Monday, February 28, 2011

Vitamin D production from UV radiation: The effects of total cholesterol and skin pigmentation

Our body naturally produces as much as 10,000 IU of vitamin D based on a few minutes of sun exposure when the sun is high. Getting that much vitamin D from dietary sources is very difficult, even after “fortification”.

The above refers to pre-sunburn exposure. Sunburn is not associated with increased vitamin D production; it is associated with skin damage and cancer.

Solar ultraviolet (UV) radiation is generally divided into two main types: UVB (wavelength: 280–320 nm) and UVA (320–400 nm). Vitamin D is produced primarily based on UVB radiation. Nevertheless, UVA is much more abundant, amounting to about 90 percent of the sun’s UV radiation.

UVA seems to cause the most skin damage, although there is some debate on this. If this is correct, one would expect skin pigmentation to be our body’s defense primarily against UVA radiation, not UVB radiation. If so, one’s ability to produce vitamin D based on UVB should not go down significantly as one’s skin becomes darker.

Also, vitamin D and cholesterol seem to be closely linked. Some argue that one is produced based on the other; others that they have the same precursor substance(s). Whatever the case may be, if vitamin D and cholesterol are indeed closely linked, one would expect low cholesterol levels to be associated with low vitamin D production based on sunlight.

Bogh et al. (2010) recently published a very interesting study. The link to the study was provided by Ted Hutchinson in the comments sections of a previous post on vitamin D. (Thanks Ted!) The study was published in a refereed journal with a solid reputation, the Journal of Investigative Dermatology.

The study by Bogh et al. (2010) is particularly interesting because it investigates a few issues on which there is a lot of speculation. Among the issues investigated are the effects of total cholesterol and skin pigmentation on the production of vitamin D from UVB radiation.

The figure below depicts the relationship between total cholesterol and vitamin D production based on UVB radiation. Vitamin D production is referred to as “delta 25(OH)D”. The univariate correlation is a fairly high and significant 0.51.

25(OH)D is the abbreviation for calcidiol, a prehormone that is produced in the liver based on vitamin D3 (cholecalciferol), and then converted in the kidneys into calcitriol, which is usually abbreviated as 1,25-(OH)2D3. The latter is the active form of vitamin D.

The table below shows 9 columns; the most relevant ones are the last pair at the right. They are the delta 25(OH)D levels for individuals with dark and fair skin after exposure to the same amount of UVB radiation. The difference in vitamin D production between the two groups is statistically indistinguishable from zero.

So there you have it. According to this study, low total cholesterol seems to be associated with impaired ability to produce vitamin D from UVB radiation. And skin pigmentation appears to have little  effect on the amount of vitamin D produced.

I hope that there will be more research in the future investigating this study’s claims, as the study has a few weaknesses. For example, if you take a look at the second pair of columns from the right on the table above, you’ll notice that the baseline 25(OH)D is lower for individuals with dark skin. The difference was just short of being significant at the 0.05 level.

What is the problem with that? Well, one of the findings of the study was that lower baseline 25(OH)D levels were significantly associated with higher delta 25(OH)D levels. Still, the baseline difference does not seem to be large enough to fully explain the lack of difference in delta 25(OH)D levels for individuals with dark and fair skin.

A widely cited dermatology researcher, Antony Young, published an invited commentary on this study in the same journal issue (Young, 2010). The commentary points out some weaknesses in the study, but is generally favorable. The weaknesses include the use of small sub-samples.


Bogh, M.K.B., Schmedes, A.V., Philipsen, P.A., Thieden, E., & Wulf, H.C. (2010). Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation. Journal of Investigative Dermatology, 130(2), 546–553.

Young, A.R. (2010). Some light on the photobiology of vitamin D. Journal of Investigative Dermatology, 130(2), 346–348.

Friday, February 25, 2011

Is there a link between telomeres and dietary fiber?

New evidence published in Archives of Internal Medicine has it that eating more dietary fiber, particularly from whole grains, could lead to a longer life. The large study found a high-fiber diet reduced risk of heart disease and cancer, as well as infectious and respiratory illnesses.

This is great news for those eating diets high in fiber. What’s also interesting is that another reason why dietary fiber is protective to health is because of its influence on telomeres. Telomeres are the protective caps at the end of chromosomes, and their length is considered the closest way to measure lifespan in humans.

As reported in a prospective cohort study published in the March 2010 issue of American Journal of Clinical Nutrition (AJCN), telomere length is positively associated with higher fiber intake in women. Dietary fiber from whole grains appears to provide the strongest benefit.

In addition, in the AJCN study, the researchers found telomere length was negatively associated with increased waist circumference and higher intake of omega-6 fatty acids in the diet.

Because the study was only observational, the authors reported that further investigation is necessary to further illuminate the link between dietary fiber and telomere length.

Whole grains examples are rolled oats, buckwheat, whole wheat, and wild rice. The grains contain the entire grain kernel, which include the bran, germ and endosperm. Less than 5 percent of Americans consume the minimum recommended amount of whole grains, which is about 3 ounce-equivalents per day, according to U.S. Department of Agriculture.

Americans barely receive half the amounts of dietary fiber recommended daily. How much dietary fiber is enough? The recommended amounts are 25 grams of fiber for women and 38 grams of fiber for men.
The AJCN study was among the first to document the relationship between diet and telomere length. The authors of the study concluded that the results provided more support that an improved diet and lifestyle would indeed help to slow the aging process.

"Telomere shortening is accelerated by oxidative stress and inflammation, and diet affects both of these processes," the authors report.

Studies have also found that the following changes in diet and lifestyle are all positively associated with telomere length:
  •  not smoking
  • exercising regularly
  • maintaining a normal body weight
  • healthy management of stress
  • consuming sufficient long-chain omega-3 fatty acids from fish weekly
  • maintaining a healthy vitamin D status
  • consuming a quality multivitamin daily
  • consuming antioxidants such as CoQ10 and green tea

Park Y, Subar AF, Hollenbeck A, Schatzkin A. Dietary Fiber Intake and Mortality in the NIH-AARP Diet and Health Study. Arch Intern Med 2011.
Cassidy A, De V, I, Liu Y et al. Associations between diet, lifestyle factors, and telomere length in women. Am J Clin Nutr 2010;91:1273-80.

