Clues toward the Cause of Long COVID

I previously shared some of the amazing data from the paper "Muscle abnormalities worsen after post-exertional malaise in long COVID" by Appelman et al. 

The paper will undoubtable become a classic in the field of Long COVID, providing a fascinating series of clues that the researchers followed past several dead-ends to their interesting implications. 

First, and most importantly, the researchers confirmed beyond a shadow of doubt that Post-Exertional Malaise (PEM) is a real disease, with myriad muscle and metabolic abnormalities in the Long COVID patients following intense exercise.  Metabolomics provided additional key findings, including the first clue: a possible blockage of glycolysis in Long COVID (see diagrams in previous post).  

A Clue: Glycolysis Blockage

In the glycolysis pathway, the phosphoenolpyruvate (PEP) levels of Long COVID patients were increased, while pyruvate levels were decreased, indicating a disruption or imbalance in enzyme activities within the pathway.   This could be due to a decreased activity of the enzyme pyruvate kinase (PK), which converts PEP to pyruvate in the final step of glycolysis.  Reduced PK activity would result in a buildup of PEP.  With less PEP being converted to pyruvate, the downstream levels of pyruvate would be lower.  

There are several interconnected regulatory pathways that can reduce the activity of pyruvate kinase (PK), the two most relevant being Oxidative Stress and Hypoxia.  Increased levels of reactive oxygen species (ROS) or oxidative stress can lead to the oxidation and inactivation of PK.  Under hypoxic conditions (low oxygen levels), the transcription factor HIF-1 (Hypoxia-Inducible Factor 1) can be activated, which can lead to the downregulation of PK expression and activity.  This is part of the cellular adaptation to hypoxia, where glycolysis is regulated to favor the production of metabolic intermediates for other pathways.

Hypoxia?

In the context of Long Covid and post-exertional malaise (PEM), hypoxia from microclots has been suggested to increase lactic acid production. However, in this study the metabolomics showed decreased* lactic acid, because glycolysis was shut down at PEP by loss of PK activity, not at pyruvate by loss of pyruvate dehydrogenase (PDH).  

The researchers looked for but did not find decreased muscle oxygen perfusion or any differences in microvasculature.  The researchers noted decreased oxygen utilization, but this could be due to anything that disrupts metabolism and does not indicate hypoxia as a specific issue.  

They noted amyloid plaques in the extracellular matrix; the plaques were not blocking the microcapillaries and it is unclear what role they play in the pathophysiology of Long COVID: are they a cause of PEM, or a consequence?  

Their observation that Long COVID patients' muscle force was not dependent on The Citric Acid (TCA) cycle enzyme succinate dehydrogenase (SDH) can also be explained by impaired metabolism upstream of TCA Cycle, i.e. in glycolysis.

Oxidative Stress

Therefore, it seems likely that the regulatory pathway most likely to contribute to reduced pyruvate kinase (PK) expression and activity is the oxidative stress pathway.  

Long Covid patients have been reported to exhibit higher levels of oxidative stress markers, such as lipid peroxidation products and decreased antioxidant levels, compared to healthy individuals or those who have recovered from acute COVID-19 infection.  Physical exertion and exercise can lead to an acute increase in reactive oxygen species (ROS) production, potentially exacerbating oxidative stress in individuals with Long Covid and triggering PEM symptoms.

Some studies have suggested that Long Covid patients may experience mitochondrial dysfunction, which can further contribute to increased ROS generation and oxidative stress.

Next Steps

The paper concluded with these results, but the logical next step would be to use metabolomics to assess free radical concentrations.  One theory is that COVID spike proteins form "pores", or holes in the mitochondrial membranes, disrupting the mitochondria and releasing free radicals into the cell.  

The researchers did look at COVID nucleocapsid protein, but found it in both the control and Long COVID groups in equal concentrations, suggesting that remnant viral protein doesn't explain the pathophysiology of Long COVID.  But maybe remnant virus affects the Long COVID patients differently?  

The researchers noted immune cell infiltration into muscle tissue, which could be in response to a signal from excess free radicals, or could be due to some other reason like persistent COVID infection/expression.  

Lactate?

This study seems to indicate the lactate is not an important variable for the pathophysiology of Long COVID.  However, the details about how lactate was measured limit these conclusions. The researchers measured lactate from three different sources:  metabolomic blood (venous) and muscle lactate measured before and after PEM, and capillary (i.e. finger prick) lactate measured during exercise.  Venous lactate measured one week after PEM induction showed a slightly increased level in Long COVID patients, but none of the other metabolomic lactate measurements showed any difference.  The capillary lactate also showed a slightly elevated blood lactate level before exercise in the Long COVID patients, but the difference was not significantly different.  

