A year in books: Neanderthals to the National Cancer Act to now

January 19, 2016 by Artem Kaznatcheev

A tradition I started a couple of years ago is to read at least one non-fiction book per month and then to share my thoughts on the reading at the start of the following year. Last year, my dozen books were mostly on philosophy, psychology, and political economy. My brief comments on them ended up running a long 3.2 thousand words. This time the list had expanded to around 19 books. So I will divide the summaries into thematic sets. For the first theme, I will start with a subject that is new for my idle reading: cancer.

As a new researcher in mathematical oncology — and even though I am located in a cancer hospital — my experience with cancer has been mostly confined to the remote distance of replicator dynamics. So above all else these three books — Nelson’s (2013) Anarchy in the Organism, Mukherjee’s (2010) The Emperor of All Maladies, and Leaf’s (2014) The Truth in Small Doses — have provided me with insights into the personal experiences of the patient and doctor.

I hope that based on these reviews and the ones to follow, you can suggest more books for me to read in 2016. Better yet, maybe my comments will help you choose your next book. Much of what I read in 2015 came from suggestions made by my friends and readers, as well as articles, blogs, and reviews I’ve stumbled across.[1] In fact, each of these cancer books was picked for me by someone else.

If you’ve been to a restaurant with me then you know that I hate choosing between close-to-equivalent options. To avoid such discomfort, I outsourced the choosing of my February book to G+ and Nelson’s Anarchy in the Organism beat out Problems of the Self by a narrow margin to claim a spot on the reading list. As I was finishing up Nelson’s book — which I will review last in this post — David Basanta dropped off The Emperor of All Maladies on my desk. So I continued my reading on cancer. Finally, Leaf’s book came towards the end of the year based on a recommendation from Jacob Scott. It helped reinvigorate me after a summer away from the Moffitt Cancer Center.



The Emperor of All Maladies: A Biography of Cancer

(2010) by Siddhartha Mukherjee

In the 6 years from 1899 to 1905, the Krapina Rock Shelter — 55 km North of Zagreb, Croatia — yielded one of the largest collections of human remains from the Upper Pleistocene. It is inside one of those remains that our story could be said to begin: a fibrous dysplastic neoplasm in a Neanderthal rib (Monge et al., 2013). A 120,000 year old tumour. Of course, this particular tumor is not the birth of cancer. The disease is probably as old as multicellularity. But this rib is the oldest confirmed case of cancer in humans. Cancer as a malady of man. And it is the story of cancer in man that Mukherjee tells.

His book is a well written popular-science/history blend. It alternates between the cases of individual patients from the author’s clinical experience and stories from the history of cancer research and treatment. Since my knowledge of the clinical aspects of cancer and its history is very spotty, this book taught me a lot. Of particular interest to me was the story of the rise and fall of the radical mastectomy.

The radical mastectomy — developed and first performed in 1882 by William S. Halsted and defended by his supporters until the mid-1970s — was an operation that removed not just the affected breast, but also the underarm lymph nodes and the chest wall muscles. It aimed to remove all the cancer and leave safe margins to reduce the risk of relapse. It was performed on almost every woman, regardless of the cancer’s severity at diagnosis. It left women disfigured and debilitated. And it didn’t work.

More precisely, it worked no better than smaller and less devastating mastectomies or lumpectomies. Especially if they were combined with chemotherapy. This radical failure was because the radical mastectomy was based on a fundamentally incorrect understanding of breast cancer. A surgeon like Halsted, only armed with a scalpel, saw breast cancer as spreading gradually out from its epicenter.[2] He would cut the women further and further to catch it. But breast cancer does not spread in such a way, it is either contained in its local tissue (in situ) — and a small operation will do — or it has broken through the basement membrane and invaded the whole body — and no amount of surgery will undo it, only systemic treatments like chemotherapy.

Of course, science always needs to be corrected, so an improvement in our understanding of breast cancer is no surprise. What is surprising, however, is how long it took the new understanding to take hold. How stubborn Halsted’s disciplines were. And how essential extra-scientific forces like the women’s and patients’ rights movements were to the elimination of the radical mastectomy.[3]

If you want to get these main stories from Mukherjee’s book without having to read then PBS has recently made Cancer: The Emperor of All Maladies — a documentary based on the book. I haven’t seen the 6+ hours that make up this series, but I did see a selection of snippets during a prescreening at Moffitt. It was well done, but prioritizes the individual stories of patients over the general trends of science even more than the book. Definitely a tearjerker.

Here is a trailer:

The book is less sentimental than Ken Burns’ documentary. Given its historic focus, the book gives a perspective that defuses some of the sensationalism and knowledge-utopianism that plagues pop-sci. However, it is still not a work of careful science, history, or philosophy and succumbs to the optimism of “sure, we were unbelievably wrong before, but something very similar to what is fashionable now is definitely on the right track, we just need to take it to its logical conclusion.” You can see this optimism — with only slight tempering — from 4:02 onwards in the above trailer.

