Earlier this week, I posted a blog criticizing the conclusions reached in a highly publicized paper written by a group of scientists at Johns Hopkins Medical Center. The authors conclude that "bad luck", rather than environmental or genetic causes, is responsible for the bulk of human cancers. My prior blog post explained why Hopkins is wrong.
After the blog was written, I received some very interesting feedback from a LinkedIn group (Science writers), much of which centered on the different ways that people use the words "luck" and "cause". Though mathematicians will despair, the word "good luck" is routinely applied to just about anything that has desirable outcome. So if a high school student gets a perfect score on the SAT exam, he or she was very very lucky. If you would interject to say that luck had nothing to do with it ("It was all due to student's high intelligence!"), you would be informed that the intelligence was a matter of luck, being as the student had done nothing to earn his or her intelligence. If you were to suggest that the "cause" of the high score was hard work, you would be told that "hard work" was just one of many conditions that led to the high score (e.g., "lucky" intelligence, a good night's sleep the night before, growing up in a stable living environment where current events, history and literature are discussed). There being many different "causes," it wouldn't make much sense to think in terms of any specific cause, and you might as well chalk it up to just plain good luck.
Getting back to biology and disease, consider these hypotheticals:
If you have 5 people living with an Ebola patient, and three of the five come down with the disease, would you say that these three came down with Ebola because they were "unlucky"? Or would you say that these three came down with Ebola because they were infected with the virus [and the other two were not]?
Would you say that the Ebola virus caused the infection in these three individuals? Or would you say that many factors, such as "luck", the environment, low innate viral resistance, poor nutrition, all set the stage for their infections, and that the Ebola virus was just one of many ingredients in the brew?
There's a real danger with using "luck" to describe events that we do not understand or cannot predict. Likewise, causation can be deceptive when dealing with a multi-step process that plays out over years or decades (like cancer).
When I think about "cause" I'm usually applying the "but-for" criteria ("but-for" this, that would not have happened). So, for me, Ebola virus causes Ebola hemorrhagic fever, and infections are not a matter of luck. Likewise, for me, there are "but-for" causes of cancer (e.g., chemicals, viruses, predisposing genes), and many important modifying factors that probably don't rise to the level of "but-for" causes (e.g., cell proliferation, DNA repair, genomic and epigenomic influences, regression-causing events, immune status); and cancer is not caused by bad luck.
Today, cancer has become the quintessential "bad luck" disease. In a prior blog, I described examples of "bad luck" cancers that transformed into "specific cause" cancers, when we studied the data. My personal opinion is that most cases of cancer are associated with known "but-for" causes. As we learn more and more about the different types of cancers, particularly the huge variety of rare cancers, we continue to find specific causes for specific cancers. I just assume, perhaps incorrectly, that every cancer has a cause.
I urge everyone reading this blog to also read my prior blog, which provides a full rebuttal to the Johns Hopkins "bad luck" cancer hypothesis.
- Jules Berman
tags: johns hopkins, press release, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell renewal, probabilistic models, data modeling, randomness, chance, misfortune, accident, unpredictable, causation, causative role, but-for, but for, sine qua non
Showing posts with label rare cancer. Show all posts
Showing posts with label rare cancer. Show all posts
Friday, January 9, 2015
Monday, January 5, 2015
Human diseases are not caused by bad luck
Earlier this week, I posted a blog criticizing the conclusions reached in a highly publicized paper written by a group of scientists at Johns Hopkins Medical Center. The authors conclude that "bad luck", rather than environmental or genetic causes, is responsible for the bulk of human cancers. My prior blog post explained why Hopkins is wrong.
After the blog was written, I got some very interesting feedback from a LinkedIn group (Science writers). Much of the discussion centered on the meaning of "luck", as it applies to biological processes.
Terms such as "luck", "accident", "misfortune", and "unpredictable" are often used, inappropriately, to describe complex events that we do not fully understand. For example, we speak in terms of "motor vehicle accidents" to describe vehicular crashes, even when we have discovered non-accidental causes (e.g., driving while intoxicated, driving on the wrong side of the road, failure to yield). We use the term "cerebrovascular accident" to describe strokes, even in individuals who have abundant risk factors (e.g., high blood pressure, e.g., occluded carotid artery). When we come down with a cold, we often say that it was our bad luck or our misfortune to get sick, even when we know that the cold was caused by a virus.