However, the baseline measurements were not taken in a fasted condition, and because eating normally raises resting lactate it cannot be determined from this study if fasted lactate might show other differences that are important to Long COVID.

Post Exertional Malaise in Long Covid

 Severe exercise-induced myopathy has been found in long COVID post-exertional malaise (PEM).  

Just look at these long COVID patients (in red) pushing close to 20 mmol/L lactate on the exercise bike!  That is serious dedication for a group of patients who know what the consequences will be.

After the exercise test, blood metabolomics show elevated glycolysis, but decreased pyruvate and TCA cycle metabolites.

Muscle biopsy metabolomics show decreased purine synthesis and TCA cycle.

Key:

Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3

UV Florescence

 iNat has a great project dedicated to UV florescence.  

Fluorescence generally means you’re absorbing one wavelength and emitting another. most UV flashlights emit light that is mostly invisible to humans, except for maybe a little that folks would describe as purple or pale blue.

So if you shine a UV light on something and see other colors emerge, you’ve almost certainly got fluorescence. but if you see the same purple or pale blue that your flashlight emits, then it’s possible that’s just reflection.

From left to right: visible light, UVIVF, and UV reflected light.  From: https://www.wildflower.org/magazine/native-plants/a-different-light

This article with beautiful UV and visible light photos helped me understand the difference between UV reflective and UV-induced fluorescence (UVIVF) images. However, I think many people, including the author of that article, are still confused about the biological meaning of UVIVF. For example, the False Gromwell writeup implies that insects can see UVIVF to help find flowers that are otherwise inconspicuous.

But UVIVF is never normally visible…except maybe as an added glow. The best example is laundry detergent that makes whites brighter. By adding a UVIVF chemical to the detergent, clothes actually slightly glow in any UV light, making them appear brighter.  

Meme by apermar.  Veritaseum explains more on Youtube.

Photographs of UVIVF in darkness show the extra brightness we see in sunlight, but usually don’t notice.  However, UVIVF may be biologically important to some animals, such as scorpions, frogs, and flying squirrels.  Taboada et al. (2017) documented biofluorescence in response to UV light can contribute between 18 and 29% of the total light emitted from some species of tree frogs under natural, dimly lit conditions.  

Flying squirrels fluorescence is hypothesized to aid in camouflage against a backdrop of lichens emitting similar fluorescent spectra, or potentially in Batesian mimicry of co-occurring predatory owls with similar biofluorescent profiles.

Biofluorescence could be a useful tool to document amphibians where the small, cryptically colored, and/or nocturnally active species can be hard to locate among leaf litter or dense vegetation. 

The study of UV florescence is relatively new, with new discoveries being made every year.  For example, 2017 was the first documentation (published paper) of an amphibian with natural fluorescence. A 2020 paper then found fluorescence widespread among amphibians.  iNat users had documented fluorescent amphibian from frogs starting in 2018 and salamanders in 2021.

A photo I took with a 390-405 nm (just barely UV) blacklight.  Most UV photographers use a 365nm (UV-A) flashlight, sometimes with extra filters to block all of the blue and violet light. 

More discussion of florescence can be found on the iNat forum.  

Taboada, Carlos; Brunetti, Andrés E.; Pedron, Federico N.; Neto, Fausto Carnevale; Estrin, Darío A.; Bari, Sara E.; Chemes, Lucía B.; Lopes, Norberto Peporine; Lagorio, María G.; Faivovich, Julián (2017-03-13). "Naturally occurring fluorescence in frogs". Proceedings of the National Academy of Sciences. 114 (14)

Lamb, J.Y.; M.P. Davis (2020). "Salamanders and other amphibians are aglow with biofluorescence". Scientific Reports. 10 (1): 2821.

Science & Technology - 2022 Year in Review

AI

 2022 was the big year for Artificial Intelligence, the year when AI became a household word.  The image generators were first, like Dall-E, but by the end of the year the latest GPT release (Chat-GPT) had taken over.  

Overview of some of the big AI releases:  link

Space

Big milestones in space included the successful first images from the James Webb Space Telescope (JWST), showing individual stars inside galaxies at the very beginning of time.  Link to images from JWST.

The DART asteroid-impact missions was a success!  Video reviews here and here.  

And sadly, the Planetary Society's crowd-funded solar sail, Lightsail 2, crashed back into the Earth's atmosphere after 3 years sailing on sunlight.  Link.

Environment

While its hard to pick the top environmental story, the fact that Earth warmed at an all-time record pace created climate disruptions everywhere.  

On the positive side, researchers have created a form of ultra-white paint that can reflect more energy than is absorbs.  Buildings coated with this paint would have a natural cooling ability that could reduce ambient temperatures and reduce energy required for AC.  I'm very hopeful that this can become cost effective and widely used in desert cities.  Link.

