Last month, after eleven years and input from more than 22,000 patients, clinicians, and researchers across every world region, a condition affecting one in eight women was officially renamed. Polycystic ovary syndrome (PCOS) has officially been renamed polyendocrine metabolic ovarian syndrome (PMOS).

The announcement came in a paper published in The Lancet and presented at the European Congress of Endocrinology. Fifty-six leading academic, clinical, and patient organizations were involved. The rollout will take three years and require updates to clinical guidelines in 195 countries.

The old name was wrong in almost every way. It centered the ovaries in what is essentially a metabolic and endocrine condition involving insulin resistance, excessive androgen production, and hypothalamic-pituitary dysregulation.

It described cysts that aren’t actually cysts but arrested follicles. These outdated diagnostic criteria contributed to diagnostic delays affecting up to 70% of patients.

The Lancet paper doesn’t mince words about what the old name caused. PCOS was “inaccurate, implying pathological ovarian cysts, obscuring diverse endocrine and metabolic features, and contributing to delayed diagnosis, fragmented care, and stigma, while curtailing research and policy framing” for a disease affecting 170 million people worldwide.

This is one of medicine’s most prestigious journals formally acknowledging that a name caused harm.

Now, if only they would admit the same about the PACE trial. But I digress.

If a misleading name for one condition required eleven years, 22,000 participants, and a three-year global implementation plan to correct, the uncomfortable question that follows is: how many other names are doing damage right now?

Probably more than we would like to admit. Medical nomenclature has never been neutral.

Diagnoses of certain conditions are not entertained in some clinics, as though disease existence is predicated upon personal beliefs. Positive findings indicate evidence of disease, as if it’s wonderful news to uncover a tumor. The patient failed to respond to anti-TNF therapy, as if it wasn’t the drug that failed the patient.

So much of medicine feels like theater with patients the unwitting specimens.1

Names encode the assumptions, priorities, and power structures of the time period in which they were coined. These initial definitions are propagated through medical school curricula, insurance billing codes, and grant funding applications long after the science has moved on.

The gap between what a name implies and what the pathobiology reveals can be measured in delayed diagnoses, underfunded research, dismissed patients, and needless suffering.

The map is not the territory, but in medicine, the map often has power disproportionate to its utility.

Burning a Hole in Your Stomach

Sometimes the cost of a bad name can be measured in decades of ineffective treatment. In the 1980s, Barry Marshall was trying to convince the medical establishment that peptic ulcers were caused by a bacterium.

The prevailing view was that the stomach maintains a pH low enough to denature most proteins and kill most microorganisms, so the idea that bacteria could survive there, let alone colonize the gastric mucosa and cause chronic disease, was absurd.

The name peptic ulcer disease alluded to the digestive enzyme pepsin and centered the gastric environment as the causal context.

Stomach acid was the problem. Bacteria couldn’t possibly be.

The prevailing model missed the mechanism that allows Helicobacter pylori to survive harsh stomach conditions. The bacterium produces urease, an enzyme that catalyzes the breakdown of urea into ammonia and carbon dioxide. The ammonia neutralizes the acid immediately surrounding the organism, creating a hospitable microenvironment within a gastric lumen that would kill anything else.

Marshall could not get his findings taken seriously through normal channels and famously drank a culture of H. pylori, developed gastritis, and treated it with antibiotics to prove his point. For this work, he and Robin Warren eventually received a Nobel Prize.

But for years, the name peptic ulcer disease directed clinical attention toward acid suppression, surgical intervention, and stress management while the bacterial etiology went ignored.

Shrinking the Denominator

Post-Treatment Lyme Disease Syndrome (PTLDS) is an egregious example of encoding a very specific assumption about causation that limits the research question before it is even asked.

The name implies that persistent post-infectious symptoms in Lyme disease are somehow contingent on whether the patient first received antibiotics. Post-treatment. As if the potential biological processes driving chronic symptoms require a history of treatment to occur. That’s not how immunology works.

Post-infectious syndromes can occur in patients treated promptly, in patients treated late, and in patients who were never treated or diagnosed at all. The treatment timeline is largely irrelevant to whether Borrelia burgdorferi’s effects on the host immune system produce lasting dysregulation.

Centering the name on treatment rather than infection is a choice that conveniently sidesteps the scale of the problem. If post-infectious sequelae can occur independent of treatment history, the true prevalence of long-term Lyme-related illness is dramatically larger than what current estimates capture.

The denominator is not people treated for Lyme disease. It is people who have ever been infected with Borrelia burgdorferi, which includes years of undiagnosed and untreated cases in under-surveilled populations.

To their credit, some of the most prominent researchers in this space like immunoengineer Michal Tal at MIT and microbiologist Amy Proal at PolyBio Research Foundation have effectively moved past the post-treatment framing by treating long-term Lyme disease symptoms as a post-infectious syndrome that may or may not share mechanistic features with myalgic encephalomyelitis and long COVID.

The institutional nomenclature still hasn’t caught up with emerging science. But patients don’t have the luxury of waiting to be acknowledged.

So You’re Just Tired All the Time?

My life permanently changed after a bout with swine flu. First, my doctors said it was post-viral syndrome. Then they said it was chronic fatigue syndrome. Suffice it to say, that didn’t really clear things up.

My best friend at the time responded, “So you’re just tired all the time?”

No, it’s like I can’t breathe all the time, I wanted to say, but it was no use. She didn’t understand, and she never would. She said she wasn’t like me — that she couldn’t just lay in bed and stare at the wall all day.

If she were lucky, she would never find out that it’s not a choice to be bedridden, writhing in pain, struggling to breathe, feeling as though you’re being electrocuted and strangled and set on fire all day long.

She made it sound like a lazy vacation. Most able-bodied people do.

They don’t understand that there are quite literally fates worse than death. And many patients have to endure these trials every single fucking day.

There’s no vacation from the constant pain and sleep deprivation. No way to just check out. No off days. No matter what.

Another girl in my class thought that if I wasn’t vomiting or running a fever, I should be in school. She practices internal medicine now. I wonder if any of her opinions have changed since we were in grade school together. Given the antiquated state of medical curricula, probably not.2

Myalgic encephalomyelitis is still commonly referred to by its old name, chronic fatigue syndrome. The name was chosen in the 1980s partly because it was considered less alarming than myalgic encephalomyelitis and partly because fatigue was the most obvious symptom to a field that had not yet taken the condition seriously enough to characterize its more distinctive features.

Patient advocates have fought for decades for the ME framing precisely because they understood what was at stake. A condition called chronic fatigue syndrome attracts less research funding and different clinical attitudes than a condition called myalgic encephalomyelitis.

It generates different responses from insurers, employers, and disability adjudicators. The name makes assumptions about the nature and severity of the condition.

A few weeks ago, late night host Jon Stewart made an insensitive joke comparing chronic fatigue syndrome to what researchers experience when they have to answer the same question too many times.

I doubt his team would have been comfortable making a similar joke about cancer or multiple sclerosis or kidney failure, yet the quality of life for patients with ME is far lower than that of patients with these more “validated” devastating conditions.

Warning: Audio in the video below is quite loud for those who have auditory sensitivities.

