The M⁵ Medical Manifesto

A modest proposal to radically overhaul healthcare

“Nothing in biology makes sense except in the light of evolution.”

First espoused by evolutionary biologist Theodosius Dobzhansky in his seminal 1973 essay, most scientists agree with this consensus opinion. But relying on empirical observation alone can lead to myopic conclusions. We know that structure determines function. Red blood cells are non-nucleated in order to carry more oxygen. Opposable thumbs allow us to grasp objects of different shapes.

If we are unable to determine the job of a given structure, we are quick to label it vestigial. If we cannot find a function for something, we assume one doesn’t exist. But absence of evidence is not evidence of absence.

The appendix, long considered an anatomical anachronism, was recently shown to serve as a safe-house for commensal gut bacteria during bouts of gastrointestinal illness. Our assumption that lymph nodes are absent in brain tissue was later proven erroneous by the discovery of the glymphatic system.

In some cases, our empirical observations only provide incomplete information. Shifting our perspective from the macro to the micro can help shed light on our evolutionary past. We often consider the unit of selection for natural selection to be the respective members of a given population.

But every single human member is host to trillions of other microbial members, including bacteria, archaea, fungi, protists, and viruses. Evolution acts not on humans but holobionts, a term that encompasses hosts plus all their microbial symbionts. In other words, evolution acts on ecosystems.

Body Language

We are living, breathing ecosystems consisting of thousands of complex networks that relay millions of signals every day. And our bodies speak a wide array of molecular languages including Notch, Jak-STAT, Hippo, and Hedgehog. Our gut microbes communicate amongst each other using languages like quorum sensing, and they communicate with us through toll-like receptors (TLRs) and gut-associated lymphoid tissue (GALT).

Nearly all disease can be traced back to a breakdown in communication. Signals may be improperly relayed, misinterpreted, or lost in translation. In type two diabetes, beta cells in the pancreas become deaf to the signal of insulin. In type one diabetes, cells go mute and fail to release insulin at all. John Donne once intoned, “No man is an island.” Nor is any organ, tissue, microbe, or cell.

Our systems are in constant communication with one another, but the majority of our medicinal therapies don’t account for the complexity of our biological circuitry, instead taking a “scorch the earth” approach to infectious diseases and cancers and an immunosuppressive approach to autoimmunity.

Treatment of tuberculosis often destroys the bone marrow, statins are notorious for depleting carnitine and coenzyme Q10, and the collateral damage of antibiotics is akin to that caused by trying to kill a mosquito with an AK-47. Many drugs exhibit toxicity through mechanisms that damage the mitochondria and interfere with cellular respiration.

But what if there were a better way forward? Systems biology and network medicine aim to examine the bigger picture and target molecular misunderstandings in a way that maximizes potential benefit and minimizes potential side effects.

Nodes in a Network

Why are patients with one autoimmune disease extremely likely to have at least one other? Which mechanisms explain why Ehlers-Danlos syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS) form a diagnostic triad? How can we account for the high degree of overlap between neurodivergent conditions like autism, ADHD, OCD, and dyslexia?

The high incidence of certain disease comorbidities can be explained if we look a little deeper. We can assign molecular mechanisms to clinical presentations formerly considered idiopathic. In late 19th century, surgeon Sir Benjamin Brodie voiced his opposition to medical specialization as follows:

“Diseases generally are so connected with each other, and a knowledge of one is so necessary to a right understanding of another, that no one who limits his attention to any given disease, can be so competent to investigate its nature, and to improve its method of treating it, as those are who have a wider field of observation, and who are better acquainted with general pathology.”

Our temporal understanding of disease is often flawed. We imagine that one event triggers another and so forth in a linear domino chain effect. But the mapping of connections is not one to one; the mapping is many to many. Once we have failure at enough nodes and exhaust the body’s ability to compensate, we start to observe the emergence of symptoms.

The average four-year medical school curriculum spends just a single day on the topic of nutrition, but nutritional insufficiency serves as a prime example of the limits of medical specialization. Nutritional deficiencies mimic many commonly encountered diseases but seldom make the list of differential diagnoses. The symptoms of B12 deficiency closely mirror those of Alzheimer’s disease and other types of dementia. Both can present with elevated levels of homocysteine and brain atrophy.