Post originally written to be posted here.

Wednesday, February 23, 2011

A Brightly Coloured Bell-Jar

I gave this paper to colleagues at the Centre for Medical Humanities last week and they are uploading it onto their Blog in three parts @  
(thanks again to Polly Morgan)

Tuesday, February 22, 2011

Pornography in the Primordial Soup

Panel of scientists debate on "What is Life?"

Sometime between 4 and 3.5 billion years ago, the emergence of life had intense beginnings on a young planet in the midst of a so-called primordial soup—consisting of water vapor, carbon monoxide, carbon dioxide, nitrogen, and ammonia and shaped by strong winds, electrical storms, volcanic eruptions, and ultraviolet radiation.

In 1953, Stanley Miller and Harold Urey put Earth's primitive conditions to test for the first time in a famous laboratory experiment. It yielded variety of amino acids and organic compounds. The researchers realized something more: that no early form of life could have ever survived the world of today, because of the presence of oxygen that directly attacks at the bonds that holds together complex molecules.

Scientists also now know that the original blueprint of life was not DNA, but short RNA strands that may have also served as their own biological catalysts, before enzymes ever evolved, providing for self-replication. This early RNA world would eventually give rise to DNA, which used RNA as its template for encoding the genetic information to build proteins.

Still, there are several other questions that remain surrounding life's origins such as How can life be defined? Where did it happen? What came first: replication or metabolism? Could life have happened elsewhere in the universe? What would an alternative form of life and biochemistry look like?

Last weekend, to discuss the questions, a small panel of six scientists gathered at workshop at Arizona State University with a major goal of charting out the steps between the RNA world and greater complexity. Some would say theirs was a hopeless cause and a waste of time.

Then, on Saturday, February 12, a public debate  took place between them with an overarching theme entitled, "What is Life?" Theoretical physicist and cosmologist Lawrence Krauss, ASU professor and director of ASU's Origins Project defended the exercise as uniquely human.

"It's a profound and deep question that hits at everything we think about," Krauss said, noting how the question has a powerful draw. "It sounds like a simple question, the answer isn't so simple. In fact, every time I think about that question, I think about pornography."

He referred to a 1964 Supreme Court case where Justice Potter Stewart once was asked to explain the definition obscene pornography. "I know it when I see it," the judge responded. Krauss said, "In some sense, life is like that."  

Life: Complexity with a Specified Direction

Evolutionary biologist Richard Dawkins further  elucidated the significance of the question in characteristic eloquence, "This may be the only planet in the universe that contains eyes to see it, brains to think about it, and wonder about it. I don't believe that. I suspect there is plenty of life in the universe, but this is the only kind of life we know about."

According to Dawkins, because the laws of physics apply all over the universe, it is likely that life could have materialized many times by the process of evolution by natural selection. Life, then, would have to be defined as anything that is highly statistically improbable, but that appears to have a specified direction.

"You have to add that 'specified direction' because with hindsight you could say any old heap of rubbish is statistically improbable in that there has never been a heap of rubbish exactly the same," Dawkins said. "What's special about life is that living things are statistically improbable in a direction, which you could have specified in advance. It's not always exactly the same, but birds are good at flying, fish are good at swimming, moles are good at digging. All living thins are good at something, whereas lumps of rock aren't.    

Whatever life is, it is characterized by its complex molecules that must somehow create the energy to convert raw material into a structure, all while excluding anything that may be toxic to those reactions of metabolism and reproduction. This is why geneticist and Nobel Laureate Lee Hartwell argued, "Inevitably, life will be cellular. Cells will have been selected to have an optimum size and optimum structure for whatever lifestyle they happen to have."

Searching for a Second Genesis

A sort of definition of what to look for was heartening for NASA planetary scientist Chris McKay, "What Lee said was a beautiful synthesis of how we can search for life, and I want to take that to the specifics of how do we do it in near tem missions in our solar system."

There is an advantage to finding other forms of life in our own solar system, argued McKay, because "then we'd know that life is common in the universe." The task of finding other forms of life in the solar system, even on our own planet, is one promoted by cosmologist and astrobiologist Paul Davies.

Davies doesn't see things quite the same way as McKay. "How can we find this second sample of life? Chris has said one way you can do that is you can go somewhere else in the solar system and find it there. That's great. But it's also very expensive. Is there another way? Well, no planet is more Earth-like than Earth itself. Shouldn't it have occurred many times right here on our home planet? How do we know it didn't?"

While Davies looks for alternative life on Earth—a process that he boldly claims can be completed in less than a decade—biologist and entrepreneur Craig Venter is more interested in creating synthetic life.

Venter explained how he and his colleagues synthesized DNA and chromosomes and inject it into E. coli, which he likened to creating a computer program that builds its own computer, or as he puts it, "A situation where the software actually leads to building its own hardware, but we're trying to go much further. We had to learn how to boot up this bacterial genome."

Change the DNA, change the software, and you change the species, Venter explained, and as others have pointed out, his team did use a living cell, but the cell was the first one to ever have synthetic DNA.

Living Artificial Intelligence

Among these scientists, one thing was certain: the definition of life could not be agreed upon in the face of alternative forms of life in the universe, in our own solar system, on the Earth, or from creating life from scratch. But, perhaps, a definition of life isn't needed after all because, as Krauss put it, anyway, it could change.

"Let me throw it in a completely different direction," Krauss offered in the debate."When computers become conscious, which they will—my Mac is far closer than the PC—will we call them life? And they'll object if we don't, I suspect. I think the definition is a moving target."

After all, the difference from what Venter is accomplishing—with software that makes its own hardware—and computers is that computers simply haven't done that yet (made their own hardware), but when they do, which will happen in at least one or two decades, Krauss said, "they will become the dominant forms of intelligent life on the planet and biology will have to incorporate that in order to keep up."

