Does it surprise anybody?  Not I…

Severe Childhood Obesity is a new classification which is described as being a weight that is greater than the 99th percentile for gender and age.  The researchers out of Wake Forest University Baptist Medical Center are the first to use this classification of obesity in children.  The measure isn’t perfect, children have a high variance in height and growth spurts come at different ages having far different effects on height and weight.  But it is a stable measure across time and very indicative of how our children are measuring up to their peers.

From the years 1976-1980 the rate of severe obesity was 0.8%, climbing to 3.8% in the years 1999-2004.  Another worrying data point from the study is that a third of children that were severely obese have metabolic syndrome.  Metabolic syndrome is a measure of high blood pressure, cholesterol and insulin levels which grouped together are risk factors for heart attack, stroke and diabetes.

The researchers said, “these findings demonstrate the significant health risks facing this morbidly obese group…this places demands on health care and community services, especially because the highest rates are among children who are frequently underserved by the health care system.”

At a time when the nation is caught up in a health care debate it is evident that in order to decrease our costs in the future we have to target our children and teach them healthy eating.  This has to be a concerted effort at home and in schools (we send our kids to school to learn and here’s what they learn) to eat healthier, exercise and generally care more about what we put in our bodies.

ResearchBlogging.orgSkelton, J., Cook, S., Auinger, P., Klein, J., & Barlow, S. (2009). Prevalence and Trends of Severe Obesity Among US Children and Adolescents Academic Pediatrics DOI: 10.1016/j.acap.2009.04.005

According to Margaret Wente they do, in her Globe and Mail editorial from last week she unwisely states “get fat, live longer.”  The problem Margaret has here is using one study to come to a conclusion when there is a mountain of evidence out there and most of it points toward moderate weights being far more healthy and associated with a lower mortality.  From the editorial:

Here’s more bad news for all those folks who are nagging us about our weight. The evidence is very clear that, unless you are morbidly obese with health problems, losing lots of weight is bad for you, not good.

I have to disagree Margaret, weight loss is usually marked by healthy activities, which is more important than baseline weight or even significant weight loss; those with an active and healthy lifestyle continually show lower mortality than those with sedentary lifestyles.

Travis at Obesity Panacea (maybe the best health blog name on the net) has a smart takedown of the article which does well at explaining how this study fits into the body of obesity research.  The results of the study become more clear when put in the correct context and all confounding factors are taken into consideration.  Travis wraps the whole situation up nicely in his post.

So what’s the take-home message from thislengthy post (aside from ignoring health advice from Margaret Wente)?  Body weight affects your health, but not as much as diet and exercise.  So focus on those healthy behaviors, and you’ll be moving towards a longer, healthier life.

ResearchBlogging.orgOne aspect we’ve discussed before about cancer development is the requirement that the cells (more specifically cancer stem cells) become immortal, able to replicate into daughter cells indefinitely. This is seen most prominently in HeLa cells, cervical cancer cells taken from Henrietta Lacks, who died in 1951. These cells have an overactive telomerase enzyme and have continued to replicate in research labs around the world since they were collected.

Telomerase is an enzyme that adds short pieces of DNA onto the end of chromosomes (telomeres) after replication, necessary because the mechanism for replication shortens the telomeres with every round. If enough of the telomere is lost a signal is sent to the cell to quit replication. In stem cells and progenitor cells this signals the end of self renewal.

Another pathway able to produce renewal and proliferation is the Wnt/β-catenin pathway. This pathway has been shown to be important in maintaining cells in a stem cell-like state and are thought to be able to initiate tumorigenesis.

The blue dye shows where Axin2 is being expressed from TERT induction

The blue dye shows where Axin2 is being expressed from TERT induction

A paper published July 2 in Nature has shown how these two pathways are linked, finding a molecular bridge between the immortality and stem cell/proliferative pathways in the cell. The researchers were looking at a portion of telomerase called TERT (telomerase reverse transcriptase). Early looks at the molecule found that overexpression in mice could lead to anagen in the epidermis, the same result that happens when β-catenin is overexpressed.

Using the gastrointestinal tract of mice, where Wnt signaling through β-catenin is required for stem cell maintenance, the researchers showed that inducing TERT expression in the crypts significantly upregulated Axin2 expression, a gene target of the Wnt/β-catenin signaling pathway (figure b). This in vivo display of pathway convergence is great evidence for the link between the two. Furthermore, the research team used catalytically inactive TERT to show that its function in Wnt signaling is not based on its telomerase activtiy.

The link between these two pathways I guess shouldn’t be too surprising. In cells which are programmed to be stem cells and divide many times throughout an organism’s life it should be expected that a pathway to maintain chromosomal integrity would communicate with the pathway that is pushing the cell to divide. What may be surprising is just how intimately these two are linked with the actual telomerase enzyme associated directly with the chromatin and Wnt signaling targets.

