Archive for the ‘Research and Health’ Category
I have done a couple of recent posts on the idea that practice (the so-called 10,000 hour rule) is more important than talent in reaching elite levels of performance. The main conclusion from all of this is that practice can make most people really good at most things but talent (and also exposure to given activity) are required for truly exceptional levels of performance. When the topic of talent comes up the assumption is that it is inherited from our parents and other ancestors. This then leads to the idea that talent is genetic and that eventually genes that confer the chance for exceptional performance are out there waiting to be identified.
You can take the same general line of reasoning and apply it to things like height, weight, or even your risk of getting certain diseases like high blood pressure and diabetes that tend to “run in families”.
Let’s Start With Darwin
Charles Darwin’s ideas pre-date the concept of genes. He made lots of observations about how animals vary from place to place and adapt to their environment. One of fundamental ideas is that via the process of natural selection, animals and plants best suited to their environment are more likely to survive and reproduce. This reproductive success is dependent on the transmission of key characteristics to the offspring which increase their odds of survival. When this happens generation after generation certain composite traits called phenotypes emerge.
Galton is Next
After Darwin, his cousin Francis Galton came along and started to make statistical estimates of heritability for things like height and intelligence. His observations showed a strong correlation between parents and offspring for many phenotypes and he commented that:
“I have no patience with the hypothesis occasionally expressed, and often implied, especially in tales written to teach children to be good, that babies are born pretty much alike, and that the sole agencies in creating differences between boy and boy, and man and man, are steady application and moral effort. It is in the most unqualified manner that I object to pretensions of natural equality. The experiences of the nursery, the school, the University, and of professional careers, are a chain of proofs to the contrary.”
Galton’s statistical work was later extended and amplified by Pearson and Fisher who are familiar to anyone who has ever taken a basic statistics class. The figure below is from a paper by Fisher in 1919 showing his estimates of how height was inherited from parents and earlier ancestors.
The First Version of Genes
About the same time that the statisticians got busy the work of Gregor Mendel was rediscovered. Mendel did breeding experiments with peas of different phenotypes and showed via so-called “laws of inheritance” how the various characteristics were transmitted from generation to generation. None of his observations could be explained in a satisfactory way by earlier ideas about how phenotypes were transmitted from generation to generation. In about 1909 Wilhelm Johannsen came up with the idea of both genotype and phenotype and:
“Johannsen’s most notable experiments concerned his so-called ‘pure lines’ of the self-fertile princess bean, Phaseolus vulgaris. Studying the progeny of self-fertilized plants, he selected the character of bean weight and found that both the lightest and the heaviest beans produced progeny with the same distribution of bean weights, i e they were genetically identical. He concluded that the variations in bean weight were due to environmental factors and he introduced the terms genotype (for the genetic constitution of an organism) and phenotype (for the characteristics of an organism that result from the interaction of its genotype with the environment). Johannsen favoured the view of de Vries that inheritance was determined by discrete particulate elements and abbreviated de Vries’s term ‘pangenes’ to ‘genes’.”
In this view we have the idea that genotype = phenotype with some modification by the environment. It also explains why Fisher assumed his estimates of the heritability of height could be explained by this early definition of “what is a gene”.
Genes and Evolution
The ideas about the statistics of heritability, genes and the fossil record were then integrated in the 1930s and 40s into something called the “Modern Synthesis” of evolutionary biology:
“The synthesis, produced between 1936 and 1947, reflects the consensus about how evolution proceeds. The previous development of population genetics, between 1918 and 1932, was a stimulus, as it showed that Mendelian genetics was consistent with natural selection and gradual evolution. The synthesis is still, to a large extent, the current paradigm in evolutionary biology.”
The Changing Definition of a Gene
What happens next is that DNA is discovered and the more general version of a gene is replaced by one based on the idea that DNA is a “read only” genetic code and that has been oversimplified to infer that DNA = phenotype. There is actually something called the “Central Dogma of Molecular Biology” that has been perhaps unwittingly over extrapolated to infer that DNA=phenotype. The term “Central Dogma” also has a strangely medieval religious ring to it.
