Functional Biochemical Mechanism Against Disease Biology Essay

Michael J. Gonzalez, DSc, PhD, FACN¹; Jorge R. Miranda-Massari, PharmD²; Jorge Duconge, PhD 3; Myriam Z. Allende-Vigo, MD4; Francisco J. Jiménez Ramírez, PharmD2; Kenneth Cintrón, MD5; Jose R. Rodriguez-Gomez, MD, PhD6; Glorivee Rosario, PhD7; Carlos Ricart, PhD7; Juan A. Santiago-Cornier, MD ,PhD8; Rafael Zaragoza-Urdaz, MD, PhD9; Alex Vazquez, DC, NC, DO10 , Steve Hickey, PhD11, Miguel Jabbar Berdiel, MD12; Neil Riordan, PhD13; Thomas Ichim, PhD14; Oscar Santiago, MD15 and Pramod Vora, PhD16

University of Puerto Rico, Medical Sciences Campus, School of Public Health, Department of Human Development, Nutrition Program, San Juan PR.

University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, Department of Pharmacy Practice, San Juan PR.

University of Puerto Rico, Medical Sciences Campus, School of Pharmacy Department of Basic Sciences , San Juan PR.

University of Puerto Rico, Medical Sciences Campus, School of Medicine, Department of Endocrinology, San Juan PR.

10475 Centurion Parkway , Ste.220, Jacksonville Fl.

Carlos Albizu University, San Juan Campus, Clinical PhD Program, San Juan PR.  

University of Puerto Rico, Cayey Campus, Department of Biology, Cayey, PR.

Clinical Research Center, San Jorge Children’s Hospital, San Juan PR.

 University District Hospital (UDH), Centro de Enfermedades Hereditarias e Inmunodeficiencias, San Juan, PR.

University of Western States, Nutrition and Functional Medicine Program, Portland, OR.

Faculty of Computing, Engineering and Technology, Staffordshire University,

Staffordshire, England, ST18 0DG.

Villa Grillasca, Ave. Muñoz Rivera 1227, Ponce PR.

2223 W Pecos Rd. Chandler, AZ.

Medistem inc., 9255 Towne Centre Drive, suite 450, San Diego CA.

Ponce School of Medicine, Department of Pathology, Ponce PR.

92 Corporate Park, Ste. C #705, Irvine CA.

Address correspondence to: Dr. Michael J. Gonzalez, University of Puerto Rico, Medical Sciences Campus, School of Public Health, Department of Human Development, Nutrition Program, GPO Box 5067, San Juan PR 00936-5067. Email:michael.gonzalez5@upr.edu

Key Words: Metabolic Correction, chronic disease, genetotrophic disease, biochemical individuality, nutrient insufficiency, functional medicine, orthomolecular medicine.

Abstract

Human development and physiology depends on a myriad of biochemical-physiological processes, many of which are co-dependent and interrelated. The rate and extent of many reactions are dependent on the enzymatic activity which, at the same time, depends on the bioavailability of micronutrient co-factors such as vitamins and minerals. In order to achieve a healthy physiological state, the organism requires that biochemical reactions occur at a controlled rate. To achieve this state it is required that metabolic reactions reach what can be considered an optimal metabolic equilibrium. A combination of genetic makeup, dietary patterns, trauma, diseases, toxins, medications and environmental stressors can elevate the demand of nutrients needed to reach this optimal metabolic equilibrium.

In part I, the general concept of Metabolic Correction is presented and elaborates on how it is becoming increasingly important as we become aware of the presence of genetic variants that affect enzymatic reactions causing metabolic disturbances that favor or promote the disease state. In addition, part 1 reviews how prominent scientists have contributed in a fundamental way to our understanding of the importance of micronutrients in health and disease and in the development of the Metabolic Correction concept.

Part 2 of this series discusses how metabolic correction can balance unmet nutritional needs, decrease medication induced nutrient deficiencies and adverse effects and compensate for the increase demand of nutrients caused by diseases and toxins. The application of metabolic correction can have a significant impact in lowering morbidity and mortality and its financial cost to our society.

