p53: The gene that cracked the cancer code - a review

I wouldn't think that an entire popular science book could be written about one protein, unless that protein is p53. As of this writing, a PubMed search reveals 82,179 scholarly articles about p53. Thus, p53 The Gene That Cracked the Cancer Code by Sue Armstrong has an abundance of source material. Even with the all that information to cover, the author does an excellent job explaining the relevant research in a clear and concise way, using a chronological structure with the main source being interviews with the scientists that did the original research. Unlike many popular science books, Armstrong relies more on the direct quotes from the primary source, ensuring that she gets everything right.

Briefly, p53 (named because the protein is about 53 kilodaltons on a protein gel–a naming convention that swept through some circles of scientific research, but has since been eclipsed by more colorful naming styles) was discovered in 1979. While David Lane is typically credited first, Arnold Levine, Lloyd Old, and Pierre May also deserve acknowledgement for the discovery. Considered to be a tumor suppressor, p53 has cellular roles in genome stability, DNA repair, apoptosis/cell death, and cell metabolism. This book primarily focuses on p53's role as the "guardian of the genome", a term penned to describe that ability of p53 to keep the cell's DNA free of mutations. This role is the primary connection of p53 to cancer: normally, p53 induces cellular suicide (apoptosis/cell death) in cells with DNA damage. p53 is the most commonly mutated gene in cancer and when p53 is mutated, it loses its ability to protect from DNA damage, which can lead to excessive cell growth, a hallmark of tumorigenesis.

Like so many of the books on cancer that I have covered before, this book hit many of the key topics in the area of cancer research. What is unique about this book is that it leads the reader through the sometimes winding roads of scientific research. This includes an in-depth discussion of the p53 mutation database, which collects all the mutations in p53 that have been linked to a variety of cancers. This database has been a rich source of information for researchers over the years. For example, in 1996 researchers showed that lung cancer cases showed p53 mutations in a particular hotspot on the p53 gene. Interestingly, these same mutations were shown by the Pfeifer lab to be induced by the carcinogenic substance in cigarette smoke, benzopyrene diol epoxide (BPDE). This publication was a major win for the 1998 class action lawsuit against Big Tobacco.

Map of p53 mutations and their frequency.

The p53 database has also helped reveal the link between liver cancer, Hepatitis B, and aflatoxin, a poison produced by a fungus that grows on peanuts and other grains when they are stored without adequate ventilation. Typically, HepB causes liver cancer only after many years. However, in places like Asia and Africa, the risk is compounded by the exposure to aflatoxin, a carcinogen known to cause DNA damage. Aflatoxin can induce a mutation in p53 (at codon 2449), which can essentially turn p53 from a tumor suppressor into an oncogene.

The book delves into several of the most damaging p53 mutations. For example, Li-Frameni syndrome (LFS) is a genetic disordered characterized by the early and frequent acquisition of cancer at "every conceivable site in the body". The disease was first described in the early 1980s, but the connection to p53 was not established until the 1990s. A variety of mutations in p53 have been associated with LFS, but the most common hotspot connected to LFS is involved in p53's ability to bind to DNA.

Perhaps the most interesting story in the book describes the cancer clusters in Brazil. Sue Armstrong contributed the story of "Brazil's Cancer Curse" to Mosaic Science; it is a fascinating story and gives a great sense of her writing style. As discussed in the book Toms River, cancer clusters are typically assumed to be caused by a pollutant. Likewise, the Brazilian doctors wondered if that might be the case. However, the research about LFS was starting to garner attention, leading Brazilian clinicians to suspect p53 was also be responsible in the Brazilian cancer cluster. Indeed, sequencing of the p53 gene in affected individuals reveals a mutation at codon 337 to be the most common. Where the story gets really interesting is when scientists attempt to understand how an uncommon mutation fixed in the population at such high frequency. While the source is still debatable, the p53 mutation is now thought to be the result of a founder effect and bottleneck (as described for BRCA mutations in The Wandering Gene).