However, it turns out that the genome and the products coming from it are subject to all sorts of environmental influences and that the idea of a linear – one way street – transfer of information from gene to protein to phenotype is a gross over simplification. There is even evidence that acquired characteristics can be inherited. These newer ideas about what might be described as a more flexible genome also explain why it has been so hard to find discrete DNA snippets that fully or even mostly explain many things including the statistical estimates of heritability exceptional longevity, height, BMI, intelligence and the risk for many common diseases.
For those of you who want to take a deep dive into these issues the link below is to a lecture by Denis Noble who has argued for a far more nuanced view of how genetic information is converted into phenotypes and how this influences how phenotypes are inherited from one generation to the next.
Back to Talent
Many human characteristics including things that might be called talent have a high statistical probability of being inherited from our parents and ancestors. When the pre DNA definition of gene is used, then it is pretty easy to think about a sort of non-specific genetic explanation for them. However, when the DNA based definition of a gene is used it is hard to find discrete or obvious DNA based genetic explanations for most things. So, don’t expect a blood test anytime soon that is going to tell you that your kids are can’t miss at anything, and even if they have all the “genetic” talent in the world will they get exposed to what they might be great at and will they be willing to practice both intelligently and relentlessly? The author Aldous Huxley (Brave New World) who comes from a long multi-generation family line of exceptional achievers said:
“There is no substitute for talent. Industry and all its virtues are of no avail.”
On the other hand a standard concept from the sporting world is that you “can’t coach desire”.
Perhaps the truly elite performer in any endeavor needs to have it both ways.
There are a large number of vitamins and other supplements that are purported to improve metabolic health, cardiovascular risk and perhaps have anti-aging effects. The idea is that is that these products do things like lower blood pressure, improve blood lipids, and reduce the risk of diabetes. The consumer market for these products is huge with about 27 billion dollars spent in the U.S. during 2009.
Do They Work?
There are a couple of ways to answer the do they work question. The first way is to survey the population and see what the health of users and non-users looks like. When this was done in about 300 multiple supplement compared to about 600 non-users, the supplement users came out ahead for many variables associated with better long term health.
Dietary supplements consumed on a daily basis by more than 50% of Multiple Supplement users included a multivitamin/mineral, B-complex, vitamin C, carotenoids, vitamin E, calcium with vitamin D, omega-3 fatty acids, flavonoids, lecithin, alfalfa, coenzyme Q10 with resveratrol, glucosamine, and a herbal immune supplement. The majority of women also consumed gamma linolenic acid and a probiotic supplement, whereas men also consumed zinc, garlic, saw palmetto, and a soy protein supplement……After adjustment for age, gender, income, education and body mass index, greater degree of supplement use was associated with more favorable concentrations of serum homocysteine, C-reactive protein, high-density lipoprotein cholesterol, and triglycerides, as well as lower risk of prevalent elevated blood pressure and diabetes.
Pretty convincing, except who knows what other health behaviors the supplement users were engaging in. For example, they might have been exercising more or eating a generally healthier diet than non-users.
So, what happens to the blood pressure, lipids and glucose levels to matched groups of people given multiple supplements prospectively? Do they make a difference? When about 60 generally healthy middle aged men and women were randomized to receiving either a standard multivitamin or a multivitamin and supplement cocktail containing resveratrol, quercetin, carnitine, alpha-lipoic acid, curcumin, pomegranate extract, fish oil, cinnamon bark, green/white/black tea complex and sesamin:
“The main outcome measures were arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors. Twenty-four weeks of daily supplementation with 10 dietary supplements did not affect arterial stiffness or endothelial function in nonobese individuals. These compounds also did not alter body fat measured by DEXA, blood pressure, plasma lipids, glucose, insulin, IGF-1, and markers of inflammation and oxidative stress. In summary, supplementation with a combination of popular dietary supplements has no cardiovascular or metabolic effects in non-obese relatively healthy individuals.”