Extracto

Las funciones del cuerpo humano dependen de una plétora de de procesos bioquímicos, muchos de los cuales son co-dependientes. La velocidad y el grado de completamiento de muchas reacciones dependen de la actividad enzimática, que a su vez depende de la disponibilidad de micronutrientes. Para poder alcanzar un estado fisiológico saludable, el organismo requiere que las reacciones bioquímicas ocurran a una velocidad controlada el cual podríamos denominar como un equilibrio metabólico óptimo. La demanda de nutrientes necesarios para alcanzar el equilibrio metabólico óptimo son afectados por la composición genética, los patrones alimenticios, traumas, enfermedades, toxinas, medicamentos y los estresores ambientales. En la parte 1 se presenta el concepto de corrección metabólica y como este cobra una creciente importancia según aumenta nuestro conocimiento de las variantes genéticas que controlan las reacciones enzimáticas responsables de los disturbios metabólicos que permiten o promueven el estado patológico. Además en esta primera parte se resume la contribución de científicos prominentes a nuestro entendimiento de la importancia de los micronutrientes en la salud y enfermedad así como el desarrollo del concepto de corrección metabólica.

En la parte 2 de esta serie se discute como la corrección metabólica puede balancear necesidades nutricionales incumplidas, así como resolver desgaste de nutrientes inducidos por medicamentos y efectos adversos, así como también compensar por el aumento en la demanda de nutrientes causada por enfermedad y toxinas. El uso de la corrección metabólica puede tener un impacto significativo disminuyendo morbilidad y mortalidad y sus costos a nuestra sociedad.

Nutrition, Metabolism and Physiological Function

Normal metabolic activities require over forty vitamins and micronutrients (1) in addition to fat, protein, and carbohydrates. In addition, two essential fatty acids (omega-3 and omega-6) and approximately eight essential amino acids are also needed for this process (2). Likewise, other important nutrients such as: Coenzyme Q10, Acetyl L Carnitine and lipoic acid, must be considered in our quest for physiological optimization (3). Virtually, every metabolic pathway requires these micronutrients for their completion.

The optimal concentration of every nutrient will facilitate physiological functionality. A deficiency may interfere with a biochemical pathway and require adaptation. Such adaptation means that while many partially depleted individuals do not function at 100 % efficiency; but do not present with apparent disease or symptoms in the short term. However, the chronic effects are difficult to study and may be involved in common degenerative conditions. A leading hypothesis is that a person supplied with the optimum nutrition will gain disease prevention and improved physiology. In the past, this hypothesis has been highly productive in reducing human illness, such an example is the identification of the nutritional deficit that causes the previously common disease pellagra. Assuming that all such nutritional illnesses have been discovered is unwarranted. Optimal concentration of nutrients needed by individuals may vary even for a single subject. Certain individuals have a greater need for specific nutrients. Moreover, individual need may vary extensively according to particular physiological requirements (4, 5). This variation could be caused by: digestive problems, malabsorption, food sensitivities, difficulty in the metabolism of certain amino acids, fatty acids, complex carbohydrates, low levels of neurotransmitters precursors and many other causes [1].

Many health professionals do not recognize the array of critical functions of vitamins, minerals and other nutrients at the cellular level, and especially their role as cofactors in enzyme reactions. The importance of micronutrients in human metabolism and biosystem control has not been completely elucidated, partly because of the complexity of cellular/physiological systems. Nevertheless, we know that critical enzymes require metals as copper, zinc, manganese, selenium, and vitamins such as the B-complex; as an integral part of their functional molecular structure or as part of their mechanism of action (6). Enzymes play a critical role in regulating and orchestrating the plethora of vital biochemical reactions that take place in living organisms.

Metabolic nutrition is generally recognized as the study of how diet and nutrition affects the body’s physiology. Nutrition, in general, is a complex interdisciplinary science but its importance is central to the maintenance good health. Aside from starvation or the overeating prevalent in Western societies, there are three levels of nutrition: poor, fair, and good. Poor nutrition is manifested as severe underdevelopment of the young as well as deficiency diseases such as beri-beri, scurvy, pellagra, rickets, kwashiorkor and numerous variations (1). Fair nutrition is good enough to prevent well-defined deficiency but not good enough to promote good health and proper development. This second-rate nutrition is, unfortunately, the kind which we have become accustomed to accept in a world full of junk food and is often regard as satisfactory (7). Good nutrition is the one that provides the needed energy in addition to high quality protein, carbohydrates, fats and the necessary vitamins and minerals. The concept of a balanced diet was developed to prevent deficiency diseases, based on the knowledge that appropriate food items will provide the minimum requirements of the nutrients needed by the body. A balanced diet is an approximation that appears to provide sufficient nutrition in the short term according to current knowledge. This good nutrition may be insufficient to provide physiological optimization and an excellent health state. Importantly, a current hypothesis is that food by itself may not provide sufficient vitamins and micronutrients for preventing deficiency/insufficiency (8).