At the end of the debate, the inevitability of life in the universe was the lesson really learned, given that there could be life lurking almost anywhere.

Be it in a biological world, a  synthetic world, or another kind, life can defined as simply… we'll just know it when we see it.

To read more about the entire weekend conference on origins of life, see Dennis Overbye's article in the New York Times.

UPDATE: the science network has now published the video of this debate. Click on the video to watch below.

Monday, February 21, 2011

The China Study II: Wheat, dietary fat, and mortality

In this post on the China Study II data we have seen that wheat apparently displaces dietary fat a lot, primarily fat from animal sources. We have also seen in that post that wheat is strongly and positively associated with mortality in both the 35-69 and 70-79 age ranges, whereas dietary fat is strongly and negatively associated with mortality in those ranges.

This opens the door for the hypothesis that wheat increased mortality in the China Study II sample mainly by displacing dietary fat, and not necessarily by being a primary cause of health problems. In fact, given the strong displacement effect discussed in the previous post, I thought that this hypothesis was quite compelling. I was partly wrong, as you’ll see below.

A counterintuitive hypothesis no doubt, given that wheat is unlikely to have been part of the diet of our Paleolithic ancestors, and thus the modern human digestive tract may be maladapted to it. Moreover, wheat’s main protein (gluten) is implicated in celiac disease, and wheat contains plant toxins such as wheat germ agglutinin.

Still, we cannot completely ignore this hypothesis because: (a) the data points in its general direction; and (b) wheat-based foods are found in way more than trivial amounts in the diets of populations that have relatively high longevity, such as the French.

Testing the hypothesis essentially amounts to testing the significance of two mediating effects; of fat as a mediator of the effects of wheat on mortality, in both the 35-69 and 70-79 age ranges. There are two main approaches for doing this. One is the classic test discussed by Baron & Kenny (1986). The other is the modern test discussed by Preacher & Hayes (2004), and extended by Hayes & Preacher (2010) for nonlinear relationships.

I tested the meditating effects using both approaches, including the nonlinear variation. I used the software WarpPLS for this; the results below are from WarpPLS outputs. Other analyses of the China Study data using WarpPLS can be found here (calorie restriction and longevity), and here (wheat, rice, and cardiovascular disease). For yet other studies, click here.

The graphs below show the path coefficients and chance probabilities of two models. The one at the top-left suggests that wheat flour consumption seems to be associated with a statistically significant increase in mortality in the 70-79 age range (beta=0.23; P=0.04). The effect in the 35-69 age range is almost statistically significant (beta=0.22; P=0.09); the likelihood that it is due to chance is 9 percent (this is the meaning of the P=0.09=9/100=9%).

The graph at the bottom-right suggests that the variable “FatCal”, which is the percentage of calories coming from dietary fat, is indeed a significant mediator of the relationships above between wheat and mortality, in both ranges. But “FatCal” is only a partial mediator.

The reason why “FatCal” is not a “perfect” mediator is that the direct effects of wheat on mortality in both ranges are still relatively strong after “FatCal” is added to the model (i.e., controlled for). In fact, the effects of wheat on mortality don’t change that much with the introduction of the variable “FatCal”.

This analysis suggests that, in the China Study II sample, one of wheat’s main sins might indeed have been to displace dietary fat from animal sources. Wheat consumption is strongly and negatively associated with dietary fat (beta=-0.37; P<0.01), and dietary fat is relatively strongly and negatively associated with mortality in both ranges (more in the 70-79 age range).

Why is dietary fat more protective in the 70-79 than in the 35-69 age range, with the latter effect only being significant at the P=0.10 level (a 10 percent chance probability)? My interpretation is that, as with almost any dietary habit, it takes years for a chronically low fat diet to lead to problems. See graph below; fat was not a huge contributor to the total calorie intake in this sample.

The analysis suggests that wheat also caused problems via other paths. What are them? We can’t say for sure based on this dataset. Perhaps the paths involve lectins and/or gluten. One way or another, the relationship is complex. As you can see from the graph below, the relationship between wheat consumption and mortality is nonlinear for the 70-79 age range, most likely due to confounding factors. The effect size is small for the 35-69 age range, even though it looks linear or quasi-linear in that range.

As you might recall from this post, rice does NOT displace dietary fat, and it seems to be associated with increased longevity. Carbohydrate content per se does not appear to be the problem here. Both rice and wheat foods are rich in them, and have a high glycemic index. Wheat products tend to have a higher glycemic load though.

And why is dietary fat so important as to be significantly associated with increased longevity? This is not a trivial question, because if too much of that fat is stored as body fat it will actually decrease longevity. Dietary fat is very calorie-dense, and can be easily stored as body fat.

Dietary fat is important for various reasons, and probably some that we don’t know about yet. It leads to the formation of body fat, which is not only found in adipocytes or used only as a store of energy. Fat is a key component of a number of important tissues, including 60 percent of our brain. Since fat in the human body undergoes constant turnover, more in some areas than others, lack of dietary fat may compromise the proper functioning of various organs.

Without dietary fat, the very important fat-soluble vitamins (A, D, E and K) cannot be properly absorbed. Taking these vitamins in supplemental form will not work if you don’t consume fat as well. A very low fat diet is almost by definition a diet deficient in fat-soluble vitamins, even if those vitamins are consumed in large amounts via supplements.

Moreover, animals store fat-soluble vitamins in their body fat (as well as in organs), so we get these vitamins in one of their most natural and potent forms when we consume animal fat. Consuming copious amounts of olive and/or coconut oil will not have just the same effect.


Baron, R. M., & Kenny, D. A. (1986). The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. Journal of Personality & Social Psychology, 51(6), 1173-1182.

Preacher, K.J., & Hayes, A.F. (2004). SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behavior Research Methods, Instruments, & Computers, 36 (4), 717-731.