I fear that this confidence is misplaced. For Mukherjee, the cutting edge is the Hanahan & Weinberg (2000,2011) reductionist “hallmarks of cancer” perspective. Cancer as a disease of genetic error in the individual cell. For me, this is the entrenched orthodoxy against which a more holistic ecological perspective on cancer — that is central to my research– has to struggle against.[4] But, if you are like me — a cancer researcher that doesn’t interact directly with patients and hasn’t been directly affected by cancer — then I still highly recommend reading Mukherjee’s book or watching the documentary. It is important for removing the distance of replicator dynamics and seeing the actual people that you are trying to (eventually) help.

The Truth in Small Doses: Why We’re Losing the War on Cancer — and How to Win It

(2014) by Clifton Leaf

Unlike Mukherjee, Clifton Leaf is neither a doctor nor a cancer researcher. He is a journalist — a business journalist for Fortune magazine. In fact, his book is an in-depth expansion of his 2004 Fortune article: Why We’re Losing the War on Cancer (and How to Win It). Unlike Mukherjee, he focuses much less on the individual stories of patients and much more on the mechanisms behind the research. But like Mukherjee, this book is moving and personal — not the dry account of research practice by a systems engineer or economist. A number of chapters are structured around the quests of individual researchers. And in chapter 4 Leaf recounts his mother’s long struggle with and death from cancer; his own battle with Hodgkin’s lymphoma as a teenager; and the amazing heroism, stoicism, and devotion from his father. This first person account is even more moving than anything in the The Emperor of All Maladies.

But The Truth in Small Doses does not aim to tell the story of cancer and its treatment. That story is just evidence for Leaf’s argument: we are not winning the war on cancer. And if we want to win it then we need drastic changes to the cancer research culture. If Mukherjee wrote a biography of cancer then Leaf was aiming for the obituary of modern cancer research.

The main point is summed up by this graphic from his book and 2010 TEDMED talk:

We hear much about our progress in the war against cancer. We read promising statistics based on age-adjusted death rates. But the cancer burden — the cost of cancer in lives, time, money, and physical and emotional pain — continues to increase. Since the passing of the 1971 National Cancer Act, annual deaths from cancer drastically outpaced population growth while the deaths from other leading causes like heart disease, stroke, and even car accidents, declined steadily. How can we say that the war on cancer is being won?

Leaf attributes this slow progress to the bureaucratic institutionalization of risk aversion in cancer research. It is not a matter of putting more money into cancer: we’ve been doing that generously since 1971 — the NCI alone[5] has spent over $90 billion on cancer research between 1971 and 2011 (Marshall, 2011). It is about how that money is invested. We cannot focus all (or most) of our effort on cancer as it is defined to medical students today — after it has broken through the basement membrane into the circulatory and lymphatic system. That is like trying to cure heart-disease by building better defibrillators. We have to invest more heavily in early detection and (chemo)prevention, look into prophylactic approaches like diet and lifestyle. It is better to never get cancer than to be cured of it.

Leaf spells out how the cancer research culture has ossified since 1971. How funding is distributed unevenly and invested in making incremental changes at the same few research centers. How we fund a few bigger and bigger projects, instead of funding individual researchers and smaller projects. The whole time I was nodding along to his diagnosis, but I don’t know what to make of his proposed treatment.

Like so many others — including the writers of the National Cancer Act — Leaf tries to stress the analogy of the war on cancer to the moon shot. He tries to use the moon-landing for cancer to stir up a nationalist fervor and pride to overcome cancer.[6] And his plan forward endorses Farber’s engineering approach to cancer care:

patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure for cancer, for us to have the full solution of all the problems of basic research … the history of Medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures.

Leaf chose his case-studies to support this view. He focuses on pragmatic iconoclasts like Joe Hin Tjio & Frederick Hoffman, Judah Folkman & Mina Bissell,[4] Denis Burkitt, Benno Schmidt, and Michael Sporn. These are all great examples, and I found the story of Denis Burkitt‘s Long Safari (see Burkitt, 1962) to be particularily inspirational,[7] but they seem cherry-picked. For example, the tale of the the radical mastectomy that Mukherjee tells, and Leaf omits, occurred in the pre-NCA days that Leaf romanticizes. Yet that saga saw all the ossification, risk-aversion, and reluctance to change that Leaf attributed to the post-NCA cancer culture. So even before the Byzantine systems of today, mass medicine was risk-averse and conservative. It misapplied engineering improvements — cut further and further with the radical mastectomy — based on faulty understanding of the science. How can we be confident that doubling-down on engineering over basic science now will make more progress than regress?

