti-PD1 story of BMS-936558 broke. Cancer immunotherapy was not a hot story yet. In fact, as a student, I had watched in peripheral vision the work of Steve Rosenberg at the NIH. For years, he toiled to make cancer immunotherapy work better. To a large extent, he was hampered by the field of immunology being still young and inchoate. I thought his data uninteresting even though his efforts were heroic. Others who came at the cancer immunotherapy problem by looking for tumor specific antigens also turned in unimpressive results. The company Cell Genesys which tried to take inactivated whole tumor cells as cancer vaccines failed miserably in 2008. Companies that manipulated dendritic cells for cancer therapy seemed to have done better, but the benefits were not overwhelming even though Dendreon got its Provenge approved by the FDA in 2010. I had in fact invested in Dendreon over fifteen years ago when it was still a private company, but was all too happy to sell the shares at a good profit when the company had its NASDAQ IPO. It is easy for investors to be dazzled by novel scientific discoveries which promise to solve unmet medical needs; it is hard to find investors who have the fortitude to stay with a company through its arduous journey of drug development and regulatory approval.
It was against this discouraging background of cancer immunotherapy that a friend told me about a cancer immunotherapy company named Aduro. It was a company in distress because its investors had just bolted. Three top tier west coast venture firms had invested in Aduro. When a patient in the Phase 1 trial developed a fever after the administration of the therapy, the investors decided to withdraw their support from the company. Once again, I looked at the clinical data, anecdotal data only, to be sure, and I thought they were promising. In fact, from the oncolytic virus experience, we thought that a patient having a fever after the administration of the virus presaged a favorable outcome. So on top of the bleak state of affairs of cancer immunotherapy and against the background of three venture groups having just given up on the company, I decided to invest in Aduro. From there, we took on the very challenging case of pancreatic cancer. You can imagine how gratifying it was when the Phase 2 data showed a highly significant survival benefit. This data was presented in ASCO last year. The company is now gearing up to do a Phase 3 trial. It still has a long hard road ahead; these are the challenges which are part and parcel to biotech investments. If my objective was only to make money, real estate would have been a more attractive asset class.
The third company that I would like to talk about is a company by the name of Stealth Peptides. This is a company with a therapeutic peptide which targets the mitochondria. When I was introduced to the scientist who found these peptides, the science included just a paper in the Journal of Biological Chemistry and some unpublished experiments with animal disease models. I had not heard anyone talk about the mitochondria since I took my basic cell biology course, a lower division undergraduate biology course I took in Harvard College when I switched from physics to biology. Fortunately, I had kept the text book from the course which was by then, about thirty years old. I went and looked up the section on mitochondria. I also went back to my Lehninger Biochemistry textbook, that sleek brown book which has got to be one of the most beautiful textbooks ever designed.
In order to tell the Stealth Peptides story, I would like to digress for a moment into a booklet which was published in 1944. It is the book What is Life written by Erwin Schrödinger of the quantum mechanics wave equations fame. It was during the Second World War that Schrödinger left Austria for a fellowship in Trinity College Dublin, Ireland. In 1943, he gave a series of lecture there which came to be published as the booklet What is Life. In these lectures, he probed the question of what is life by propounding two questions. In one, he asked how living things perpetuate order from order. This question has to do with how genetic traits are maintained stably from generation to generation of living organisms. It was in answering this question that he proposed an aperiodic crystal which informed Watson and Crick to come up with the double helix structure of DNA when they saw the x-ray diffraction data. In the second question he propounded in this book, he asked how living things escape from the second law of thermodynamics, that is, from entropy and therefore decay. The answer, of course, is energy. If his first question has to do with how we are born, his second question has to do with how we manage to keep on living. If his first question has to do with genetics, his second question has to do with bioenergetics. Subsequent developments in science have addressed his first question with over half a century of genetics and now genomics. We may call this the genocentric era. What I surmise is that we are now entering into an era of bioenergetics. If the nucleus was the focus of the genetics era, the mitochondria will be the focus of the bioenergetics era.