HIIT Science

 All information is from https://hiitscience.com

HIIT Science will be a classic in exercise physiology.  It breaks down high intensity interval training into 6 different types of training, depending on energy system (aerobic, anaerobic, neuromuscular) to be trained:

"Envisage receiving a stressful hit on your neuromuscular/ musculoskeletal system – day in day out – session after session. As per Figure 1, these would all be HIIT Types #2, 4, 5, & 6. I’m sure you can imagine how this would likely result in a train wreck for most individuals. More often than not, we need substantial periods of recovery (often days) between such sessions to allow the neuromuscular/ musculoskeletal system to adapt appropriately (think how long it takes for muscle soreness to go away)."  https://hiitscience.com/why-the-hiit-types/

Each type is built around specific intensities and interval times:

"Traditionally, HIIT is performed by running or cycling....When such equipment is unavailable, HIIT can even be performed skipping using a jump rope or by completing stationary movements (e.g., squats, frontal or lateral lunges, push-ups, jumps) during the interval period (Table 1). These latter HIIT variations require more familiarisation and are likely more demanding on the neuromuscular system (6), but they can also be effective through their ability to target both cardiovascular and neuromuscular systems simultaneously (5)."  https://hiitscience.com/high-intensity-interval-training-the-key-strategy-to-maintain-fitness-during-periods-of-reduced-activity/

They argue that passive recovery is more beneficial than active, since it allows for more work during each interval.  https://hiitscience.com/recovery-bout-intensity-of-hiit-active-or-passive/

Bottom line:

- Shorter rests increase HR and leads to more cardio conditioning

- Longer sets increase burn and lead to more anaerobic conditioning

- Higher intensity/weights increase neuromuscular stress and lead to more muscle growth

- Focus on all three increases stress and leads to exhaustion, longer time between workouts, and loss of fitness

Bear's Ears Research on Legacy Human Plant Communities

The research is quite interesting. They have determined that a large suite of plants used by people in the past are more likely to be found in the vicinity of archaeological sites on Bear’s Ears NM. Basically people were planting medicinal and other useful plants, and those plant communities have persisted at these locations in greater numbers to modern times. We see similar things here in Arizona with agaves, yucca, devil’s claw, and a few other plants. In AZ the phenomenon is sometimes referred to as “Legacies on the Landscape.”

https://www.pnas.org/content/118/21/e2025047118

But looking through the Supplemental table for the paper, they basically included every species that grows up there.  Not surprisingly, native peoples utilized most of the naturally-occurring botanical resources on the landscape.   So their results are really more that cultural sites are associated with biodiversity in general, not specific assemblages of “cultural” species.  

Also, the paper implies that the causality goes native people>plant diversity, but it could just as easily go plant diversity>native peoples, since native people would be more likely to settle in places with more plant diversity (e.g. places with water).

I would be more interested in a paired-down list of the plant species that are truly cultivated and remain associated with prehistoric sites.  For AZ, agave, yucca, devil’s claw, and a few other plants.  Definitely Wolfberry (Lycium pallidum).  They list Wild Potato, Solanum jamesii, which is interesting and does occur in AZ above the rim…..they also list Chenopodium sp, which is a common weed so I’m not convinced that is a good marker of anything.

Chenopodium are usually ubiquitous in pollen and macrobotanical samples taken from archaeological contexts. The typical interpretation is that these plants were used way more than we think. Hard to know whether weedy plants were being intentionally planted or if they started growing more in areas where people were eating, processing, and depositing seeds through their waste. There are a few Chenopodium species that were domesticated prehistorically. In the western US these are amaranths, goosefoot in the eastern US, quinoa in South America, etc.

Carbon offset controversy

 

https://carbon180.medium.com/in-search-of-carbon-removal-offsets-42abf71b3ccc

https://forestpolicypub.com/2020/12/10/bloomberg-green-on-the-nature-conservancy-and-meaningless-carbon-offsets/

Regenerative Agriculture Controversy?

 https://www.wri.org/blog/2020/05/regenerative-agriculture-climate-change

https://agfundernews.com/opinion-where-the-world-resources-institute-got-it-wrong-about-regenerative-agriculture.html

https://undark.org/2020/01/31/podcast-43-regenerative-agriculture/

What is a Scientist?

"Science is a way of thinking, not an answer."

I hope to explain what science really is, and why its such a good thing (one of the most important in life).  But first, let's start with some examples:

Is Mr A a scientist? He worships spaghetti monster. Doesn't matter, lots of Christians are scientific and they worship similar gods.

Is Mr B a scientist?  He believes Earth goes around sun, is made of atoms, and humans evolved from prehistoric primates because he reads science books.  Doesn't matter what you believe.  Just because its in a book....

