Abstract
Humans suffer the highest burden of chronic disease in every age group ever in human history. Why? While many theories have been proposed, presented here are thoughts on a unified theory of disease to understand causes and provide guidance for health restoration and disease prevention. My thesis is that the combination of high and increasing body load of heavy metals, meta-metals and persistent and non-persistent environmental chemicals; multiple nutrient deficiencies and insufficiencies and loss of “unimportant” molecules from the food supply; dis-synchronization with the environment; and genetic susceptibility combine to disrupt physiology and cause disease.
Introduction
I’ve been involved in medicine now for over one half a century. I started as a research assistant in conventional medicine, then progressed to student of naturopathic medicine, practicing physician and midwife, founding president of Bastyr University, author (over 100 articles, many in PubMed, author/coauthor of 7 books for consumers and 6 textbooks for doctors), international speaker, researcher, designer and implementor of corporate wellness programs, public policy advocate, member of federal commissions, board member on several leading non-profits in the field—the list is long. Over these 50 years, I have directly cared for more than a thousand patients, indirectly cared for tens of thousands of corporate employees, taught thousands of students and in conferences, over 100 000 healthcare professionals. As might be expected, I have seen and learned a lot about health and disease. This learning has been personal as well. I’ve seen what has happened to so many family, friends and colleagues as some worked hard to promote their health, while others were content to adopt a typical American diet and lifestyle. Too many are now dead, suffering serious chronic disease or pretty much done with an active life. I think the time has come to talk about what I’ve learned.
We suffer the highest burden of chronic disease in every age group ever in human history. I believe the causes are clear. This editorial is an effort to put together these causes and show how they synergistically destroy health and increase disease. The good news is that every single one of these causes is addressable. I am not including the genetic causes of disease in this discussion. While obviously important, especially for those with inborn errors of metabolism, the reality is that genetics accounts for at most 15% of disease. Even that 15% is modifiable by sophisticated application of the concepts discussed below.
I presented the first version of my emerging “Thoughts on a Unified Theory of Disease” at the annual conference of the Institute for Functional Medicine given online Spring 2020. Here I continue to develop these concepts.
Themes
As I have studied and thought about health and disease, several themes have emerged that capture underlying concepts with huge clinical impacts. Presented in this editorial is an overview of these themes which, will be explored further in future editorials. The last theme is a place holder for additional concepts I am currently exploring. Hence the title “Thoughts on a Unified Theory of Disease” to clearly indicate this is evolving. The Themes presented combine several themes from my IFM lecture as I look to combine those that are similar and related to leave room for new concept areas as I want to limit to seven.
Theme 1: Nutrient Deficiencies and Insufficiencies are Rampant
A simple review of NHANES or searching PubMed reveals that majority of the public is deficient in many nutrients, as seen in Figure 1. In some cases, a substantial portion of the population consumes less than 50% of the RDI for several nutrients.
Figure 1.
Nutrient Deficiencies are Common1
Of additional concern, these numbers are based on RDIs which I think are grossly inadequate in several areas and have addressed in previous editorials.
In the large corporate wellness program I designed for a client in Canada where I directly measured nutritional status of 4,500 oil field workers, 99% had one or more nutrient deficiencies and most had many (unpublished data).
Multiple factors have combined to result in dramatically lower nutrient levels in humans:
-
Modern agriculture has adopted strategies that decrease nutrients known important in health
Seeds have been chosen to increase size and improve ease of growth, while sacrificing nutrient density
Fertilizers have been developed to increase size and rate of growth, decreasing the nutrient density
Some of the toxic chemicals sprayed on fields to inhibit weed growth have been shown to decrease mineral absorption in the food crops
People are choosing less nutrient dense foods
Transportation and storage result in loss of nutrients.
The net result is substantial loss of trace minerals in chemically-grown foods as well, illustrated in Figure 2.
Figure 2.
Loss of Trace Minerals from the Food Supply2
Look at the dramatic loss of copper in vegetables. Physiology is dependent upon enzyme systems that are dependent on trace minerals—which are leaving the food supply.
Theme 2: Body Load of Metabolism Damaging Toxic Metals and Chemicals is High, and Increasing
I have written many editorials here on how the increasing body burden of metals and chemicals is causing substantial ill health and overt disease. To leave space for the other Themes, I am limiting this overview to just a brief mention of 2 toxins—lead and arsenic. As can be seen in Table 1, lead causes 18% of all-cause mortality and about 1/3 of cardiovascular mortality.
Table 1.
