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Smoke Screens: Searching for the Causes of Lung Cancer

January 31, 2014 | Matthew Tontonoz

Fifty years ago this month, the U.S. Surgeon General released his now-famous report classifying smoking as a cause of lung cancer. A landmark in the field of public health, the report brought the full weight of the nation’s highest medical office to the burning question of the day. Its conclusions “hit the country like a bombshell,” in Surgeon General Luther Terry’s words. Yet the report was less a product of groundbreaking new science than the capstone on a body of research stretching back decades.

In fact, the history of scientists’ efforts to understand what causes lung cancer is in large part the history of our modern understanding of cancer. A look back at the major players in the field offers a revealing glimpse into why cancer treatment took the shape that it did, and why our knowledge of tobacco's dangers was so long in the making.

Alarming Trends

In the early decades of the 20th century, people on both sides of the Atlantic began to be concerned by the steep rise in the incidence of lung cancer. Health statistics showed that there were only 140 known cases of lung cancer worldwide before 1900; by 1935, there were 5,049 cases. The incidence rate had tripled. Numerous factors were proposed to explain the rise, among them air pollution from industry and automobile exhaust, use of x-rays, lung damage caused by the 1918 “Spanish Flu,” and tobacco use. Of these, air pollution seemed to many to be the most likely cause.

“If I had had to put money on anything at the time, I should have put it on motor exhausts or possibly the tarring of roads,” recalled the British epidemiologist Richard Doll later in life. “The whole road system in the country had changed with the advent of the motor car, and we knew that the tar that was put on roads contained many carcinogens.”

By contrast, tobacco seemed a less likely cause. After all, tobacco was a “natural” product, commonly smoked by many Americans at the time, including a majority of physicians.

Air pollution was seen as a more likely culprit for several reasons. A long history of scientific work suggested that coal tar was carcinogenic—able to produce cancer. In 1775, an English physician named Percivall Pott noticed a strange correlation between being diagnosed with scrotal cancer and having previously worked as a chimney sweep. Chimney sweeps were often young boys whose small size allowed them to shimmy up chimneys, exposing them to coal tar. Pott’s observation inspired another doctor, more than a hundred years later, to test the relationship between coal tar and cancer. In 1916, Katsusaburo Yamagiwa, a Japanese researcher, succeeded in experimentally producing cancers in rabbits by painting their ears with coal tar. A few years later, in 1925, researchers in England isolated several chemical compounds in coal tar that were carcinogenic. The compounds were all ring-shaped molecules called polycyclic aromatic hydrocarbons (PAHs).

The discovery of discrete cancer-causing chemicals was a major breakthrough in cancer research. Not only did it open up a new theoretical framework for thinking about cancer, it also allowed researchers to create cancer in the laboratory, so that it could be studied. Many of the established tumor cell lines, including some still in use today, were created by treating laboratory animals with various carcinogens found in coal tar and petroleum products. It is from these tumor cell lines that we have gained most of our contemporary knowledge of cancer.  

From Carcinogens to Chemotherapy

The person most responsible for pursuing the chemistry of cancer was Dr. Murray J. Shear, a biochemist with the Office of Cancer Investigations at the U.S. Public Service, then affiliated with Harvard Medical School in Boston. Shear’s lab performed detailed studies of chemical carcinogenesis from about 1931 to 1937, when the lab merged with another to form the National Cancer Institute (NCI), and Shear moved to Bethesda, MD.

From an early interest in chemicals that cause cancer, Shear broadened his scope to include a search for those that might cure it. He was inspired in this search by the work of Dr. William Coley, considered to be the “Father of Cancer Immunotherapy.” In the late 1930s, not long after Coley’s death, Shear set out to isolate the chemical factor in Coley’s toxins that had produced such potent anti-cancer effects. Shear believed that if he could isolate and purify the chemical, he would be able to obtain more consistent and reproducible results than Coley himself did. In 1943, Shear succeeded in isolating a chemical factor that fit the bill. It was a type of sugar he called lipopolysaccharide, or LPS.

LPS (also known as endotoxin) was a seemingly miracle substance: when injected into mice with tumors, it caused the tumors to shrivel up and die. Shear hoped that LPS might be used therapeutically to treat patients with cancer. Naturally, many others did as well.

William Laurence, a science reporter for the New York Times wrote in July 1944: “This, of course, marks a great step forward in the search for chemical agents to destroy cancer. It is the first pure chemical so far found that seems to have a specific highly destructive effect on cancers in animals.”

Despite initial high hopes, LPS ultimately proved too toxic to be used as a form of treatment. Side effects were severe. Nonetheless, the discovery inspired a methodical search for other chemical compounds that might have anti-cancer effects. Shear’s approach of testing compounds in mouse tumor lines became the model for other large-scale drug screening efforts that eventually took root at Sloan-Kettering Institute, the NCI, and other institutions in the 1950s. It was through such massive drug screening programs that many of our most commonly used chemotherapy drugs were identified, including 6-mercaptopurine (6-MP), the nitrogen mustards, and paclitaxel (Taxol). For that reason, Shear is known today as the “Father of Chemotherapy.” (It is, of course, an irony that Shear’s work on Coley’s toxins proved to be the beginning of chemotherapy rather than immunotherapy.)

Tobacco and Cancer: Fast Facts

  • Cigarette smoke contains more than 60 known carcinogens, including radioactive polonium.