Hayes, A. F., & Preacher, K. J. (2010). Quantifying and testing indirect effects in simple mediation models when the constituent paths are nonlinear. Multivariate Behavioral Research, 45(4), 627-660.

Sunday, February 20, 2011

Clore Fellowships; just what happened next to the Sneezing Man and Who Cares?

An invitation to apply for a Fellowship on the Clore Leadership Programme
The Clore Leadership Programme is currently inviting applications from exceptional individuals with the potential to take on significant leadership roles within culture. Sponsored by the Cultural Leadership Programme, these Fellowships are open to candidates with at least 5 years' paid work experience either in employment, self-employed or freelance, usually in the cultural sector. Applicants should be able to demonstrate a knowledge, understanding and passion for culture. The Fellowship Programme aims to shape emerging creative leaders through in-depth learning, tailored as far as possible to the needs, aspirations and circumstances of about 20 individuals a year. Fellows also benefit from unparalleled access to senior cultural leaders and to extensive networks.
The closing date for all applications is by 12 noon, 11 March 2011. For further details on the Programme and to access the online application form, please visit

Who Cares?
Friday 15 April 1 – 4.30pm, Whitworth Art Gallery
Free but booking is required as places are limited
Museums, health and wellbeing is a partnership between healthcare professionals, six major museums in the North West and researchers from the Psychosocial Research Unit at the University of Central Lancashire. The programme is showing how museums can help to improve the health and wellbeing of participants. Some of the work is about enriching lives through handling objects, looking at art or making art. Other projects, when working closely with health professionals, directly address the participants’ mental state.
For more information contact: Myna Trustram:
To book: 0161 275 7450

Comics and Medicine Conference
(In the USA, but very interesting)

Dr Langley Brown
Arts for Health is thrilled to be working with Dr Langley Brown on the development of its International Arts and Health Archive which is now housed within the Faculty of Art and Design’s Righton Building. We very much hope that this resource will be available to the public very soon.

Online arts funding sites
Art projects are showcased for funding by the public, and receive online sponsorship/pledges from the public to secure funding (known as crowd funding). A useful development in online networking for supporting of the arts.
A plea for Final Cut Studio training for Clive
If anyone offers introductory training in Final Cut Studio, please can you email Clive with the details? Many thanks.

What happened next to the sneezing man?


Evolution of Lactose Tolerance in Africa

Sarah Tishkoff
Most African populations have lactose intolerance, but as recently as 3 kya a few pastoral populations have gained the ability to digest milk, which provides evidence of yet another example of ongoing evolution in human population since the time of their origins.

Sarah Tishkoff has been studying this phenomenon of recent lactose tolerance in African pastoralist populations. She shared her findings on Sunday morning at #AAASmtg in Washington DC.

The ability to digest milk as infants is with the expression of lactase-phlorizine hydrolase (lactase), which is specifically expressed by brushborder cells in the small intestine.

But shortly after weaning, the expression of lactase decreases sharply -- that is, except in populations that are lactase persistent. In 2002, an elegant genetic study found the gene for lactase in European populations.

Tishkoff showed us in charts and on a map how she performed genetic studies on the African pastoralist populations with lactase tolerance. Based on the findings, she found a perfect example of convergent evolution -- that several of the populations had developed lactose tolerance in different ways genetically -- because of strong selective pressures to drink milk.

With her latest study and archeological data, she is now tracking the origins of pastoralism. She showed us a map (Smith 1992) where it's clear that most lactose tolerance emerged only in the last few thousand years, but at different times. Her research confirms that pastoralism was brought into southern Africa only recently, most likely from the Great Lakes region.

"So, are humans still evolving? Yes," Tishkoff said.

Why was milk selective pressure so strong? There has been a lot of debate, Tishkoff said, such as whether it is the source of water, protein, or calcium. But it's not everywhere, so there has to have been a cultural transformation in each region.

"There's only some environments that can handle that cultural development," Tishkoff said, but in each case, there has to be an underlying genetic variation and the different variants suggest that perhaps for some populations had a more difficult time with the change or took longer to adapt to it than others.

The Nature of Human Skin Pigmentation

Nina Jablonsky
On Sunday morning at #AAASmtg in Washington DC, Nina Jablonski talked to use about human skin pigmentation as an example of natural selection.

"Human skin is colorful, it's mostly naked, it's sweaty, and it's tough yet sensitive," Jablonski said. The gradient of human skin pigmentation is very clear in the old world, as it's lighter in the northern countries and darker in Africa.

But why did human skin pigmentation evolve as it did? When you look at other apes and humans, our relatives have lightly pigmented skin covered by dark hair -- this was the ancestral pigmentation of our lineage.

"When you think of Lucy's species, you can think of lightly pigmented skin covered by dark hair," she said, noting that eventually as the hominins became more naked they developed more melanin.

When Homo ergaster 1.6 mya was foraging in the savannah, the species would have needed more naked and sweaty skin for keeping cool. In addition, Jablonski's research has found that permanent dark pigmentation evolved 1.2 mya, at the same time as these other developments -- an interesting development!.

Exposed skin could lead to disease states, so by increasing the amount of pigmentation, H. ergaster protected the species and the pigmentation was selected on.

Ultraviolet radiation (UVR) had a lot to do with the advent of darker skin pigmentation. On a map (by George Chaplin based on NASA TOMS7 satellite data) of annual average UVR, Jablonski was able to clearly show the strength of UVR.

"We evolved initially in equatorial Africa and then we had two waves of dispersal from Africa," Jablonski said. "This really changed the selective genes for human skin fundamentally."

The key thing about ultraviolet radiation is that wavelengths do different things to the human body. In general, UVR does a lot of damage, such as DNA damage leading to skin cancer.

Skin cancer generally affects people as they're older beyond their reproductive years. However, the sun has a definitive effect on folate metabolism. One of the key things we see as important, is the effect on folate metabolism on birth defects. Because folate is needed for making DNA and the competition for folate is intense in the presence of UVR,  "why not increase the amount of melanin -- a superb natural sunscreen -- the evolution of permanent melanin was extremely important in high equatorial radiation levels."

