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
Showing posts with label cancer research. Show all posts
Showing posts with label cancer research. Show all posts
Friday, January 2, 2015
Saturday, August 4, 2007
New Ontology research funding opportunity at NIH
On August 3, 2007, NIH announced a new funding opportunity.
http://grants.nih.gov/grants/guide/pa-files/PAR-07-425.html
Title: Data Ontologies for Biomedical Research (R01)
Release/Posted Date: August 3, 2007
Opening Date: December 18, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): December 18, 2007, August 18, 2008, December 22, 2009, and August 21, 2009 for the four separate receipt dates..
Application Submission/Receipt Date(s): January 18, 2008, September 18, 2008, January 21, 2009, and September 21, 2009
Expiration/Closing Date: September 22, 2009
Excerpt: "This FOA encourages the use, improvement, or development of techniques, tools, and better practices for integrating data sets by supporting projects that integrate existing data sets. Specifically, in this FOA, applicants should identify two (or more if they are very closely related) data sets (presumably contained in databases) that are not currently integrated. They should describe the vocabulary used in each database and should develop an ontology that will be suitable to join both data sets. The applicant must justify the importance in unifying these two data sets. NIH anticipates that once important data sets in a topical area have been unified that others in that area will adopt the emerging standard."
It seems that NIH is looking for relatively small grants, but this is probably the best approach. One of the advantages of ontologies is that they permit you do integrate data easily and cheaply. It wouldn't make any sense to develop this technology if every project was a mega-million dollar effort.
This announcement is another indication that major biomedical funding agencies understand the importance of specifying and integrating data. I hope that the research community responds with high-quality applications.
-Jules Berman
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
http://grants.nih.gov/grants/guide/pa-files/PAR-07-425.html
Title: Data Ontologies for Biomedical Research (R01)
Release/Posted Date: August 3, 2007
Opening Date: December 18, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): December 18, 2007, August 18, 2008, December 22, 2009, and August 21, 2009 for the four separate receipt dates..
Application Submission/Receipt Date(s): January 18, 2008, September 18, 2008, January 21, 2009, and September 21, 2009
Expiration/Closing Date: September 22, 2009
Excerpt: "This FOA encourages the use, improvement, or development of techniques, tools, and better practices for integrating data sets by supporting projects that integrate existing data sets. Specifically, in this FOA, applicants should identify two (or more if they are very closely related) data sets (presumably contained in databases) that are not currently integrated. They should describe the vocabulary used in each database and should develop an ontology that will be suitable to join both data sets. The applicant must justify the importance in unifying these two data sets. NIH anticipates that once important data sets in a topical area have been unified that others in that area will adopt the emerging standard."
It seems that NIH is looking for relatively small grants, but this is probably the best approach. One of the advantages of ontologies is that they permit you do integrate data easily and cheaply. It wouldn't make any sense to develop this technology if every project was a mega-million dollar effort.
This announcement is another indication that major biomedical funding agencies understand the importance of specifying and integrating data. I hope that the research community responds with high-quality applications.
-Jules Berman
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
Friday, June 1, 2007
Funding opportunity in precancer research
The U.S. National Cancer Institute (NCI) has put out an innovative Request for Applications (RFA) for precancer research. As you know, I support the idea that attacking precancers is the best way to eliminate human cancer. There's every reason to think that precancers can be treated successfully with low-toxicity agents that interfere with the pathways of precancer growth and progression or that enhance the pathways of precancer death. Most of the research in this field will be data-intensive. Those who know how to specify their data will probably welcome the data sharing provisions in the RFA.
The RFA, focused on breast precancers, just came out, and can be viewed at:
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-07-047.html
Release/Posted Date: May 30, 2007
Opening Date: September 14, 2007
Letters of Intent Receipt Date: October 14, 2007
The RFA uses an R01 funding mechanism (that's good).
The RFA cites our November 2004 conference on precancers that was co-sponsored by George Washington University.
From the RFA: "The NCI as well as experts in the extramural scientific community recommend further research related to the biology of the pre-malignant state in human breast cancer. An expert panel convened at the November 2004 NCI Workshop on Pre-Cancers identified delineation of the biological, genetic, and functional characteristics of pre-cancers as major scientific needs (Cancer Detect Prev. 2006;30(5):387-94). The distinctive early lesions that occur have characteristic properties that should permit them to be detected, diagnosed, and prevented from progressing to invasive cancer. The Workshop participants noted a number of impediments to conducting research on pre-cancers, including:
* insufficient understanding of normal and pre-cancer biology;
* limited access to appropriate specimens;
* a highly subjective, histology-based classification scheme; and
* the lack of strategic partnerships among research communities."
-Jules Berman tags: cancer research, data sharing, funding, nci, precancer, science
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
The RFA, focused on breast precancers, just came out, and can be viewed at:
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-07-047.html
Release/Posted Date: May 30, 2007
Opening Date: September 14, 2007
Letters of Intent Receipt Date: October 14, 2007
The RFA uses an R01 funding mechanism (that's good).
The RFA cites our November 2004 conference on precancers that was co-sponsored by George Washington University.
From the RFA: "The NCI as well as experts in the extramural scientific community recommend further research related to the biology of the pre-malignant state in human breast cancer. An expert panel convened at the November 2004 NCI Workshop on Pre-Cancers identified delineation of the biological, genetic, and functional characteristics of pre-cancers as major scientific needs (Cancer Detect Prev. 2006;30(5):387-94). The distinctive early lesions that occur have characteristic properties that should permit them to be detected, diagnosed, and prevented from progressing to invasive cancer. The Workshop participants noted a number of impediments to conducting research on pre-cancers, including:
* insufficient understanding of normal and pre-cancer biology;
* limited access to appropriate specimens;
* a highly subjective, histology-based classification scheme; and
* the lack of strategic partnerships among research communities."
-Jules Berman tags: cancer research, data sharing, funding, nci, precancer, science
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
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