  • 80%-90% of all lung cancers are caused by smoking.

  • Lung cancer is the leading cause of cancer-related deaths in men and women worldwide.

  • Lung cancer killed 160,000 Americans last year, and 10 times that globally.

  • Roughly 100 million people in the 20th century died from tobacco use.

Smoking Gun

Throughout the 1940s, cancer researchers continued to search for the factors behind the rise in lung cancer. While working at the NCI, Shear and colleagues performed an experiment in which they collected soot from a variety of sources, including air from the Holland Tunnel in New York and air vents in Chelsea, MA, and Pittsburgh, PA, and injected it into mice, finding that it was able to produce skin cancers. (Pittsburgh soot was reportedly the most carcinogenic.)

By 1950, however, epidemiological studies had strongly implicated tobacco smoke as the probable cause of the steep rise in lung cancer. Numerous groups in both England and the U.S. found a strong statistical correlation between having been a heavy smoker and developing lung cancer; the longer the length of time a person smoked, the higher was his chance of developing cancer.

A few years later, in 1953, scientists were able to show in the lab what the epidemiology strongly suggested: cigarette tar is able to produce cancer in laboratory animals. Taking previous researchers’ earlier work with coal tar as a cue, Ernest Wynder, Evarts Graham, and colleagues began painting the skin of mice with cigarette tar. As they reported in the journal Cancer Research, 44% of mice painted with tobacco tar on their backs eventually developed skin cancer.

In retrospect, this work should have clinched the case for tobacco as a cause of lung cancer. As Charles Cameron, medical director of the American Cancer Society, noted in 1956, “If the degree of association which has been established between cancer of the lung and smoking were shown to exist between cancer of the lung, and say, eating spinach, no one would raise a hand against the proscription of spinach from the national diet.” But it was at this time the tobacco industry launched its calculated strategy to intentionally cast doubt on the findings of medical science, effectively creating “controversy” where really there was none.

“Doubt Is Our Product”

Wynder’s damaging report from 1953 lit a fire under tobacco industry executives, who met in secret that year at the Plaza Hotel in New York City to contrive their response. There, behind closed doors, they hatched the plan that would set medical science back decades and cost millions of lives. It was at this meeting that the heads of leading tobacco companies agreed to pursue a policy of casting doubt on the validity of scientific findings linking tobacco and cancer and maintaining that the link was “not proven.” As a tobacco executive from Brown & Williamson admitted bluntly in 1969, “doubt is our product.”

The centerpiece of the tobacco industry’s PR strategy was an institute it created to fund scientific research. The supposed aim of the Tobacco Industry Research Committee (TIRC) was to collect evidence pertaining to the question of whether tobacco was a cause of cancer. Tobacco company executives took out a full page ad in newspapers around the country to announce the creation of this body. But as historians such as Robert Proctor and Allan Brandt have shown, the TIRC was more about PR than anything else. Run out of the offices of the PR firm Hill & Knowlton, the TIRC funded “safe” research projects that could be counted on to avoid the topic of tobacco and cancer. The purpose of such research was, in Robert Proctor’s words, “to look in such a way as not to find.”

Ironically, the person chosen to head the TIRC was C. C. Little, a well-known geneticist and also a Coley Award winner, who as a young scientist had established the purebred mouse strains on which practically all existing cancer work had been done (including Wynder’s famous 1953 experiment). Little had begun his career interested in the genetic basis for cancer. He helped establish, in 1929, the Roscoe B. Jackson Memorial Laboratory at Bar Harbour, ME, which became a central clearing house for purebred strains of mice, and to this day supplies millions of designer mice for laboratory research to scientists all over the world.

Little was an appropriate choice to lead the TIRC, since his genetic bias led him to de-emphasize environmental causes of cancer. He also seemed to enjoy stoking controversy. In a 1956 editorial published in Cancer Research, Little stuck to his guns about the tobacco-cancer link being “not proven.” Evarts Graham, in an editorial retort, chided Little’s obstinacy, noting that the evidence for a causal relationship between cigarette smoking and lung cancer was “stronger than that for the efficacy of vaccination against smallpox,” which was, after all, “only statistical.”

It was to put an end to this phony controversy that Surgeon General Luther Terry decided to convene a committee in 1962 to review the problem. The eventual report reflected the conclusions of 10 scientists, all experts in their respective medical and scientific fields, who were chosen to critically evaluate all the existing evidence on the subject of tobacco and cancer—some 7,000 publications. Their conclusion, reached after more than 12 months of consideration, was definitive: smoking is a cause of lung cancer.

Since the 1964 report was released—on a Saturday, to avoid upsetting the stock market and to have maximum publicity in the Sunday papers—rates of smoking have steadily declined. In 1965, Congress required warning labels to be printed on cigarette packages, and in 1970 the label was updated to read, “Warning: The Surgeon General Has Determined that Cigarette Smoking Is Dangerous to Your Health.” After a steady 60-year increase, the incidence of lung cancer finally began to drop in the 1990s.

That’s the good news. The bad news is that 20% of Americans still smoke. Even more shocking, rates of cigarette smoking in developing countries—China especially—are rising fast.

Increasingly, e-cigarettes are touted as a safer option for smokers, but the jury is still out on just how healthy such a “nicotine delivery device” is. While not itself a carcinogen, nicotine is highly addictive, and comes with dangers of its own in high quantities. The tobacco industry, it seems, will do just about anything to keep us hooked.   

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