Reflections on diabetes, focus on type 2 diabetes

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A year ago I promised a friend I would write about type 2 diabetes (from here on abbreviated as T2D). She has T2D and wanted to know more about it, after being justifiably horrified by the high percentage of amputees and blind people at the diabetes clinic she attends. I started to do my research and discovered that there is an astonishing amount of information about diabetes on the web.

Diabetes affects millions of people worldwide. At the recent United Nations Summit on Non-Communicable Diseases (held in New York in September 2011) the number of people with diabetes world wide was estimated at 366 million, with 4.6 million deaths attributed it in 2011 alone. The number of people diagnosed with and dying of diabetes is rising. The web site of the International Diabetes Federation has plenty more frightening statistics concerning the scope of problem. (http://www.idf.org/)

First, an overview -at its simplest, diabetes is uncontrolled high blood glucose levels, a.k.a. hyperglycemia, with two major causes: a lack of insulin, and insulin resistance.

Insulin is a hormone that is made by the islet cells within the pancreas. As levels of sugars and carbohydrates (complex sugars) in the bloodstream rise during digestion, insulin is secreted by the pancreas. Most cells in the body have insulin receptors, and with insulin, these cells are able to absorb the sugars. In the absence of insulin, cells are unable to take the sugars in and the cells starve. In a word, the person with no insulin starves to death at a cellular level.

Type 1 diabetes (T1D) was formerly called juvenile-onset diabetes. The pancreas stops producing insulin. This is normally caused by an autoimmune reaction against the insulin producing cells (beta islet cells) of the pancreas.  It can occur at any age although it usually develops in children or young adults.

Type 2 diabetes is caused by insulin resistance or insufficient insulin production. The insulin is there, but the cells seem unable to recognise it. The biggest risk factors associated with developing T2D are being overweight and sedentary, conditions that are becoming more common everywhere. With obesity comes the added complication of high lipid levels (also known as high cholesterol). So the type 2 diabetic suffers from both high blood sugar levels and high blood lipid levels.

T2D is more common in people over 40 though the age of diagnosis is dropping as more people become overweight earlier. Dean Ornish states in a TED talk that diabetes has increased by 70% in 30 year olds in the past ten years. T2D is no longer a disease of the middle aged. (http://www.ted.com/talks/dean_ornish_on_the_world_s_killer_diet.html)

High blood sugar levels are poisonous. They wreak havoc by gumming up proteins and causing nerve and blood vessel damage. As an example of how this damages nerves and blood vessels,  I will tell the story of an acquaintance. This man is in his 60’s, moderately overweight and does not exercise. A few years ago he developed a sore on his leg. Maybe he bumped his leg, or maybe he didn’t notice his socks rubbing against his leg creating a small sore. He didn’t notice because he doesn’t feel things as well as he should.  He has nerve damage caused by hyerglycemia. His sore didn’t heal because of reduced blood flow, also a consequence of high blood sugar levels. The sore grew and eventually became infected, gangrene followed. Last year he had to have his leg amputated. Unfortunately his story is all too common.

Circulation problems are a serious complication for diabetics. Hyperglycemia causes peripheral nerve damage (tingling, numbness), reducing sensation, especially in the extremities: feet, lower legs. It also causes vascular damage impairing circulation.. This makes for a deadly combination. People with T2D also have the added complication of high cholesterol levels which cause plaque formation (atherosclerosis)

Almost everything I have written so far is available on any number of web sites devoted to diabetes. For the rest of this blog I am going to focus on T2D. The things I am going to look at are more esoteric: i.e. why people get T2D and what things predispose a person toward T2D.

In spite of all of extensive searches, I was unable to come up with an explanation for why people get T2D. It is as big a mystery to the doctors and scientists researching T2D as it is to me. Gain some weight, lead a sedentary lifestyle, get T2D.

My personal theory is that we did not evolve to carry around this much extra “energy” for extended periods of time (i.e. years). For thousands of years mankind lived in an environment of feast and famine, with famine being more common than feast. In times of plenty it was a good survival strategy to save that excess food as fat. Then during lean times, like famine, war, drought, or illness, the energy stored as fat was there to bridge the gap, to provide sustenance that the environment was not providing.

Today people have a greater abundance of food available to them than any other time in history. Our bodies don’t know what to make of it. T2D is a message that the extra energy stores are FULL, there is no more room! Consequently, the sugars in the blood are unable to enter these “full” cells because those cells have stopped recognizing insulin. Unfortunately the message that one’s cells are full does not seem register with the appetite centers, or people would stop feeling hungry and stop eating when their cells were full.

