Book summary #1 — The Emperor of all Maladies: A Biography of Cancer
By Siddhartha Mukherjee
Short intro to the book
This is a magnificent “biography” of cancer — from its first documented appearances several thousand years ago to the relentless battles we have been fighting to decipher, control, cure and conquer this disease in the past century. It’s a story of human ingenuity, resilience, and perseverance; it’s also a story of failures, deaths, misconceptions and human limits. This book is the winner of the Pulitzer Prize and named top book of 2010 by a dozen major news agency. Ken Burns subsequently made a 6-hour documentary based on this book.
Book highlights and my reflections
When I was young, cancer was such an alien term. It was one of those rare and horrifying diseases that you only see in the movies. In the past 10 years, things have changed significantly for my family. Colon cancer and lung cancer took my uncle and my great uncle’s life, within 6 months of the diagnose. Their deaths happened so suddenly and brutally that I didn’t even get a chance to understand the nature of their disease. Shortly after that, my dad’s two sisters got diagnosed with cancer and went through a long period of chemo (and are luckily now both in remission). A year ago, doctors found signs of early-stage cancer in my dad’s stomach during another operation. In the past decade, cancer hit our family like a tornado and completely changed the way I look at cancer. Data suggests that one in three women and one in two men will have cancer at some point in their lifetime. That means, every one of us will either get cancer or know someone intimately who will be diagnosed with cancer. Cancer will become the new normal of our life.
I started this book with a lot of questions about this disease. What is cancer? What causes cancer? Are we close to curing cancer? … This book answered some of those questions but left more open. Before I read this book, I hated and dreaded cancer, because it caused so much pain and suffering in my dad’s family. After reading this book, I am mind-blown by how cancer is so deeply intertwined with human evolution for the past tens of thousands of years. I am impressed by the elegance of cancer’s biological design. I am also in awe of the human ingenuity, resilience, and perseverance in our long battles against cancer.
I want to share some of the truths about cancer that I found fascinating.
- Civilization didn’t create cancer, it unveiled cancer
As of 2010, a quarter of all American deaths, and about 15 percent of all deaths worldwide will be attributed to cancer. This number has skyrocketed in the past 100 years — it almost seemed as if civilization caused cancer.
The link is correct, but the causality is not. Civilization did not cause cancer, but by extending human lives and curing other diseases, it unveiled cancer. More specifically, three factors explain this link:
- Cancer is an age-related disease. The mutations accumulated in our cells grow exponentially as we age, and hence the probability of cancer goes up exponentially as well. By extending human lives, we unveiled cancer
- The data is relative to other diseases. By drastically reducing deaths from infections, plaque, child labor, malaria, tuberculosis etc. we elevated the status of cancer compared to other deadly diseases.
- Civilization exposed us to more carcinogens such as smoking, air pollution, radiation etc.
2. Cancer is deeply intertwined with our basic biology — how cells grow and die
There is a “six degrees of separation from cancer rule”: You can ask any biological question, no matter how seemingly distant — what makes the heart fail, or why worms age — and you will end up, in fewer than 6 genetic steps, connecting with the fundamental genetic biology of cancer. The explanation behind this rule is that the two main types of genes in play in cancer biology happen to be essential for the growth and death of normal cells as well. They are the “on” and “off” switch for cells.
a) Proto-oncogene — the “on” switch. Proto-oncogenes help cells grow. When a proto-oncogene mutates (changes) or there are too many copies of it, it becomes a “bad” gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cells grow out of control, which can lead to cancer. This bad gene is called an oncogene.
b) Tumor suppressor gene — the “off” switch. Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process is known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.
That is also why cancer has been with us since the beginning of human beings and will probably always be with us until the end of human beings. It also explains the almost insurmountable challenge of cancer cure. How do you define therapies so targeted and specific that it controls the growth of cancer cells without killing normal cells as well?
3. The six hallmarks of cancer
Weinberg and Hanahan made an audacious attempt to summarize all types cancers: “we suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alternations in cell physiology that collectively dictate malignant growth”
a) Self-sufficient in growth signals (autonomous drive to proliferate — muted oncogenes)
b) Insensitivity to growth-inhibitory (antigrowth) signals (muted tumor suppressor genes)
c) Evasion of programmed cell death (apoptosis) (suppress/inactivate genes and pathways that normally enable cells to die)
d) Limitless replication potential
e) Sustained angiogenesis (cancer cells acquire the capacity to draw out their own supply of blood)
f) Tissue invasion and metastasis (spreading throughout the body)
4. Not all cancers are created equal
Cancer is not one single type of disease, but rather a family of diseases. The reason why they are all grouped under the family name “cancer” is that those diseases all involve abnormal cell growth that has the potential to invade or spread to other parts of the body (see the six hall-marks above). However, calling everything “cancer” is deceiving because the nature of the disease, the cause, the prevention, the treatment, the prognosis, the relapse rate, and the survival rate is drastically different from one cancer to another.
For example, local cancer and metastatic cancer are fundamentally two types of diseases with very different survival odds. Liquid (e.g., Leukemia) and solid cancer (e.g., lung cancer) vary in treatment. Some cancers are highly inheritable (for example, women with BRCA1 or BRCA2 gene mutations have a 60–70% chance of developing breast cancer in their lifetime); Some cancers are predominantly acquired (for example, lung cancer from smoking). Some cancers are almost curable (Children’s acute lymphoblastic leukemia has a 90–95% 5-year survival rate in North America); and some cancers are almost death sentence (pancreas cancer has lower than 10% 5-year survival rate and some form of brain cancer almost 0%)
We don’t fully know what makes certain types of cancer more metastatic or less responsive to therapies or more likely to relapse
5. The battle against cancer started more than 4000 years ago and is still ongoing today. We fought, and cancer fought back.
