A recent toast to James Watson highlights a tolerance for bigotry many want excised from the scientific community.
A transgene designed to attract methylation to the promoter of a tumor-suppressor gene leads to tumorigenesis in a mouse model.
July 25, 2014|
WIKIMEDIA, RAMAChanges in gene methylation alone can trigger cancer, according to a mouse study published today (July 25) in the Journal of Clinical Investigation. Working in mouse stem cells, researchers from Baylor College of Medicine in Houston, Texas, introduced a genetic segment designed to attract methyl groups—chemical modifiers that lead to gene silencing—into the mouse genome, upstream of the gene p16, which normally functions to regulate cell division. This transgenic segment was made up of motifs from the human genome, which—as a previous study has shown—are associated with promoter methylation and gene silencing during human development.
Baylor’s Lanlan Shen and her colleagues have now shown that among mice in which this methylation magnet was introduced, 27 percent developed lung cancer, leukemia, or sarcomas, while wild-type controls did not develop tumors. Five percent of mice that inherited one copy of the transgene and one wild-type copy also developed tumors.
“For many years we’ve been very convinced that DNA methylation changes and epigenetic silencing contribute to human cancer, and there have been a lot of observations that support that concept,” Peter Jones, research director and head of the cancer epigenomics lab at Michigan’s Van Andel Research Institute who was not involved in the work, told The Scientist. “What [this] paper does, which I think is very clever, is to selectively silence a tumor-suppressor gene—that’s the p16 gene—in a mouse model system and then show that those mice do develop cancers. This shows that epigenetic silencing can lead directly to the formation of cancer.”
“There are several lines of evidence suggesting the important role of epigenetics in cancer, including the fact that all cancers show epigenetic change, and most cancer mutations affect the epigenome,” Andrew Feinberg from the Johns Hopkins School of Medicine Center for Epigenetics in Baltimore, Maryland, told The Scientist in an e-mail. Feinberg added that while this study is not the first to show than epigenetic changes alone can cause cancer, it “adds one more valuable image to the big picture.”
For at least a decade, the number of known associations between epigenetic changes and cancer has been growing. Abnormal methylation can be found in most cancers, and mutations in the enzymes that add methyl groups to DNA have been associated with some cancer types. In most human cancers, Shen said, the promoter of p16 contains methylated cytosine residues. However, it had been unclear whether p16 methylation and silencing were a cause of cancer or a consequence of it.
In mouse embryonic stem cells, the researchers found that the methylation-inducing transgene construct upped methylation at the p16 promoter and decreased p16 transcription, compared to a control transgene. The difference in methylation between the control and experimental groups emerged after stem-cell differentiation, which was expected, since the transgene motifs regulate methylation during development in humans, Shen said.
Additionally, model mice born with the methylation-inducing transgene developed more tumors and lived shorter lives than control mice, in addition to exhibiting p16 promoter methylation and gene silencing.
“This is the first demonstration that gene promoter methylation can actually cause cancer,” said Shen.
However, Richard Meehan, who studies epigenetics in development and disease at the University of Edinburgh, argued that the paper does not directly demonstrate cause-and-effect. The authors, Meehan wrote in an e-mail to The Scientist, did not expressly show that altered methylation—and not some other means of transcriptional repression also associated with the transgene—initiated gene silencing.
Asked whether the results showed that the methylation, and not some other effect of the transgene insertion, caused cancer, Jones said: “The idea of using a sequence which attracts methylation and shows that this gives rise to an increase in tumorigenesis, I think, is pretty solid evidence.”
“It’s a very clever paper,” added Jones. “I think the results are very clean and clear. It’s a gene [that] is known to be methylated,” Jones said, referring to p16. “It’s known to be methylated very early in the cancer process. . . . In the test tube, [my lab has] shown directly that the methylation of this particular region silences the gene, so I think all the dots have been connected and this was just a final cherry on the top of the cake, so to speak, to show this causality.”
“It certainly shows that the methylation of the gene—and losing the gene this way—is important to something that happens that might be permissive to cancer or sets up some early changes,” said Stephen Baylin, deputy director of the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins School of Medicine. Baylin noted that it was possible that other mutations might also have contributed to tumorigenesis.
Shen said she hopes that her team’s results point the way to future treatments. Now that promoter methylation has been shown to cause cancer, Shen is optimistic that reversal of methylation—using commercially available demethylating agents—might be a mechanism for cancer treatments in the future.
D. Yu et al., “Targeted p16lnk4a epimutation causes tumorigenesis and reduces survival in mice,” Journal of Clinical Investigation, 2014.
July 28, 2014
Re: "...argued that the paper does not directly demonstrate cause-and-effect."
I get that a lot, too. Although there is no other model that directly links the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via nutrient-dependent amino acid substitutions and cell type differentiation, which is controlled by the physiology of reproduction, most evolutionary theorists seem to want serious scientists to prove there is no other way to directly demonstrate cause and effect.
Serious scientists seem to have reached the point where what is already known about how ecological variation leads to -- or fails to lead to -- ecological adaptations is even sometimes challenged by molecular biologists. The challenges attest to the pervasive influence the evolutionary theorists have had despite the clarity of how nutrient stress and social stress epigenetically effect morphological and behavioral phenotypes.