Which brings up the question of why some people more likely to get T2D than others? My cousin has it but her husband doesn’t. A few things that influence your susceptibility to T2D are genetics, epigenetics, mysterious environmental factors, and diet.

Genetics you should be familiar with. We speak of getting our curly hair from our dad, or our eyes from our mom, and so we did. The program for making those traits is in your genes, one half of which you got from your mother and half from your father. We also inherit the propensity to get certain diseases from our parents. If a relative has T2D, you are more likely to get T2D. The closer that person is related to you –parents, siblings, aunts and uncles, grandparents- the more overlap there is in your genetic code, the greater the likelihood of you getting the same diseases.

Epigenetics is harder to define. It is one of the ways that the environment alters how the genetic code is read, and this modification is passed from parent to child. You inherit genes from your parents, epigenetic changes to the genetic code alters how those genes are expressed.

Some examples: if a woman was malnourished during her pregnancy her children have a higher probability of being overweight, getting T2D and schizophrenia. (Prenatal Famine and Adult Health, Annual Review of Public Health, Vol. 32: 237-62 (Volume publication date April 2011) and (http://www.clinsci.org/cs/095/0115/0950115.pdf).

What happens to a man prior to puberty has epigenetic consequences for his male children. Using birth records and records of crop production in northern Sweden, the Avon Longitudinal Study of Parents and Children (ALSPAC) has discovered some surprising links between fathers and sons. If food was scarce (crop failure resulting in famine) prior to the male child’s puberty, his sons have a lower risk of getting cardiovascular disease. But the boys who experienced years of really good crops (feast) before puberty have sons and grandsons with an increased mortality to T2D. (http://www.nature.com/ejhg/journal/v10/n11/full/5200859a.html)

Studies done in the UK have shown that if a man starts smoking before he goes through puberty his sons will have a higher body mass index, i.e. be overweight, which increases the risk of getting T2D. (http://www.nature.com/ejhg/journal/v14/n2/pdf/5201538a.pdf).

In essence, the environment our parents and grandparents grew up in alters our risk of getting certain diseases, including T2D. And what we do and have done has epigenetic consequences for our children. A sobering thought.

Being overweight or obese is the single biggest risk factor for T2D. In the USA, almost one third of the adult population is obese! It is an epidemic. And it isn’t just people who are getting fatter, animals are also getting fatter. In a study headed by David Allison the weight of 20,000 animals from 24 populations (feral as well as domestic) living with or around people in North America were analysed. Weights of animal groups from 50 years ago were compared to weights from the present. The surprising results were that feral rats got fatter as did house pets and laboratory animals (whose diet has presumably not changed).  It appears that there is something in the environment (a pollutant?) that is also making us gain weight. Or maybe the feral animals are eating our leftovers? (http://rspb.royalsocietypublishing.org/content/early/2010/11/19/rspb.2010.1890.abstract and http://www.the-scientist.com/news/display/57821/)

What we eat has changed over time. Fast food and processed food is far more available today than it was in the past. In a recent paper by Jenny P-Y Ting, macrophages (a component of the immune system) were exposed to palmitate, an unsaturated fat found in many processed foods. The macrophages released interleukin-1 beta, a substance released during inflammation. Interleukin-1 beta reduces insulin signalling in liver, fat and muscle cells. Put another way, the inflammation caused by palmitate “blinds” these tissues to the action of insulin. (http://www.nature.com/ni/journal/v12/n5/pdf/ni.2022.pdf) Being blind to insulin is the same as being insulin resistant. So one’s diet, specifically the fats in one’s diet, can lead to insulin resistance.

In the end, the best we can do is follow the advice given to us.  Exercise more, eat less, eat fewer processed foods and more fruits and vegetables, and keep our weight under control. The importance of exercise in the control of T2D cannot be understated. Get up and move your muscles! Exercise has decided health benefits, and if you have T2D it is especially true (http://www.medscape.com/viewarticle/739548?). Not only were we not meant to carry around fat for prolonged periods, we were not designed to be so sedentary either.

Additionally do not fall for the stereotype that only really fat people get T2D. I am constantly surprised at how little overweight one needs to be to get T2D. It could happen to any of us.