Ms. C read a website that earth is flat and evolution is a hoax.  Is one "right" and one "wrong"?  Maybe, but saying one is "science" and one isn't isn't the point.

What is a Scientist?

1) Open mind

2) Respect institutions that promote learning (process)

3) Experimentation

Sleep Apnea: Research and Self-Experimentation Results

 Abstract

I tested several sensors that claim to measure sleep apnea through optical measurement of blood oxygen content.

Background

Blood oxygen arterial saturation (Sa02) is approximated by Sp02.  At 5,000 feet elevation, Sp02 should be above 92%. Values under 90% are considered low.  Hypoxemia is dangerously low blood oxygen, defined as Sp02 <88% for more than 5 minutes.   (Hypoxia is low tissue oxygen levels)

An oxygen saturation level over 95 percent is considered normal. Anything below 92 percent oxygen may be a sign of breathing problems during sleep, such as sleep apnea or another disorder like severe snoring, COPD or asthma.  (Low levels can also be caused by anemia.)

Sleep apnea is characterized by a cessation of airflow lasting 10 seconds or more. Hypopnea (shallow breathing resulting in desaturation) is a decrease in airflow lasting 10 seconds or more with a 30% oxygen reduction and a 3 to 4% desaturation from the baseline. It is not uncommonpatients with sleep apnea to desaturate below 88%. 

Note: low Sp02 is an indicator of sleep apnea and is not necessarily the mechanism of the bad effects.  It may be possible to not have hypoxemia, but still have interrupted sleep.  

Sleep apnea and hypopnea can cause small awakenings that disrupt normal sleep cycles.  This can cause irregular heart beats, high blood pressure, blood sugar excursions, strokes, heart attacks, etc.  Most common effect is to create chronic, elevated stress response.  

Results

- Fitbit Charge 2 never showed any apnea episodes

- Biostrap showed several, including some that my wife didn't remember

- Wellue 02 ring showed several mild episodes per night.  Based on other testing, this sensor seemed potentially the most accurate, but location on finger wasn't comfortable.  Also ended up not being accurate because I sometimes sleep on my arm, cutting off circulation, which reduces Sp02.

Conclusion

I have been diagnosed with mild sleep apnea and my wife has no known apnea.  We both tried the Sp02 wearable sensors and they consistently showed the same level of apneas between us, either none (Fitbit) or mild (Wellue 02 Ring).  Based on the lack of a clear and actionable signal from these sensors, I no longer use them to track apnea events.  Instead I focus on trying to minimize possible breathing issues and promote general good sleep hygiene to try to improve restfulness. 

OTEC: Ocean Thermal Energy Conversion

OTEC has the potential to harness the power of the ocean, while pumping water from the depths to the surface has challenges and opportunities. It can fuel plankton growth and may help sequester carbon.

1982 National Energy Laboratory Report on OTEC

The xerox scan of the old scientific report is dark and stained, with primitive printing and poor font and layout.  But the columns and official investor report style belie the real science presented, without preamble or typical science summary.

The 1-mile long cold water pipe was deployed successfully in 1981, thanks to "Calm weather and much hard work."  The pipe extends from the surface to 2,000 feet deep. It can pump 500 GPM of deep cold 9-10 C) water. The warm water pipe pumps 2,000 GPM of surface seawater (24-28C).  When allowed to foul freely, it showed immediate increase in resistance to heat transfer, which biofouling countermeasures ameliorated.

The article presents a glowing portrait of research advancing at a fast pace, but is offset with somber photos of cloud-mottled skies and the inclusion of disturbing headings like "biofouling countermeasures". (Biofouling is when nimals get sucked in, and the system can become clogged by marine animals and plants.  This could also be used positively to grow algae) Funding is flowing in from multiple sources like the cold and warm water siphoned from the rich offshore resources...

The project is strategically located with nearby availability of cold, deep ocean water and a warm ocean surface layer that is not subject to strong seasonal cooling. The warm water intake only 15 feet offshore may explain the much more rapid initiation of biofouling than previous experiments.  A 300 foot extension has been designed and was to be installed in 1983.  They plan to add 2 new 500 GPM pumps to replace the original coldwater pump that only pumped from Feb to June at 340 GPM before failing.  They propose reconfiguring the OTEC-1 coldwater pipe to provide a capacity of 22,000 GPM, which would "satisfy their coldwater needs for the foreseeable future."







What ever became of all of this? The Makai Engineering website presents research from the 2010s that seems directly related to work done in the early 1980's, as if a 30 year gap is missing from the story, a lull in research perhaps while people's careers stagnated, limited by something mundane like the size or strength of piping availability or funding.  Maybe the ocean was still there but the money stopped coming from Washington.  Reagon took the solar panels off the white house, and the country went back to sleep for 30 years while a couple of billion people were born and the climate inched toward the 2 degree warming threshold. 