Tert knockout homeotic mutationsAnother reason I love this paper is the amazing images of Xenopus homeotic transformations. Since the Wnt pathway is also involved in axis formation and early patterning when you knock out TERT you do some weird things to the frog’s body plan. These images show how the vertebra and ribs are shifted from their location or display axis abnormalities, further putting the nail in the coffin for the link between TERT and Wnt signaling.

The significance of this finding may lead to another chemical therapeutic target in the future. Now two pathways may be able to be controlled in one swoop. Ideally a drug would be able to knockout TERT activity which would have the dual effect of ending immortality in that cell and forcing it out of a stem cell state. Since most cancers have the higher morbidity and mortality with more stem cell like cells in primary tumors this could be a means at a genetic double shot. Once you can get cells to commit to a differentiation status it is very hard for them to reclaim the ability to proliferate and produce daughter cells.

As the authors say:

“Our findings provide a mechanism to understand previous observations showing that TERT overexpression activates epidermal stem cells, as well as previous findings linking TERT to proliferation, survival and stem-cell biology in diverse contexts. Our data reveal unanticipated level of convergence between the telomerase and Wnt/β-catenin signalling pathways with important implications for understanding development, stem-cell regulation and cancer.”

Park, J., Venteicher, A., Hong, J., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., McLaughlin, M., Veenstra, T., Nusse, R., McCrea, P., & Artandi, S. (2009). Telomerase modulates Wnt signalling by association with target gene chromatin Nature, 460 (7251), 66-72 DOI: 10.1038/nature08137

Senators Sam Brownback (R-KS) and Mary Landrieu (D-LA) have introduced the Human-Animal Hybrid Prohibition Act of 2009 to the Senate on July 9.  Along with 20 cosponsors the two Senators have set out what they think will be sensible guidelines for human-animal hybrids. From Brownback’s blog:

“The issue is that when you make changes in the germ-line, such changes are passed along to one’s offspring. You could make a change now that could be passed along through the gene-pool for the rest of humanity. We do not know what the full effect of this could be, and it could be disastrous.

Ugh, I hate when people pull out the disaster around the corner speech.  Sam has no clue about how this works but he does represent a decent amount of thought in the US.

As a preface to what I think about the bill I am putting my belief out there that I don’t really think there is anything special about humans versus other animals.  We’ve all trecked the same course of time to reach this evolutionary phase.

I’ll first note that chimeras have been around for a while in biomedical research.  It is of a great advantage to be able to express human cells and tissues inside our closest relatives, the mammals (a humanster makes an anemia drug for us). No ethics committee in the world will let you purposely give someone parkinson’s, diabetes, or cancer. But the attraction to this approach from medical researchers is that you can give a mouse any disease you want.  By placing human tissues in mice and simulating a disease of that tissue researchers can more highly characterize the cell biology, biochemistry, and treatments of the disease.

The questions of developmental biology are many and deep, even with human embryonic stem cells (hESCs) we can only coax the formation of the 3 germinal layers with no axial morphogenesis.  Early human development remains as a bastion of unanswered questions, from the general morphological changes to genetic structure and expression.  Some scientists have started to tackle this these questions by integrating hESCs in mouse blastocysts like Daylon James from The Rockefeller University.

A  majority of embryonic chimeras generated from morula aggregation showed localization of hESCs (green in panels K, M, and N) to host ICM with retention of Oct-3/4  (red in K–N) and absence of Cdx2 (blue in panels K, L, and N).

A majority of embryonic chimeras generated from morula aggregation showed localization of hESCs (green in panels K, M, and N) to host ICM with retention of Oct-3/4 (red in K–N) and absence of Cdx2 (blue in panels K, L, and N).

The real question comes for most people when you start engineering a mouse brain with most or all of its neurons that are human, maybe before the architecture of the brain is even laid down.  Granted neurons aren’t even half of the cells in the brain but I could see how this may cause hesitance on the part of people wondering if this is a now sentient mouse.  I don’t know if there is an answer out there about that issue but I would wager a lot of money that you would have a mouse brain expressing human neurons and functioning like a mouse brain.

The language of the bill itself will have to be carefully looked at and I worry about any legislation that lays down rules for the direction of science.  It is hard to decide what the face of biomedical research will look like in 25 years, what techniques and new biological tools will we have?  Will it be possible to express whole human systems in a primate and study heart disease on human hearts?  Is a monkey with a human heart a monkey, a human, or a human/monkey hybrid?  Is a person with pig heart valve a human, pig, or a human/pig hybrid?

I am afraid that these questions are hard to answer and handcuffing exploration by the legislature will only silence discussion on how to ethically conduct these experiments and preserve the stature of the human species.  In the future the techniques will be innovative and able to manipulate DNA and hybrid questions with much more certainty but we have to at least leave the market open to exploration and discussion.

I guess in the end my view of life and the connectedness of all species will most likely knock me out of contention for ethicist on this issue.  It is just very hard for me to agree that a monkey and a slug are more closely associated (both ‘animals’) than humans and monkeys.

I know I didn’t discuss the bill much itself but I will have to do more research on the direction of such studies and look at the wording more carefully because honestly it isn’t very clear.