When we flip a coin, we like to think that the outcome occurs randomly, because there is a 50% chance of heads or of tails. But we all know, at some level, that the outcome of the toss is predetermined at the moment that the coin flips into the air. The laws of physics come into play, with a complexity that defies human prediction. Coin tosses, and roulette spins, are examples of processes that can be modeled, mathematically and intuitively, as probabilistic events. But we shouldn't confuse a probabilistic model with a physical reality.
Biology and medicine are replete with examples of phenomena that were attributed to "bad luck" until we finally determined their causes. For example, until the dawn of the twentieth century, the cause of malaria was unknown. There must have been something in the air (mala aria = bad air in medieval Italian). In 1880, Laveran identified the causative agent, a protozoan, in the blood of affected patients, for which he was awarded the Nobel prize in 1907. Through the centuries, people suffering from infectious diseases, vitamin deficiencies, and environmental toxins were considered "unfortunate", meaning "without luck."
Do not presume that modern-day scientists are too enlightened to be taken in by "chance" phenomenon. For many years, medical scientists sought a cause for sudden infant death syndrome (SIDS). Children were dying in their cribs, unpredictably, as though they had the bad luck to just stop breathing. In the past half century, we have learned that the majority of cases of SIDS are associated with sleeping conditions that limit the infants ability to breathe (e.g., sleeping on stomach, in hot room, with overabundance of soft bedding, etc.).
Today, cancer has become the quintessential "bad luck" disease. The literature gives us lots of examples of "bad luck" cancers that transformed into "specific cause" cancers, when we studied the data.
For example, In a landmark paper published in 1971 by Herbst and coworkers, the authors found an increase in the number of young women who developed an extremely rare cancer: clear cell adenocarcinoma of the cervix or of the vagina. The mothers of these young women had ingested a nonsteroidal synthetic estrogen (diethylsilbestrol, DES) during their pregnancies. In utero exposure to the drug caused a specific rare tumor to occur in the daughters. The offspring were classic "bad luck" cancer victims, having done nothing to put themselves at risk. Herbst had to go back a generation to find the real cause.
Women who developed mesotheliomas, a very rare cancer, in the 1970s and 1980s, were also the victims of "bad luck", until cancer epidemiologists found the common factor that linked these cases. These women had washed the asbestos-laden clothes of their fathers or husbands, who worked in the shipyards during World War II. Their brief exposure to asbestos resulted in mesotheliomas 20+ years later.
Much of what we observe in biology and medicine looks exactly like luck... until we understand the cause. The effect of "bad luck" hypotheses, as they apply to biology and medicine, is to halt scientific progress. Why would scientists waste their time looking for the causes of cancer, if cancers are caused by "bad luck"? The U.S. Environmental Protection Agency certainly can't protect us from bad luck!
I urge everyone reading this blog to also read my prior blog, which provides a rebuttal to the Johns Hopkins "bad luck" cancer hypothesis.
- Jules Berman
tags: johns hopkins, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell renewal, probabilistic models, data modeling, randomness, chance, misfortune, accident, unpredictable
After the blog was written, I got some very interesting feedback from a LinkedIn group (Science writers). Much of the discussion centered on the meaning of "luck", as it applies to biological processes.
Terms such as "luck", "accident", "misfortune", and "unpredictable" are often used, inappropriately, to describe complex events that we do not fully understand. For example, we speak in terms of "motor vehicle accidents" to describe vehicular crashes, even when we have discovered non-accidental causes (e.g., driving while intoxicated, driving on the wrong side of the road, failure to yield). We use the term "cerebrovascular accident" to describe strokes, even in individuals who have abundant risk factors (e.g., high blood pressure, e.g., occluded carotid artery). When we come down with a cold, we often say that it was our bad luck or our misfortune to get sick, even when we know that the cold was caused by a virus.
When we flip a coin, we like to think that the outcome occurs randomly, because there is a 50% chance of heads or of tails. But we all know, at some level, that the outcome of the toss is predetermined at the moment that the coin flips into the air. The laws of physics come into play, with a complexity that defies human prediction. Coin tosses, and roulette spins, are examples of processes that can be modeled, mathematically and intuitively, as probabilistic events. But we shouldn't confuse a probabilistic model with a physical reality.