This dark paper seems to hold secrets of the past, arcane mad science experimentation. All that is not said, like the sea creatures sucked up.  So that today when ocean researchers wonder about the effects of cold water outfalls they have to design and bring their own small pipes and pumps.

2008 Reserach: Artifically Induced Upwelling
Used to understand how marine microbial ecosystems respond to large-scale perturbations. Diatoms will consume nitrogen, leaving some amount of phosphorus in the water, which will stimulate a second-stage bloom of nitrogen-fixing cyanobacteria. These blooms are often observed during summer months in open ocean waters when there are almost no nutrients at the surface and the winds generally are calm. What triggers the blooms and where are the nutrients coming from? We need to know.

Vast, seemingly barren regions comprise more than two-thirds of our oceans and nearly 40 percent of the entire Earth.  Need to replace about 10 percent of the surface waters with upwelled water to fuel a bloom.  Some scientists have looked at iron fertilization as a way to trigger biological growth in nutrient-poor areas of the ocean, but “everything responds to iron,” Letelier said. “You can’t control what grows.”

The researchers believe they can control plankton growth by determining which species respond to specific nutrients, and then adjusting the rate of nutrient feeding by the frequency and duration of water pumping.

Where the ocean is about 4,500 meters deep, the bottom layers of water have too much CO2 because of the decaying organisms that have sunk to the floor.  Their studies have shown, however, that water at a depth of 300 to 700 meters has the proper ratio of nitrogen and phosphorus to trigger a two-stage phytoplankton bloom.

Currently, they are able to pump about 50 cubic meters of water per hour (=4 GPM) using wave energy. "If we want to generate a bloom in an area of one-square kilometer, we would need to replace about 10 percent of the surface waters with upwelled water, which would take about a month at the rate we pumped.”

The scientists used undersea gliders in their Hawaii study to monitor the water from the pump so they have an idea how widely and quickly it disperses, and how much of an impact it can have on surface waters.





Resources
List of OTEC plants around the world: https://en.wikipedia.org/wiki/Ocean_thermal_energy_conversion

1982 report about OTEC work at NEL Hawaii: https://nelha.hawaii.gov/wp-content/uploads/2014/01/NELH_AnnRpt_1982.pdf

Upwelling Press Release: https://today.oregonstate.edu/archives/2008/sep/scientists-test-%E2%80%9Cartificial-upwelling%E2%80%9D-learn-more-about-complex-ocean-ecosystem-be

More NEL reports: https://nelha.hawaii.gov/resources/library/

Makai Engineering: https://www.makai.com/ocean-thermal-energy-conversion/

Science Education: What It Takes To Be A Scientist

Motivation: We Are All Scientists Now
Anything can be science...and any detail could be important...(example: Future Perfect Moon Rock episode)

What it takes To Be A Scientist
Attention. You have to care.  Notice something.
Passion. You really get into something. Become an expert. This is more important than grades, social approval, etc.  Do you know what you're talking about?  Be Authentic.
Record.  Journal. Journaling.  Observations, names, dates. Data.
Analyze.  Logic!  Math!
Share.  This used to mean publishing in a journal.  Now it means put it on the cloud somehow: blog, social media, whatever.
Engage.  hang out with other people who share your interest.  This last step can be overwhelming and counterproductive if you skip the other steps.  Don't fit yourself to your group, find a group that fits you! This is part of growing up.

Examples of Things to Notice
shopping: prices
diet: food log
sports: hot hand
environment: observations of birds, insects, plants, plant diseases, mushrooms (need to know names!)
weather: compare forecast to observations

While doing science with humans is possible, the best thing is to get out in nature where there are unlimited questions and more freedom to ask them.  Also, nature is the origin of the traditional sciences, like geology, chemistry, astronomy, biology. 

To teach sciences like chemistry, that can seem abstract, going through discoveries, the exploratory process, alchemy, etc can be helpful. 

Teach science from the basics.  Like how chemistry discovered metallurgy, and how that was made possible by high heat.  Astronomy and biology were made possible by lenses.  Or teach botany by looking at botanical explorers from Textbook of Pharmacognosy by Wallis, T. E. (Thomas Edward).  Another way to make science relevant is by teaching practical applications, like chemistry in baking/washing clothes.

