Obvious but Invisible

In this 3-part series, we will target some of the most important and revolutionary foundations in health and medicine. We’ll do this through:

Discussing what is missing from many current medical models regarding chronic illness pathophysiology, prevention, and treatment and why
Preparing a conceptual outline for a more effective systemic model for preventing and treating chronic illness
Providing more clarity around the terminology (or lack thereof) of systemic dysfunction in living systems, and offering some evidence-based terms for consideration in application of future research targets
Offering some practical guidance on applying principles of systems-based medicine to your own life

Why are so many people struggling to overcome relatively minor imbalances in health as well as the often-debilitating symptoms of more severe chronic illness despite having consulted with nearly every kind of medical doctor or specialist - “alternative/holistic” or “traditional” alike?

Today, we’ll talk about some possible answers to this question. Our answers here may seem obvious at first glance, but they remain tragically invisible to many patients and practitioners.

Getting Back to Body Basics

Bodies are complex systems. A key property of complex systems is that they are irreducible. This means that there are properties present in the system as a whole that cannot be explained in full simply by dissection into the individual parts. What is you cannot be reduced to the activity of one limb of your body or even one organ. You are a collection of relationships that come together in very precise and individual ways. The question of “is it the chicken or the egg?” is a classic example of an irreducible dilemma. It is neither the chicken nor the egg, but both at the same time that allow the other to exist and perpetuate. This is a core feature of a complex system. Are you feeling confused? Let’s break it down.

In science, we’ve come to understand quite a lot through reduction of something big into its component parts. Sometimes this process yields incredibly useful insights. But when you have increasingly complex systems such as the human body and you need to answer increasingly complex questions about what makes them tick, this reductionistic model breaks down. Why? It can’t fully and accurately depict what is going on. The body as a whole contains unique properties that are present only when you see the interaction between the parts, not when you look at the solitary parts by themselves. This is related to a scientific principle we call “emergence” and to study it better, we need models that are capable of reflecting these complex larger-scale interactions. The field of systems biology is one area of science studying these emergent properties in living systems more closely. There are some very daunting and unique challenges placed upon the shoulders of scientists peeling back the curtain of complex living systems (1).

Complex systems have many characteristics that I’ll discuss more in-depth in the future and that many others have discussed far more extensively (2). For now, it’s sufficient to appreciate that a complex system resists being over-simplified and defined only by its isolated parts. Nothing occurs in isolation within a complex system; every part influences every other part. Systems biology tries to figure out how *best* to study complex living systems in ways that may be far more effective at predicting and influencing outcomes in these systems. How do our findings apply to medicine?

In many clinical settings, we still employ predominately reductionistic medicine, despite its many shortcomings. We can easily illustrate the perceived positives and negatives of practicing reductionistic medicine with the following two examples:

Example 1:

An otherwise very healthy 23 year old patient is in the ER with excruciating pain from a broken leg incurred from a fall while climbing a tree. We logically reduce her pain to an isolated break in the bone, pointing to the abnormal x-ray and saying “all the problems here are from this broken leg!”. In this case this assertion is probably true! We set the bone, stabilize the leg in a cast for a time and tell the patient to rest up and stay out of trees.

Example 2:

Another patient who is in the ER is experiencing pain from a broken bone, except this time she’s a 70 year old woman with a history of osteopenia, depression, IBS, and fatigue. We’ll possibly address her hip fracture with surgery - perhaps give her a prescription for pain meds - but her bone break isn’t at all like the break our previous tree-climber experienced. This patient has other problems that are themselves likely related to why she broke this bone in the first place and they will influence the outcomes of our proposed treatments. Her diagnosis and treatment warrant a deeper exploration. A doctor might recommend a drug for osteopenia/osteoporosis like Fosamax and an over-the-counter (OTC) calcium citrate supplement to attempt to address the osteopenia piece - though this will not be nearly enough to adequately treat this patient. These treatments themselves may increase the severity of her other symptoms in part due to her history of IBS and her higher likelihood of experiencing negative GI side effects from metabolic prompts. Her depression as well as her other diagnoses, as we will soon learn, may also be linked to this dysfunction in the GI tract. Ultimately, this effort to reduce her clinical presentation to a handful of disjointed diagnoses and then apply a set of intensive “spot treatments” may backfire. If the meds used to address her osteopenia do worsen her GI function, that will further decrease her ability to absorb much-needed bone mass-supportive nutrients from her food and exacerbate her fatigue, not to mention the likelihood that her ongoing GI dysfunction was likely a primary contributor to her osteopenia (as well as depression and fatigue, etc) from day one. Haphazardly adding more pressures to her system in the form of drugs and supplements may do little to truly help the big picture and may in fact cause more harm.