p53 structure (Wikipedia)

I think I learned the most in the section about the clinical approaches to treating p53 mutations. Here, Armstrong has done a deep dive into the literature about the latest drugs and trials connected to p53 function and dysfunction. Thus, the book is up to date on the available p53-related drugs (as of its publication in November 2014). Armstrong describes several different approaches to treating p53-related cancers, including drugs like Advexin, which uses a viral vector to induce cells to express wild type p53. For reasons that are unclear, Advexin has had mixed success in the US and is still awaiting FDA approval. Perhaps more interesting, is the research on PRIMA-1 (an acronym for p53 re-activation and induction of mass apoptosis), a drug designed to work on mutants of p53 that no longer bind DNA. Essentially, PRIMA-1 induces mutant p53 into its wild type shape, allowing it to re-activate and bind DNA. Thus, PRIMA-1 should target a wide range of p53 conformation mutants and leave wild type p53 alone. Both of these have been major roadblocks in the deisng of previous p53 therapies, especially since p53 is at the center of so many regulatory pathways. The drug is currently in Phase 2 trials. (Here, Armstrong takes a tangent into the history of chemotherapy, specifically its connection to the German use of mustard gas in WWII. This was a fascinating story that I recommend reading more about, for example here or here.) 

Sue Armstrong's p53 book distills a large amount of scientific literature into an interesting and readable book. I don't think I would recommend this as the first book to read if you are just starting to learn about cancer research. To me, the best starting place would be The Philadelphia Chromosome (some might recommend Mukherjee's The Emperor of All Maladies). However, this is an excellent book for those familiar with cancer and looking for the next level of science writing on the topic.

Toms River by Dan Fagin - New Jersey, Superfund, and cancer clusters

Toms River, once a quintessential Jersey shore town, is the focus of Dan Fagin's Pulitzer prize-winning book Toms Rivers: A Story of Science and Salvation. When Toms River welcomed the Swiss chemical company Ciba-Geigy (now known as Novartis) in 1952, they did not know that the company had left towns in both Switzerland and Ohio due to complaints about air and water pollution. The Swiss company owned and operated the Toms River Chemical Corporation for over 30 years without incident even though it was treating the local rivers and oceans as a dumping ground for its chemical waste. In the name of job creation and economic development, the people of Toms River turned a blind eye. (Of course, this is still the case. In places with a weak economy, job creation means absolution for any environmental sin.)

Toms River Chemical Corporation expanded rapidly, building a fortress-like factory isolated from the town by acres of forest. To the executives of Ciba-Geigy, the lesson from Basel and Cincinnati was that they should keep their waste practices hidden from residents to operate with impunity. Treating their toxic waste to even minimal standards would cut into the bottom line. The company had standing, unlined pools where untreated waste would be dumped year after year; the sandy soil of the Jersey shore readily absorbed the waste, giving the company the unforeseen benefit of disappearing waste. Unfortunately for the people of Toms River, those toxic chemicals didn't really disappear, especially from the water table. Complaints about the water supply tasting and smelling like chemicals precipitated the 1965 development of a pipeline to dump untreated wastes offshore. Even though this toxic waste pipeline ran through their backyards, the people of Toms River had seemingly no idea that it was present. At least not until a leak in the pipeline created a sinkhole on a city street in 1984. A company spokesman said that the effluent was simply salt and water, but the chemicals in the waste were likely the cause of the leak. Moreover, tests performed by independent agencies suggested that this "salt water" was highly mutagenic and not safe for sea life.