Lead Causes a Lot of Disease and Mortality3
| Unadjusted HR (95% CI) | HR (95% CI) | Population attributable fraction (95% CI) | Avoidable deaths (95% CI) | |
|---|---|---|---|---|
| All-cause mortality | 3.79 (3.18 to 4.50) | 1.37 (1.17 to 1.60) | 18.0% (10.9 to 26.1) | 412 000 (250 000 to 598 000) |
| Cardiovascular disease mortality | 4.44 (3.47 to 5.68) | 1.70 (1.30 to 2.22) | 28.7% (15.2 to 39.5) | 256 000 (138 000 to 352 000) |
| Ischaemic heart disease mortality | 5.31 (4.06 to 6.93) | 2.08 (1.52 to 2.85) | 37.4% (23.4 to 48.6) | 185 000 (116 000 to 241 000) |
All models are adjusted for age (continuous and age-squared), sex, household income (<$20 000 or ≥$20 000 per year). Ethnic origin (white, black, or Mexican-American), body -mass index (normal [<25.0 kg/m2], overweight [25.0 to 29.9 kg/m2], or obese [≥30.0 kg/m2]), smoking status (never, current, or former), hypertension (systolic blood press ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), urinary cadmium (tertile [μg/g], alcohol consumption (four or fewer or more than four drinks per month), physical activity in previous month (none, one to 14 times, 15 or more times), healthy eating index (tertiles), serum cholesterol (continuous), and glycated haemoglobin (continuous). Hazard rations (HRs) for continuous concentrations of lead in blood represent the risk for an increase in log-transformed concentrations of lead in blood from 1.0 μg/dl to 6.7 μg/dl (0.048 μmol/L to 0.324 μmol/L (tenth to 90th percentiles).
Figure 3 (from the same reference) shows the obvious dose-dependent toxic effects. Note especially that these levels are all below the CDC recommended level of less than 10.0 ug/dL. Yes, the supposedly “safe” level is strongly associated with major disease.
Figure 3.
Dose-Dependent Effects of Lead on All-Cause and Cardiac Mortality6
I ask readers if they are aware of any other factor causing so much disease. Yes, public health has done a great job decreasing release of lead into the environment—thank you! However, as most of the lead is stored in bone, when going through menopause and andropause, almost everyone loses bone resulting in release of that lead. Interesting that the time of maximum disease manifestations matches up so well with the release of lead (and other toxic metals like mercury) from the bone. The good news is that the average blood levels of lead have gone down. The bad news is that there is no safe level of lead, and too many people have disease-inducing levels.
The other big one is arsenic. Arsenic contributes to or causes a huge amount of disease. Of particular concern in cancer. Figure 3 speaks for itself—arsenic appears to cause 1/4 to 1/3 of the major cancers.
Both naturally occurring and industrial pollution have resulted in significant arsenic contamination of both public and private water supplies, rice, and chicken as well as other sources. A stunning 35% of the US population exceeds 10.0 ug/g creatinine, the level known to induce disease in humans.5,6 Inexplicably, arsenic levels are increasing in the US.
As I have said in a previous editorial, screening for arsenic and lead should be part of the standard of care.
Sub-Theme 1/2: Nutrient Deficiencies + Toxin Exposure Synergistically Increase Damage
When plants are grown on soil contaminated with toxic metals and chemicals, their ability to absorb nutrients is impaired. Conversely, when nutrient levels in living creatures are low, their enzyme systems are more susceptible to the toxins that compete for their cofactor binding sites. In addition, while some toxins upregulate specific detoxification enzymes, others impair production and decrease detoxification function.
As can be seen in Table 2, toxins in the soil impair plants’ ability to absorb minerals and produce nutrients.
Table 2.
| Arsenic: ↓ Mn, Fe, Mg, K, P |
| Cadmium: ↓ 62% vitamin A; ↓ 75% vitamin C; ↓ Zn |
| Glyphosate: ↓ Mn |
When a person is both deficient in one or more B vitamin and exposed to lead, their risk of hyperhomocysteinemia increases significantly, as shown in Figure 5.
Figure 5.
Low B-Vitamin Levels and High Lead Levels Synergistically Increase Homocysteine
Lead, arsenic and paraquat (and many others) directly poison many detoxification enzyme systems making exposure to other toxins even more damaging.9,10
Theme 3: Modern Agriculture Has Dangerously Distorted the Food Supply
While modern agriculture has impressively increased the quantity of food available, there is solid research showing that trace minerals are substantially decreased. But I think there is an even more serious problem. Our scientific community has decided only about 50-100 minerals and molecules are essential for human health. However, plants contain over 50 000 minerals and molecules! Why did we think it was appropriate to ignore most of what is in foods?