I want to see the cancer research culture change as much as Leaf, but in what direction? Do we need more top-down Apollo Program style order and coordination, or do we need more community-regulated scientific anarchy and exploration?

Anarchy in the Organism (Cancer as a Complex System)

edited (2013) by Simeon Nelson

The central metaphor of Nelson’s book is summed up best not by any text within the work, but by Clifton Leaf’s description of cancer in The Truth in Small Doses (pg. 68):

Though the expanding tumor is the most familiar aspect of cancer … cancer is not merely an illness of rapid cell growth. Fundamentally, it is a disease of subversion. Cancer is a subversion of rules, the corruption of an organism’s cohesion and structural order. When a single cell begins to exploit its biological machinery to promote its own survival and proliferation above all else — stealing resources from its neighbors, failing to perform its normal duties, ignoring the greater good of the organism — cancer has begun.

Cancer is anarchy.

This book is a collection of 8 essays by 9 different authors, providing background and context for Simon Nelson’s multimedia art installation at the UCH Macmillan Cancer Center and associated live performances at the University of Hertfordshire and symposium at the Wellcome Collection Conference Center in London. I had not seen the installation or performance before reading the book, and had to reconstruct it in my mind from the descriptions in text and the numerous beautiful illustrations. As I was writing this review, I found a video of the performance that you can watch for context:

Five of the essays in the book detailed parts of this performance and installation. Overall, this left me unmoved; I feel that art, like a good joke, shouldn’t need explaining. But one essay — Complexity, Heterogeneity and Medicine by Castillo-Sepulveda and Tirado — was a pleasant surprise. These two authors are social psychologists that are heavily influenced by Whitehead’s process philosophy. They suggest that we should not think of cancer as the tumour or mass of misbehaving cells in some part of the body (which unfortunately, is the only thing that the live performance seems to focus on). First — and obvious to the cancer researcher in the days since Halsted — after metastasis cancer is not localized to any specific part of the body, it becomes a systemic disease. Second, and more important, many patients do not have any direct experience with the ‘biological cancer’. Sometimes they don’t even show symptoms before treatment. Instead, for such a patient, cancer is a series of procedures and interactions with doctors. It is protocols. It is chemo and hair loss. It is waiting in the reception for that dreadful discussion with your doctor. Sometimes, all of their pain comes from the side-effects of the treatment, treating something they never felt but that showed up on a doctor’s diagnostic screens. As Patient No. 2 reports (pg. 73):

I have had cancer … and I didn’t feel pain, all the damage to me [has] been done by them, to heal something that I have not seen, that did not hurt and I didn’t feel. … Because someone saw a picture of I do not know what, they have done to me…. And they made me happen…. But I didn’t feel anything before.

This gives a very different operationalization for the meaning of ‘cancer’ than what I typically consider. Together with Mukherjee and Leaf, this shows me just how distant my mathematical conception of cancer is from those that are unfortunate enough to suffer through the disease and treatment. It encourages me to focus my research on understanding treatment side-effects and toxicity and getting people off chronic drugs that they might no longer need. It reminds me that cancer is not an abstract growth function. Cancer is a malady of man.

Notes and References

Of course, if you want to offer material support to TheEGG and directly determine what I will read this year then consider donating something from TheEGG wishlist. Gifts will jump to the front of the reading queue and help shape the content on this blog. The radical mastectomy is a great example of how our techniques of interventions (or measurement) inadvertently shape our theories. The local nature of surgery made clinicians stick unreasonably long to theories that stressed the local properties of cancer. This makes me wonder if the current focus on the intrinsic properties of individual mutant cells in cancer is due (in part) to the widespread use of tools like genetic sequencing on other -omics. If you only have a hammer… In the future, I want to pursue this radical mastectomy case-study from Mukherjee’s book further so that I can understand the lessons it offers on the philosophy and sociology of science and medicine. The best source for that seems to be Barron H. Lerner’s (2001; paperback: 2003) Breast Cancer Wars: Hope, Fear, and the Pursuit of a Cure in Twentieth-Century America — which is the central source for Mukherjee’s account — although I am open to other suggestions. For example, Leaf devotes much more space to discussing the work of Judah Folkman and Mina Bissell that showed the importance of the micro-environment. This is one of the central works that helps us move away from the reductionist fixation on the genetics of and biochemical process in the single cell to a more holistic ecological account of how cancer co-opts healthy tissue. Mina Bissell delivered a very informative TED talk on this in 2012:



It surveys her work from the 80s and 90s on the importance of the architecture and microenvironment (Bissell et al., 1982) in Rous virus associated chicken sarcoma (Dolberg & Bissell, 1984) and breast cancer (Petersen et al., 1992; Weaver et al., 1997). Although this work is well respected, 30 years later the focus of most researchers still seems to miss the microenvironment. When cancer research funding is discussed, it is common to see only the NCI mentioned. I think this is because they release official yearly statistics that are easy to understand and cite. And although the NCI is (one of) the biggest cancer research funders, a lot of cancer research funding also comes from foundations, private industry, and other organs of the NIH and state and federal government. I had a hard time finding recent sources for total cancer funding in the US, with the most recent being McGeary & Burstein (1999). They provide a nice comparison of funding breakdown between the year 1974 and 1997, I have adjusted their graphic by having the areas of the circles reflect the change in total funding (from $2.7 billion in 1974 to $5.2 billion in 1997):



Given the yearly NCI budgets for the 5 years since the total of $90 billion from 1971 to 2011 and the trend of NCI’s shrinking proportion of total US cancer research funding, I think it is safe to estimate that total spending in the 45 years since 1971 is on the order of a quarter of a trillion dollars. For me, Leaf’s biggest weakness seems to be his baby-boomer engineering can-do and American exceptionalism. He writes on pg. 294: The laws of gravity and motion are the stuff of high school science classes the world over. But only one nation in history has been able to land a spacecraft on the moon, let alone a man, let alone bring him back. The comparison seems strange to me, since there is no equivalent to the ‘laws of gravity and motion’ for cancer. Sure, we might teach some version of the “hallmarks of cancer” in highschool, but that is far less reliable than the physics of rocket propulsion. Even there, it was over 60 years from Konstantin Tsiolkovsky‘s derivations of the rocket equations in 1896 and Sputnik 1 in 1957. Further, in his first unilateral US achievement, he must be forgetting the Soviet Lunokhod program. But I am not just being bitter about the dismissal of Russian science for nationalistic sake. The top-down engineering approach to cancer research that Leaf is proposing seems much closer to what the Soviet Union would have implemented as its funding strategy. Why not compare the successes (or lack of) US cancer research between 1971 and 1991 to that in the Soviet Union? What about research in the UK or continental Europe? Of course, I imagine that finding sources for comparisons will be difficult. As Shimkin & Shope wrote after a trip to the USSR in 1956: In cancer research, as in other aspects of medical investigations, we were impressed by the thorough and intimate knowledge of the American and British work displayed by the Soviet scientists. We were also dismayed by our own ignorance of the work and accomplishments of our Soviet colleagues. It is our impression and conclusion that the Soviet Union has many talented, original scientists, working in laboratories that are adequately equipped, and that their contributions deserve and require our thoughtful attention and evaluation. It surprises me that Mukherjee focus a lot on Rous’ chicken virus but I don’t remember him discussing Burkitt’s research. Yet that search led directly to the first identification of a human oncovirus — the Epstein-Barr virus. I guess the history of cancer is too massive for any one book. But this means that even if you read Mukherjee’s The Emperor of All Maladies, you will find new history in Leaf’s book. See also footnote [4].

Bissell, M. J., Hall, H. G., & Parry, G. (1982). How does the extracellular matrix direct gene expression? Journal of Theoretical Biology, 99(1), 31-68.

Burkitt, D. (1962). A “tumour safari” in East and Central Africa. British Journal of Cancer, 16(3): 379.

Dolberg, D. S., & Bissell, M. J. (1984). Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature, 309(5968), 552-556.

Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1): 57-70.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5): 646-674.

Leaf, C. (2014). The Truth in Small Doses: Why We’re Losing the War on Cancer-and how to Win it. Simon and Schuster.

Marshall, E. (2011). Cancer research and the $90 billion metaphor. Science, 331(6024), 1540-1541.

McGeary, M., & Burstein, M. (1999). Sources of cancer research funding in the United States. Prepared for National Cancer Policy Board, Institute of Medicine.

Monge, J., Kricun, M., Radovčić, J., Radovčić, D., Mann, A., & Frayer, D. (2013). Fibrous Dysplasia in a 120,000+ Year Old Neandertal from Krapina, Croatia PLoS ONE, 8 (6) DOI: 10.1371/journal.pone.0064539

Mukherjee, S. (2011). The emperor of all maladies: a biography of cancer. Simon and Schuster.

Petersen, O. W., Rønnov-Jessen, L., Howlett, A. R., & Bissell, M. J. (1992). Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proceedings of the National Academy of Sciences, 89(19): 9064-9068.

Shimkin, M. B., & Shope, R. E. (1956). Some Observations on Cancer Research in the Soviet Union. Cancer research, 16(10.1): 915-917.

Weaver, V. M., Petersen, O. W., Wang, F., Larabell, C. A., Briand, P., Damsky, C., & Bissell, M. J. (1997). Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. The Journal of cell biology, 137(1), 231-245.