Fibromyalgia carries a similar burden. The name describes what the clinician observes, widespread musculoskeletal pain, instead of the neurological sensitization, autonomic dysregulation, and neuroimmune mechanisms that research increasingly implicates. It has historically attracted psychosomatic framing, skepticism about its legitimacy as a diagnosis, and clinical attitudes ranging from mild condescension to outright dismissal. It disproportionately affects women.

The Wandering Womb & Women’s Health

Let’s return to the original sin of medical nomenclature.

Hysteria derives from the Greek hystera, meaning uterus. For centuries, countless symptoms in women — pain, fatigue, paresthesia, seizures, paralysis — were attributed to a wandering womb. The diagnosis was not a description of biology. It was misogyny laundered as medicine.

Hysteria was a stand-in for what medicine couldn’t explain, and the name placed the inexplicability inside the patient rather than inside the field.

The word has been erased from diagnostic manuals. The clinical attitudes haven’t been.

Multiple sclerosis was diagnosed as hysteria in women for years. Myalgic encephalomyelitis was called “hysteria” and “yuppie flu” before the accumulating evidence of immune dysregulation, autonomic dysfunction, post-exertional malaise, and mitochondrial dysfunction made dismissal increasingly untenable.

Endometriosis is named for the tissue type found outside the uterus. The name describes anatomy instead of the inflammation and immune dysregulation that characterizes the condition and drives much of its pathology. It carries an average diagnostic delay of ten years, a delay that isn’t due to diagnostic complexity but a clinical culture that normalizes severe menstrual pain in women.

Premenstrual dysphoric disorder (PMDD) frames a condition with documented hormonal, neurological, and inflammatory mechanisms primarily as a mood disorder, contributing to stigma, undertreatment, and a research agenda organized around psychiatric intervention rather than the upstream hormonal and neuroimmune drivers behind it.

Conditions that disproportionately affect women are systematically named for their most visible and dismissible features. The names reflect the perspective of the clinician observer rather than the experience of the patient.

Renaming PCOS is an institutional acknowledgment that this dynamic exists and that correcting it requires deliberate, sustained, patient-centered effort. It is an argument to urgently ask and address which names currently in use are doing the same work that PCOS did for decades.

The question every clinician, researcher, patient advocate, and engaged patient should be asking is not just what to call a condition but also: What does this name prevent us from seeing? What questions does it foreclose? Whose experience does it make harder to take seriously? Who benefits from the current framing?

PTLDS forecloses the question of post-infectious prevalence in undiagnosed patients. Idiopathic forecloses the question of etiology in conditions medicine hasn’t yet taken seriously enough to investigate. Chronic fatigue syndrome forecloses the question of neurological and immunological disease in patients who have spent decades being told they are tired when they are ill.

Too often in medicine, the map is the obstacle preventing patients from receiving care. And those who have been navigating the gap between what a name implies and what they are actually experiencing have always known this.

Many are still waiting for medicine to acknowledge the truth.

As an amateur coder, I frequently have to anticipate instances in which user behavior might not conform to what is expected. In other words, I have to be prepared for edge cases.

A user might enter non-numerical characters in a phone number field. A form might require conditional logic. A customer in another country might require different payment processing options.

Ignoring edge cases doesn’t make them go away. It just makes you sloppy and bad at your job. You need to be prepared for all the different ways in which users might engage with your site because you don’t get a second chance to make a first impression.

In healthcare, however, it seems perfectly acceptable to shirk this responsibility and deny the existence of edge cases or medical zebras, patients with rare or complex illnesses.

Medicine does not take kindly to zebras, and if you think you’re one, the profession will vehemently insist that you simply need new glasses. You’re just anxious. Stressed. Depressed. Drug-seeking. Attention-seeking. Noncompliant. Argumentative. Difficult.

You get the picture. If a physician can’t figure out what ails you in 20 minutes spread across four outpatient visits, your symptoms are deemed psychosomatic.

Gaslighting and medical PTSD are unfortunately the norm for zebras.

The medical system is perfectly content in catering to the average, which doesn’t really exist in the first place, while minimizing, psychologizing, and stigmatizing the rest.

If you think that dismissal is fringe, you’d be mistaken. It’s as mainstream as white coats in medicine. These attitudes have been pervasive for centuries, not decades.

Allergic to Uncertainty

In 2007, Gerald Weissmann, Professor Emeritus at NYU School of Medicine and then editor-in-chief of the FASEB Journal, wrote an editorial titled “‘Chronic Lyme’ and other medically unexplained syndromes” in which he argued for the psychosomatic etiology of various conditions, including myalgic encephalomyelitis, irritable bowel syndrome, and fibromyalgia.

Curiously, Weissmann drew parallels to female hysteria in a laughable attempt to bolster his position, which could be summarized as, “Remember when female hysteria was a thing? Well, this is the modern-day equivalent, so it’s also psychosomatic.”

Skeptics worry, however, that the hallmark of these “diseases” is that diagnosis requires the complete absence of objective physical or biochemical derangement. They wonder whether such patients are not really victims of a complex set of socially and medically constructed diseases—much as the “railway spine,” “chronic appendicitis,” or “female hysteria” favored by 19th century clinicians.

Female hysteria is a cautionary tale about psychologizing women’s pain, not encountering credulous patients. The term was historically used to describe any number of conditions that primarily affected women, including multiple sclerosis, epilepsy, endometriosis, lupus, and postural orthostatic tachycardia syndrome.

The lesson of female hysteria is not that women imagine illness. It's that medicine has a 200-year track record of ignoring women’s health issues and then gaslighting them about it.

Invoking the notion of female hysteria as a valid argument for the existence of socially constructed diseases is nothing short of misogyny. But I guess when you’re the editor of the journal, you’re allowed to be as historically illiterate and tone-deaf as you like.

Weissman went on to liken chronic fatigue syndrome to Munchausen syndrome by proxy, a form of child abuse and mental illness where a caregiver, often a mother, exaggerates, fabricates, or induces physical or psychological symptoms in a child to gain attention or sympathy.

Chronic fatigue syndromes are also found in children; the condition might be called “Münchhausen’s fatigue by proxy.”

This type of dangerous, uninformed accusation that a child with inexplicable symptoms is simply being abused has resulted in sick children being physically removed from their homes on suspicion of abuse.

Andrew Abrahams and covered this topic in the documentary Complicated, which describes the stories of children with Ehlers-Danlos syndrome (EDS), a group of complex, misunderstood conditions affecting everything from bones and joints to blood vessels and the GI tract.

Even when medical documentation and letters from physicians attest to the physical nature of a child’s disease, parents have lost custody of their children based on the opinions of uneducated social workers and doctors.

Weissman erroneously stated that chronic fatigue syndrome and other medically unexplained are more common among children from rich families, which he believed precluded an infectious etiology, as though differential access to healthcare were not an obvious confounding variable.

This is a textbook case of collider bias. Wealthier families tend to have better access to healthcare services that allow for diagnosis, so stratifying on this basis creates a spurious correlation between socioeconomic status and disease. The underlying condition may be more prevalent in poorer populations, but we aren’t measuring it.