Biology and medicine are replete with examples of phenomena that were attributed to "bad luck" until we finally determined their causes. For example, until the dawn of the twentieth century, the cause of malaria was unknown. There must have been something in the air (mala aria = bad air in medieval Italian). In 1880, Laveran identified the causative agent, a protozoan, in the blood of affected patients, for which he was awarded the Nobel prize in 1907. Through the centuries, people suffering from infectious diseases, vitamin deficiencies, and environmental toxins were considered "unfortunate", meaning "without luck."
Do not presume that modern-day scientists are too enlightened to be taken in by "chance" phenomenon. For many years, medical scientists sought a cause for sudden infant death syndrome (SIDS). Children were dying in their cribs, unpredictably, as though they had the bad luck to just stop breathing. In the past half century, we have learned that the majority of cases of SIDS are associated with sleeping conditions that limit the infants ability to breathe (e.g., sleeping on stomach, in hot room, with overabundance of soft bedding, etc.).
Today, cancer has become the quintessential "bad luck" disease. The literature gives us lots of examples of "bad luck" cancers that transformed into "specific cause" cancers, when we studied the data.
For example, In a landmark paper published in 1971 by Herbst and coworkers, the authors found an increase in the number of young women who developed an extremely rare cancer: clear cell adenocarcinoma of the cervix or of the vagina. The mothers of these young women had ingested a nonsteroidal synthetic estrogen (diethylsilbestrol, DES) during their pregnancies. In utero exposure to the drug caused a specific rare tumor to occur in the daughters. The offspring were classic "bad luck" cancer victims, having done nothing to put themselves at risk. Herbst had to go back a generation to find the real cause.
Women who developed mesotheliomas, a very rare cancer, in the 1970s and 1980s, were also the victims of "bad luck", until cancer epidemiologists found the common factor that linked these cases. These women had washed the asbestos-laden clothes of their fathers or husbands, who worked in the shipyards during World War II. Their brief exposure to asbestos resulted in mesotheliomas 20+ years later.
Much of what we observe in biology and medicine looks exactly like luck... until we understand the cause. The effect of "bad luck" hypotheses, as they apply to biology and medicine, is to halt scientific progress. Why would scientists waste their time looking for the causes of cancer, if cancers are caused by "bad luck"? The U.S. Environmental Protection Agency certainly can't protect us from bad luck!
I urge everyone reading this blog to also read my prior blog, which provides a rebuttal to the Johns Hopkins "bad luck" cancer hypothesis.
- Jules Berman
tags: johns hopkins, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell renewal, probabilistic models, data modeling, randomness, chance, misfortune, accident, unpredictable
Friday, January 2, 2015
Hopkins is wrong. Role of bad luck in cancer not shown!
Amidst much fanfare, Johns Hopkins issued a news release, dated Jan. 1, 2015, under the banner, “Bad Luck of Random Mutations Plays Predominant Role in Cancer, Study Shows" The subtitle to the banner is, "Statistical modeling links cancer risk with number of stem cell divisions.”
Whoever wrote the Hopkins news report doesn't seem to understand that the subtitle contradicts the title. The title implies that the authors have proven an assertion (i.e., that bad luck causes cancer). The subtitle indicates that they have only established an association (i.e., there is a statistical link between cancer incidence and random mutations occurring as stem cells divide). It seems like a quibble, but there is an immense conceptual gulf between a "link" and a "cause". It's easy to find a correlation, but it's hard to prove a causal role. In many cases, correlations simply disappear when the original data is reanalyzed with different analytic methods, or when some of the original assumptions are changed, or when new data is obtained, or when information from some other study provides better results that support an opposing hypothesis.
The Hopkins researchers reviewed the literature to find, "the cumulative total number of divisions of stem cells among 31 tissue types during an average individual’s lifetime." These numbers for the different tissues, correlated closely with the risk of cancer occurring in those tissues. Having arrived at the correlation, "using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent." Of the 31 tissues they studied, the tumor incidence in 9 of the tissues did not fit their "bad luck" correlation. Tumor incidence in these tissues, according to the news report, must come from some other source, such as environmental carcinogens. The 22 tissues that fit their model were deemed the "bad luck" tumors.
The bad luck hypothesis is not new. Cancer researchers have been trying to titrate the various suspected causes of cancer for decades. In the 1970s, when there was a large push to find chemicals in the environment that cause cancer, it was widely accepted that about 85% of cancers were caused by environment agents; 15% were caused by other things, such as genes, and this last 15% would also include "bad luck" mutations. These numbers were based on statistical inferences from data on the geographic variations in cancer incidence, looking at how the types of cancers occurring in populations changed in different locations on earth and in response to identified carcinogens.