Reductionistic medicine won’t work for this latter patient and most people struggling with advanced chronic disease or even minor stubborn health imbalances have more in common with the latter case here than they do the former. Furthermore, the answers to the most pressing questions about longer-term disease prevention in even the healthiest individual are to be found in a non-reductionist framework of systems biology, not in reductionistic “spot treatment” prescription. Reductionism, therefore, is the exception - not the rule - in effectively describing and addressing medical concerns and health in living systems.

The harsh reality is that we as a larger medical community are failing utterly at understanding imbalances in complex living systems. We are particularly failing at understanding and managing chronic disease states - some with more subtle cumulative aberrations over time - diagnosing/ labeling, and treating them appropriately. Appropriate treatment necessarily includes producing successful “big picture” clinical outcomes that stand the test of time in the individual.

Unfortunately, both the so-called “traditional” and “alternative”/“holistic” medical communities frequently commit similar sins of naivety with regard to the system they claim to treat.

Does your Doctor Get it?

An awareness of the inter-connectedness of the body is the stated ethos of the Integrative and Functional Medicine (IFM) community who rose to acclaim after seeking to differentiate themselves from the “traditional” medical community. The former stated that they would treat the body “as a whole”, where, they argued, the latter had failed to do so.

This was a very refreshing proclamation and one definitely headed in the right direction in many ways. Sadly, many IFM practitioners still appear to lack adequate understanding of the very system they advertise medical sagacity for. Many of the tools they use to “treat” the system are ignorant of the deeper systems-based physiology involved, ridiculously expensive in nature, and largely unnecessary for the patient to achieve good clinical results. In some cases, the advice offered through these tools can even sabotage patients’ long-term recovery goals.

In place of typical routine blood work and pharmaceutical drugs or surgery offered by so-called traditional medicine, IFM practitioners will often offer pricey “functional” laboratory tests (food allergy tests, neurotransmitter tests, genetic mutation tests, etc) and possess a vast and growing dependency upon supplements (including herbs, isolated nutrients, and other bioactive compounds) as primary treatment foundations for addressing the results of these tests. When a patient tells me they are thinking about having ANY test done, functional or otherwise, I always remind them:

A test is only as good as the tools you have to treat the results of the test!

Your doctor may recommend a lot of fancy tests. But does he or she possess tools that meet our criteria for optimal systems-based medicine?

Systems Medicine

Now that we know a body is a complex system and not just a collection of isolated parts, how do we practice superior systems-based medicine?

Let’s take a new example of a patient who, after various tests and medical history review, is told she has hypothyroidism, migraines, and depression. In the case of the traditional medical doctors, they may care very little about why or how a patient got to the current place she is at in her disease pathology. They will likely prescribe thyroid hormone replacement medication to treat the hypothyroidism, perhaps a drug like Imitrex to manage the migraines, and perhaps also an SSRI or SNRI for the depression. Spot treatment at its finest!

In the case of the IFM practitioners, they may ask a bit about why or how this patient got to the current place she’s at - though the way they address the answers to those important clinical question may leave much to be desired. They may or may not recommend some thyroid replacement medication, though they will likely give this patient a long list of supplements to take. These supplements may include B complex vitamins, vitamin C, magnesium, GABA, 5-HTP, selenium, herbal blends, probiotics, “adrenal support” formulas, among many others. They may run genetic tests and identify an MTHFR mutation and proclaim “aha! This genetic mutation is why you have migraines!” and then promptly put the patient on high dose methylfolate supplements in an attempt to “correct” for the mutation. Is this better than the traditional doc’s approach? Is this the best treatment for this patient?

Almost certainly not - and you’ll begin to understand why soon.