First appearance: The first appearance of cancer in human documentation is from 2500 BC by the great Egyptian physician Imhotep. He described a case of what we now think as “breast cancer” — “bulging mass in the breast”. Under the section titled “therapy”, he offered only a single sentence: “There is none,”
First treatment: The first documented treatment of cancer is from 500 BC. Atossa, the queen of Persia, self-prescribed the most primitive form of a mastectomy and ordered a Greek slave to cut off her breasts. She has since disappeared from historical documentation — we don’t know how long she lived after the treatment
Radical Mastectomy: Between 1800 and 1900, surgeons devised increasingly aggressive operations to attack the roots of cancer in the body (based on the wrong belief that cancer always originated locally and then spread to nearby body parts first) Halsted’s “radical mastectomy” — an operation that extirpate the breast, the muscles beneath the breast and the associated lymph nodes. This type of operations left tens of thousands of women disabled, bedridden, suffering from chronicle pain and reduced life quality. and even eventually die from the complications after surgery. Yet evidence suggests that such radical surgery did not necessarily increase the odds of survival, particularly for metastatic breast cancer.
Chemotherapy: The discovery of chemotherapy can be traced back to WWI. People accidentally discovered that the chemical weapon “nitrogen mustard” used by Germans drastically reduce white blood cells. Scientists thus started using nitrogen gas and folic acids to treat leukemia (one of the scientists is Sidney Farber, an iconic figure in cancer treatment). Although the effect of those chemicals lasted only a few weeks in the beginning, and patients had to return for another set of treatment, this was the first step to realizing that cancer could be treated by pharmacological agents
In the couple of decades after the first discovery of chemotherapy, scientists have been fanatically trying to find new drugs for different types of cancer, running thousands of clinical trials and pushing the human endurance to the extreme by introducing multi-drug therapies (known as chemo cocktail). The common belief then is to use as many chemo drugs and apply as long a period as possible, without physically killing the patient. This belief led to the discoveries of many effective chemo drugs for specific cancers, but also led to huge controversies on whether the radical chemotherapy result in better survival rates in the long-term
Prevention — finding carcinogens: As early as in the 18th century England, scientists have started linking cancer rates with occupations. They discovered that cancer rate has picked up significantly among children who work in factories, coal, and chimneys — the first mention of “carcinogens”. However, it was not until the second half of the 20th century did the public and politicians start to take the case of chemical carcinogens (e.g., smoke) seriously. And even then, with undeniable scientific research indicating the direct link between smoking population and increased rate of lung cancer, it still took scientists, doctors and advocates decades of efforts to fight against tobacco lobbyist to raise public awareness and push for policy changes. The battle against smoking is now won in the US and many developed countries — lung cancer rate has been dropping in the US, after a significant pick up a couple of decades ago. Yet tobacco companies have turned their attention to developing countries and many developing countries including India and China still have a significant young smoking population. The consequence of this shift will be evident in the subsequent years as lung cancer rate will surely pick up in those population.
In addition to chemical carcinogens, scientists have also discovered many viral carcinogens that cause cancer. The most notable of those are HPV virus, which causes 5% of total diagnosed cancers worldwide and nearly all cases of cervical cancer.
In all those cases of chemical and viral carcinogens, awareness and prevention are the best cure.
Targeted cancer therapy: The challenge (and hope) of cancer therapy has always been finding a targeted and specific treatment that suppresses the growth of cancer cells but not normal cells. Recent development in gene mapping (and immunotherapy) has opened a new door for cancer therapy. If we can find a specific gene mutation that’s highly correlated with a certain type of cancer, then there’s hope to develop targeted treatments. One great success story is Herceptin. Herceptin works by tagging a specific gene “Her-2” (the way we “tag” a gene is by developing an antibody that specifically binds with the genetic sequence of that mutated gene) and using our immune system to destroy cancer cells. “Herceptin” is the perfect “specific and targeted” therapy for “Her-2” positive cancer patients. However, we know so little about cancer genome today that only very limited types of cancers have effectively targeted immunotherapy
6. The Cancer Genome Atlas — hopes for the future
The human endeavors to cure cancer with gene therapy so far has been largely trial and error. We don’t have a map — a comprehensive understanding of the cancer genome; neither do we have an effective tool — an easy way to delete, replace and edit mutated genes.
However, two recent efforts are bringing hopes for both:
In 2005, NCI (National Cancer Institute) launched a massive project “The Cancer Genome Atlas”, a compendium of every gene mutated in the most common forms of cancer. This effort could ultimately prove to be the equivalent of more than 10,000 Human Genome Projects in terms of the sheer volume of DNA to be sequenced. By sequencing the entire genome of several tumor types, every single mutated gene will be identified — it will mark the beginning of the comprehensive “map” of cancer
The discovery of CRISPR-Cas9 gene editing technology also completely revolutionized the tools we have at hand. I will go into more details about CRISPR in the next two posts (I am reading a book on CRISPR now). But in a nutshell, it is a much faster, cheaper, more accurate, and more efficient genome editing method than other existing ones.
With the development of new “map” — Cancer Genome Atlas and new advanced tools — CRISPR, there’s excitement and hope that we will be able to dig our way out of the dark land of cancer in the years to come.