Resources

https://get21stnight.com/2019/12/27/why-introductory-chemistry-is-boring-a-long-term-historical-perspective/

science? example: https://wefunder.com/lppfusion?auto_login_token=cqcK4xYxqbRvcbLm

Questioning is part of science: Socratic Grilling  https://slatestarcodex.com/2020/03/06/socratic-grilling/

Chemistry table of smells: https://jameskennedymonash.wordpress.com/2013/12/30/table-of-organic-compounds-and-their-smells-250-smells/

Ponderosa Mortality After Fire

The best data comes from Hull Sieg, Carolyn, et al. "Best predictors for postfire mortality of ponderosa pine trees in the Intermountain West." Forest Science 52.6 (2006): 718-728.

This graph shows probability of death based on both “crown consumption” (actual burning of the crown) and “crown scorch” (browning of needles due to heat injury). It shows that probability of tree death increases above 50% when Crown Scorch increases past 75%, whereas tree death is above 50% when crown consumption is only 25%. A combination of the two is determined to be the best predictor of tree mortality.

Here are some diagrams of crown scorch and crown consumption. In general, if there are brown needles on the tree that is scorch, if they are black or missing it is consumption.



(from Tree and forest restoration following wildfire by Peter Kolb)

Glyphosate Fear-Mongering

Despite recent court cases, glyphosate is not recognized as a carcinogen or toxin as these terms are normally understood in environmental toxicology.  Yes, there is some research linking glyphosate with increased cancer risk, but that is not the scientific consensus.

I don't think this blog post on glyphosate can be counted as scientifically accurate, even though it does cite scientific research. Websites that sell fear based on a few studies while ignoring the body of scientific literature are not reliable sources for decision-making. 

I am writing as a concerned science-lover. For me (and I could be wrong), I see glyphosate fear-mongering as no different from conspiracy theories about vaccine harms or global warming.  Yes, there are scientific papers showing that vaccines cause autism and that global warming is not happening, but any article that only cites those papers without weighing (or at least mentioning!) the current scientific consensus would be misleading at best.

Focusing on glyphosate seems especially misguided given the other chemicals used in agriculture and commonly found in our food supply (e.g. chlorpyrifos).  While glyphosate may be the popular boogeyman of the year, science-based reporting should at least acknowledge that it is probably the least toxic of any chemical pesticides currently being used. 

A better approach than just selling fear:  promote solutions, such as better testing of all chemicals in our food supply. 

The Problem with Nutrigenomics

"Personalized nutritional counseling is a burgeoning field. Several companies, including Vitagene, Nutrigenomix and DNAFit, are already offering individualized dietary counseling.  Their efforts are based mostly on genetic testing, but scientists have only just begun to explore the links between DNA and good nutrition. “I think companies offering personalized dietary advice are probably running ahead of the evidence,” said John Mathers, director of the Human Nutrition Research Center at Newcastle University in Britain." [NYTimes Blog]

Introduction

Science skeptics have recently reviewed these services, and found plenty of quackery. [Science Based Medicine] [Skeptical Raptor]

However, there is some research to back up the idea that genetic testing can provide insights into metabolic disorders.  There may be as many as 200 SNPs for which there are proven metabolic effects, and only a subset of these alter nutrient requirements in a significant portion of the population [e.g., the rs1801133 MTHFR SNP and folate requirement in 15–30% of the population (Solis et al., 2008) and the rs12325817 PEMT SNP and choline requirement in 20–45% of the population (da Costa et al., 2006)].

What do genetic testing services measure?

The human genome consists of about 3 billion nuceleotide bases, each of which is either A,C, T, or G.  A reference genome based on the similarities of all genotyped humans has been assembled, along with a corresponding reference database of all of the point "mutations" where individuals differ from that baseline.  So far, scientists have documented about 150 million of these single nucleotide polymorphisms, called SNPs.  The average person doesn't have all of these differences, however; most people have about 3 millions SNPs that differentiate them from the reference human genome.   Since 3 million is about 0.1% of the 3 billion base pairs, most humans differ from each other by about 0.1% of our DNA. Ancestry genomic testing services like 23andme test for a few hundred thousand SNPs for $100-$200.  For $1000-10,000 a complete genomic sequence can be obtained.  (there are about 3 billion bases total.  

Examples: MTHFR – metabolic pathways and nutrigenomics

In humans, SNPs in the gene MTHFD1 increase the demand for betaine as a methyl-donor, thereby increasing the dietary requirement for choline. Another SNP in the gene PEMT prevents the activation of this gene by estrogen, thereby decreasing endogenous production of phosphatidylcholine (a source of choline) in the liver and increasing the dietary requirement for choline. [Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Ziesel]

But note that it is not so simple.  There are several forms of the MTHFD1 gene, for example MTHFD1L and MTHFD2. If MTHFD1 is commonly mutated, it may be a pseudogene.