Weissman referred to patients with unexplained syndromes as “individuals who enjoy the dignity that all disease confer.” Forgive me, but I fail to see how losing one’s health, home, livelihood, friends and family confers dignity.

Physicians like Weissman feel that patients want to be sick, as though we have nothing better to do than sit around all day being attention-seeking hypochondriacs. As though we don’t have dreams and goals and ambitions of our own. As though we are somehow subhuman.

Not only are these attitudes not rare, but they receive virtually no pushback. Medical culture sanctions violence and violations of autonomy, as describes through her writing.

What we condone tells us something about what we value.

Despite his stance on unexplained medical conditions, Weissman was enthusiastically celebrated for his contributions to rheumatology research and lauded as a paragon of medical virtue throughout his life.

If a physician endorsed flat earth theory or denied climate change however, the public response would be outrage and concerns about competency. Tell patients that their symptoms are psychosomatic, and everything is copacetic.

Trial by Error

Since Weissmann viewed patients and advocates as people who “march against medical science,” it’s perhaps no surprise that he invoked none other than British psychiatrist Simon Wessely, psychologizer extraordinaire, creator of the cognitive behavioral model (CBM) of chronic fatigue syndrome, and defender of the abomination that is the PACE trial.

The PACE (Pacing, Graded Activity, and Cognitive Behavior Therapy: A Randomized Evaluation) trial significantly shaped the scientific community’s understanding of ME/CFS, causing irreparable harm to patients by negatively affecting research funding, treatment modalities, and public attitudes towards the illness.

The three principal investigators — Peter White, Trudie Chalder, and Michael Sharpe (two psychiatrists and a psychotherapist) — concluded that adding cognitive behavioral therapy and graded exercise therapy to specialist medical care improved outcomes for people with ME/CFS but adaptive pacing provided no benefit. Although not listed as a byline author, Simon Wessely served as a consultant on the trial.

Many patients and researchers around the world were skeptical of the study results because graded exercise often produced the hallmark symptom of post-exertional malaise (PEM), a delayed exacerbation of symptoms following activity that was previously tolerated.

PEM is distinct from deconditioning, characterized by significant declines in VO₂ max and anaerobic threshold with exertion as measured by 2-day cardiopulmonary exercise test (CPET), the only validated biomarker that currently exists for ME/CFS and also one that notably wasn’t utilized in the trial design.

The lack of 2-day CPET screening allowed for contamination of the patient population, meaning the trial likely enrolled patients with PEM due to ME/CFS as well as patients who experienced fatigue as the result of other medical conditions.

In other words, the trial was testing an intervention on a population it hadn't even bothered to properly characterize and generalizing the results to patients it may never have studied in the first place.

The trial was unblinded, plagued by glaring methodological errors, and failed to produce any objective measurements of improvement among enrolled patients.

Jonathan Edwards, an Emeritus Professor of Connective Tissue Medicine at University College London, called the trial “valueless for one reason: the combination of lack of blinding of treatments and choice of subjective primary endpoint. Neither of these alone need be a fatal design flaw but the combination is.”

He elaborated that “the authors have not been meticulous in trying to avoid bias that might arise. On the contrary they appear to have acted in ways more or less guaranteed to maximize bias.”

After a five-year battle, Alem Matthees, an Australian patient with ME/CFS, succeeded in getting Queen Mary University of London to release the original trial data under the UK Freedom of Information Act.

A re-analysis of the trial data by Matthees and two statistics professors demonstrated that major changes to the thresholds for recovery had inflated recovery estimates four-fold and that recovery rates in the cognitive behavioral therapy and graded exercise therapy groups were not significantly higher than in the group that received specialist medical care alone.

The SF-36 Physical Functioning subscale is a measure that asks participants to rate their limitations while performing daily activities such as running and lifting heavy objects to walking to bathing.

Respondents can answer ‘Yes, limited a lot’ (score 0), ‘Yes, limited a little’ (score 1), or ‘No, not limited at all’ (score 2). The total score across 10 activities is multiplied by five, so the maximum score of 100 indicates no impairment with any type of activity.

To be eligible to join the PACE trial, participants had to score 65 or lower on this scale. The original study protocol defined recovery as a score of 85 or above. The “revised” recovery threshold of 60 was not only far below the original recovery threshold but also beneath the original entry level threshold of 65 for admittance into the trial.

In other words, if patients deteriorated during the course of the trial, they could still be classified as recovered. The revised recovery threshold score was close to the mean score of patients with Class II congestive heart failure.

Despite significant backlash from scientific and patient communities and numerous calls for retraction over the decades, The Lancet defended the study, and the fraudulent findings continued to poison the well of post-infectious disease research.

Clinical Comorbidities or Clusters?

Weissmann endorsed Wessely’s argument that unexplained medical syndromes don’t describe unique clinical entities, that the same cluster of symptoms receives different names depending on which type of specialist sees the patient. What a rheumatologist calls fibromyalgia, a gastroenterologist would call IBS, and a neurologist would call dysautonomia.

He believed that these unexplained syndromes converged on a psychosomatic origin. But Dr. Lawrence Afrin, a hematologist-oncologist, believes these conditions converge on mast cells. Three years after Weissmann published his editorial, the first set of diagnostic criteria for mast cell activation syndrome (MCAS) appeared in The Journal of Allergy and Clinical Immunology.

Unlike mastocytosis, which is a clonal disorder characterized by overproduction of mast cells by the bone marrow, MCAS is characterized by normal numbers of mast cells that degranulate inappropriately, releasing inflammatory mediators like histamine, heparin, and cytokines. In other words, you don’t have too many mast cells, but the ones you do have are prone to misbehaving.

Because mast cells are present in virtually every tissue and mediate inflammatory responses across every major organ system, MCAS exhibits a high degree of clinical heterogeneity.

The gastroenterologist might observe irritable bowel syndrome (IBS) or gastroesophageal reflux disease (GERD). Neurology may find small fiber neuropathy (SFN), postural orthostatic tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), or neurocardiogenic syncope (NCS). The dermatologist notes urticaria and flushing. The allergist notices anaphylactoid reactions without IgE elevation. Each specialist sees a piece of the puzzle. No one sees the bigger picture.

Afrin illustrates this point in many of his presentations using the analogy of the blind men and the elephant, the ancient parable in which each man touches a different part of the animal and names what he feels. In Afrin’s version, each specialist observes a different consequence of mast cell activation syndrome, treating symptoms in isolation while unaware of the common drivers.

In 2007, Albert-László Barabási and his colleagues introduced the concept of the human disease network, or diseasome, to address these types of shortcomings. By mapping relationships between diseases based on shared genetic components, they demonstrated that disorders we treat as distinct clinical entities are deeply interconnected at the molecular level.

Barabási elaborated on the implications in an NEJM editorial that same year, coining the term network medicine to describe what a systems-level view of disease could offer that organ-based medicine cannot.

Patient-scientist explains that the clustering of conditions like EDS, POTS, MCAS, and ME/CFS at high rates likely reflects shared biology rather than unfortunate coincidences. Below is a disease network that I created with D3.js to illustrate the concept.