In practical terms, inadequate dietary intakes of vitamins and minerals are widespread, and may be explained by excessive consumption of calorie-rich, nutrient poor, refined food (1). Caloric excess often accompanies sub-optimal intake of micronutrients. This is the Hidden Hunger Concept (9). Hidden hunger is defined as high caloric consumption with a low micronutrient density producing nutrient insufficiency. These inadequate intakes may produce metabolic disruptions (10) and increased risk of chronic disease. Episodic shortages of micronutrients were common during evolution. Natural selection favors short-term (emergency) survival at the expense of long-term health (10). Short-term survival was achieved by allocating scarce micronutrients by triage and internal physiologic control mechanisms (10). As micronutrients become scarce, an adaptive mechanism for allocating scarce micronutrients is activated. This triage means, prioritization of the use of relatively scarce nutrients to the most fundamental life preserving functions potentially at the expense of long-term survival. In metabolic reactions, enzymes involved in ATP synthesis would be favored over DNA repair enzymes; as well as over production of immune system components and neurological chemicals. The degree of adaptation is limited and negative metabolic repercussions arise. Homocysteine is a recently identified example of a metabolic byproduct that accumulates with shortage of B vitamins with implications for cardiovascular and neurological health. Nutrient depletion disturbs normal biochemical controls and the healthy physiological equilibrium, potentially favoring a state conduscent to chronic disease (1, 5). Since vitamins such as folic acid and pyridoxine require metabolic processes for their activation, the presence of certain genetic variants (polymorphism) with defective enzymes may hinder this activation and therefore contribute for accumulation of toxic metabolites such as homocysteine.

Homocysteine (Hcy) is considered a potentially toxic amino acid and a risk factor for inflammation, cardiovascular disease, stroke, blood clot formation, dementia and Alzheimer's disease among other degenerative diseases. It is postulated that the methylation of Hcy to Methionine could result in reduction of adverse cardiovascular events, strokes, blood clot formation, peripheral neuropathy, dementia and Alzheimer’s disease. Elevated homocysteine levels occur when a high prevalence of a genetic polymorphism of the enzyme that converts folic acid to the physiologically active 5-methylolate. Elevated homocysteine levels are correlated with a low intake of reduced by 5-methylfolate, pyridoxal-5-phosphate, methylcobalamin and betaine and supplementation can be corrective (12, 13). Hispanics have shown a relatively high prevalence of this functional polymorphism (i.e., MTHFR C677-T, a.k.a. rs1801133) on the gene encoding the enzyme methylene-tetrahydrofolate reductase (MTHFR) (14-16). MTHFR catalyzes the conversion of 5, 10-methylenetetrahydrofalate to 5-methyltetrahydrofolate (physiologically active form), a co-substrate for homocysteine (Hcy) remethylation to methionine (17). Pyridoxal-5-phosphate, methylcobalamin, and betaine also play a role in this important biochemical reaction (4). This polymorphism, presents changes (errors) in DNA nucleotides a C→T missense mutation (cytosine to thymidine) at position 677 of the MTHFR cDNA, leading to a valine substitution at amino acid 222, encoding a thermolabile enzyme with reduced activity that results in elevated levels of the metabolic by-product Hcy (i.e., hyperhomocysteinemia) (18, 19).

The Concept of Metabolic Correction

Metabolic Correction provides a biochemical explanation of the utilization of nutrients as enzymatic cofactors, precursor molecules, regulator molecules and metabolites for preventive and therapeutic action against disease (11). This functional biochemical/physiological concept clarifies how improvements in cellular biochemistry and adaptive physiologic control helps the body achieve metabolic or physiological optimization. Figure 1 illustrates this concept.

Figure 1 illustrates the concept of Metabolic Correction.