However, melanin comes with a downside. It slows production of vitamin D precursor in the skin, which is essential for calcium metabolism and bone health, as well as incredibly important to the maintenance of a strong immune system.

If we look at our hairy timeline, 6 mya we had hair and light skin, then with dispersal from Africa into India and Asia, then eventually Indonesia and Europe, what did UVR have as an influence?

To Jablonski, it is the combination of needing to protect against DNA damage and folate metabolism as much as possible, but while naturally selecting for less skin pigmentation for keeping the skin light enough to absorb enough UVB rays to create vitamin D.

Indeed, we have an independent evolution of depigmentation of humans in Asia and in Europe. And we also know that the Neandertals experienced the same selection of depigmentation. There are many genes involved in pigmentation and Jablonski said she has even found in some populations, where the amount of UVR changes by season, that people have adapted to change the amount of melanin in their skin throughout the season

Nowadays, accelerated rates of movement around the world, has put humans in environments that are poorly matched, Jablonski said, which has created serious health problems such as with rickets in children, birth defects, and even metabolic syndrome.

For the purposes of education on health, we need to teach that skin color is an adaptation. It is the most visible product of evolution by natural selection on the human body. This is why we need to use it to teach evolution, Jablonski said.

Additional note posted Tuesday, Feb 22. I discovered afterward that Jablonski has a wonderful TED talk that I think everyone should watch, so I posted it below.

Saturday, February 19, 2011

Designing biology

Photo credit: Sara Fulcher on Flickr
Where can we find a cure for cancer, new semiconductor technology, or the solution for turning waste plant materials into biofuels? The answer is enzymes that are produced through "directed evolution," according to Frances H. Arnold, professor of chemical engineering and biochemistry at the California Institute of Technology.

Arnold's lab doesn't synthesize enzymes as other labs do. She and her team "evolve them" toward a certain desired goal in the same way that nature has done it for 3.5 billion years.

Aronold presented an overview of her budding field of work to an audience at American Association for the Advancement of Science annual meeting (#AAASmtg) in Washington DC. The field of directed evolution is relatively new and includes few people at the present time, but Arnold sees high hopes for the future.

"When I started engineering proteins a long time ago, there appeared to me an algorithm that dos a really good job and that's evolution," she said. "Evolution works because the regions that life has discovered and explored are rich in function. Directed evolution exploits smooth paths in the fitness landscape."

The fact is, DNA is cheap and easy. Designing it isn't.

"We're getting really good at making DNA. The price is dropping every day," Arnold said. "But we don't know what to write. We can synthesize any sequence. We can insert new code (referring to Craig Venter's recent success), but we don't know how to write it. We don't even know how to write a single protein."

And, when it comes to enzymes for use inside a complex biological system, she says,"Details matter. We don't understand the details."

Freed from constraints of worrying about biological function, directed enzyme evolution allows Arnold's team to explore new pathways and possibilities.

Arnold presented a few of her enzymes that have been created through directed evolution. Her source materials are from every possible place -- the "heel of your shoe," for example -- and she doesn't limit herself to what's available.

Frances Arnold
By combining several different enzymes and selecting for specific active sites, she can produce more stable proteins that perform practical work.

Where is directed enzyme evolution going in the future? Arnold says that functional protein can be used in several ways. One example Arnold gives is in materials chemistry, such as the work of Angela Belcher of MIT, who uses virus proteins to enrobe minerals onto protein coats.

"You can make a virus that really loves to bind to a single-walled carbon nanogen," Arnold said, which would be a boon for semiconductor technology.

There is really no end to the influence that directed enzyme evolution could have on the world, from highly specific targeting in biological systems to technology.

In short, there's no doubt of an exciting future in intelligently designing new biology.

How environmental change shaped human evolution

Anna Di Rienzo
Humans originated in Africa and then dispersed all over the world to environments that differ in terms of climate, biodiversity, etc, which has brought selective pressures on different populations. At #AAASmtg in Washington DC on Saturday, Anna Di Rienzo presented her research on the how this dispersal has left signatures of adaptation to the pressures. Here are my notes from the talk.

The "Out of Africa" theory has it that humans left Africa 50 Kya and then Neolithic revolution happened 14 Kya. They shifted away from foraging subsistence to horticulture. We also know that levels of human skin pigmentation changed with latitude of populations. In addition, body size and proportions changed. For example, Inuit have quite different proportions for the cold North.

Metabolic traits differ across human populations also, causing disease related traits to occur such as high blood pressure, high triglycerides, or high cholesterol. A prominent example is the rising prevalence of type 2 diabetes. "It's been long proposed that it’s a [genetic] susceptibility to change in lifestyle and diet," Di Rienzo said.

There is a prevalence of inter-ethnic differences in disease and traits. Environmental risk factors clearly play a role in shaping differences. There is a growing conseus that genetic factors also contribute. Is there evidence for genetic – in addition to cultural and physiological – adaptations? How much of the phenotypic diversity is adaptive? What is the contribution of local adaptive traits?

These question led to many studies on signals based on haplotype structure such as lactase persistence, which is common in Europe and in agropastoralist populations, but rare elsewhere. The ability to digest milk in adult life became advantages with the introduction of animal farming, Di Rienzo said. Another example is the FY allele that is fixed in most sub-saharan Africa and is virtually absent everywhere else. FY codes for a chemokine receptor (antimalarial).

Selection for polygenic traits is expected to generate subtle changes in allele frequency at multiple loci. Standard approaches are unlikely to capture these signals. The signature of selection is for monogenic (small shifts) versus polygenic traits.

Her approach is for search of information about environmental selective pressures. She searches for correlations between alledle frequency and environmental variables. She takes into account the geographic structure of human populations shaping distribution.

She used a large dataset of more than 642,000 autosomal SNPs. Environmental variables included climate, ecoregion, and subsistence. Climate includes seasons, ecoregion with temperature, humidity. The genome-wide evidence for environmental adaptations is that most of the genome doesn’t contain genes or variants that affect the function of the genes.