Occam’s razor meets Hickam's dictum. The former espouses the principle of parsimony, insisting that the explanation that makes the fewest assumptions is probably the right one. The latter contends that a patient can have as many diseases as they damn well please.

In practice, neither principle is inherently right or wrong. Depending on a patient’s clinical presentation, one approach or the other might be safer. In cases of complex chronic illness, the tension sometimes dissolves.

The patient with four accumulated diagnoses is experiencing one underlying biological vulnerability expressing itself across multiple systems simultaneously. The multiple diagnoses are Hickam's. The common cause is Occam's.

The diverse clinical presentations of MCAS shouldn’t be taken to imply that every case of POTS or IBS or GERD is due to aberrant mast cell behavior, but if a patient has many relevant diagnoses across multiple organ systems, that should raise suspicion of a potential mast cell-mediated disorder.

It’s also important to avoid the trap of thinking everything is a manifestation of MCAS, as patients with MCAS have also been known to have Hodgkin lymphoma and other serious diseases. If you’re presenting with alarm symptoms, don’t ignore them.

“Medically unexplained syndrome” is not a diagnosis but a placeholder, a reason to keep looking. Weissmann treated uncertainty as a reason to psychologize, stating that afflicted patients are “in very real pain— but of the mind—and the mind chooses symptoms that will be taken as evidence of physical disease.”

A model that only recognizes inputs it was designed for isn't intelligent but overfitted. Medicine built its diagnostic frameworks around the most measurable manifestations of disease, called everything beyond that range unexplained, and then gaslit patients unfortunate enough to find themselves on the outside.

The edge cases didn't go away. They filled waiting rooms, filed for disability, and turned to online patient forums to compare notes with other outcasts. It’s high time we mind the gap and expand our range.

In 1843, Oliver Wendell Holmes Sr. read a paper before the Boston Society for Medical Improvement titled The Contagiousness of Puerperal Fever. He wasn’t even an obstetrician. He noticed a physician had died just one week after performing a postmortem exam on a woman who had died of puerperal fever and came to the conclusion that birth attendants were carrying the disease from patient to patient via their hands.

He ended his presentation with eight concrete steps to prevent puerperal fever:

Because Holmes’ paper was published in a journal with a very small circulation, it went largely unnoticed until it was republished in 1855 as a booklet entitled Puerperal Fever, as a Private Pestilence.

The medical establishment overwhelmingly rejected his claims.

Leading Philadelphia obstetrician Charles D. Meigs dismissed his arguments as the “jejeune and fizzenless dreamings” of a sophomoric writer. Textbooks towed the same line, urging doctors to rid themselves of any notion that they could ever become “the minister of evil” to their patients. When confronted with clusters of deaths in a single practice, Meigs wrote that he preferred to attribute them to “accident, or Providence” rather than to a contagion he could not conceptualize.

Holmes responded to all of this rhetoric with admirable restraint. Of his critics, he wrote: “I take no offence and attempt no retort. No man makes a quarrel with me over the counterpane that covers a mother, with her newborn infant at her breast.”

Four years later and an ocean away, Ignaz Philipp Semmelweis arrived at the same conclusion through his own observations.

In 1846, Professor Johann Klein appointed Semmelweis as first assistant obstetrician at Vienna General Hospital. There were two divisions of the maternity clinic. In the first, medical students who also performed autopsies attended births. In the second, only midwives attended. The first clinic’s maternal mortality rate was three times higher than the second.

The breakthrough came when his friend Professor Jakob Kolletschka, a forensic pathologist, succumbed to a cut he sustained during an autopsy. Semmelweis examined Kolletschka’s autopsy findings and found them to be identical to those of mothers dying of childbed fever.

The conclusion was obvious: doctors were carrying “cadaverous particles” from the dissection room to the delivery room on their hands.

Semmelweis instituted a policy of handwashing with chlorinated lime before delivering babies. Mortality in his ward dropped from ~18% to under 2%.

When he mandated washing medical instruments, it fell to just 1%.

He published. He presented. He wrote letters.

The medical establishment overwhelmingly rejected his claims.

Despite being one of the first to witness the reduction in maternal mortality, Professor Johann Klein was hesitant to endorse the theory and declined to renew Semmelweis’ contract.

Semmelweis returned to Hungary and took an unpaid position. When his assistant later tried to publish their results in the Vienna Medical Weekly, the editors dismissed it as misleading information.

The Book That Should’ve Changed Everything

In 1861, Semmelweis published his major work, The Etiology, Concept, and Prophylaxis of Childbed Fever, a full-length account of everything he had observed and argued for over 14 years.

The work was not well received.

When inevitably faced with strong opposition, Semmelweis personally responded to each criticism by sending abusive letters to those who disagreed with his views, denouncing them as mother murderers and alienating himself further from his peers.

His book should have been his vindication. Instead it accelerated his unraveling.

The bitter relationship with his medical peers had a devastating impact on his mental health, leading to amnesia, anxiety, and severe depression. He was admitted to an Austrian asylum, where he was confined and beaten. Semmelweis succumbed to septicemia within 14 days of admission due to a wound infection from the beatings.

The man who discovered that dirty hands kill mothers died of a dirty wound in a psychiatric institution.

Semmelweis paved the way for the germ theory of disease, a concept later advanced by Louis Pasteur, Joseph Lister, and Robert Koch. Today he is called the savior of mothers.

Holmes, the more composed of the two, survived to see partial vindication, though it was not until the subsequent publications of Semmelweis, Lister, and Pasteur that the battle was finally won.

His reputation was eclipsed not by defeat but by his own brilliance in another domain, as he became one of America’s most beloved poets. Even his own profession came to value him more as a wordsmith than as a fearless defender of mothers.

Two men who had the same insight faced the same resistance to an uncomfortable truth. Neither lived to see their ideas fully embraced.

The Pain of Being Ahead of Your Time

The story gave medicine a name for a specific kind of institutional failure.

The Semmelweis reflex describes the reflex-like tendency to reject new evidence because it contradicts established norms, beliefs, or paradigms.

The leading obstetrician Meigs was firmly against Semmelweis’s doctrine because “doctors are gentlemen, and gentlemen’s hands are clean.” That’s not a scientific claim but an identity-based one. And identity is much harder to revise than hypothesis.

The core driver is the threat to professional self-image. Accepting handwashing meant accepting that doctors had been unknowingly killing the very patients they were sworn to protect. The resistance was psychologically self-protective, which is exactly what makes it so dangerous. The cost of being wrong was unbearable, so the new evidence was rejected instead.

In the preface to his book The Myth of Mental Illness, Psychiatrist Thomas Szasz said Semmelweis’ story instilled in him “a deep sense of the invincible social power of false truths.”

The Semmelweis Reflex is Alive & Well

The Semmelweis reflex is not a relic and modern-day examples contain the same basic elements: evidence arrives, identity resists, patients suffer.

FMT for C. difficile

When researchers first proposed that fecal microbiota transplantation (FMT) could treat recurrent C. diff, the response from mainstream medicine ranged from skepticism to open mockery. When FMT showed 80-98% efficacy for C. diff after antibiotics repeatedly failed, the FDA initially classified it as an Investigational New Drug, requiring a formal IND just to administer it in life-threatening cases. The mechanism was and still is incompletely understood, as non-viable donor material paradoxically often helps.