What About Vitamins?
The data on vitamins is generally worse. At least one analysis that has evaluated all of the studies on vitamin E supplementation suggests that relatively high doses might increase all-cause mortality. Others have concluded that there is likely no effect. There might also be issues with vitamin A. When the effects of vitamin C and vitamin E on longevity and lifespan are evaluated in “model organisms” like fruit flies and rodents, the data is all over the place. Here is a summary for the vitamin E studies:
Twenty-four studies were included in the final analysis. While some studies suggest an increase in lifespan due to vitamin E, other studies did not observe any vitamin E-mediated changes in lifespan in model organisms. Furthermore there are several studies reporting a decrease in lifespan in response to vitamin E supplementation. Different outcomes between studies may be partly related to species-specific differences, differences in vitamin E concentrations and the vitamin E congeners administered. The findings of our literature review suggest that there is no consistent beneficial effect of vitamin E on lifespan in model organisms which is consistent with reports in human intervention studies.
To Take or Not To Take?
Based on the summaries above, it is hard to make a convincing argument that anyone without evidences of a primary vitamin deficiency should be taking vitamins. This is especially true if your diet is high in fruits, veggies, “good fat” and you are physically active. Pretty much everything vitamins and supplements are supposed to fix can be optimized with a reasonable diet and plenty of exercise.
What opinion leaders in biomedical research were thinking 20 or 30 years ago seems pretty remote from the news last month that the American College of Cardiology and American Heart Association released new guidelines on statin therapy to reduce the risk of cardiovascular disease. It also seems pretty remote from the more recent news that the FDA told the genetic screening company 23andME to suspend their direct to consumer health related genetics testing and advice. At first glance these two stories are unrelated, but bear with me while I make the case that both stories are fundamentally about the limitations of something called personalized medicine and the routine use of genetic testing to customize therapy for individual patients.
The net effect of the guidelines is to recommend that far more apparently healthy people be treated with statins to prevent cardiovascular disease. The new guidelines have been controversial from the start and criticized for reasons including: 1) what data and studies were used to develop the guidelines, 2) the accuracy of the calculator used to estimate who is at what risk and in need of treatment, and 3) the deemphasizing of cholesterol monitoring to adjust therapy. There was also yapping about links between some of the guideline writers with the pharmaceutical industry and just the confusion associated with changing recommendations on how commonly used drugs should be used. What most people fail to realize when they read about the next best medical thing is that medical evidence and recommendations shift and change over time. In a recent review of how medical evidence changes more than a third of what is considered state of the art underwent significant challenge or revision over 10 years. So the fact that the new statin guidelines are controversial and why they are controversial is not surprising.
Direct to Consumer Genetics Testing
23andMe was essentially banned from offering to direct consumer information about disease risk based on genetic testing. The main concerns outlined by the FDA relate to the basic validity and reliability of the testing, how assessments of risk were being communicated to the consumer, and the unpredictable nature of how a consumer might respond to a “positive” test. For common non-communicable diseases (the stuff the kills most of us like diabetes, cardiovascular disease, obesity, and many forms of cancer) there are hundreds of gene variants that put people at increased risk. However the increased risk for each variant is typically tiny and pales in comparison to behavioral risks much of the population engages in. In reality no one really has a good handle on the real risk associated with most gene variants and there is much less insight into how they should influence medical decision making. The other dirty little secret here is that it has been difficult to replicate risk variants across studies, and for a number of diseases the gene variant profiles are the same in people with and without the clinical disease. There are also the predictable issues of what findings in one ethnic group might mean in a different group.