Food provides macro and micro-nutrients that are required for the production of energy, in addition to precursors of functional and structural molecules necessary for healthy metabolism, tissue repair and detoxification. Genetic variants, diseases, contaminants, and medications can increase the demand for certain nutrients. If the demand goes beyond tissue storage, then a co-factor insufficiency arises. Co-factor insufficiencies will create a decrease in specific enzymatic activity. Decreases in enzymatic activity can impact energy production, tissue repair, biosynthesis of bioactive molecules, detoxification and the healthy physiological state.

History of Metabolic Correction

Metabolic Correction is based on the work of several iconoclastic medical pioneers (20). In 1947, Dr. Roger J Williams contributed to the development of the understanding of the biochemical-genetic origin of disease with the development of the concept of Biochemical Individuality (21). He described anatomical and physiological variants among individuals and how they related to their individual responses to the environment and their particular physiology. He coined and gained recognition for the term biochemical individuality and how it relates to differing nutritional requirements for optimal function among different individuals. An early example of molecular biology and molecular medicine was originated by Dr. Linus C. Pauling, in a landmark article on the mechanism of sickle cell anemia (22). Dr. Pauling defined a new perspective on the origin of disease based upon the recognition that specific mutations of the genes can create an altered biochemical environment and therefore the modified physiological function associated with a particular disease. In 1950, Dr. Roger J. Williams established the term genetotrophic disease to explain diseases which resulted from genetically determined nutritional needs not being met by an individual’s diet and resulting in poor gene expression (23) and loss of adaptive physiologic control. Patients with genetotrophic conditions have increased need for one or more nutrients in order to achieve healthy physiologic functioning. Adaptation to the nutrient deficit might cause no apparent short-term effects but may eventually result in chronic disease. These genetotropic conditions can be clinically associated with functional polymorphisms on genes encoding key components of the altered metabolic pathways. As the homocysteine example demonstrates biochemical control can be restored when sufficient of the required nutrients (Cofactors) are provided to correct the deficit. Genetotrophic disease is related to conditions that improve dramatically with the addition of appropriate nutrients. Examples of this can include muscular dystrophy, allergies, mental diseases, cardiovascular disease, arthritis, multiple sclerosis, and cancer (24). Many chronic diseases can be conceived as subtle polymorphism-associated genetotrophic diseases, as long as nutrient(s) supplementation fills a specific metabolic need that improves the patient’s physiology, thus condition. Dr. Williams’s research approach was an early forerunner of personalized or Functional Medicine which is a current focus of medical research. Diet and nutritional status influence phenotypic functions and control gene expression through epigenetic related mechanisms. Dr. Williams pointed out that human biochemical variation in function was of relevance to understanding health and disease mechanisms and this idea is a primary consideration in today’s research environment of personal genomics and individual targeted medical solutions (24).

Between the 1950’s and 1960’s, Dr. Henry Turkel was the first to demonstrate clinically that nutrition and supplementation can modify gene expression and biochemical controls in Down’s syndrome (25). Turkel was probably also the first clinician to use metabolic correction as therapy when he influenced harmful gene expressions in mentally retarded children by removing accumulated metabolic by-products with nutrition and high dose supplements. He demonstrated an improvement in cognition, physical health and physical appearance in Down’s syndrome patients (25).

In 1973, Dr. Bernard Rimland, used an enhanced B complex formula with extra vitamins B5 and B6, plus Vitamin C and iron to aid emotionally disturbed children. Out of 190 severely disturbed kids, 164 showed some improvement over 90 days (26).

In 1980, Dr. Ruth Flinn Harrell and her colleagues gave a comprehensive vitamin and mineral supplement to a group mentally retarded children. It only took four months of supplementation to increase the children IQ's by 5.0 to 9.6 points. The unsupplemented children acting as controls showed no significant change. Considering that these patients had different retardation syndromes (including Down's syndrome), the IQ gains were highly significant (27).

The word orthomolecular was introduced by Dr. Linus Pauling in a paper in the journal Science in 1968 (28). The idea was to provide the right molecule to correct a metabolic imbalance and restore the biochemical control system. Dr. Pauling defined orthomolecular psychiatry as the treatment of mental disease by the provision of the optimum molecular environment for the mind, especially by regulating the concentrations of substances normally present in the body. He later broadened this definition to the health of the whole individual describing it as orthomolecular medicine (11). Genetic factors influence not only the physical characteristics of individuals, but also their biochemical milieu. Biochemical pathways of the body have significant genetic variability and diseases such as atherosclerosis, cancer, schizophrenia, or depression are associated with specific biochemical abnormalities (high homocysteine, reduced oxidative phosphorylation, increased kryptopyrrole, decreased serotonin) which may be causal or contributing factors of the illness. Importantly, the hypothesis that "optimum" molecular concentrations of substances may be achieved solely by dietary means has little direct supporting data. The need for essential nutrilites (vitamins, essential amino acids, and essential fatty acids) is expected to differ for each individual from the (average) daily amounts recommended for the general population (1, 10).