Semmelweis didn’t know what “cadaverous particles” were either. He just knew that removing them from the clinical encounter saved lives. The data always precedes the mechanism. The reflex is most active when outcomes outpace mechanisms.

Low-dose ketamine for treatment-resistant depression

Ketamine was FDA-approved as an anesthetic in 1970. Its antidepressant properties were first published in peer-reviewed literature in 2000. It took twenty years and a rebranded, patent-protected intranasal formulation before mainstream psychiatry meaningfully engaged with it.

The delay wasn’t primarily about the data, which was compelling, with some studies showing response rates upward of 70% in patients who had failed multiple prior treatments. It was about the molecule’s cultural identity as a club drug, which made clinical legitimacy feel contaminating. The drug’s reputation preceded its evidence. Patients with treatment-resistant depression waited two decades while that reputation was renegotiated.

COVID-19 airborne transmission

By spring 2020, independent aerosol scientists were raising urgent alarms that superspreader events accumulating in choirs, restaurants, and poorly ventilated indoor spaces couldn’t be explained by large-droplet contact alone. The evidence clearly pointed to airborne transmission. The WHO and CDC clung to the droplet model anyway for the better part of a year.

Scientists pushing for the airborne framework described the experience in terms Semmelweis would have recognized: ignored, dismissed, told to stick to their lane. The WHO did not formally acknowledge aerosol transmission as the dominant route until 2021.

How We Should Proceed

There’s a note of caution worth including here. The Semmelweis reflex can also be invoked inappropriately, used as a rhetorical shield by people whose ideas genuinely don’t hold water. Not every rejected idea is ahead of its time. Some are simply wrong, and legitimate skepticism is not the same as reflexive dismissal. The history of medicine is full of ideas that were rightfully rejected.

But the pattern is distinguishable. Semmelweis and Holmes had data. They were not asking anyone to believe them on blind faith; they were asking people to look at the numbers. The resistance came not from the absence of evidence but from the psychological cost of accepting what the evidence implied: that the physicians themselves were the vector. That the institution was the problem.

The Semmelweis reflex recognizes cost to professional identity, institutional pride, and established paradigm as drivers of resistance to change.

The gap between evidence and acceptance is often vast and represents just how vigorously institutions respond to threat.

In his final days, Semmelweis wrote:

“When I look back upon the past, I can only dispel the sadness which falls upon me by gazing into that happy future when the infection will be banished, the destroyer of life annihilated, the weeping mothers will no longer be found, and the number of human beings who die from infection will no longer be counted. The conviction that such a time must inevitably sooner or later arrive will cheer my dying hour.”

He didn’t live to see it. But he was right.

In healthcare, that gap is everywhere.

Mind the Gap exists to identify, examine, and explain these gaps. And how patients can keep from falling through them.

What I Mean by the Gap

The gap between bench and bedside. Research often takes decades to reach clinical prime time, but patients don’t have the luxury of waiting. Patients with rare, complex, and poorly understood conditions are left without answers, without treatments, and without allies. Holding stakeholders accountable means asking hard questions about what gets lost, delayed, or distorted between the lab and the clinic.

The gap between what patients experience and what medicine measures. When there is a disconnect between what a patient reports and what a test can detect, medicine has a troubling habit of concluding that the problem lies with the patient. What gets measured gets managed, and what can’t be measured just doesn’t exist. When we don’t have answers, symptoms are psychosomatic, conditions are idiopathic, and the system is downright idiotic.

The gap between research frameworks and biological reality. The tools and frameworks medicine uses to study disease were not built to capture the full complexity of human biology. When a single-day exercise test can't capture a condition defined by delayed physiological deterioration, when a pulse oximeter gives people of color falsely reassuring readings, when a psychological framework is applied to a biological disease, patients suffer.

The gap between research and reality for rare and complex diseases. Millions of people live with conditions that have no approved treatments, no clear diagnostic criteria, and no straightforward path through the healthcare system. Mind the Gap will cover the state of the science, the politics of research funding, and the lived reality of navigating a system that wasn’t built for network medicine. As patient advocate writes: "Infection-associated chronic conditions isn't an umbrella; it's a rug, and we're all being swept under it."

The gap in how medicine sees minority patients. Medical textbooks have historically featured white skin. Diagnostic tools from pulse oximeters to lung function tests to kidney function equations have been inaccurate for people of color. Clinical trials have underrepresented women and minorities for generations. Black mothers in the United States are three to four times more likely to die from pregnancy-related causes than white mothers, regardless of income or education. Black and brown patients are systematically undertreated for pain. Mind the Gap covers the structural racism embedded in medical knowledge itself.

The gap between how medicine is portrayed in popular culture and the reality. From prestige dramas to viral health content, media shapes what patients believe, expect, and ask about. I’ll pull back the curtain on what popular TV shows and press get wrong about medicine, diagnoses, and the healthcare system.

The gap between what institutions say and what they do. Research programs, funding bodies, and clinical guidelines reflect priorities, politics, and power. The Shirky Principle reminds us that institutions often try to preserve the problem to which they are the solution. Mind the Gap investigates the space between institutional promises and observational realities with particular attention to how those gaps harm the most vulnerable patients.

Who This Is For

Mind the Gap is for patients who have been dismissed and disillusioned by healthcare, clinicians who know the system is broken and want to improve it, and researchers willing to question their own frameworks. This space is for anyone who has ever felt that medicine was speaking a language designed to exclude them.

You deserve to understand the system you are navigating. You deserve to see the gaps clearly. And you deserve to know that falling through them was never your fault.

During our evolutionary history as a species, food shortages were common, and the ability to store energy as fat was advantageous for survival. In the modern world however, where food is easily accessible, the same behaviors that once helped us may now hamper our progress.

When we discuss metabolism, we usually only focus on our own contributions to physiological processes in our bodies. But the contribution of our microbial inhabitants is equally, if not more, important.

A sizeable body of evidence has shown that the human gut microbiota determine the effects of both diet and exercise on weight loss and metabolism.

Got Guts?

Our intestines are home to trillions of microorganisms. While most microbiome research so far has focused on bacteria, we also harbor many different types of archaea, protists, fungi, and viruses.

These microbes contribute to digestion and immunity, protect against pathogens, provide nutrients, influence our risk for chronic diseases, drive social behavior, and impact our metabolism.

Certain bacterial signatures predict body-mass index (BMI), while baseline microbiota profiles help explain why some dieters shed pounds easily and others plateau.

The Energizer Bunny in Your Gut

In 2006, Dr. Jeff Gordon’s lab began to elucidate the connection between diet, the gut microbiota, and obesity. His early research discovered that the microbiomes of obese mice are enriched in genes that allow more energy to be harvested from the diet. Studies estimate that around 10% of the calories in a typical Western diet come from these microbial conversions.

Transplanting the gut microbiota of obese mice into lean mice resulted in obesity even without an increase in food consumption. Studies have also shown that transplanting gut microbiota from obese humans into germ-free mice leads to greater weight gain and fat accumulation than transplants from lean individuals.

