If you’ve been on the Internet at all in 2015, you’ve probably stumbled across headlines like “Two-thirds of cancers are due to ‘back luck,’ study finds” (CBSNews), “Most cancers are caused by bad luck not genes or lifestyle say scientists” (The Telegraph), “Cause of cancer revealed: majority of cases down to ‘bad luck’ rather than lifestyle, diet or genetics” (Huffington Post). The paper in question by Drs. Tomasetti (PhD) & Vogelstein (MD) from Johns Hopkins, has taken the media, blogosphere, and social networks by storm. Even the science bloggers have something to say about it – Dr. Paul Knoepfler (cancer researcher), Dr. Andrew Maynard (public health professor), Aaron Meyer (bioengineer) – and it’s not praise.
After reading all these reports and the original paper, I’m left wondering if this is really breakthrough science (not really), or just a massive misappropriation of public relations (probably)?
Let’s start from the beginning. What does the paper entitled “Variation in cancer risk among tissues can be explained by the number of stem cell divisions,” published in the journal Science, really present?
The study seeks to identify the contribution of stem cell divisions in a particular tissue (i.e. organ) with the risk of cancer in that same tissue. The authors believe that this would be an explanation of cancer risk not accounted for by environmental (e.g. smoking, UV radiation) or genetic (ethnicity, heritable mutations) factors.
The bottom line of their rationale: cancer develops as a result of mutations, which occur during cell divisions; the more cell divisions, the greater the likelihood of mutations. Stem cells – by virtue of their long lifespan – could be hypothesized to have a high number of cell divisions in their lifetime; thus, increasing their likelihood for acquiring mutations. It then stands to reason that tissues with a higher number of stem cells would have a higher chance of developing cancer. From this thought process, the authors ask the question: does the total number of lifetime stem cell divisions in a tissue correlate with the lifetime risk of cancer in that tissue?
To answer their question, the authors graphed lifetime risk of different cancer types against the lifetime number of stem cell divisions for that particular tissue (estimated from values previously published in the scientific literature). From this graph, they identified a significant and fairly strong positive correlation: more stem cell divisions were associated with an increased risk of cancer.
The authors also performed an analysis that identified a group of tissues, with high risk of cancer and fewer stem cell divisions, as being more dependent on environmental and/or genetic factors.
Interesting. The thought process is logical, and their conclusion makes sense. Anyone with a shred of common sense, who stopped to think for a moment, could draw this conclusion, or simply find it any biology/genetics textbook. In fact, the only novel contribution to cancer biology this paper makes, is an attempt to determine a specific number for cancer risk.
I really do find this conclusion acceptable and completely logical as a thought experiment. However, I have some concerns as to how the science stacks up.
- The study chose to use several important cancer theories in its rationale; however, it neglects one of the most important: the multi-hit hypothesis. The idea that multiple ‘hits’ need to occur for cancer to develop. Simply put, the same cell requires multiple and cumulative mutations to become cancerous. Let’s say that ten mutations are required for a particular cancer to form; these are ten mutations in the same cell, not one mutation in ten cells. As it stands, the current study does not differentiate between the two scenarios. It uses the total lifetime stem cell divisions, which could cause a tissue with a large number of stem cells that divide infrequently to have an inflated ‘risk,’ compared to a tissue with low numbers of stem cells that divide quite often. In reality, the latter is plausible, as it allows multiple ‘hits’ to accumulate in the same cell. The authors should have considered the rate of stem cell division and number of stem cells in a tissue as independent risk factors, in addition to total lifetime stem cell divisions.
- As already stated by Dr. Paul Knoepfler, the study assumes that all cancers follow the cancer stem cell (CSC) model of tumorigenesis, and that the CSC must have come from a normal stem cell. The CSC model has not been indicated for all cancers, nor have CSC researchers come to a consensus regarding the cell of origin for CSCs.
- It is also worth mentioning that the majority of the data used in the estimation of the total lifetime stem cell divisions are largely derived from mouse models. In the current paper, the authors identify that mouse and human intestinal tissues are not equivocal (supplementary data); so then, why are mouse data used in the other calculations? The data that are of human origin are typically from in vitro (in a dish) or mathematical models. While animal, cellular, and computer modeling are acceptable for basic sciences research, applying those conclusions to whole-body human beings is a little difficult (and not good science).
- When looking to identify risk factors, proper study design assesses a potential risk factor in the same individuals in which the outcome of interest is being examined. For example, smoking is a risk factor for lung cancer because researchers followed a large number of smokers and non-smokers over time, and observed increased occurrence of lung cancer in smokers, compared to non-smokers. This study took stem cell data from one place, and compared them to U.S. statistics from another (e.g. the Surveillance, Epidemiology, and End Results (SEER) database). The authors did not measure stem cell divisions in people and observe the occurrence of cancer. What they did is akin to your parents telling you to finish your dinner because there are starving children in Africa!
Again, the thought experiment is great, but the execution of the experiment struggles to meet the most basic tenants of scientific rigour.
As for the reporting of this study by the media, it seems that what little science was present, has been lost. To the news reports propagating that cancer is “just bad luck,” I have to say STOP – that is (a) not accurate, and (b) not important!
Claiming ‘bad luck’ is suggesting that there is no biology involved and that nothing is increasing the risk of cancer. This is frankly not true. The conclusion of the paper is that the more stem cell divisions in a particular tissue, the more likely it is to develop a tumour: the tissue has a higher probability of acquiring cancer-causing mutations. This is biology. This is the same fundamental process by which environmental factors increase cancer risk. True bad luck is Primrose Everdeen’s name being chosen, or what happens to Mr. Play-it-safe from Alanis Morisette’s Ironic.
Unfortunately, this “bad luck” misnomer resonates well with almost everyone. It ignores biology (which is scary), and gives people the rationale that cancer can happen to anyone, at any time, so why bother quitting smoking or changing your diet? (By the way, the paper does not negate the important contribution these factors make.) Because of this more favourable, and less guilt-inducing, presentation by the media, the study (unnecessarily) receives a great deal of publicity. While this study is being touted as a breakthrough to the public, as a researcher and future clinician, I’m left wondering why this is being reported that way (because it’s not), and the discovery of a new antibiotic, with no detectable resistance, is getting zero face time?
Do I think Drs. Tomasetti and Vogelstein had a cool idea? Sure. Do I think it deserved to be published? Maybe. Do I think it was Science calibre? No. Do I think it should have gotten the publicity it did (taking away space from other, more important work)? Definitely not.
Editor’s note: While we might not approve of the science, it’s hard to dispute that this is an excellent example of how public relations can be used to promote (whether appropriate or not) a particular discovery. For an explanation of how this happened (things to consider for promoting your next stem cell discovery?), check out Stacey Johnson’s Luck is on their side in “bad luck” cancer study.