Here are some very good websites about diabetes:

http://www.diabetes.org/

http://www.resoundinghealth.com/page/embed?_url=http://www.joslin.org/about-joslin.html

http://www.diabetes.org.uk/

The website of the International Diabetes Federation. The statistics are frightening.  http://www.idf.org/diabetesatlas/

Dean Ornish’s TED talk. It is only 3 ½ minutes long, so watch it!http://www.ted.com/talks/dean_ornish_on_the_world_s_killer_diet.html

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The amazing potential of induced pluripotent stem cells (iPSC)

My interest in stem cells was heightened, even re-inspired, by a talk I saw recently at The Royal Society. Dr. Ian Wilmut, the man who created Dolly the sheep, the very first cloned animal, gave a brilliant and thought provoking talk about induced pluripotent stem cells (iPSC). I have read about iPSC but was not familiar with their incredible potential in investigating the biochemical basis of disease, in drug discovery, and for the treatment of many diseases and injuries.

Dr Wilmut started the talk with the question that has intrigued researchers for many years: “How does the single cell of the embryo become all of the tissues of the adult?” A cell with this ability is known as pluripotent, and the embryo is the perfect example of a pluripotent cell -in the course of embryogenesis it divides and differentiates into the 200 tissues present in the body. A similar point can be made about stem cells: they are not all created equal: some can become anything (i.e., are pluripotent), and some, such as adult stem cells, can only become certain types of cells (i.e., mulitpotent).1

In contrast to adult stem cells, the therapeutic potential of pluripotent cells seems limitless. You could use your pluripotent cells to replace any damaged or defective tissue in the body. Inject your pluripotent cells into a heart to replace cells damaged in a heart attack. Stimulate your pluripotent cells to become cartilage and repair a joint. And a myriad of other applications. However, until recently, the only source of pluripotent cell lines were embryos (embryonic pluripotent stem cell lines). Embryonic stem cells are pluripotent and grow for a very, very long time in tissue culture (essentially forever), making them ideal tools for research. As long as the embryos were from mice, rats or fruit flies, there were no problems. Human embryonic cell lines (hESC) are derived from human embryos, specifically from viable embryos that remained unused after in-vitro fertilisation and were destined to be destroyed. The use of a viable human embryo in this manner is seen as a violation of a life and as a consequence there are many who object to the use of human embryonic stem cells in research or at all. The controversy concerning the ethics of using cells derived from human embryos is not likely to go away.2

Fortunately there are alternatives to hESC lines, which are the induced pluripotent stem cells (iPSC) that Dr. Wilmut spoke of in his talk. iPSC are created from cells (usually adult skin cells) that have been induced to revert to their pluripotent state (no embryos destroyed!). iPSC lines share many of the desirable characteristics of hESC  in that they are pluripotent and grow for a very, very long time in tissue culture.

iPSC are made by reprogramming differentiated cells. The first iPSC were created by introducing four transcription factors into differentiated cells using retrovirus vectors. The process is inefficient, slow, and may make the cells cancerous, a danger of any therapy using retroviruses. Fortunately progress has been made overcoming these problems, and a new way to make iPSC was recently published. Dr Wilmut mentioned the work done by Derrick Rossi’s laboratory using synthetic messenger RNA was to reprogram the cells. The synthetic RNA method is faster and more efficient than the use of retroviruses, and had the added advantage that the DNA of the cells is left unaltered.

Another issue with hESC lines is that they represent an unknown genetic quantity. Dr. Wilmut observed that there is no knowledge of the genetic history of the embryo. Although many genetic defects can be tested for, one cannot predict what hidden defects the hESC lines may contain. In contrast iPSC are made from tissue donated by a person with a known medical history. This also allows for the possibility to make iPSC from people with specific diseases: with enormous potential for research and drug discover. For example Dr. Wilmut’s, laboratory is interested in the cause and cures for motor neuron disease. They have created an iPSC line from cells from a motor neuron patient and are using this iPSC to investigate the biochemical basis of the disease, and potential drug therapies.

Additionally, Dr. Wilmut envisioned making approximately 16 iPSC lines which would be compatible to most people (covering the major histocompatibility families). These cell lines could be used in the therapies outlined below negating the need, expense and time of creating individual iPSC lines for each patient, at least until making iPSC lines becomes as fast and easy as collecting the donor cells!

Below are some therapeutic areas where the uses of hESC lines are actively being investigated. iPSC lines could easily be used in place of the hESC in any of these treatments.