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Metabolism 101

Most of us are already familiar with how important physical activity is for our long-term health, but physical activity doesn’t just include structured, planned exercise like working out at the gym or running.

Some individuals — think fast talkers and fidgeters — move quite a bit even at rest and therefore exhibit very high NEAT, or non-exercise activity thermogenesis. Daily tasks contribute to energy expenditure in the form of NEAT, which includes activities like:

• walking your dog

• washing dishes

• cooking & cleaning

• driving

• typing

• vacuuming

• folding laundry

• gardening and yard work

• pacing while talking on the phone

• carrying groceries

• building IKEA furniture

• dancing in the shower

While many weight loss programs tout the benefits of exercise, far fewer account for the impact of this significant but often overlooked source of energy usage. Let’s go over some basics of energy metabolism:

The total amount of energy we consume on a daily basis is known as total daily energy expenditure (TDEE), which is the sum of all energy used for both resting and non-resting activities.

The bulk of the energy we consume on a daily basis goes towards maintaining basal metabolic rate (BMR), or resting energy expenditure, which includes all the energy used to keep you alive.

BMR encompasses activities like vital sign regulation, breathing, blinking, sleeping, and brain function. BMR also positively correlates with lean body mass since muscle requires a considerable amount of energy to maintain.

Non-resting energy expenditure can be subdivided into thermic effect of food (TEF), non-exercise activity thermogenesis (NEAT), and exercise activity thermogenesis (EAT).

• Thermic effect of food (TEF), or diet-induced thermogenesis, includes energy used for digestion. Calories from protein exhibit the highest TEF, followed by calories from carbs and calories from fat.

• As the name implies, exercise activity thermogenesis (EAT) involves physical activity like walking, swimming, jogging, cycling, or lifting weights.

• Non-exercise activity thermogenesis (NEAT) tends to be a greater contributor to total daily energy usage than exercise and encompasses all energy expenditure that isn’t used for sleeping, eating, or sports-like exercise. In other words, NEAT accounts for movement that isn’t structured exercise.

Total daily energy expenditure = basal metabolic rate + non-exercise activity thermogenesis + thermic effect of food + exercise activity thermogenesis

TDEE = BMR + NEAT + TEF + EAT

Since BMR is determined by lean mass and organ size, and TEF varies only with diet composition, NEAT is often the swing factor between weight-stable Susan and everyone else.

NEAT As a Component of Total Daily Energy Usage

While exercise constitutes a mere 5% of total daily energy expenditure in sedentary people (but up to ~20% with regular training), NEAT can account for up to 3x as much energy but can be significantly harder to track. In highly active people, the ratio can flip.

People who work physically demanding jobs like construction work and farming may burn up to 2,000 calories more than individuals who work desk jobs. NEAT has been shown to directly mitigate gains in fat during periods of overfeeding.

When researchers at the Mayo Clinic fed non-obese volunteers 1,000 calories in excess of daily maintenance requirements, differences in fat accrual varied 10-fold depending on varying levels of NEAT. Individuals with the highest levels of NEAT hardly gained any extra weight.

Overall, NEAT has been on the decline with the advent of modernization and urbanization. City and office environments encourage sedentary lifestyles, and video games and virtual reality have replaced outdoor activity among schoolchildren.

Increasing levels of NEAT can be as simple as taking the stairs instead of the elevator, parking further away from store entrances, or stretching while watching Netflix.

Is Sitting the New Smoking?

If most of our waking hours offer an opportunity to increase NEAT, is our current epidemic of sitting the problem? Turner Osler, a research epidemiologist at the University of Vermont, researches “sitting disease,” which he describes as

a constellation of obesity, hypertension, diabetes, and heart disease that frequently come as a package deal.

Herman Pontzer, an anthropologist at Duke University and author of Burn, has studied our evolutionary behaviors for the past 20 years and says that sitting (at least the way westerners do it) can be incredibly harmful for our health.

Hunter-gatherer groups like the Hadza of northern Tanzania spend as much time resting as people in Western countries do, but they don’t use chairs. The Hadza squat or kneel when resting, engaging their muscles in a way that reduces cardiovascular disease risk.

Even into their 70s and 80s, the Hadza maintain healthy lipid profiles, blood pressure measurements, and blood glucose levels, according to Pontzer’s data. The Hadza’s use of active resting postures may directly contribute to their long-term health.

When your muscles contract, they up-regulate an enzyme called lipoprotein lipase (LPL) in the walls of nearby blood vessels. LPL breaks circulating triglycerides into free fatty acids, which the working muscle cells can then absorb and burn for energy.

Can Standing Desks Help?

Appeals to cardiovascular disease prevention aren’t motivating enough to galvanize behavioral change, but the immediate promise of back pain relief is. Adopting active sitting postures may solve both problems simultaneously by spurring neuromuscular systems into action.

But standing desks sometimes have the opposite effect. In 2018, a group of researchers followed over 7,300 people for 12 years. Half the participants worked in sitting occupations, the other half in standing jobs. After adjusting for confounding variables, the static standing group experienced double the rate of heart attacks.

According to Osler, standing desks encourage an unfavorable posture that causes blood to pool in your extremities rather than circulate throughout your body. For this reason, standing still in an assembly line or standing guard at Buckingham Palace are probably detrimental to blood vessel health.

Think Yourself Thin?

Does the mentally demanding task of trying to solve a difficult chess problem or crossword puzzle burn more energy than a lazy Sunday spent scrolling through social media? Science suggests yes.

“You will in fact burn more energy during an intense cognitive task than you would vegging out watching Oprah,” says Ewan McNay, an associate professor of psychology and behavioral neuroscience at the University of Albany.

Exhibit A: practice problem from my college physical chemistry textbook

Weighing in at just under 2% of your total body weight, your brain consumes a whopping 20% of your total energy expenditure, making it the body’s most energetically expensive organ.

Your brain prefers to use glucose for fuel and consumes a significant amount of energy to keep you alert, monitor your environment for threats, and communicate with other organs.

But McNay argues that the change in energy expenditure observed with tough mental tasks is modest as best, with only 100–200 additional calories burned for every eight hours of mentally demanding work.

The brain’s dependence on glucose requires refueling in order to keep operating at peak performance, and the additional calories consumed would likely outweigh any extra energy burned during cognitively challenging tasks.

TL; DR

• Energy expenditure in the form of NEAT (non-exercise activity thermogenesis) can significantly contribute to weight loss.

• NEAT can account for 200–700 calories in most adult and up to 2,000 calories of daily energy usage in heavy-labor occupations.

• Daily activities such as household tasks can accelerate fat loss by contributing to NEAT.

• Movement should be encouraged, and time spent sitting or standing passively should be kept to a minimum.

If you’re building in biotech, you’re likely already aware that the SBIR and STTR programs in the United States expired on September 30th, 2025 and haven’t been reauthorized. For many founders, these programs represented the most accessible source of non-dilutive capital to help breakthrough technologies get off the ground without giving up equity.

The A2 Pilot Awards, another major source of early-stage funding for companies focused on aging, won’t re-open for applications until fall 2026.