Remember, virtually all nutrition research is short term, or if long term, are in animals.
Epidemiological research on food and nutrition shows far greater benefits for food than than single nutrient interventions. We are a complex matrix, addressing only a small part of the matrix independently of the rest will virtually always result in far less benefit.
I wonder if those reading this editorial were as astounded as I was when I saw the huge amount of beneficial physiological effects from the non-psychogenic cannabinoid research and the remarkable health benefits and cancer prevention from turmeric. I suspect these surprising benefits are due to making up for the loss of “unimportant” molecules in chemically-grown foods.
Sub-Theme 3: Organically-Grown Foods are Clearly More Healthful than Chemically-Grown Foods
I often look at the research comparing nutrient quality and toxin contamination of organically grown foods to those that are chemically-grown. Virtually all the research only looks at the “important” molecules. Researchers who have determined that chemically-grown foods are okay only looked at carbohydrates, protein, fat, vitamins and minerals. While there are some important differences in these as noted above, the magnitude of deficiency does not appear to be enough to explain the difference in clinical results. That got me to wondering how many other molecules are present in foods. I was very surprised to find many apparently important clinical benefits from some of these “unimportant” molecules have been discovered in plants, and researchers have speculated the number might be as high as 200 000!11 So in our reductionistic arrogance, we’ve decided 99.9% of the molecules are unimportant.
I first became aware of the clinical significance of this when working on my contribution to our IMCJ 19.s1 article, Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery. I was looking for natural molecules that function as zinc ionophores to increase cellular levels of zinc where it impairs the replication of viruses. In my search I came across an interesting super-computer modeling report that looked at 2000 molecules to determine which bound to the SARS-CoV2 spikes—a standard drug discovery process. I was surprised and intrigued to see that 2 of the top 5 were natural molecules—a flavonoid and carotenoid.12 Looking at the research on flavonoids and carotenoids, shows that many are also antiviral. This then led me to look at their levels in foods and soon revealed dramatic differences in the levels of many molecules in organically- and chemically-grown foods. Not only were many of these important molecule lower in chemically-grown foods, many weren’t even molecules present! Figure 6 illustrates this very well. This study grew tomatoes in a green house and was very well controlled with the only difference being the type of fertilizer. Also of interest is that they looked at molecule levels throughout the full growing year.
Figure 6.
Chemically-Grown Foods Have Greatly Lower Levels of Carotenoids and Flavonoids13
As can be seen, pretty much the only molecules that were conserved in chemically-grown foods were the ones that provided the traditional color of the food. There are many more examples.
There are good reasons plants evolved to produce all these molecules. They are anti-bacterial, anti-fungal, anti-viral, anti-insect, anti-oxidant, anti-cancer, etc. The health benefits for humans are obvious. Of particular interest is that many of these beneficial effects are independent of biochemistry. By this I mean they have direct physiological effects.
Now some speculation. While the causes are controversial, most everyone is aware of the relentlessly increasing incidence of epidemics and pandemics. Of course, increasing population density and international travel are clearly a component. But how about the idea that the loss of these natural, plant-based antiviral molecules from the food supply has removed an important component in protection from infection that was part of our evolutionary development? Seems to me that high blood levels of these antivirals would slow viral replication, giving our immune system more time to activate its many effective components. Just a few hours head start for the immune system would be a huge advantage.
Obviously, a lot of important concepts here that I will discuss in a future editorial.
Theme 4: Human Physiology is Massively Parallel—There are Few Single Pathways
Our huge investment as a society researching biochemistry, physiology and pathology has resulted in great advances in healthcare. However, of necessity, the vast majority of this research had to focus on the most important and impactful pathways—in the majority of the population. But more and more research is showing that less researched and lower priority pathways can have a huge impact on health and disease risk. A good example is the detoxification of the new to nature molecule acetaminophen. Figure 7 shows the many pathways.
Figure 7.
Detoxification of Acetaminophen
As can be seen, while there is a preferred pathway (mercaptate here) for most efficient and least damaging breakdown and excretion, there are several backup pathways. I believe we have focused too much on the big trees, while ignoring the smaller trees that together make up the full forest of physiology.
This lack of consideration of these lesser pathways contributes to the problems with modern foods discussed above. Many of these lesser pathways appear depend upon molecules in food that are no longer present. May not be the primary pathway that shows up in the biochemistry textbooks, but still important.