Nutritional deficiencies can present as either frank (think scurvy from vitamin C deficiency or goiter from iodine deficiency) or subclinical forms with the latter characterized by a far more insidious reduction in physiological function.

Subclinical magnesium deficiency, for example, predisposes individuals to the inflammaging common to many complex chronic diseases, including atherosclerosis, diabetes, hypertension, osteoporosis, and cardiovascular disease.

Normal serum magnesium levels do not rule out magnesium deficiency, as extracellular magnesium accounts for only 1% of total body stores, and many drugs including thiazides induce magnesium depletion that is not detectable by routine monitoring of serum levels.

Because of the many organ systems affected, a patient presenting with magnesium deficiency may be prescribed inhalers for asthma, beta blockers for arrhythmia, NSAIDs for muscle aches, antiepileptics for ataxia, antidepressants for depression, steroids for inflammation, and appetite stimulants for cachexia.

This symptom-based approach to disease needlessly subjects the patient in question to a host of pharmacological side effects and potentially dangerous interactions among medications, none of which will address the patient's underlying pathology.

Instead of employing systems analysis, modern medicine commonly conceals symptoms in the hopes that the body will eventually heal itself and regress to the mean. The “diagnose then drug” paradigm fails to identify the overarching problem let alone the prognosis.

Divide and Conquer

Medical specialization applies a reductionist framework that obscures the larger clinical picture. Treating various organs or symptoms as separate entities isn’t conducive to chronic disease management, as cellular crosstalk and signaling along information highways like the hypothalamic pituitary adrenal (HPA) and gut-brain-skin axes illustrate how various organs, tissues, cells, and microbes work in concert through a number of diverse processes to maintain our incredibly complex bodies.

Complex chronic illnesses are those in which many different organ systems are affected simultaneously. Patients may present with dozens of painful symptoms only to be thrown at the altar of medical specialization.

A neurologist for nerve pain and migraines, a psychiatrist for anxiety and depression, a gastroenterologist for diarrhea, a hematologist for anemia, a rheumatologist for joint pain, a dermatologist for skin rashes, an endocrinologist for thyroid issues, a urologist for cystitis, and an immunologist for allergies.

No one ever suspects that a common set of causes could be behind the burning in one’s brain, bowels, bladder, and bones. Even medical institutes built to tackle medical mysteries in multidisciplinary teams such as the Mayo Clinic and Cleveland Clinic significantly struggle to alleviate the plight of patients with complex chronic illnesses.

The promise of precision medicine offers advancements within the existing framework of medical specialization, but better medicine requires a paradigm shift to networks, systems, and multiomics.

Power Failure

“Things fall apart; the center cannot hold.”

— William Butler Yeats, “The Second Coming”

In our bodies, individual cells maintain a steady state equilibrium by locally counteracting molecular entropy through the input of energy. For every one molecule of energy consumed in the form of ATP or adenosine triphosphate, the sodium-potassium pump found in the membrane of all animal cells exports three sodium ions and imports two potassium ions, each against their concentration gradients.

In a typical adult, the activity of sodium-potassium ATPase pumps is estimated to account for 20-40% of resting energy expenditure, and their importance in sustaining life can’t be overstated.

Certain genetic mutations that interfere with proper functioning of the sodium-potassium pump have been shown to cause rapid onset dystonia-parkinsonism, characterized by involuntary muscle contractions and the inability to voluntarily move one’s muscles and limbs. Alcohol is thought to impair motor coordination by inhibiting sodium-potassium pumps in the cerebellum.

Energy is necessary to both maintain and repair structures, and disease directly implicates a deficit in energy production and metabolism. Network medicine can enable us to work backwards from symptoms like fatigue and brain fog to locate where deficits in energy production are occurring.

Deficits in energy production can occur as the result of insulin resistance, microbiome dysbiosis, intestinal barrier dysfunction, malnutrition, infection, chronic inflammation, or drug-induced mitochondrial damage.

Imagine the following: You present to the doctor with persistent chest pain and a nagging cough, and lab results point to bacterial pneumonia. A two-week prescription of antibiotics clears the infection, but you’re left with crippling fatigue, brain fog, joint pain, and malaise.