Spinal cord injuries: The biotech firm Geron has applied to the FDA and received approval to implant neural stem cells derived from hESC into people paralysed by severe injuries to the lower spine. The first treatment was performed in Atlanta, GA this week to a person with a recent spinal cord injury. It is a landmark moment as it is the first time that hESC lines have been used in a human in the USA. Concern over the appearance of cysts in test animals put the clinical trials on hold, but new screening procedures and animal tests reassured the FDA enough to allow the study to proceed.

Eyes: Advanced Cell Technology (ACT) has applied to the FDA for permission to use hESC-derived retinal pigment epithelium cells (RPEs) into the eyes of patients with Stargardt’s Macular Dystrophy. Treatment of age-related macular degeneration will probably follow Stargardt’s Macular Dystrophy as the next use of hESC-derived RPEs in human patients.

Parkinson’s disease: Geron is pressing forward with research into the use of hESC for the treatment of Parkinson’s disease. The hESC are differentiated into dopaminergic neurons3, which would be injected into the brains of patients with Parkinson’s disease. Preclinical trials are still being performed to assess the safety and efficacy of the treatment.

Skin: At the forefront of this field are Dr Christine Baldeschi and colleagues, of  the INSERM and Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-STEM, France), who have published an article in Lancet describing the use of hESC to make skin. The hESC were driven towards keratinocyte lineage pharmacologically. The cells were then grown in culture on an artificial matrix, which was then grafted onto mice. Twelve weeks after grafting the skin grafts had a structure similar to human skin. The possibilities these results open up are wonderful. Burn patients could receive larger skin grafts derived from hESC in addition to grafts made from their own skin. hESC-derived skin grafts could be used to rectify horrible skin diseases like epidermolysis bullosa. And hESC could possibly be induced to form palmo-plantar epidermis (PPE) for use on the ends of weight bearing stumps on amputees.

Heart: Biotech firm Geron pops up again. They have made cardiomyocytes4 from mouse embryonic stem cells, which when injected into heart muscle are stably integrated. Their hope is to use hESC-derived cardiomyocytes to treat congestive heart failure and repair damage caused by heart attacks.

Another field where iPSC or hESC would be of great help is in the generation of replacement organs. The major hurdles of figuring out how to engineer replacement organs seem to have been overcome. Dr. Shay Soker at Wake Forest University in North Carolina grew an artificial liver by taking animal livers and removing all of the cells using detergent leaving a collagen support structure. Immature liver cells and blood endothelial cells were added to the structure and incubated in a bioreactor. A week later there was formation of liver tissue and liver-associated function. Success! But the question of where are they going to get the cells for future livers, kidneys or pancreases remains? I think iPSC can be as good a source of cells, if not better, as hESC for these replacement organs.

In conclusion, this is why iPSC are so important: anything for which hESC have been or are being used iPSC can be used instead. They are pluripotent and therefore they have enormous potential to help cure many diseases, they can be used to investigate disease, and they can be used for drug screening. Additionally iPSC have the advantage over hESC in that they are socially acceptable and they are a known quantity genetically.

If you are interested in hearing Sir Ian Wilmut’s talk it will available soon on the following link: http://royalsociety.org/All-our-Web-casts/

For more information about the Centre for Regenerative Medicine and Dr. Wilmut’s current research follow this link: http://www.crm.ed.ac.uk/about

The paper by Derrick Rossi’s laboratory on the use of synthetic mRNA to make iPSC: Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Cell Stem Cell. 2010 Nov 5;7(5):618-30.


1 See my previous post “Adult Stem Cells and their changing dogma” for a more complete overview.
2 In 2001 president George W Bush restricted the use of federal funds to just a few hESC lines. The restrictions have since lifted, but the controversy remains.
3 i.e. neurons that make dopamine, which are the neurons that die in Parkinson’s disease.
4 Cardiomyocytes are heart muscle cells.
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Adult Stem Cells and the changing dogma

When I read news stories about stem cells I wonder if the general populace realizes that our bodies are full of stem cells, known as adult stem cells? That adult stem cells are an established and vital part of our treatment of cancer? And that adult stem cells are being tested in a large number of clinical trials to test their use against diseases as varied as epidermolysis bullosa, heart disease, and diabetes? I doubt it. The ignorance surrounding stem cells is astounding, especially considering the important role they play in treating cancer victims and more.