Complexities interpreting SNPs

No simple test can unravel the intricacies of the human genome, and consumers should be suspicious of anyone claiming to be able to interpret measurements of tens of thousands of genes, with millions of genetic variations, some of which have effects on hundreds or thousands of the small molecules of metabolism (and perhaps on thousands of peptides or proteins involved in metabolism).

[A grand challenge for nutrigenomics.  Steven Zeisel. 2010.]

Mistakes in genomics data

Note that 23andme data, like any large genome scan, can have mistakes in it.  For example, the Enlis genomics blog found more than 500 likely mistakes in a sample of 23andme raw data!  (Enlis)

Furthermore, many important nutritional SNPs are not testing by 23andme.

Solution: Metabolic Testing
There is a genetic test for MTHFR variations. But there’s also a cheaper and more accurate way to test for whetherMTHFR variations are causing disease. We simply check the levels of homocysteine in the blood...In other words, the homocysteine levels determine our actions, not the MTHFR test results.[Cleveland Clinic]

Future of blood testing?

Data is power, and these four potentially-revolutionary blood- or breath-testing companies could help generate next-generation medical insights:

University of Southampton, Sharp Labs Europe is developing a mobile lab-on-a-chip 5-10 years

Integrated Diagnostics has a "sniffer" test to look for lung cancer. http://www.indidx.com/articles

V-chip to test 50 different blood chemical markers with microfluidics is still in development. 5-10 years

Theranos lab testing is already cheap and easy online, but they have recently been investigated by the FDA for failing to prove that their tests are accurate.

A Disturbing History of Nutrition Science

What is the biggest mistake scientists have ever made?  Nina Teicholz's The Big Fat Surprise, a wonderful history of the awful state of nutrition science, suggests that science's worst mistake may well be the idea that saturated fat is unhealthy.  She makes a convincing case that nutritional guidelines over the last half century, by focusing on fats rather than sugars, have resulted in the premature deaths of millions of Americans and others around the world.

Even more interesting than turning conventional wisdom on its head, this book is an eye-opening journey into how an entire field of science can be hijacked by special interests and strong personalities. Moreover, this book holds important lessons about how the process of science is still susceptible to the same biases and group-think as the rest of society.

Nina Teicholz sums up the story of how nutrition science went wrong:

"Well-intentioned experts, hastening to address growing epidemics of chronic disease, simply overinterpreted the data. Scientists hypothesized that dietary fat was to blame...  This hypothesis became accepted as truth before it was properly tested.  Public health bureaucracies adopted and enshrined this unproven dogma.  The hypothesis became immortalized in the mammoth institutions of public health.  And the normally self-corrected mechanism of science, which involves constantly challenging one's own beliefs, was disabled.  While good science should be ruled by skepticism and self-doubt, the field of nutrition has instead been shaped by passions verging on zealotry. ...Once ideas about fat and cholesterol became adopted by official institutions, even prominent experts in the field found it nearly impossible to challenge them."  

"What I found, incredibly, was not only that it was a mistake to restrict fat but also that our fear of the saturated fats...has never been based in solid science.  A bias against these foods developed early on and became entrenched, but the evidence mustered in its support never amounted to a convincing case and has since crumbled away."

Let the sorry story of nutrition science be a lesson for the scientists and promoters of scientists in other fields.  We like to think that science is independently and objectively building a tower of knowledge for the ages, one rock at a time, but the reality is that our science is a product of our society, our beliefs, our biases, and our assumptions.

What Do Carnivores Dream About?

Anyone with a house cat already knows the simple truth of a new study on the comparative physiology of sleep across mammals. Carnivores sleep much more than would be expected compared to herbivores and omnivores:

Carnivores:

Herbivores:

Omnivores:

Of course, these data don't answer the original question, but only raise more questions.

This website uses the data to conclude that humans should eat a vegetarian diet, because human sleep requirements match those on the Herbivore sleep regression, and we don't get as much sleep as other omnivores of the same body weight.  But based on discussion in The Story of the Human Body: Evolution, Health, and Disease by Daniel E. Lieberman humans in their modern form -- i.e. that would be recognizable as human today -- cooked their food, which consisted of vegetables and meat and fish.  None of the other animals in this study cook their food.  Perhaps our higher quality diet allows us to spend less time digesting and more time alert?

But herbivores spend very little time asleep!  In fact, from this data, one might conclude that a limit on the size of herbivores is the number of hours in a day.... the largest herbivores spend almost the entire day (and much of the night) awake and, probably, eating.  In contrast, carnivores sleep the most, presumably because they can satisfy their nutritional requirements with less time and effort.

Why don't humans sleep more?