But don’t despair. While SBIR and STTR have high visibility, they’re far from the only game in town. In this article, I’ll cover the grants, prizes, foundation funding, and alternative capital sources that can keep biotech innovation moving forward.

1. Focused Research Organizations (FROs)

What they are: FROs fund ambitious, multi-year research projects that are too large for a single lab but too risky for traditional funding. They’re designed specifically for the chasm between academic discovery and c…

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🗝️ TL;DR:

• Nicotine = plant alkaloid, brain stimulant, addictive
• Nicotinic acid (niacin) = vitamin B₃, vital for energy & DNA repair, non-addictive
• Similar names because chemist Hugo Weidel oxidized nicotine into nicotinic acid in 1873; nutritionists rebranded it “niacin” in 1942 to avoid confusion

How a 19th-Century Lab Experiment Created Decades of Confusion

The story begins in 1828 when German chemists Wilhelm Posselt and Karl Reimann first isolated nicotine from tobacco leaves. They named it after the tobacco plant Nicotiana tabacum, which itself was named after Jean Nicot, the French ambassador to Portugal who popularized tobacco in France in 1560.

Fast forward to 1873, and chemist Hugo Weidel was experimenting with nicotine in his laboratory. Through a process called oxidation, he broke down nicotine and created a new compound.

Following the naming convention of the time, he called it nicotinic acid because it came from nicotine. In 1942 U.S. nutrition authorities adopted niacin (from nicotinic acid vitamin) to prevent the public from thinking fortified bread contained nicotine.

Much like Jekyll and Hyde1, nicotine can be chemically oxidized to nicotinic acid in the lab, but there is no metabolic path between the two in humans.2

Here’s the kicker: Just because nicotinic acid was derived from nicotine doesn’t mean they function similarly in the human body. In fact, they couldn’t be more different.

Structure Determines Function

Understanding why these compounds behave so differently starts with their molecular structures:

Nicotine (C₁₀H₁₄N₂): A complex molecule featuring two connected ring structures—a six-membered pyridine ring attached to a five-membered pyrrolidine ring. This specific arrangement allows nicotine to perfectly fit into nicotinic acetylcholine receptors in your brain.

Nicotinic Acid (C₆H₅NO₂): A form of niacin, the other being nicotinamide (C₆H₆N₂O), with just one six-membered ring and a carboxylic acid group attached. This structure allows it to be easily incorporated into cellular metabolism pathways.

On one hand, you have a key (nicotine) that fits a specific lock (brain receptors). On the other is a building block (nicotinic acid) that gets incorporated into the foundation of a house (cellular metabolism).

The nicotine/nicotinic acid confusion illustrates a broader principle in biochemistry: molecular structure determines function. Small changes in how atoms are arranged can completely alter how a compound behaves in biological systems.

Caffeine energizes you while adenosine makes you sleepy despite being structurally similar. Testosterone and estrogen have vastly different effects despite both being steroid hormones, and different forms of vitamin E have varying biological activities.

How to Remember the Difference

To remember the distinction between these compounds, use these two simple acronyms:

Nicotine ACTS:

• Addictive

• Cholinergic (acts on acetylcholine receptors)

• Tobacco’s active ingredient

• Stimulant

Nicotinic acid MENDS:

• Mitochondrial function

• Essential vitamin (B3)

• Necessary for metabolism

• DNA repair

• Supports cellular health

Nicotine ACTS on your nervous system with immediate effects, while nicotinic acid MENDS and maintains your cellular machinery through slower, fundamental processes.

When Nicotine Enters Your System:

• Rapid absorption: Nicotine reaches your brain within seconds of inhalation

• Receptor binding: It attaches to nicotinic acetylcholine receptors

• Neurotransmitter release: This triggers the release of dopamine, norepinephrine, and other chemicals

• Physical effects: Increased heart rate, blood pressure, and alertness

• Addiction pathway: The dopamine release creates the potential for dependence

When Nicotinic Acid Enters Your System:

• Metabolic conversion: Your body converts it into NAD+ (nicotinamide adenine dinucleotide)

• Energy production: NAD+ is crucial for cellular respiration and ATP synthesis

• DNA maintenance: It supports DNA repair mechanisms

• Cellular health: Helps maintain the integrity of skin, nerves, and digestive system

• No addiction potential: It doesn’t interact with reward pathways in the brain

Smoking Cessation vs Essential Nutrition

In medical contexts, nicotine appears in carefully controlled forms. Smoking cessation products like patches, gum, and lozenges use measured doses to help people quit smoking without the harmful effects of tobacco. Scientists are also investigating its potential for treating certain neurological conditions though therapeutic use requires careful dosing to avoid addiction.

Nicotinic acid has an entirely different profile. It’s essential to treat and prevent pellagra, a disease caused by severe niacin deficiency that can lead to dermatitis, diarrhea, dementia, and if left untreated, death.

Historically, nicotinic acid was commonly prescribed for cholesterol management, though newer drugs are now preferred for that purpose. As an essential vitamin for metabolism and cellular function, it’s generally safe, but can cause flushing, gastrointestinal distress, insulin resistance, and liver toxicity at pharmacological doses (≥1–2 g/day).

Key Takeaway

The next time you see nicotine and nicotinic acid mentioned together, remember that one ACTS on your brain with powerful, addictive effects, while the other MENDS your cells through essential metabolic processes.

Understanding this distinction can help you make more informed decisions about your health and have more productive conversations with healthcare providers.

The research is compelling; studies consistently link grip strength to lower risks of cancer, heart disease, and all-cause mortality. It's dirt cheap to test, takes seconds to perform, and the correlation with health outcomes is remarkable.

Sounds like a no-brainer, right? Improve your grip strength, live longer. But here's the catch.

When Measures Become Targets

Goodhart's Law states, "When a measure becomes a target, it ceases to be a good measure." If we chase grip strength alone, we're unlikely to achieve the health outcomes we desire.

This is the same trap educators fall into with standardized testing. When schools start teaching to the test, test scores might improve while actual learning stagnates or even declines. Students become proficient at test-taking strategies without developing critical thinking skills or deep subject knowledge. The metric improves, but the underlying goal of better education suffers.

Grip strength works the same way. It's an excellent biomarker because it reflects multiple interconnected aspects of health: total muscle mass and bone density, tendon stiffness and joint health, nervous system coordination, and perhaps most importantly, an overall active lifestyle.

People with strong grips don't just have strong hands; they tend to move more, lift more, and eat better. Good grip strength isn't the cause of their health. It's the side effect. Healthier people naturally test higher on any measure of physical fitness, from VO2 max to resting heart rate. Focusing on a single metric can fool us into thinking that the metric creates the health when it really just reflects it.

Get a Grip: The Gaming Problem

Imagine someone who decides grip strength is their path to longevity and spends an hour daily doing nothing but grip strengthening exercises. Their numbers might soar, but they could still be sedentary, poorly nourished, and heading toward metabolic dysfunction. They've gamed the metric without addressing the underlying health factors it's meant to reflect.