Natural selection acts only on variants that have both functional and phenotypic effects. Is there an excess of test SNPs relative to control SNPs among those with lowest minimum p-values?

The test SNPs used are enriched for SNPs with functional effects. Control SNPs are unlikely to have functional effects (e.g. far from genes).

In all cases, a significant excess of the test relative to control SNPs indicating that environmentals select pressures shaped the geographic distribution of variation in the human genome.

The results suggested genome-wide evidence for environmental adaptations,” Di Rienzo said.

Pancreatic lipase-related protein 2 hydrolyzes galactolipids, is the main component in plants. The truncated PLRP2 protein, which occurs at a higher frequency in those populations with higher consumption of cereal grains. PLRP2 is associated with cereal rich diet.

Two examples of patterns at individual SNPs are “foraging” and “nonforaging” and she shows a slide with patterns showing differences in Africa, Europe and other. In each geographic location, there is a shift in allele frequency that allude to differences in diet of the populations.

The shift in allele frequency is not dramatic, but small. The top signals are with categorical variables like roots & tubers, foraging, polar ecoregion, and a dry ecoregion. Top climate variables have to do with seasons.

“Selection doesn’t act on genes, it acts on phenotypes. The phenotypes are enriched with signals for environmental correlations,” Di Rienzo said.

Disease classes are influenced by environmental selective pressures. Climate influenced cancer, CVD, immune, infection. Subsistence influenced metabolic and reproduction phenotypes. 

The overlaying signals of environmental correlations and genome-wide association studies show this flow:

SNP is affected by environmental correlations and GWAS, then selective pressures produce phenotype. It’s also known that pathogen diversity follows a gradient on climate factors, which can affect immune, autoimmune adaptations.

Di Rienzo made these conclusions from the data:

- Strong GWAS to climate, ecoregion and subsistence
- Signal of adaptation to environmental pressures are subtle, but consistent shifts in allele frequency
- Adaptation to local environ and common disease may have similar gene architecture
- Signals of climate correlations make a contribution to diseases of immune response and pigmentation traits

More information can be found at dbCLINE

Wednesday, February 16, 2011

How much vitamin C do you really need?

Note: Vitamin C is fascinating topic and there's no better way to understand it than through the eyes of my boss, Dr. Rockway. I'm glad I had the pleasure of editing her article and posting it here. David

By Susie Rockway, Ph.D.

Vitamin C, or ascorbic acid (ascorbate), is the most frequently taken dietary supplement in North America. Yet, despite its widespread use, national surveys report that 15 percent of the population still doesn't get enough vitamin C to meet recommended amounts for health.

Initially, the Recommended Daily Intake (RDI) for vitamin C was set at 60 milligrams, the amount required to prevent scurvy. The deficiency disease—commonly characterized by bleeding gums and loosened teeth helped identify the vitamin as having an essential role in collagen formation.

However, more recent research has now made it clear that more dietary vitamin C is needed to saturate body tissues such as the brain, heart, liver, and adrenal glands.

Consequently, in 2000, the RDI was raised to 90 and 75 milligrams daily for men and women. The new values were based on studies suggesting that plasma vitamin C should be maintained at specific levels (~80 µmol/L) for good health and antioxidant activity.

This is how the "debate on how much of vitamin C is needed" began—with scientists discussing two questions:
  • How much vitamin C is really needed to make an impact on plasma levels?
  • Are plasma levels really the best indication of tissue saturation levels?
Of Mice and Vitamin C

While there is still not any consensus on this matter, a new, carefully designed study just published in the February issue of American Journal of Clinical Nutrition provides some clues for answering these questions.

In the study, New Zealand researchers compared "normal" mice vitamin C tissue saturation levels with "knockout" mice that were genetically engineered to lack the enzyme needed for synthesizing vitamin C in the body.

Without dietary vitamin C, they saw that tissue concentrations of ascorbate became deficient weeks before the onset of scurvy symptoms in the mice, similar to humans. During these weeks, the scientists observed that the mice exhibited signs of impaired collagen synthesis, changes in aortic wall structure, formation of atherosclerotic plaque, and activation of inflammatory processes.

Sustaining Tissue Concentration

The scientists observed that each tissue became deficient at different rates. For example, the brain maintained its vitamin C longer than other organs; however, after just two weeks of deficiency, vitamin C in the brain became depleted. To replenish these tissues to normal levels, plasma concentration had to be maintained saturated with daily ascorbate intakes.

In addition, they found that tissue levels of ascorbate became saturated more quickly when the mice ate kiwi fruit versus sodium ascorbate in water—the flavonoids present in kiwi are thought to enhance absorption of vitamin C by maintaining it in a reduced state (versus an oxidized state).

Lastly, based on the new evidence, the researchers wrote that the current RDI should receive no less than a 60 percent boost—from 75 milligrams per day to at least 120 milligrams per day—to keep not only plasma levels saturated, but also tissue levels of the brain, and organs that are unable to be measured with current methods.

The vitamin C researchers stressed the need for people to maintain an ongoing and constant vitamin C intake to sustain tissue concentration—which means consuming the scientists' recommended amounts regularly.

What Weight Has to Do with Vitamin C

Another less well-known role of vitamin C is its involvement as a cofactor in the biosynthesis of carnitine, a molecule required for burning fat as energy fuel (fatty acid oxidation).

Interestingly, there is a direct inverse relationship with obesity (adiposity) and plasma vitamin C concentrations—as plasma ascorbate levels are decreased, fatty tissue increases (adiposity increases).

This association has led researchers to wonder whether or not decreased vitamin C levels cause less carnitine to be synthesized and if there is a relationship between less carnitine and less burning of fat for fuel.

Preliminary findings are that subjects who are vitamin C depleted have lower levels of carnitine leading to a 25 percent decrease in fatty acid oxidation (per kilogram body weight) than individuals whose vitamin C status is adequate.