Some definitions first: Stem cells are progenitor cells that give rise to differentiated cells.  Most references to stem cells are for those cells that specifically give rise to a lineage of cells found in a specific tissue to replace cells lost to aging (wear and tear), disease or injury. They are known as adult stem cells and they are multipotent, able to only become a limited number of tissues. Pluripotent cells are stem cells that can become any tissue type. Pluripotent stem cells are also distinguished by their ability to replicate indefinitely. Multipotent adult stem cells divide for a very long (though still finite) time, and differentiated cells only divide for a limited number of divisions. I think of this as nature’s “planned obsolescence” program.

The stem cells that most people are familiar are blood (haematopoietic) precursor stem cells from bone marrow, which divide to become red and white (immune) blood cells. However they are not the only adult stem cells: dermal stem cells are the source of the different cell types present in skin, and hepatic stem cells divide to become the different cells in a liver, and so on throughout the body. Another source of haematopoietic stem cells is umbilical cord blood. Although it is taken from the umbilical cord of a baby, the baby is a fully differentiated human, and therefore the stem cells are adult stem cells, committed to making blood and immune cells like the adult stem cells from bone marrow.

The use of adult stem cells in medicine is wide spread, with bone marrow stem cells the most frequently used clinically. The high levels of chemotherapy or radiation therapy used to eradicate cancer can additionally kill the stem cells present in a person’s bone marrow, depriving them of their immune system and the ability to make red blood cells. In these cases the use of their own stem cells (an autologous transplant of cells taken prior to the radiation or chemotherapy) or stem cells from another person (an allogeneic transplant) are used to restore the patient’s immune system and red blood cells. In allogeneic transplants the donor must have similar immune system markers, known as the histocompatibility complex.

How common is the use of adult stem cells in medicine? ClinicalTrials.gov is a registry of federally and privately supported clinical trials conducted in the United States and around the world. Using “stem cell” in the search field yields 3275 clinical trials. My interest is in the number and kind of clinical trials being conducted consequently these numbers are all inclusive: clinical trials enrolling patients, active trials (not recruiting), terminated and suspended trials.

Narrowing down the search by using “autologous stem cells” yields 976 clinical trials. Of the first 100 trials listed, 85 trials were of cancer patients receiving their own bone marrow stem cells following chemotherapy or radiation therapy. Of the other 15 clinical trials, 14 investigate the use of blood marrow stem cells in the treatment of non-haemotopoietic diseases: seven trials were investigating the use of blood marrow stem cells to treat heart disease, two trials of blood marrow stem cells for the treatment of brain injury, two trials of blood marrow stem cells for the treatment of amyloidosis, one trial of blood marrow stem cells for the treatment of Crohn’s disease (inflammatory bowel disease), and one trial of blood marrow stem cells for the treatment of diabetes. There was one clinical trial using stem cells derived from the patient’s own fat cells (lipoasperates) for the treatment of anal fistula[1]. Recent research has indicated that adult stem cells are more pluripotent than originally thought and these 15 clinical trials are examining this hypothesis. I would like to emphasize that these are not the only clinical trials investigating the use of adult blood marrow stem cells for treatment of non-cancerous diseases, they are 15 out of the first 100 of 976 clinical trials in my search of the ClinicalTrials.gov website.

Another search of the ClinicalTrials.gov website using “umbilical stem cells” in the search field results in 150 clinical trials. What is surprising about the clinical trials listed is the amazing diversity of diseases for which the umbilical cells are being tested as a treatment. This is not a complete list but it gives an idea of the surprising variety of diseases in which the pluripotent potential of multipotent cells is being investigated: liver cirrhosis, ulcerative colitis[2], diabetes, critical limb ischemia, idiopathic dilated cardiomyopathy, bronchopulmonary displasia, epidermolysis bullosa[3], osteopetrosis, cartilage injury, cerebral palsy, inherited metabolic diseases, sickle cell anemia, and cytomegalovirus and adenovirus infection.

The dogma of adult stem cells being committed to certain cell lineages is being challenged with surprising results. I look forward to reading about the outcomes of these trials, and benefiting from the positive effect they will have on the treatment of disease in the future.

For more information about stem cells follow this link: http://www.isscr.org/public/adultstemcells.htm

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Is there more we could be doing for amputees?

