Bittersweet Adaptation: How Genes For Survival May Be Giving Us Diabetes

The famous phrase has it that evolution is a process of the “survival of the fittest.” However, it should be noted that this doesn’t imply some great evolutionary gymnasium, with species pumping and sculpting themselves into the most sexually appealing shapes of the day. Rather, the phrase means something more like “the survival of the aptest”—that is, that those whose bodies are genetically best “fitted” to their environment are those who are most likely to survive and to pass their extra-suitable genes on to future generations.

Recent research has brought this distinction very much to life for humans living in the sugar- and fat-rich developed world, one in which burger joints and donut shops are often found on every other block. In what is, in evolutionary terms, a brand new environment, genetic adaptations that were essential for early human survival—those designed to preserve as much fat and energy as possible—are now perhaps major contributing factors in making many of us unfit. Here are two mutations that may be implicated in the conditions of obesity and diabetes.


In mammals, the CMAH gene codes for an enzyme responsible for adding oxygen atoms to sialic acids, thus creating sugars that coat cells’ membranes. However, about 2-3 million years ago, the CMAH gene in humans underwent a mutation, rendering the enzyme inactive. The result, according to a recent study from UCSD, 1 is that obese individuals end up being more prone to type 2 diabetes than they would if the gene were still intact.

To study the effect of mutated CMAH genes, Jane Kim and her colleagues developed a mouse model that mimicked the human defect in the CMAH gene. They then compared two groups of mice: one with a functional CMAH gene, and one with the human-like mutated CMAH gene. When fed a high-fat diet, both groups of mice became obese and developed insulin resistance. However, only the mice with the CMAH gene mutation experienced pancreatic beta cell failure. Pancreatic beta cells normally make and release insulin, a hormone that controls blood sugar levels. This blood sugar impairment may help to explain why obese humans are particularly prone to develop type 2 diabetes.


The GIP gene codes for a protein that stimulates insulin production in humans after eating a meal. However, a certain genetic variation—identified by Sheau Yu Hsu of Chang Gung Memorial Hospital and fellow researchers at Texas A&M Univeristy2—results in certain human populations having higher fasting levels of blood glucose than those with the older, more ancestral form of the gene—thus rendering them more prone to developing diabetes.

Hsu and his colleagues chose to study the GIP gene variant by looking through 207 genetic regions that have been associated with diabetes or obesity and determining which regions have increased in prevalence since humans began migrating out of Africa about 60,000 years ago. They then used Hapmap—a catalogue of genetic variations among global populations—to find genes that show frequently occurring variations in Asians and/or Europeans but not in Africans.

To compare the ancestral form and the newer variant of the GIP gene, Hsu’s group then selected an even narrower population: pregnant women. They found that out of approximately 120 East Asian pregnant women, those who carried two copies of the newer genetic variant had significantly lower levels of GIP in their blood. This implies that they produced less insulin, leaving them at risk of maintaining unhealthily high blood glucose levels—a condition which ultimately results in type 2 diabetes.

Why were these genetic mutations carried through the human population?

According to Hsu, “These gene variants and the resulting higher blood sugar levels may have helped women maintain successful pregnancies in the face of inevitable famines that occur in an agriculturally based society.” Furthermore, certain genetic variants that increase the risk of diabetes also decrease risk of certain diseases and infections.3

Back in a time when the risks of dying from untreatable illnesses or starvation far outweighed the dangers of diabetes, these variants were favorable. However, with the advent of modern medicine and industrialized agriculture, diabetes has become the more dire concern. The challenge now is to identify which variations have left us more prone to conditions such as obesity and diabetes—and then to find solutions.

Resources from Wiley on This Topic
Evolution After Gene Duplication

by Katharina Dittmar and David Liberles

Evolution: A Developmental Approach

by Wallace Arthur

Human Bioarchaeology of the Transition to Agriculture

by Ron Pinhasi and Jay T. Stoc

1. Kavaler, S., Morinaga, H., Jih, A., Fan, W., Hedlund, M., Varki, A., & Kim, J. (2011). Pancreatic -cell failure in obese mice with human-like CMP-Neu5Ac hydroxylase deficiency The FASEB Journal DOI: 10.1096/fj.10-175281

2. Chang, C., Cai, J., Cheng, P., Chueh, H., & Hsu, S. (2011). Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation Diabetes, 60 (3), 726-734 DOI: 10.2337/db10-1331

3. Corona, E., Dudley, J., & Butte, A. (2010). Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases PLoS ONE, 5 (8) DOI: 10.1371/journal.pone.0012236

Curing Cancer with Dwarfism, Down syndrome, and Vegetables

With the world abuzz about dwarfism preventing cancer, we wondered: what other sorts of genetic tinkering can, unexpectedly, prevent or cure cancer?