Theme 5: Loss of Synchronization with the Environment
Everyone is aware of circadian rhythms and their importance in health. Most of the focus has been on the big, whole body rhythms like the 24-hour sleep cycle. However, few appear to be aware that, often independent of the 24-hour cycle, every organ has its own circadian rhythm. Indeed, even cells have their own circadian cycle. These cycles induce epigenetic changes to optimize enzyme production and activation according to—or in prediction of—physiological need. Many of the drivers of these cycles are dependent upon specialized receptors that constantly surveil the environment. These then induce epigenetic changes to modify physiology to optimize function in a constantly changing environment. Figure 8 shows a simplified model of circadian oscillators in human physiology.
Figure 8.
Simplified model of the mammalian circadian oscillator14
Key to this environmental sensing are several receptors, especially the aryl hydrocarbon receptor (AhR). Normally, this receptor responds to endogenous molecules such as arachidonic acid, heme and tryptophan metabolites, and exogenous molecules such as flavonoids, carotenoids and berberine. Not surprising considering the substantial metabolic effects of these molecules. Unfortunately, these receptors also react to new to nature molecules such as halogenated dioxins, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), several types of pesticides and many other commonly exposed chemicals.15 Table 3 shows how several of these chemicals bind to receptors and the genes they modify. Notice especially DEHP (Bis[2-ethylhexyl] phthalate), the most common phthalate used as a plasticizer. DEHP composes 1% to 40% of common plastics—and does not remain there.
Table 3.
Common Environmental Chemicals Disrupting Circadian Sensors14
| Circadian gene | Toxin | Receptor |
|---|---|---|
| BMal1 | WY14643 | P PARα |
| TCDD | AhR | |
| Per1 | FICZ | AhR |
| TCDD | AhR | |
| Per2 | TCDD | AhR |
| Per3 | DEHP | P PARα |
| Cry1 | FICZ | AhR |
| DEHP | P PARα | |
| Cry2 | FICZ | AhR |
| Dbp | DEHP | P PARα |
Humans are constantly exposed to these chemicals in tablecloths, floor tiles, shower curtains, garden hoses, rainwear, dolls, toys, shoes, medical tubing (!), furniture, and swimming pool liners. Even worse, these and other kinds of phthalates are used as carriers for the fragrances used in cosmetics, personal care products, laundry detergents, colognes, scented candles, air fresheners, etc. Their use is so common they even show up in the water supply. Yes, humans have a significant daily (probably hourly) exposure to many of these circadian rhythm disruptors.
Clearly, we’ve seriously disrupted this finely tuned environmental synchronization system with chemicals that activate (or deactivate) these receptors independent of physiological need. The impacts are subtle, but widespread and the effects likely additive and synergistic. Many of these systemic effects help explain the strong correlations between body load of specific environmental toxins and most chronic disease. Especially where the direct mechanism of damage has not been determined.
Future Themes
I’m working on several more themes I think quite important, but require more review of the research before I can write about them.
Putting It All Together
Well accepted in the medicine is that gross nutrient deficiencies, high toxic exposure and serious genetic mutations clearly and directly cause disease. Examples include mercury causing Minamata disease, lead causing gout (we need to now recognize that arsenic appears to cause as much gout as lead); vitamin D deficiency causing rickets, vitamin C deficiency causing scurvy, and inborn errors of metabolism causing cystic fibrosis and sickle cell anemia.
But how about life-long low level exposure to hundreds of metals, meta-metals and chemicals in virtually every aspect of our living environments, chronic nutrient insufficiencies, loss of “unimportant” molecules and genetic susceptibilities that only manifest in the context of—toxins and nutrient insufficiencies?
Conclusion
Putting this all together, as shown in Figure 9, a very strong case can be made that the vast majority of chronic disease is due to the combination of rampant nutrient deficiencies and insufficiencies (including “unimportant” molecules); high body load of metabolism-damaging metals, meta-metals and chemicals; loss of synchronization with the environment; and genetic susceptibility genetic susceptibility, all of which combine to produce the highest burden of chronic disease in all age groups ever in recorded human history.
Figure 9.
Combination of Toxin Exposures, Nutrient Insufficiencies and Genetic Susceptibilities Is the Primary Cause of Chronic Disease
The good news is that as we understand these Themes and recognize which are most important for each of our unique patients, we have a template for understanding why people are sick and the pathways that have to be addressed to improve health, reduce disease risk and even reverse established disease (when the pathology is not too advanced).
I will continue to address and expand upon these important Themes in future editorials. Your thoughts most appreciated.
Figure 4.
Arsenic is a Major Cause of Cancer4
Biography
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