Great advances have been made in prosthetics for amputees. These include the use of sensors, hydraulics and microprocessors in the prosthetics to provide the wearer with a more natural gait. Plastics, carbon fibre and other materials are used to make artificial limbs that are lighter and stronger. Specialized limbs have been developed for running, swimming and snow sports. But all prosthetics share a common weakness: the method by which they are attached. Custom sockets are moulded from the stump, a sock is fitted over the stump and the socket attached by belts, cuffs or suction. Any friction between the stump and the socket results in sores or abrasions that are extremely painful. These sores limit the use of any prosthetic and consequently impact the owner’s mobility. If the skin at the bottom of the limb could be made tougher, more resistant to mechanical stress, then these problems could be avoided. The skin on the palm of our hands or the bottom of our feet is known as palmo-plantar epidermis (PPE) and is far more capable of withstanding mechanical stress than normal epidermis. If there were a way of converting the skin at the end of a weight-bearing limb to PPE, many of the above mentioned problems would be alleviated.

In the immediate future a solution for this problem would be to graft PPE onto the bottom of the weight-bearing stump. Skin grafts are a relatively common medical procedure. Skin taken from the palm or bottom of the foot would continue to exhibit the characteristics of PPE after being placed on the new site. However there is not that much PPE available for use as donor skin for the grafts. Cultured epithelial autografts (CEA) is a technique developed for use on burn patients with only a small amount of skin available as donor skin. The ability to amplify a small amount of PPE into a larger surface area graft would be appropriate when used on an amputee given the small amount of PPE available as donor skin. Additionally scientists at the US Armed Forces Institute of Regenerative Medicine at Wake Forest, North Carolina, have recently developed a method of “printing” skin using an inkjet printer. This technology could used to create PPE skin grafts.

Ultimately the ideal solution would be a cream that one could rub on the stump causing the normal epidermis to transform into PPE. This is a very difficult task, as complicated as changing skin cells to heart cells, requiring one to alter the epigenetically set program of a differentiated cell. Is it possible to stimulate the expression of a protein in a cell where that protein is not normally expressed? Once a cell has differentiated the promoter sites are blocked by epigenetic modification of the DNA. Reprogramming cells has been done in vitro, (e.g. in stem cell research) but not in situ.

There are many factors that distinguish PPE from normal epidermis. The primary protein expressed by skin is keratin, which keratin is expressed being determined by cell type and degree of differentiation. Normal skin (interfollicular epidermis) predominantly expresses the K1-K10 pair, whereas in PPE K9 is prominently expressed in the thick epidermal ridges with K6, K16 and K17 in the thinner secondary ridges. Additionally PPE is thicker, does not have hair follicles, and is far more resistant to mechanical stress. Keratins clearly play a very important role in providing mechanical strength to skin. When there is a genetic defect in keratin the consequence is skin fragility. There is a good correlation between the severity of the genetic defect, how the function of the proteins is compromised, and the severity of the disease. Therefore increasing the level of K9 may increase the mechanical strength of skin, but this would have to be tested.

Another promising target to change the character of normal skin to make it more like PPE would be the HOXA13 gene. A paper by Rinn  and co workers* examines the role that HOXA13 plays in maintaining the distal specific transcription program in PPE fibroblasts. The HOX gene family of homeodomain transcription factors act to specify cell positional identity during development. In adult fibroblast HOXA13 is required to maintain the expression of WNT5A and the induction of K9. To put this more simply, HOXA13 is necessary for K9 expression and is responsible for maintaining a part of PPE identity during homeostasis and regeneration. However, because the experiments were done on cultured cells it is not possible to say how much of the character of PPE is determined by HOXA13. Again this hypothesis would have to be tested.

Ultimately a cream that toughened skin would transform the lives of the millions of amputees who do not have access to skin grafts, sophisticated medical facilities or good quality prosthetics. I am speaking of  the people who are the victims of senseless civil wars in Africa, of landmines laid in conflicts that are now over, of earthquakes (as in Haiti recently). It is worth pursuing.

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I would like to thank Jonathan Jones and Pierre Coulombe for their insight, advice and support. I would also like to thank Choleton Senior (a personal trainer at LA Fitness on Moscow Road, London) for providing inspiration and insight into the life of an amputee.

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*A dermal HOX transcriptional program regulates site-specific epidermal fate. Rinn JL, Wang JK, Allen N, Brugmann SA, Mikels AJ, Liu H, Ridky TW, Stadler HS, Nusse R, Helms JA, Chang HY. Genes Dev. 2008 Feb 1;22(3):303-7.

Pierre Coulombe    http://web1.johnshopkins.edu/coulombelab/index.php/Main_Page

Jonathan Jones       http://www.joneslab.northwestern.edu/Welcome.html

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