Laron syndrome is a genetic disorder that causes dwarfism. Individuals with Laron syndrome possess a mutation on the GHR gene, rendering the gene defective and body insensitive to human growth hormone—hence stunted growth.

In a study recently published in Science Translational Medicine,1 scientists studied 100 Ecuadoreans with Laron syndrome and compared them to 1,600 relatives who were normally proportioned. Over the 22-year course of the study, none of the subjects with Laron syndrome were diagnosed with diabetes, and only one individual reported any tumorous growth (a benign ovarian tumor). Comparatively, of relatives living under the same conditions over the same timeframe, 5 percent were diagnosed with diabetes and 17 percent with cancer.

The Food and Drug Administration has already approved growth-hormone-blocking drugs to treat acromegaly, a type of gigantism, and in the future, these sorts of drugs may be used to prevent cancer or diabetes in high-risk populations.

Down Syndrome

Individuals with Down syndrome possess an extra 21st chromosome. According to a recent study published in Nature,2 this extra chromosome could decrease an individual’s risk of cancer.

One particular gene on the 21st chromosome, Dscr1, regulates blood vessel growth, or angiogenesis. Researchers found that in mice, an extra 21st chromosome—and therefore, an extra copy of the Dscr1 gene—kept abnormal angiogenesis (and resulting tumor growth) in check. To verify that the Dscr1 gene affects humans in the same way, the researchers generated stem cells from skin cells taken from an individual with Down syndrome. They then injected one group of immunocompromised mice with these Down syndrome-derived cells, and another group with cells derived from a chromosomally normal human. In the “normal” group, the mice’s tumors generated networks of blood vessels to feed themselves, but in the “Down syndrome” group, the tumors hardly formed any blood vessels at all.

With this discovery, researchers are looking for ways to target the Dscr1 pathway, starve tumors of blood vessels, and not just treat, but prevent cancer.

Cruciferous Vegetables

What do broccoli, cauliflower, cabbage, turnip, and watercress all have in common? Sure, they are all vegetables, but they could all also help reduce the incidence of cancer.

As members of the cruciferous vegetable family, these foods contain isothiocyanates (ITCs), phytochemicals that fight cancer by working on the tumor suppressor gene p53. When the gene is functioning properly, its proteins play a role in keeping cells healthy and preventing them from starting abnormal growth. When the gene is mutated, p53 fails to provide this protection.

According to a study recently published in Journal of Medicinal Chemistry,3 scientists found that ITCs can remove defective p53 proteins while leaving normal p53 proteins alone. This means that not only was your mother right—you really should finish all your broccoli—but because half of all human cancers include mutated p53 genes, the future of cancer treatment may very well include ITC-based drugs.

Resources from Wiley on This Topic
Cancer: Basic Science and Clinical Aspects

by Craig A. Almeida and Sheila A. Barry

Cancer: An Interdisciplinary View

Wiley Interdisciplinary Reviews (WIREs) Collection

Tumor Microenvironment

by Dietmar W. Siemann

Anticancer Therapeutics

by Sotiris Missailidis

1. Guevara-Aguirre, J., Balasubramanian, P., Guevara-Aguirre, M., Wei, M., Madia, F., Cheng, C., Hwang, D., Martin-Montalvo, A., Saavedra, J., Ingles, S., de Cabo, R., Cohen, P., & Longo, V. (2011). Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans Science Translational Medicine, 3 (70), 70-70 DOI: 10.1126/scitranslmed.3001845