Not so Fast: The Statin 23andME Link
Sometime in the 1980s or early 90s the idea took hold that if we simply knew enough about the individual genetic profile of each person that we would be able to customize drug therapy in specific and medical therapy in general to better treat, predict, and prevent a wide variety of disease. Most prominent academic medical centers now have huge programs based on this basic proposition. The FDA’s message to 23andME can be viewed as a “not so fast” message. Whoever is doing the testing, there is a lot left to learn before personalized medicine might really make a difference for most people seeking advice from most Drs. for most of what ails us.
In this context, the statin guidelines say the same thing the FDA did by what they don’t recommend. Instead of recommending that statin therapy be tailored based on each patients genetic profile and cholesterol level, they advocate use of a generic risk calculator derived from decades old epidemiology studies and then largely abandon the idea that it is important to follow how the drugs affect cholesterol levels. Maybe the next step is simply putting statins in the water.
As far as personalized medicine in general goes, research might ultimately get us to a genetically based diagnostic and therapeutic promised land. However, don’t be surprised if personalized medicine based on your individual genetic profiles ends up becoming the biomedical version of atomic fusion, an attractive idea that just can’t quite get there for most diseases.
The usual article on sleep and health focuses on how we are all sleep deprived and the bad things this does to us. The story is pretty simple: chronic low grade sleep deprivation leads to systemic inflammation, weight gain, excessive eating, and hormonal changes that are associated with all sorts of long term health issues. The drowsiness also leads to poor judgment, more accidents, more eating and other shorter term issues. This is all being made worse as technology ranging from artificial lighting to smartphones that make our days longer and longer. Many of us then get up earlier and jump start the day with a mega dose of caffeine.
The epidemiologists tell us that 7-8 hours per day of sleep is the optimal health sweet spot for most of us. People who routinely get by on 5-6 hours of sleep have about 1.5 times the relative risk of death from coronary heart disease. Interestingly, the risk is about 1.4 times for those who sleep a lot:
“Too little or too much sleep are associated with adverse health outcomes, including total mortality, type 2 diabetes, hypertension, respiratory disorders, obesity in both children and adults, and poor self-rated health. The relationship between duration of sleep and vascular events is U-shaped, suggesting that different mechanisms may operate at either end of the distribution of sleep duration.”
If you are worried that you are getting either too little or too much sleep there are some simple steps you can take that work for most people to promote better quality sleep. Highlights include:
- Avoid napping
- Limit the use of (caffeine) to earlier in the day
- Morning exercise
- Avoid large meals before bedtime
- Get adequate exposure to natural light
- Establish a bedtime routine
- Use your bed for sleeping as opposed to reading and watching TV
- Make where you sleep a comfortable place
As a result primarily of the obesity epidemic there is also an epidemic of sleep disturbed breathing. There is a simple questionnaire that can help determine if you have the problem and need medical follow-up.
Sleep & Exercise Performance
What about short term sleep deprivation and exercise performance? What happens when you have a competition and only get four hours of sleep the night before? What if you are in a multi-day event with little time for sleep? Many of the studies on this topic are from the 1980s and 90s and they tend to show that even 30 hours of total sleep deprivation does not do much to VO2max. Studies on longer term submaximal exercise are limited but they tend to show exercise time to exhaustion is reduced but with some subjects effected far more than others. One general finding appears to be that people rate whatever they are doing as harder to do when sleep deprived.
An interesting source of data on exercise performance and sleep deprivation comes for the literature on physical conditioning and military Special Forces. These individuals frequently do very demanding night operations for several nights in a row with limited opportunities for daytime sleep. In a series of Canadian studies that simulated several days of night operations, caffeine (1-200 mg) improved run time, cognitive performance, and marksmanship.
Another interesting idea is that recovery from days in a row of vigorous activity with short sleep can be enhanced by protein supplementation. There is a lot of discussion in military nutrition circles about 20-25 gms of protein before sleep during periods of high stress physical activity. The idea is that muscle mass will be better preserved during periods of physical stress, sleep deprivation, and limited calorie intake. It would be interesting to know if professional cyclists are adopting similar strategies during the big stage races.