The researchers speculate that reduced fat oxidation seen with vitamin C depletion may result in weight gain by two mechanisms:
  • Indirectly, decreased carnitine leads to increased fatigue during exercise and this may lead to exercise intolerance
  • Directly, by lipid (fat) accumulation
The prevalence of obesity in the world currently has led researchers to suggest that more attention is needed to the problem of vitamin C deficiency affecting at least 15 percent of the population, if not more.

  1. Vissers MCM, Bozonet SM, Perason JF and Braithwaite LJ. Dietary ascorbate intake affects steady state tissue concentrations in vitamin C-deficient mice: tissue deficiency after dietary ascorbate intake affects steady state tissue concentrations in vitamin C-deficient mice: tissue deficiency after suboptimal intake and super bioavailability from a food source (kiwifruit). AJCN 93(2):292-301, 2011.
  2. Johnston CS, Corte C and Swan PD. Marginal vitamin C status is associated with reduced fat oxidation during submaximal exercise in young adults. Nutr & Metab 3(35):1-5, 2006.

Sunday, February 13, 2011

Does protein leach calcium from the bones? Yes, but only if it is plant protein

The idea that protein leaches calcium from the bones has been around for a while. It is related to the notion that protein, especially from animal foods, increases blood acidity. The body then uses its main reservoir of calcium, the bones, to reduce blood acidity. Chris Masterjohn does not agree with this idea. This post generally supports Chris’s view, and adds a twist to it, related to plant protein consumption.

The “eat-meat-lose-bone” idea has apparently become popular due to the position taken by Loren Cordain on the topic. Dr. Cordain has also made several important and invaluable contributions to our understanding of the diets of our Paleolithic ancestors. He has argued in his book, The Paleo Diet, and elsewhere (see, e.g., here) that to counter the acid load of protein one should eat fruits and vegetables. The latter are believed to have an alkaline load.

If the idea that protein leaches calcium from the bones is correct, one would expect to see a negative association between protein consumption and bone mineral density (BMD). This negative association should be particularly strong in people aged 50 and older, who are more vulnerable to BMD losses.

As it turns out, this idea appears to be correct only for plant protein. Animal protein seems to be associated with an increase in BMD, at least according to a study by Promislow et al. (2002). The study shows that there is a positive multivariate association between animal protein consumption and BMD; an association that becomes negative when plant protein consumption is considered.

The study focused on 572 women and 388 men aged 55–92 years living in Rancho Bernardo, California. Food frequency questionnaires were administered in the 1988–1992 period, and BMD was measured 4 years later. The bar chart below shows the approximate increases in BMD (in g/cm^2) for each 15 g/d increment in protein intake.

The authors reported increments in BMD for different increments of protein (15 and 5 g/d), so the results above are adjusted somewhat from the original values reported in the article. Keeping that in mind, the increment in BMD for men due to animal protein was not statistically significant (P=0.20). That is the smallest bar on the left.

Does protein leach calcium from the bones? Based on this study, the reasonable answers to this question are yes for plant protein, and no for animal protein. For animal protein, it seems to be quite the opposite.

Even more interesting, calcium intake did not seem to be much of a factor. BMD gains due to animal protein seemed to converge to similar values whether calcium intake was high, medium or low. The convergence occurred as animal protein intake increased, and the point of convergence was between 85-90 g/d of animal protein intake.

And high calcium intakes did not seem to protect those whose plant protein consumption was high.

The authors do not discuss specific foods, but one can guess the main plant protein that those folks likely consumed. It was likely gluten from wheat products.

Are the associations above due to: (a) the folks eating animal protein consuming more fruits and vegetables than the folks eating plant protein; or (b) something inherent to animal foods that stimulates an increase in the absorption of dietary calcium, even in small amounts?

This question cannot be answered based on this study; it should have controlled for fruit and vegetable consumption for that.

But if I were to bet, I would bet on (b).


Promislow, J.H.E., Goodman-Gruen, D., Slymen, D.J., & Barrett-Connor, E. (2002). Protein consumption and bone mineral density in the elderly. American Journal of Epidemiology, 155(7), 636–644.

Thursday, February 10, 2011

Why dark chocolate is good for her heart

Listen up, men! On this Valentine's Day, why not surprise your special lady with chocolates that are healthier for her heart? Dark chocolate eaten in moderate amounts weekly is associated with improved cardiovascular fitness in women, research suggests.

Scientists are only beginning to understand why dark chocolate is heart healthy, but a new study offers this explanation—its rich content of cocoa antioxidant compounds, called polyphenols, could enhance activity of special proteins called sterol regulatory element binding proteins (SREBPs), which are involved in cholesterol metabolism.

These activated SREBPs then bind to genes on DNA (sterol regulatory element sequences) that boost liver production of another protein called apolipoprotein A1 (ApoA1), which is the major protein component of HDL "good" cholesterol.

Correspondingly, cocoa polyphenols also decreased production of another protein in the liver called apolipoprotein B (ApoB), which is the major protein component of LDL "bad" cholesterol. The study also showed cocoa polyphenols induced activity of LDL receptors, allowing more cholesterol to be removed from the bloodstream.

The scientist’s findings—suggesting that polyphenols in dark chocolate may help maintain higher “good” cholesterol levels and lower "bad" cholesterol levels—were published in the February issue of Journal of Agricultural and Food Chemistry, published by the American Chemical Society.

The researchers write, "As cholesterol metabolism is known to be regulated by several different mechanisms, it is possible that cacao polyphenols may act on multiple pathways as a regulatory receptor agonist or ligand, similar to other plant polyphenols."

So, what's the message you give with dark chocolate? Romance, of course – but with a healthy twist for your sweetheart's heart.

Source: Yasuda A, Natsume M, Osakabe N, Kawahata K, Koga J. Cacao Polyphenols Influence the Regulation of Apolipoprotein in HepG2 and Caco2 Cells. J Agric Food Chem 2011.