The mitochondria are indeed intriguing organelles within the cell. They have their own genome, albeit of a limited size but in multiple copies, and not all mitochondrial proteins are coded for by the mitochondrial genome. Mitochondria are somewhat autonomous to the host cell in the sense that they can have their own cycles of fission and fusion, but there is also constant trafficking and signaling between the mitochondria and the nucleus. The fact that ATP, the currency of energy in living things, is largely made in the mitochondria and the fact that an important part of the apoptotic process takes place in the mitochondria tells us that this organelle is of fundamental importance to life and to death. In traditional Chinese medicine, we talk about qi, the vital force. If I had to venture a biochemical representation of qi, I should think it would be ATP although I am by no means drawing an equivalent between the two. It would be a futile attempt to reconcile the two philosophical systems of traditional Chinese medicine and Western medicine. Any attempt to do so will inevitably end up in a bastardization of both.
If one were to look at the number of publications on the mitochondria in recent years, there has been an exponential increase. Mitochondrial dysfunction has been implicated in pathologies ranging from acute kidney injury, myocardial infarction, stroke, pulmonary arterial hypertension, reperfusion injury, heart failure, diabetes, diabetic neuropathy and retinopathy, cancer, neurodegenerative diseases, autism, and finally, aging. Stealth Peptides is now conducting a number of clinical trials in some of these areas.
I will not elaborate on the development programs of Stealth Peptides as they are still ongoing. I do want to comment on how the scientist initially found these peptides and how I was brought into contact with her which then led to the founding of the company. The answer is, in one word, serendipity. Dr. Hazel Szeto was working on opiates and she told her graduate student to fluorescent label the peptides and see where they went in the cell. Lo and behold, they went to the mitochondria. In turn, how did I meet Dr. Szeto? It was through her brother, an architect who had worked with IM Pei and done work for some of our real estate projects. If I had not been doing real estate on the side, Dr. Szeto and I would never have met.
Life is full of serendipity. The genocentric era of science has given us an overly deterministic view of life as if there is a central command in the nucleus which determines all outcomes. In the euphoria of the Human Genome Project, the illusion was put forward that if we only knew all the gene sequences, all diseases would be solved. Some of you, like me, had an association with Bill Haseltine, my post-doctoral mentor who founded the company Human Genome Science. Eventually, that company did not get a single drug out of sequencing the human genome. The script of life is in fact written in a much less watertight fashion in which the genome is not vested with absolute sovereignty. To one degree or another, life does leave many outcomes to chance. Those of us who engage in procreation should know that the exercise is subject to random genetic re-assortment. There are no guaranteed outcomes. For those of us with multiple offspring, the differences in their physical characteristics and personalities speak to the operation of randomness.
To be prepared for whatever serendipity serves up, and to have the courage to act on it, is a great way to live.
Let me now return to Schrödinger’s question of what is life. Even though this title was most provocative, the questions he was asking really should be phrased as how does life work. I am not sure we can ever answer the question of what is life. That sounds too much like an ontological question in philosophy. Schrödinger must have been aware of the inadequacy of defining life only in biochemical terms. Hence in 1955, he delivered another series of lectures, this time at Trinity College, Cambridge. These lectures were entitled Mind and Matter. Clearly, the question of what is life, in so far as higher life forms are concerned, cannot stop with biochemical descriptions of how life functions. There is the question of consciousness.
It is no wonder that many great biologists, after having made important contributions to a field in life science, then turned to neuroscience as their next endeavor. The quest for understanding goes beyond what is life to what makes us human. The most glaring example has got to be Francis Crick, but he is in no shortage of company of Nobel laureates from Max Delbruck early on to Marshall Nirenberg to the immunologists Gerald Edelman and Susumu Tonegawa. To understand the human brain has even become a national agenda. President Nixon declared War on Cancer; President Obama is now funding the mapping of the human brain.