As part of my medical training I have probably spent more time than most people both working and working out while sleep deprived. There are short term strategies to deal with it, but sleep deprivation is no fun and my goal in middle age is to avoid it as much as possible. Advice that is easier to give but harder to act on in our high strung world.
For most of us when I say doping you say Lance Armstrong, or Barry Bonds, or Roger Clemmons or Marion Jones. However, what about the rest of the world and our individual and collective drive for improved performance? Here are a few thoughts on the topic and questions for all of us.
Doping With Tylenol?
“Using acetaminophen, participants cycled at a higher mean power output, with an increased heart rate and blood lactate, but without changes in perceived pain or exertion. Consequently, completion time was significantly faster. These findings support the notion that exercise is regulated by pain perception, and increased pain tolerance can improve exercise capacity.”
Is this doping? Should Tylenol be banned? You can tell a similar story and ask the same questions about caffeine.
What About Middle Age?
A recent piece in the Velo News tells the story of a late 50s recreational cyclist with clinical testosterone deficiency who went on testosterone replacement therapy for a number of issues including osteoporosis. The athlete in question self-reported and asked for a therapeutic exemption so he could keep competing in local races. The exemption denied because he did not have a clearly defined endocrine problem. You can also make the case that Viagra like drugs might improve performance in some people especially at altitude. What does this mean for master athletes who take these compounds for other reasons?
For women there is at least some evidence that hormone replacement therapy (HRT) improves exercise capacity but the data are far from clear cut. What about the aging news anchor who uses botox to keep her job?
Is any of this doping when the drugs in question are used for legitimate medical purposes? Search the internet for anti-aging clinics and you will find all sorts of outfits offering unproven (usually hormonal) therapies purported to slow the aging process. Recently, some elite younger athletes have been tweaking their thyroids levels. Where does the “legitimate medical purposes” justification end and doping or snake oil sales begin?
For the twenty somethings reading this article the idea of academic doping – using ADHD drugs obtained on the black market to do better on a test is old news. This practice appears to be pervasive on college and even high school campuses. It also appears to be drifting into the rest of the world where decision making and concentration are critical.
There are all sorts of drugs that enhance or might enhance cognition and more are in the pipeline. Who gets them and when is it fair to use them? Is this just another potential edge for the children of the well-off? In a world of high stakes testing for admission to an elite school or academic program should these substances be banned and test takers subject to doping control? The discussion in the cognitive enhancement world mirrors in many ways the sports doping discussion:
“Drugs developed to treat cognitive impairments are proving popular with healthy college students seeking to boost their focus and productivity. Concerned observers have called these practices a form of cheating akin to athletes’ use of steroids, with some proposing testing students’ urine to deter “academic doping.” The ease with which critics analogize the academic enterprise to competitive sport, and the impulse to crack down on students using study drugs, reflect the same social influences and trends that spur demand for these interventions-our hyper-competitive culture, the commodification of education, and our attraction to technological quick-fixes. Rather than focusing on the technologies that are being put to troubling uses, we would be better served reforming the culture that makes these practices attractive.”
Are We All Dopers?
All of us are surrounded by performance enhancing choices beyond the things like the drugs or nutraceuticals we can inject or put in our mouths. The pervasive invasion of technology into almost every aspect of life offers even more opportunities for performance enhancement. In the end, what does it mean to be human in the 21st century:
- What happens when things like Tommy John surgery are used to pre-emptively improve pitching performance before an injury?
- Who draws what lines about what is ethical and fair?
- Should we even strive for a level playing field?
- What does it mean to be a human in a world where almost every imaginable activity might be subject to high tech performance enhancing strategies?
In the end is there any value left in the lone individual struggling against his or her own limits, or is all about return on investment thinking where the individual is just part of a supply chain leading to a more desirable outcome?
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