Monday, February 7, 2011

Film Show, Training, Residencies, Congratulations, Statistics and a Big Walk...

Witam wszystkich zainteresowanych sztuką i zdrowiem. Dziękuję że odwiedziliście mój blog. Jeżeli macie jakieś pytania odnośnie naszej działalności, piszcie do mnie. Pozdrawiam, Clive

Looking at the traffic on the blog, and who stayed on line to read the last article on 'happiness,' it's interesting to see that whilst the UK (green 83%) accounted for just over three-quarters of traffic, the USA followed next (blue 9%), followed Australia (red 4%); Poland (yellow 3%) and France (purple 2%). We also had traffic from Russia; China; South Korea; India; Puerto Rico: Germany and the Netherlands.
Whoever you are...if you're interested and want to get involved, please get in touch at
Thank you to everyone who left comments and all those who got in touch via email. 
Now: those opportunities!

RNCM Music for Health is delighted to be running a programme of music residencies at the Royal Manchester Children’s Hospital throughout 2011. The project, Medical Notes, is funded by Youth Music.
We are looking to appoint three vocalists or instrumentalists of graduate or comparable musical level and with previous experience of making music with people in health care settings to train alongside our lead musicians. The training will comprise observation of lead musicians, workshop sessions, one-to-one mentoring and supervision, artistic exchange with guest artists and running three mentored 10-week residencies at the Royal Manchester Children’s Hospital.

This is a unique opportunity for musicians with initial Music for Health experience to further develop their skills and to develop an expertise of working with hospitalised children and young people.
A training fee of £1825 is available for each trainee.

To apply, please submit your CV and expression of interest by Thursday 17 February 12 o’clock noon. Interviews and auditions for shortlisted candidates will be held on Tuesday 8 March at RNCM.

For full details, contact: Lilli Brodner-Francis
              Thanks to Melissa Laishley and Rob Vale
LIME Artist Residencies
Lime is offering free work space for up to 4 artists, one shared studio and two desk spaces in a single office/room.   Artists will have access to resources including broadband, shared use of a van, office equipment, health and arts networks, research material and information. The term of occupancy is two years with a 4 month probationary period and selected artists will be offered a contract. By way of exchange each artist will give the equivalent of 1 day per month of their time, e.g. workshop delivery, work produced or mentoring less experienced artists. 

This offer will afford the opportunity for the artist to have a physical base to work from, to work alongside other artists, to explore the arts and health context and to communicate their work within the health service to a very large and diverse audience.

All art forms will be considered. In the past we have hosted visual artists, sculptor/makers, a drama worker and a creative writer. Applications from BME artists will be of particular interest. The studio space to be shared by two artists measures 4m by 10m and has natural light on one side, power points, band saw and mixed tools and equipment. The two desk spaces will share one room.  Lime is accessed by a single double door entrance on the ground floor. The building is old and not yet converted for wheelchair access.

Selection and interviews will be conducted by Lime Lead artists and Director with one external representative.

There is no formal application pack. Please send an expression of interest via email to Your application should include: 
  • An outline of your creative practice and how this opportunity may enhance it (max 2 sides A4)
  • Six examples of your best work
  • A current CV
Application Deadline: 15th February 2011
Interview date: 8th March 2011
Start Date: 5th April
Lime information:

A BIG Walk
In May 1986, during half time at the F.A. Cup Final Tony Russell completed a lap of honour before embarking on a mammoth 2,355 mile unique charity walk (pictures  featured below)  to every professional Football Club in England and Wales, before his triumphant return to Wembley Stadium at half-time on Charity Shield day three months later in August.

In 2011, 25 years later, at the age of 56, Tony plans to complete another epic walk. Last time, his twin aims were to raise money for Cancer Research and to improve the image of football fans following the Heysel Stadium tragedy. This time, Tony wants to raise awareness of mental health issues and the value of the creative arts as an aid to recovery; and to pay a personal tribute to the bravery of the nation’s Armed Forces, many of whom now experience severe mental distress.

Tony will raise funds for  art in mental health, mental health causes and Help for Heroes. Just as before Tony plans to encourage friends, colleagues and celebrities to join him during the course of his walk, whilst he searches for the answer to "What’s It all About " 
(SMALL PRINT: Clive will be joining Tony on the part of the Northern leg of the journey)

CONGRATULATIONS to the artist Claire Ford! Following her Internship at Arts for Health, she has been awarded a Churchill Fellowship to expand her knowledge in the field of Arts/Health/Dementia and will be working closely with Arts for Health and colleagues in the USA. More details to follow.

The Lost Generation Film Project (DADAA Inc)

6:00pm to 8:30pm, Thursday 31st March 2011

At Manchester Metropolitan University

This is a unique opportunity to experience the work of DADAA and thanks to Durham University’s Centre for Medical Humanities, who have supported this event.

DADAA Inc. began as an acronym for Disability in the Arts, Disadvantage in the Arts, Australia in 1994 and has been at the forefront of the Australian Arts and Disability movement over the past 16 years. It began with project work, developing its practice and approach within large residential health care settings in the suburbs of Perth. This is where DADAA’s first staff trialled the development of Arts and Disability practices through a combination of community theatre, visual and public art, CCD projects, video production and community writing.

The Lost Generation Project is about finding the lost stories of people with intellectual disabilities, many institutionalised for most of their lives. It is about hearing these stories and recognising and celebrating people who have traditionally been socially isolated and aims to assist these people to connect to their communities through arts and culture.

The Lost Generation Project has found unique people from across Australia and provided them with the technology and skills to tell their stories on film. Each core project participant or storyteller is offered the opportunity to make a short film that tells their story.

Simone Flavelle is the Manager/Executive Producer of this project and she will be giving us the opportunity to see some of these films, an experience that cannot be underestimated.

To register for this event or get more details, email

Details of the venue and confirmation of place will be emailed out a minimum of 48 hours prior to the event. There will be a small charge of £2 on the evening for this event.

This event will happen instead of the networking evening planned for the 24th March