2. Baek, K., Zaslavsky, A., Lynch, R., Britt, C., Okada, Y., Siarey, R., Lensch, M., Park, I., Yoon, S., Minami, T., Korenberg, J., Folkman, J., Daley, G., Aird, W., Galdzicki, Z., & Ryeom, S. (2009). Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1 Nature, 459 (7250), 1126-1130 DOI: 10.1038/nature08062

3. Wang, X., Di Pasqua, A., Govind, S., McCracken, E., Hong, C., Mi, L., Mao, Y., Wu, J., Tomita, Y., Woodrick, J., Fine, R., & Chung, F. (2011). Selective Depletion of Mutant p53 by Cancer Chemopreventive Isothiocyanates and Their Structure−Activity Relationships Journal of Medicinal Chemistry, 54 (3), 809-816 DOI: 10.1021/jm101199t

Interview with R. Ian Freshney, Author and Cell Culture Expert

R. Ian Freshney, PhD, is an honorary Senior Research Fellow in the Centre for Oncology and Applied Pharmacology at the University of Glasgow. He is a world-renowned expert on cell culture technique and has authored and edited numerous successful books, including the hugely popular Culture of Animal Cells (now in its 6th Edition), and Culture of Human Stem Cells.

Here, he answers a few questions on his own techniques as an author and on the continuing role of books in modern scientific research.

  1. Culture of Animal Cells: A Manual of Basic Technique and Specialized Application, 6th Ed has been very well received by the scientific community, as have many of your other titles. What do you think sets your books apart and makes them so successful compared to other titles in the field?
    I would say there are three major components: (1) The books are designed as practical guides with detailed single-step instructions which should be sufficient without further recourse to the literature. (2) The preparation and sources of materials are explained in detail. (3) Most of the basic protocols are illustrated with easy-to-follow diagrams.
  2. What challenges did you face while putting together Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition?
    I struggled with the need to update but at the same time preserve basic procedures which have not changed markedly from the previous edition. This, of course, led to the dilemma of deciding what to retain and what to leave out. I also thought long and hard about what specialized protocols to add without compromising the basic technique role of the book.
  3. What do you find rewarding about authoring and editing books in the sciences?
    It forces me to keep up-to-date with developments in cell culture, and in turn helps me to be a better teacher of cell culture. I also get satisfaction from converting what are sometimes complex instructions into one simple straightforward procedure.
  4. What inspired you to write your first book?
    I was invited to prepare a textbook on cell culture for a college course. Previously, I had used John Paul’s book, Cell and Tissue Culture, and knew it needed to be updated.
  5. What advice would you offer to scientists writing or editing their first book?
    • Determine the precise niche that you wish to fill.
    • Plan the structure carefully beforehand but do not be afraid to deviate, within reason, to meet new demands.
    • Ensure the text is well illustrated with tables and diagrams.
    • Make sure the book is properly cross-referenced.
    • Prepare the index yourself. Even if it is to be professionally indexed you will find terms that the indexer does not.
  6. How would you compare the experiences of writing a book and writing a journal article?
    Both require a clear concise style, but the author has more freedom to express ideas and opinions when writing a book. Another major difference is that a scientific paper must address a specific topic and provide proof to substantiate the conclusions that are drawn, while a book draws on the author’s and other scientists’ experience to provide a more general review and specific guidelines or instructions.
  7. Do you find that the role of books in the scientific research community has changed over the years? Are they valued more or less today than they were 10-20 years ago?
    Rapid changes in technology mean that some books will become outdated without regular updates, which are not always feasible in printed copy. Yet, while there is an increasing tendency to provide instructions and protocols online, many people will still find reassurance from using a textbook with an established reputation.
  8. How do you envision the evolution of science writing over the next 5-10 years?
    Certain journals will still tend to be regarded as more reliable than others, as indicated by their citation indices. However, the number of free public access journals will probably increase, presumably with payment to submit articles. There will be a continuing need for editorial control of journal content due to the proliferation of unedited, non-reviewed material appearing online.
  9. What do you feel has been the most significant scientific discovery that has been made during your lifetime?
    I can really only speak for biology where the elaboration of the genetic code is probably the most significant development. The ability to regulate gene expression and the resultant plasticity of the cell phenotype will create major opportunities in cell culture and its relevance to tissue in vivo.
  10. What are you reading right now?
    This questionnaire! Otherwise, mostly novels and current journals for which I have alerts.