This news attests to the fact that every aspect of mutation-initiated natural selection and the evolution of biodiversity wills soon be replaced by models that include what is known about model organisms. All model organisms, like the yeast model organism, are examples of how all aspects of nutritional epigenetics clearly link ecological variation to ecological adaptations via nutrient-dependent pheromone-controlled reproduction.
Excerpt (see): From Fertilization to Adult Sexual Behavior
"It is now recognized that other genes on other chromosomes can induce sex reversal regardless of the individual’s SRY status (Bennett, Docherty, Robb, Ramani, Hawkins, and Grant, 1993; Kwok, Tyler-Smith, Mendonca, Hughes, Berkovitz, Goodfellow, and Hawkins, 1996; Schafer et al., 1995). Similarly, therefore, if specific genes or genomic regions are found to be primary determinants of sexual orientations, upstream and downstream genes are likely also to play crucial roles. And these multigene interrelationships will have profound impact upon phenotypes and judgments derived therefrom. Parenthetically it is interesting to note even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995)."
July 28, 2014
I have pointed this out, repeatedly, and am compelled, once again, to remind readers (and the authors of this paper), that animal models for cancer -- especially mouse models -- are largely a waste of time. Humans and animals develop different tumors, respond differently to these tumors and respond to the treatment of said tumors quite differently. Over forty years since the "War on Cancer" found its way onto the medical sciences stage, animal models have done little, if nothing, to provide concrete solutions. Only a year ago, another former Director of the NIH, made this statement:
""We have moved away from studying human disease in humans. We all drank the Kool-Aid on that one, me included." With the ability to knock in or knock out any gene in a mouse -- which "can't sue us," Zerhouni quipped -- researchers have over-relied on animal data. "The problem is that it hasn't worked, and it's time we stopped dancing around the problem...We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans." (Former NIH Director Dr. Elias Zerhouni, at NIH Record, Vol. LXV No. 13, June 21, 2013)"
As Dr. Azra Raza (Professor of Medicine), Director of MDS Center, at Columbia University, recently commented:
"An obvious truth is is either being ignored or going unaddressed in cancer research is that mouse models do not mimic human disease well and are are essentially worthless for drug development. We cured leukemia in mice in 1977 with drugs we are still using in exactly the same dose and duration today in humans with dreadful results...there are no appropriate mouse models (sic) which can mimic the human situation."
Dr. Raza continues, "...Too many emiment laboratories and illustrious researchers have devoted entire lives to studying malignant diseases in mouse models and they are the one reviewing each other's grants and deciding where the NIH money gets spent. They are not prepared to accept that mouse models are basically valuless for most of cancer therapeutics."
The veracity of these observations echoes reality (the facts) for many, many such animal models for disease. What is more, those of us (in the medical and life sciences) who speak out about this phenomenal waste of time, energy and capital resources - governmental, insitutional and private funding streams - are condemned and demonized for daring to state the facts.
In a recent article by Ray Greek, MD (a Board Certified Aneshesiologist, and pre-eminent champion of the appropriate use of animal models for applications in human medical science), he concludes:
"Dr. Raza is not the first to point our that mouse models have failed. The list of scientists who have stated more or less the same thing in science journals is long. Despite this, nothing seems to be changing. Perhaps that is because society seems to be under the impression that all scientists support the use of animal as predictive models in drug and disease research. As long as the vested interest groups get to phrase the survey questions, can buy advertising space, have the support of (sic) the media, and refuse to debate specific questoins in the presence of unbiased experts, this will not change..."
*(from my comments, above) It is a confounding fact, and one I have repeatedly faced, in my own efforts to discuss these matters in a variety of very public forums:
all too often, those individuals and organizations who endorse and promote the core dogma, in Medicine and associated Life Sciences, not only disdain being engaged by credible scientists who may question that dogma, they actively accuse anyone who questions the dogma... of heresy and misanthropy. What, then, has become of the Scientific Method... of healthy and necessary, fact-seeking scientific skepticism?
Dr. Jonas Moses
(former cancer research scientist, University of IL, Chicago)
July 28, 2014
The comments against studying cancer by studying gene expression in mice are half-baked. It doesn't matter if specifics of many cancers and metabolism of certain drugs are different in mice vs. humans (and known to be). The basic mechanisms of gene regulation have been conserved during evolution as have the functions of many genes and cell types. What can be learned by working with a room full of mice in a few years would take decades with humans and present even more serious ethical issues than does the work on mice.
As for this paper, it is "nice clean" work, as someone said, but not all that significant. A known tumor suppressor gene was shut off, and the result was an increase in the incidence of cancer. This result is not surprising and the fact that it was shut off by upstream methylation vs. deletion or other genetic knockout is not really a big deal. We already know that genes can be silenced via methylation and that silencing p16 increases cancer incidence, so we have now confirmed that 1 + 1 = 2. But, we now know definitively that environmental factors affecting parents can affect cancer incidence in their offspring... if we were unclear on that before.
July 29, 2014
"Half-baked," sir...as in you think you know more about the field than two former heads of the NIH, thousands of other scientists who don't buy the mouse model and a beginner, such as myself (who bioengineered the first three dimensional, in vitro tumor model, and published a book on my work, in 2007)? I see. I would be delighted to learn your credentials and experience in the field.
Respectfully, Dr. Moses