Back in the early '70s, there was an awareness of the special place of "rare cancers" in the discussion. The common cancers (i.e., skin, lung, colon), were all presumed to be caused by environmental toxins (e.g., UV light, cigarettes, food and water contaminants, chronic infections, etc). More than 90% of the burden of cancer in the U.S. is accounted for by just a handful of cancer types (namely, basal cell carcinoma of skin, squamous cell carcinoma of skin, bronchogenic lung cancer, adenocarcinoma of colon, adenocarcinoma of breast, adenocarcinoma of prostate, adenocarcinoma of pancreas, ovarian carcinoma, esophageal cancer, and maybe one or two others). There are over 6,000 different kinds of cancer. All but a half dozen or so of these 6,000 varieties of cancer are rare, accounting in the aggregate for fewer than 10% of the tumors occurring in humans. Many of the rare cancers have well-studied patterns of inheritance. Because there are so many known inherited rare cancers, we tend to assume (perhaps incorrectly) that the bulk of rare cancers are caused by inherited genes (i.e., not caused by random mutations occurring in individuals with cancer).
OK, so lessons learned through the history of cancer research seems to be at odds with the conclusions drawn by the Hopkins team. Let's ignore history, for a moment. Here is a list of present-day concerns that should, at the very least, tone down the conclusions reached by the Hopkins study.
1. There are animals with much higher stem cell renewal than that seen in humans. Consider the whale. Whales have tons of intestines with trillions of dividing cells. If stem cell division and random mutation account for cancer, then you would expect every whale to be chock full of intestinal cancers. They are not. Please, spare me the argument that whales are different from humans and the two species cannot be compared. If you assert that random mutations in the DNA of stem cells is the cause of cancer, then your assertion should apply equally to any organisms that contains DNA and stem cells.
2. Carcinogenesis (i.e., the biological process that leads to cancer) is known to be a multi-step phenomenon. Mutation may be the first step, but many additional steps, leading to cancer, must occur, sometimes playing out over decades. In a multi-step process, you cannot expect any single event (e.g., a random bad luck mutation) to account, by itself, for the incidence of cancer.
3. There is a high cancer rate in mice and rats, both relatively short-lived animals. Wouldn't you expect a low accumulation of random bad mutations in animals that only live a year or two? The rapid evolution of cancers in short-lived animals (i.e., weeks or months) suggests that something in addition to random bad luck mutations must account for carcinogenesis in these animals.
4. Biological systems are complex, and causation is seldom a meaningful concept when many events contribute to a single observed phenomenon. For example, random mutation may occur more frequently in tissues with rapidly dividing stem cells, but rapid division of cells may occur in response to some toxic effect or chronic condition that causes a subpopulation of cells to die. Hence, rapid division of stem cells may be the result of some other "cause". Likewise, chronic toxicity and subsequent stem cell renewal in various tissues may result from higher rates of activation of carcinogens (i.e., metabolism) in those tissues. Hence, stem stem cell renewal may be tightly coupled with a variety of biological influences other than "bad luck".
In summary, the correlation observed by the Hopkins scientists is interesting, and it probably deserves further investigation. But the assertion that "bad luck" causes most human cancers is pretty much meaningless, at the moment.
- Jules J. Berman
p.s. The topic of today's blog is covered in depth in several of my published books, particularly Neoplasms: Principles of Development and Diversity, and expanded in my next blog post.
tags: johns hopkins, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell, stem cell renewal
Whoever wrote the Hopkins news report doesn't seem to understand that the subtitle contradicts the title. The title implies that the authors have proven an assertion (i.e., that bad luck causes cancer). The subtitle indicates that they have only established an association (i.e., there is a statistical link between cancer incidence and random mutations occurring as stem cells divide). It seems like a quibble, but there is an immense conceptual gulf between a "link" and a "cause". It's easy to find a correlation, but it's hard to prove a causal role. In many cases, correlations simply disappear when the original data is reanalyzed with different analytic methods, or when some of the original assumptions are changed, or when new data is obtained, or when information from some other study provides better results that support an opposing hypothesis.