Asking deeper questions about why a patient developed her symptoms - so we can all understand how to keep her out of the same trouble in the future - is absolutely required for best practices in medicine, but it’s just the beginning. We must also ask if our chosen treatment method (drug, supplement, some combination of modalities, etc) is fully aware of the system it is treating. Here are some good questions to ask of our prescribed treatment:

Is it the most parsimonious solution to the problem at hand?
Is it the most effective in generating long-term cessation of symptoms?
What are the potential side-effects of its use over short and long-term duration?
Are there cumulative effects of using multiple supplements/drugs/modalities?
Are there any other available treatment options that could accomplish the same result with less risk?

In the case of both example treatment protocols applied above (“traditional” vs IFM) to our hypothyroid-depression-migraines patient, I will argue that they are each woefully non-parsimonious, ineffective alone for sustaining relief over time, and often have a high risk associated with ongoing and indiscriminate application. So, what are these missing foundations?

Foundations in Systems Medicine

What is the relationship between the disease states or symptoms themselves and between disease state(s) or symptoms and possible treatment(s) for a given patient? This relationship narrative is the therapeutic cornerstone and it needs to be as robust as possible, including context-dependent. It is unique for each patient and may change over time. The relationship narrative for each patient should include:

a best assessment as to why and how an individual patient got to this place in his/her illness staging up to present time
how multiple symptoms or diagnoses may be related and how each of these relationships is likely to be influenced by any and every given treatment
how the proposed treatments are likely or not to be the best for the job(s) at hand including how such treatments are likely to affect the patient’s life and health as a whole over time

Good science - and good medical science - works to address each of these above areas and more. We don't want to sell a cheap house that you can assemble easily and quickly overnight and will look impressive for a few months only to crumble in the next storm, generating more needless waste and stress when it collapses. Many healthcare practitioners believe that they have a complete set of tools and very few will admit to their gaps in knowledge - even when the gaps are quite significant. There is no way to thoroughly answer these above questions and form an ideal strategy for treatment without extensive knowledge in one of the most commonly misunderstood and overlooked areas of health science and systems medicine: metabolism.

Metabolic Medicine is Systems Medicine

How do we really do "systems medicine"? Welcome to the cutting edge of metabolic science!

Metabolism is the language of a complex biological system (your body). It is defined as the sum total of all chemical reactions taking place in your body to sustain life (3)

Metabolism is a broad term that encompasses not only the process of energy production, but every chemical reaction in your entire body taking place to sustain life. Metabolism is the language of the interconnected biological system. It is the language of the big picture. It is the language we as living organisms use to stay alive. It is quite literally the language of life.

The common understanding and usage of the term metabolism appears to be largely misrepresented; confined to refer only to the breakdown of food and its transformation into energy. We may simply think of it as the rate at which we produce energy and not much more. We hear people say things like “I want to speed up my metabolism!” or “I can’t lose weight because I have a slow metabolism”. In this way, many of us have misunderstood the scope of the term metabolism and have therefore failed to appreciate just how far-reaching and important metabolic processes are in determining all aspects of physiological function including prevention and recovery from chronic disease and imbalance. Whether we want to say “mental illness”, or “physical illness”, it’s all governed by the physical language of metabolism.

Metabolism takes place in every single cell in your body. It is taking place in order for you to read these words and process their meaning. And it isn’t just one piece of what’s happening in your body - a sidekick accompanying some other big mover - it’s the whole thing.

We very broadly categorize metabolic processes into 2 groups: catabolic and anabolic. Catabolism is the break-down of complex molecules into simpler ones in living organisms. Perhaps the most famous example of catabolism takes place as you digest the food you eat. This food will be broken down to help generate adenosine triphoshate (ATP) and other essential molecules that drive cellular activity. ATP – along with its related molecules ADP and AMP - are main drivers of hundreds of metabolic reactions. The molecular building blocks of ATP include carbon, nitrogen, hydrogen, oxygen, and phosphorus. ATP molecules contain unstable, high-energy bonds that can be transformed in reactions to release a large amount of energy which is then used by the body to drive other metabolic processes. Which brings us to anabolism. During catabolic reactions, ATP and other substrates are created and energy is stored until needed for anabolic reactions.

Anabolism is the construction or synthesis of complex molecules from simpler molecules in living organisms. This can include synthesis of DNA, hormones, neurotransmitters, antioxidants, cell membranes, tissues, organs, immune proteins, storage of energy and nutrients, and so many other vital constituents of your functioning body.