This toxic sink hole was a major turning point for the opposition to the chemical company in Toms River. The people of Toms River no longer felt safe with the waste practices of their neighbor, and they began to demand change. Around the same time, the story of Love Canal**, a town near Niagara Falls that was built on the site of a former chemical plant, had gained national attention. Love Canal residents were experiencing a variety of health problems, including asthma, miscarriages, and cancer. In 1980, the US government started CERCLA, more commonly known as Superfund. New Jersey had the most sites of any state in the US; two sites were in Toms River. One, Reich's Farm, was used as a dumping site by several local chemical companies, who paid a local entrepreneur $3.50 per drum to dispose of toxic waste. The companies included Ciba-Geigy and Union Carbide (whom you may remember from the Bhopal Disaster in India; UC is now part of Dow Chemical). The other site was the Toms River Chemical Corporation grounds.

The Superfund status meant that Ciba-Geigy would have to pay to clean up the hazardous waste on its factory grounds. In addition, the increasing pressure from residents helped ensure that the company would also have to treat their new chemical waste properly. These changes meant that doing business in Toms River was less profitable for Ciba. Predictably, the company started to decrease the size of the plant, eventually transferring their dye-making operations to Southeast Asia. (This move was purportedly to be closer to the textile industries there; the lower wages and relaxed environmental standards didn't hurt either.) However, even after the company left Toms River, the town's trouble wasn't over.

Fagin intercalates the history of Toms River with the scientific developments in environmental toxicology and cancer epidemiology. The author describes how the initial links between illness and chemical contaminants were made based on the observation that certain types of workers were more likely to have particular diseases. For example, chimney sweeps, who often cleaned chimneys naked, were more likely to get scrotal cancer, while dye workers, who were exposed to chemicals like those used in the plant in Toms River, were more likely to get bladder cancer. The first direct evidence that chemicals cause cancer came when rabbits whose ears were painted with coal tar (the starting ingredient in dye manufacturing) developed tumors (Yamagiwa and Itchikawa, 1915).

In Toms River, many chemical company workers developed cancer. It also seemed that the entire town experienced an increase incidence of cancer, particularly childhood blood and brain cancers. Such cancer clusters are difficult to study because the number of cases is not high enough to be statistically significant and because confounding factors (e.g., smoking, diet) were more likely to be the cause of the cancers. Perhaps most importantly, cancer is a complex disease, which could be considered a collection of diseases (blood cancers are different than solid tumors, which are different at each affected site). The causes of cancer are also complicated; for example, the Knudson hypothesis posits that multiple hits are necessary to cause cancer. A person might start with a genetic susceptibility (as I discussed in the case of BRCA mutations) or a viral infection (as was the situation for Henrietta Lacks) and then be exposed to pollution or some other mutagen, which would then lead to cancer. Thus, even if an entire town is exposed to the same chemical, they will experience the effects differently due to subtle genetic and environmental differences.

The later chapters detail how the cancer cluster was proven to be statistically significant (at least in some populations) and how the likely source of the cancer was identified. A case from a Superfund site in Massachusetts (which later became the basis for the book and movie A Civil Action) showed a definitive link between water pollution and a cancer cluster; this was a landmark outcome in epidemiology. In the case of Toms River, the connections were somehwat more tenuous. In 2001, the affected families received a combined $35 million settlement from Dow and Novartis (nee Ciba-Geigy). Interestingly, Novartis made headlines later that year for its development of the revolutionary drug Gleevec (discussed in my previous post about The Philadelphia Chromosome). The name change coincided with the company's move into pharmaceuticals, but was also a way to distance itself from its toxic past.

Throughout the book, Fagin's journalistic writing style is useful for the subject matter. The story can be deeply frustrating at times due to the mistakes made by Ciba-Geigy as well as at the lack of oversight and the absence of repercussions for the company. Fagin chooses to focus on the "good guys", the people who helped identify the cancer cluster and those who fought to fix the problem. Today, the people of Toms River are safer, and cancer incidence has decreased since the cleanup. However, people living close to where Dow and other chemical giants are currently operating are also experiencing cancer clusters. Despite this grim information, Fagin ends hopefully, discussing how the new developments in molecular epidemiology could improve the ability to link a disease with a pollutant. 

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** For additional information see this excellent video of the history of Love Canal with updates