Dr. Jeffrey Bland created the concept of functional medicine in 1991. Functional medicine is a form of personalized medicine that deals with disease prevention and underlying causes of illness instead of treating just the symptoms. It is based on identifying core clinical imbalances that underlie various disease conditions. Imbalances arise from environmental conditions, such as diet, nutrients (including air and water), toxins, exercise, and trauma, together with the individual’s genetic predispositions, attitudes, psychological stress and beliefs. The core clinical imbalances arise from malfunctions in biochemical and physiological controls. The multifold range of systems involved include hormones and neurotransmitters, oxidation-reduction, mitochondropathy, detoxification, biotransformation, immune responses, inflammation, digestive, microbiological, and structural imbalances from cellular membrane function to the organ systems. Improving biosystem controls or physiologic balance is the precursor to restoring health and involves more than treating symptoms (11). Functional medicine deals with the management of chronic disease by integrating the interventions at multiple levels to restore the functionality and health of patients. Functional medicine is grounded in basic science and systems theory combining research from various disciplines into clinically relevant models of disease pathogenesis and clinical management. Dr. Bland’s 1999 book in 1999 Genetic Nutritioneering, explains how proper nutrition and supplementation can modify genetic expression and can incorporate the latest findings in epigenetics to create the best possible health outcomes (29).

More recently, Dr. Bruce N. Ames presented his Triage Theory of Optimal Nutrition (3) described previously above. The human body prioritizes the use of vitamins and minerals as an adaptive system, when it is deprived of a nutrient leading to depletion. In clinical medicine, triage means deciding which patients to treat when faced with limited resources. When faced with a nutritional deficit, the human body decides which biological functions to prioritize in order to maintain the vital functions of the system giving the individual the best chance to survive and reproduce. As is the evolutionary imperative, the body will always direct nutrients toward short-term survival capability; the evolutionary concern is survival to reproduce. Chronic disease, aging, and ultimate longevity are largely irrelevant for evolutionary success. Thus systems for regulation and repair of cellular DNA and proteins that optimizes health, prevent chronic illness, and increase lifespan are actively depleted. Dr. Ames’s research explains how in the presence of nutritional deprivation the system controls may promote age-related diseases for short-term gain and stability. It follows immediately that the risk of degenerative diseases (associated with aging, including cancer, cognitive decline, and immune dysfunction), can be decreased by ensuring adequate intake of micronutrients (10, 30-33). While short-term deficiencies or insufficiencies are common, mainstream physicians may overlook them as their clinical focus is mainly to treat disease symptomatology.

Metabolic correction is a functional term introduced by Dr. Michael J. Gonzalez and Dr. Jorge R. Miranda-Massari in 2011 (34) to describe a mechanism by which nutrients are capable of correcting biochemical disruptions that promote a variety of disease states. Metabolic correction includes the previously described system concepts to explain how improvements in control of cellular biochemistry may help the body achieve and maintain health. Metabolic correction intervenes with impaired biochemical reactions that are associated with the disease state. In other words, metabolic correction is a fine tuning of the cellular controls to improve function.

Conclusion

Nutrient deficiency or insufficiency related diseases are the end product of a series of cellular biochemical adaptations due to the lack of enzymatic cofactors. The biochemical systems will compensate in the short term but the adaptation is incomplete. Deficiencies of these micronutrients may not be severe enough to produce fast and clear clinical symptoms, but the long-term consequences could lead to a greater risk of a major disease. Lack of co-factors may affect the body’s ability to maintain good health and its capacity to resist and revert disease. It also affects the body’s ability to recover from exercise, surgery, and the capability of the brain to function at a high level. Detecting and treating disease at its earliest stages of cellular biochemical abnormality, rather than waiting for clear clinical symptoms is proposed as part of this model of metabolic correction.