New Paper Continues Confirmation of Age-Defying Diet

In the last 15 years a number of research groups around the world have converged on an explanation for how dietary restrictions can lead to lifespan extension. These teams have narrowed the search to a handful of compounds.*  The central candidate, by far, is an essential amino acid called methionine, found in high amounts in meat and fish, but in very low amounts in most plant foods.

Reducing consumption of this single amino acid extends lifespan by 15-44% in every laboratory animal tested to date. This effect is sufficient to completely explain previous results that found dietary restriction of total calories led to lifespan extension. Turns out it wasn't the calories -- it was the methionine.

Methionine restriction reduces visceral fat with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Methionine restriction also prevents age-associated increases in serum lipids.(source)

A new paper published this month by Koziel et al confirms previous methionine restriction results in human cell culture, mice, rats, fruit flies, and yeast. Koziel et al used human cell culture to specifically examine mitochondrial function and showed that oxidative stress is reduced by this dietary intervention.  This work supports the traditional free radical theory of aging-by-oxidative stress.

Methionine is an interesting amino acid because it promotes growth, including muscle and bone development. It is essential, and that is the point: restriction appears to promote a healthy stress-response that can confer adaptive resilience to senescence.  Other researchers have postulated that methionine restriction causes an increase in autophagy, the process whereby cells break down and recycle unused or damaged cell components. Instead of the free radical theory of aging, this theory would postulate that Methionine restriction induces a starvation-type response where cells begin to recycle their constituents at an increased pace. In this theory, "stress" is a good state to be in, because it puts cells in an active phase of self-repair. Cite: 1 and 2.

* The two other most promising age-defying compounds are rapamyacin (an antibiotic with a plethora of strange and powerful effects throughout the body) and resveratrol.  

New Theories in Evolution and Ecology

Sometimes it can be hard to see progress in biology the way we hear about physics discovering new particles or proposing Grand Unified Theories that explain the entire universe.  It is tempting to believe biology is just too diverse, variable, and multitudinous to be tractable, and that we should content ourselves with Nature-special documentary anecdotes.

But recent research has uncovered at least three major advances toward predicting evolution, social altruism, and a universal explanation of biodiversity. We may soon be able to predict short-term (9-12 month) evolution of the flu virus, rigorously describe conditions necessary for social altruism, and extrapolate biodiversity estimates using insights from thermodynamics.

The complexity, idiosyncracy, and exceptions-to-the-rule in biology are still important, but so too are these simplifying general explanations.  The stories of new "universal laws" linked below are perhaps best thought of as null-theories; jumping-off places rather than destinations in themselves:


1) Predicting Evolution ... Testable Fitness Values (link to article by Carl Zimmer)

Simple selective pressures yield relatively simple predictions: fitness increases linearly at first, but in the long run, weird mutations may diverge populations along novel and unpredictable trajectories.  The tractable problem, then, is short-term evolution, which can still be incredibly important when it is applied to, say, the next 12 months of evolution in the flu virus.  The breakthrough came with the ability to quantify fitness to predict evolvability.

One of the biggest problems of evolutionary theory has been a lack of predictive power, because fitness could only be defined tautologically, post hoc based on survival and reproduction.  If biologists are able to assign fitness ranking with any skill (link) then we may finally be able to understand evolutionary ecology -- the rise and fall of species in their environment.  Will most threatened and endangered species prove to be genetic weaklings, as suggested by this correlational study?

2) Predicting Social Altruism ... What Makes A Good Theory? 

This is an insightful philosophy paper that deconstructs a long-standing debate about whether altruism is predicted by fundamental evolutionary pressures.  The important step forward here is a robust definition of key terms and a searching analysis of what we should expect from abstract mathematical theories.

3)  Predicting Biodiversity .... Metabolic Scaling Laws to the Rescue! 

The tractable problem is to estimate the number of species in a given area when ecologists can only count species in relatively small plots.  The breakthrough came by realizing that only two additional variables (population density and total number of species) are necessary to "collapse" idiosyncratic species-area curves into a single universal curve.

The discoverer, Dr. John Harte, explains:

"If you look at all the known species-area (S-A) curves in the world, of everyplace where somebody’s gathered species-area data, and you plot them all on one big piece of graph paper- log species vs. log area, you will find that the data points fill the graph almost completely. You get every possible behavior when you just do a plot of log S vs log A. There’s no regularity. I didn’t really think that had to be the case. What I learned from developing the theory of macroecology based on the maximum-information entropy principle, is that the theory makes a very startling testable prediction about the shape of the species-area relationship. It says that if you take any species-area curve and you plot the local slope of the log-log plot, what we call ‘z’, at any scale against a certain scaling variable that the theory identifies, namely, the number of individuals at that scale divided by the number of species at that scale, all species-area curves should collapse onto a single universal curve. And it turns out that they do"

(Quoted here.)