After countless visits to numerous specialists—internal medicine, rheumatology, neurology, gastroenterology, and more—you’re saddled with a handful of wastebasket diagnoses. Or perhaps your symptoms are psychologized and you’re suspected to suffer from conversion disorder or Munchausen's syndrome.

For far too many people, the situation described above leads to long-term disability with little relief in sight. Moving towards a healthcare system that addresses the multiple affected nodes within disease networks in concert instead of looking at organ systems in isolation will make for more effective medicine and a healthier population.

Cracking the Code

Chronic diseases are commonly characterized by the aphorism, “Genes load the gun, but environment pulls the trigger.” In reality, chronic disease is the result of the complex interplay between a host’s genetics and exposome, which accounts for factors such as socioeconomic status, nutrition, exercise, circadian rhythms, alcohol intake, drug use, air pollution, chemical contaminants, psychological stress, and gut microflora.

Identifying the various mechanisms at play in chronic diseases and accounting for environmental factors allows us to provide more comprehensive care in order to achieve lasting remission.

Consider the following analogy: When tackling drug dealing in the inner city, attempts to arrest all the offenders are unlikely to succeed because the ones left behind will be smarter and more conniving. Instead, we can invest in better jobs, education, and infrastructure so that citizens won’t have to resort to crime as a means of survival.

Addressing the environment that led to the problem in the first place will provide a more stable solution. Similarly, directly targeting infectious agents and cancers with antimicrobials and chemotherapy respectively, immediately selects for resistance, but altering the ecological microenvironment to dissuade their growth and replication can provide a more viable long-term strategy.

Cancer Is Not Caused by Mutations

“Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.”

— Susan Sontag

This duality of discrete states—healthy or sick—creates a false dichotomy. Disability is often dynamic, chronic disease symptoms wax and wane, and many individuals considered healthy may actually be in a prodromal period where symptoms have not yet been made manifest. Expanding the angles from which we collect data can help us approach health and disease in more nuanced ways and move from preventing pathology to optimizing well-being.

Perhaps complex chronic illnesses are the perfect representation of the parable of the blind men and the elephant. As we discussed earlier, each specialty only illuminates one facet of disease in accordance with its area of expertise. Similarly, looking at one type of data will only elucidate one level of disease pathology.

DNA is sometimes considered a blueprint for living cells, but looking at the genetic code in isolation can’t help you predict what the fully functional resultant organism will look like. For that, we also need to investigate other types of omics data.

The cost of genomic sequencing has fallen precipitously over the last 20 years, at a much higher rate than that predicted by Moore’s law. The cost of employing other types of sequencing technologies will likely follow suit. The benefits of utilizing multi-omics data have already been demonstrated in several settings.

Researchers at the Institute for Systems Biology recently used proteomics, metabolomics, clinical laboratory assays, genetic risk scores, and gut microbiome composition data to develop a measure called biological BMI, which more accurately reflects metabolic health than classically measured BMI.

Genomic, epigenomic, transcriptomic, and proteomic profiling of certain cancers has been used to identify clinical subtypes, model cancer pathophysiology, and predict potential drug targets.

Medicine of the future is not only multi-omic but methodical, meticulously applying an “order of operations” to disease treatment. If a patient with complex chronic illness presents with severe mast cell activation and polyreactivity, a practitioner should first address this immune-mediated inflammation and stabilize the patient before addressing other aspects of disease presentation.

Starting with systemic pathologies before proceeding to localized ones prioritizes patient safety and enhances treatment efficacy. When people with complex chronic illnesses receive the care they require, physical, mental, social, and financial health can all improve in tandem.

Big Biology integrates systems-based thinking, network medicine, microbiome science, epidemiology, comparative genomics, “One Health,” neuroethology, psychoneuroimmunology, evolutionary medicine, computational modeling, bioinformatics, multiomics, digital health data, translational science, and social determinants of health to arrive at better solutions to the problems that plague us.

The future of healthcare is personalized, precise, and proactive. The future of medicine is multi-omic, metabolic, mitochondrial, microbial, and molecular.