The Hopkins researchers reviewed the literature to find, "the cumulative total number of divisions of stem cells among 31 tissue types during an average individual’s lifetime." These numbers for the different tissues, correlated closely with the risk of cancer occurring in those tissues. Having arrived at the correlation, "using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent." Of the 31 tissues they studied, the tumor incidence in 9 of the tissues did not fit their "bad luck" correlation. Tumor incidence in these tissues, according to the news report, must come from some other source, such as environmental carcinogens. The 22 tissues that fit their model were deemed the "bad luck" tumors.
The bad luck hypothesis is not new. Cancer researchers have been trying to titrate the various suspected causes of cancer for decades. In the 1970s, when there was a large push to find chemicals in the environment that cause cancer, it was widely accepted that about 85% of cancers were caused by environment agents; 15% were caused by other things, such as genes, and this last 15% would also include "bad luck" mutations. These numbers were based on statistical inferences from data on the geographic variations in cancer incidence, looking at how the types of cancers occurring in populations changed in different locations on earth and in response to identified carcinogens.
Back in the early '70s, there was an awareness of the special place of "rare cancers" in the discussion. The common cancers (i.e., skin, lung, colon), were all presumed to be caused by environmental toxins (e.g., UV light, cigarettes, food and water contaminants, chronic infections, etc). More than 90% of the burden of cancer in the U.S. is accounted for by just a handful of cancer types (namely, basal cell carcinoma of skin, squamous cell carcinoma of skin, bronchogenic lung cancer, adenocarcinoma of colon, adenocarcinoma of breast, adenocarcinoma of prostate, adenocarcinoma of pancreas, ovarian carcinoma, esophageal cancer, and maybe one or two others). There are over 6,000 different kinds of cancer. All but a half dozen or so of these 6,000 varieties of cancer are rare, accounting in the aggregate for fewer than 10% of the tumors occurring in humans. Many of the rare cancers have well-studied patterns of inheritance. Because there are so many known inherited rare cancers, we tend to assume (perhaps incorrectly) that the bulk of rare cancers are caused by inherited genes (i.e., not caused by random mutations occurring in individuals with cancer).
OK, so lessons learned through the history of cancer research seems to be at odds with the conclusions drawn by the Hopkins team. Let's ignore history, for a moment. Here is a list of present-day concerns that should, at the very least, tone down the conclusions reached by the Hopkins study.
1. There are animals with much higher stem cell renewal than that seen in humans. Consider the whale. Whales have tons of intestines with trillions of dividing cells. If stem cell division and random mutation account for cancer, then you would expect every whale to be chock full of intestinal cancers. They are not. Please, spare me the argument that whales are different from humans and the two species cannot be compared. If you assert that random mutations in the DNA of stem cells is the cause of cancer, then your assertion should apply equally to any organisms that contains DNA and stem cells.
2. Carcinogenesis (i.e., the biological process that leads to cancer) is known to be a multi-step phenomenon. Mutation may be the first step, but many additional steps, leading to cancer, must occur, sometimes playing out over decades. In a multi-step process, you cannot expect any single event (e.g., a random bad luck mutation) to account, by itself, for the incidence of cancer.
3. There is a high cancer rate in mice and rats, both relatively short-lived animals. Wouldn't you expect a low accumulation of random bad mutations in animals that only live a year or two? The rapid evolution of cancers in short-lived animals (i.e., weeks or months) suggests that something in addition to random bad luck mutations must account for carcinogenesis in these animals.
4. Biological systems are complex, and causation is seldom a meaningful concept when many events contribute to a single observed phenomenon. For example, random mutation may occur more frequently in tissues with rapidly dividing stem cells, but rapid division of cells may occur in response to some toxic effect or chronic condition that causes a subpopulation of cells to die. Hence, rapid division of stem cells may be the result of some other "cause". Likewise, chronic toxicity and subsequent stem cell renewal in various tissues may result from higher rates of activation of carcinogens (i.e., metabolism) in those tissues. Hence, stem stem cell renewal may be tightly coupled with a variety of biological influences other than "bad luck".
In summary, the correlation observed by the Hopkins scientists is interesting, and it probably deserves further investigation. But the assertion that "bad luck" causes most human cancers is pretty much meaningless, at the moment.
- Jules J. Berman
p.s. The topic of today's blog is covered in depth in several of my published books, particularly Neoplasms: Principles of Development and Diversity, and expanded in my next blog post.
tags: johns hopkins, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell, stem cell renewal
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