Think about a car for a minute. A car runs off of chemical combustion reactions. A combustion reaction takes something complex (gasoline, for example) and breaks it down into the smaller molecules of carbon dioxide and water – in the process, creating the energy that allows the machine parts to move. We might liken this process to a catabolic one - indeed, people are all too fond of saying “food is fuel!” - though that would of course be selling food short. Just imagine if that gasoline you put in your car could also BUILD an engine! Put some gas in your car, and your car can grow a radiator or a windshield or repair a broken transmission. That would mean your car was capable of catabolism AND anabolism! That would be pretty amazing (not to mention it would save us all a lot of money)! And it would be a lot like your body. Your ‘gasoline’ is the food and nutritive compounds you take in from your environment. But in the case of your body, this gasoline not only powers your body from an energy perspective, but literally helps build, maintain, and regulate every biochemical process including the structural integrity of every cell, organ, and relationship that makes you…you.

Every day your body is breaking down food for energy, transporting, employing, and storing nutrients and other nutritive components, breaking down and detoxifying waste products, recycling and building proteins, cellular membranes, and DNA. It is constantly repairing damaged tissue, synthesizing hormones and neurotransmitters, regulating those hormones and neurotransmitters, promoting or decreasing inflammation, and supplying the immune system with its many players. And I’ve merely brushed the tip of the tip of the iceberg of all that goes on within the domain of metabolism.

Without your metabolic pathways, you wouldn’t be you. If we could put on special glasses that enable us to see what was allowing you to perform every single one of the functions of daily life – moving through your day, responding to stimuli, and even thinking the thoughts you think – we’d see the metabolic “superhighways”: countless microscopic interrelated and intricate biochemical roads forming higher order relationships wind through every point on your body. Nothing you experience as a living organism can take place independent of this map.

So, how do we apply this knowledge about the metabolic superhighways to systems medicine for the best results?

Using Metabolic Medicine

Whether we admit to it or not, we as individuals and/or medical clinicians are actually practicing some kind of metabolic manipulation every day. Our day-to-day life includes a multitude of encounters with environmental input that dictate our metabolic function in profound ways. Becoming aware of this and being able to manipulate those encounters and even customize them to a large degree can greatly affect our overall health. Because the metabolic impact of our decisions is often invisible to us, it may lead us to practice less-than-optimal metabolic manipulation.

We need to move from mindless manipulation of our metabolic machinery to mindful metabolic medicine

When there is a minor imbalance or a more severe chronic illness, we may begin to interpret this as a type of metabolic dysregulation. The dysregulation can vary in terms of severity and scope, tending to self-perpetuate in many cases due to the inherent tendency of complex systems to exaggerate flaws over time (2). However, we must avoid falling prey to reducing metabolism itself to a single chemical reaction or genetic mutation. While there are plenty of documented inborn errors of metabolism which are specific genetic diseases that affect one area of the metabolic superhighway proportionally more than other areas - such as phenylketonuria, a genetic disease that prevents one from efficiently breaking down the amino acid phenylalanine - these arguably still affect and are affected by multiple aspects of the metabolic machine and management of this disease and similar diseases must also appreciate this.

One of the most common ways the metabolic pathways influence the development of illness and imbalance is through the profound impact of metabolic function on the stress-response system and, in turn, the stress-response system’s profound influence on metabolic function. The stress-response system, also known as the neuroendocrine system, is one very large continent on the planet of metabolism and, utilizing the language of the metabolic superhighways, plays a core role in adapting to physiological pressures. This process of adaptation (or failure therein) is heavily implicated, to varying degrees, in the pathophysiology of chronic illness (4,5). This will be further discussed as we move forward.

To continue reading, head over to Part II and Part III !

References:

(1) A Aderem. Systems Biology: Its practices and its challenges. Cell; Volume 121, issue 4; 511-513, 2005

(2) Thurner S, Rudolf H, Klimek P. Introduction to the Theory of Complex Systems. 1st edition. Oxford, UK: Oxford University Press; 2018

(3) Definition of metabolism. Brittanica. https://www.britannica.com/science/metabolism . Accessed April 2019.

(4) McEwen BS. Stressed or Stressed Out: what’s the difference? J Psychiatry Neurosci. 2005. 30(5) 315-318

(5) CTsigos, I Kyrov, E Kassi, GP Chrousos. Stress, Endocrine Physiology and Pathophysiology. Endotext 2016.