Biochemical reactions are physical, consciousness is metaphysical. We know there are neurotransmitters operating in our neurons, but we do not experience neurotransmitters. We experience happiness, love, fear, anxiety, depression, etc. We do not experience combinatorials of GPCRs, we smell the aroma of freshly roasted coffee, or garlic sautéed in butter, or barbeque spareribs on the grill. We do not experience rhodopsin undergoing oxidation and isomerization, we sense the serenity when we look at an Andrew Wyeth painting, or the loneliness in an Edward Hopper painting, or feel the anticipation of winter coming to an end at the sight of a forsythia flower. What is the transducer which converts the physical into the metaphysical? Is it something physical like lithium or Prozac, or the cannabinoids? As we make progress in neuroscience, we are treading ever closer to the interface of the physical with the metaphysical. Whether we will ever fully understand that interface is unclear to me, but I do see a danger here of our view of man being reduced to a narrative that is articulated in entirely physical terms. This would be a sad travesty of scientific reductionism. There are human qualities and experiences which cannot be reduced to merely physical quantities nor should they be even if we could. Let me talk about a couple of personal experiences.
My father was not a bookish person. He never talked about literature with me. The only piece of literature he ever mentioned to me was the essay by Zhu Ziqing ( 朱自清 ) on the silhouette of his father seen from behind ( 背影 ). I am sure you all studied this essay in junior high school. How is it that his father’s act of buying him some oranges by clumsily crossing the railroad tracks elicited tears in the young man? How is it that his memory of the silhouette of his father’s back, years later, evoked such sadness in him? And why is it that through the years, this essay has evoked such rich feelings in generations of fathers and sons and daughters?
My father came to Boston for the first time to visit me in 1974. He was obviously pleased that a son of his was studying at Harvard. In spite of his considerable success in business by then, he could not help but felt intimidated by the loftiness of an university perched at the pinnacle of higher learning. He spoke of my thesis advisor with veneration for the simple fact that he was a Harvard professor.
I took my father to the Harvard Coop bookstore where a large coffee-table book on Norman Rockwell paintings caught his eyes. While Rockwell’s paintings depicted a small town Americana to which my father had no exposure, they conveyed an innocent humanity that my father instantly related to. Rockwell’s paintings portrayed a simpler time in America when human relationships and feelings were not so much masked nor distorted by material affluence. My father identified with this element of nostalgia in Rockwell’s paintings even though he was neither a pessimist regarding the future who retreated to the past for solace, nor was he a romantic who thoughtlessly ascribed a nobler value to things of the past. Nevertheless, he always clung to his past because he thought it decent not to forget the bygone – both the good and the bad, the sweet and the bitter.
That day, my father asked me to buy a copy of the Norman Rockwell book for him. Rather than buying it himself, he wanted me to buy it for him. I did and I inscribed on the front page, “To Dad, as a token of affection.”
That Norman Rockwell picture book was the medium by which my father and I communicated a tender feeling between us from the depth of his soul and mine. I would hate to reduce that tenderness to some part of the brain lighting up in a functional MRI, or perhaps a band in a gel, or some color pattern in a proteomics heat map. That tenderness was an expression of the essence of being human. It transcends, indeed obviates, material description, anatomical dissection or the laws of chemistry. Its intrinsic beauty makes mockery of our scientific reductionism. Do I really need a scientific explanation for that tenderness between my father and me, a tenderness which I still feel to this day even though my father has departed for over a quarter of a century? What goes on in the human soul has a time scale many orders of magnitude apart from the kinetics of biochemical reactions, yet one is as innately human as the other.
Let me close by saying again how pleased I am to have made the switch to studying life science, to have had a rewarding life in science and best of all, to have experienced and still appreciate life as more than just science. It is at this juncture between science and humanity that I have found a life that is full of wonders, awe and possibilities. I feel indebted to my family and friends with whom I have shared life’s journey. With grace and longsuffering, they have put up with my eccentricities and my quirkiness. I also feel indebted to my teachers and my many able colleagues who have taught me so much. While I am ever mindful of the charge that to whom much is given, much is expected, I shall remain ever so grateful for all that has been bestowed on me by God, and likewise, for the honor that you have bestowed on me today.