We see similar patterns across other health metrics. Resting heart rate is an excellent biomarker, but artificially lowering it with beta-blockers doesn't confer the same benefits as achieving it through cardiovascular fitness. Having a healthy body weight correlates with better health outcomes, but losing weight through extreme caloric restriction while losing muscle mass can be counterproductive.

The moment we start optimizing specifically for any singular biomarker, we risk losing sight of what makes it valuable in the first place. Training to the test represents a fundamental misunderstanding of how complex biological systems work.

What Complex Systems Teach Us

Rather than trying to isolate and manipulate individual variables, we need to think ecologically. Your body isn't a machine with discrete, controllable parts; it's an interconnected ecosystem where parts communicate with and influences each other.

Grip strength emerges from this ecosystem, reflecting the health of your musculoskeletal system, your nervous system coordination, your metabolic efficiency, and your lifestyle patterns. When we focus narrowly on the grip measurement itself, we're treating a symptom rather than nurturing the system that produces it.

Modern medicine excels at identifying biomarkers and correlations but often struggles with the multifaceted interventions needed to address complex diseases. We end up with patients who are progressively more quantified but haven’t developed the habits to maintain good health.

A Better Framework

The solution isn't to abandon grip strength testing entirely but to use it correctly. Here's how to leverage grip strength as part of a larger health framework:

Test grip strength as part of a comprehensive health assessment. Track changes over time alongside other metrics like waist-to-hip ratio, HbA1c, lipid panels, and VO2 max. Look for patterns and relationships between different markers.

Train comprehensively rather than specifically. Focus on compound movements, strength training, cardiovascular conditioning, and mobility work. Your grip strength will improve as a natural byproduct of overall fitness.

Consider the context. A declining grip strength score in an otherwise active person might signal something worth investigating. An improving score in someone who's started a comprehensive fitness program is encouraging confirmation they're on the right track.

Address the fundamentals. The people with the strongest grips typically prioritize sleep, manage stress effectively, maintain strong social connections, and follow consistent movement and nutrition habits.

The Deeper Pattern

Goodhart's Law reveals something fundamental about human nature: we're remarkably good at gaming systems, even when it's not in our best interest. This tendency shows up everywhere, from corporate metrics that incentivize the wrong behaviors to fitness tracking that prioritizes step counts over bone-building exercise.

The antidote is to ask: what is this measure really telling us? Which factors create the outcome we're measuring? How can we address those root causes rather than just moving the needle on the metric?

In health and fitness, this means embracing complexity instead of silver bullets. Your grip strength matters because it reflects the results of health-promoting behaviors.

Teaching to the Body

The parallels between education and health optimization don’t stop with testing. Both systems work best when we focus on developing better capabilities rather than optimizing for specific tests.

Good education creates critical thinkers who can adapt their knowledge to new situations. Good health creates resilient bodies that adapt to new stressors.

When we teach to the test, whether a standardized exam or a biomarker measurement, we might see short-term improvements in scores while undermining long-term success.

The student who memorizes answers without understanding concepts will struggle when facing novel problems. The person who trains only grip strength without addressing overall fitness will falter in the face of other health challenges.

The Path Forward

Focus on the foundation, and the biomarkers will take care of themselves. Train your whole body, not just your grip. Move regularly, lift progressively, eat nutritious meals, prioritize recovery, manage stress, and maintain social connections.

Use grip strength as one piece of your health puzzle—a valuable diagnostic tool that can help you understand how your overall approach is working. Track it over time, celebrate improvements, and investigate declines. But remember that the goal isn't to get a grip on the test. It's to get a grip on your health.

So go ahead and test your grip strength, but make sure you train your entire body.

Update: The Spooniverse has grown significantly since this was recorded and now includes a treatment database, biomarker explorer, glossary, and more. Explore the current platform →

July is Disability Pride Month, a time to celebrate the invaluable contributions of the disability community while acknowledging the ongoing work needed to create a more inclusive society.

Community Empowerment & Coalitions

Consider the numerous examples of momentous historical change that were the direct result of patient advocacy efforts:

• Thalidomide crisis response (1960s): Affected families fought for recognition, compensation, and stricter drug safety regulations globally.

• Breast cancer movement (1970s-present): Breaking the silence around breast cancer led to the creation of Susan G. Komen Foundation, increased research funding, and better screening programs.

• Disability rights movement (1970s-present): Activists fought for the Americans with Disabilities Act (1990), revolutionizing accessibility and rights for disabled individuals.

• AIDS activism (1980s-90s): ACT UP's bold protests accelerated drug approvals and boosted research funding, transforming HIV from a death sentence to a manageable condition.

• Rare disease legislation (1983): The Orphan Drug Act, driven by the National Organization for Rare Disorders (NORD), incentivized research for overlooked conditions.

• Henrietta Lacks' legacy (2010s): Her family's advocacy led to recognition of her contribution to medical research and reforms in genetic privacy.

• Mental health reform (ongoing): Patient-led initiatives have been crucial in destigmatizing mental illness and promoting community-based care.

To my fellow patients, caregivers, and allies: Our experiences are valid, our needs matter, and our voices deserve to be amplified.

We stand on the shoulders of giants whose advocacy repeatedly changed the course of history. When patients unite, real change happens.

Still, there is work to be done towards more inclusive clinical trials, stronger social safety nets, more multidisciplinary care, and healthcare systems that don't leave anyone behind.

Spotlight: The Spooniverse

The Spooniverse adopts a patient-centered approach and recognizes that those living with chronic conditions are the true experts on their own lived experiences.

The platform's name itself references spoon theory, a framework created by Christine Miserandino to explain the limited energy resources that people with chronic illnesses must carefully manage each day.

The Spooniverse serves as a comprehensive hub where patients can:

• Find specialized healthcare providers who understand their specific conditions

• Access evidence-based treatment resources tailored to their needs

• Connect with peer support networks and advocacy groups

• Discover assistive technologies and adaptive equipment

• Navigate insurance and financial assistance programs

• Share experiences and learn from others facing similar challenges

Explore here: https://www.thespooniverse.org/

Patient No More

Meet The Spooniverse, Where Patients Learn About The Diseases Their Doctors Didn't Study In Medical School.

There is a hidden world with its own language that no one wants to join yet millions of us are members. And the password is “spoonie…

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2 months ago · 30 likes · 15 comments · Helene M. Epstein

How to Support the Platform

If you’d like to get involved, here’s how:

Donate: Support the Spooniverse and other patient-centered projects that are making healthcare more accessible and connected.

Share: Spread awareness about disability rights and resources in your networks.

Engage: Volunteer with local disability organizations or advocate for accessibility improvements in your community.

The Spooniverse relies on community support to maintain and expand its comprehensive resource database, improve accessibility features, develop new tools for community connection, and ensure the platform remains freely accessible.

July might be Disability Pride Month, but advocacy seldom takes a day off.

Non-native strains

Many probiotic strains are not native to the human gut and therefore haven't evolved the specific genetic traits that allow them to survive and thrive in the gut environment. These traits include:

• Mucosal adherence: The ability to stick to the gut epithelial lining.

• Acid resistance: Surviving the harsh, acidic environment of the stomach.

Without these adaptations, non-native probiotic strains struggle to establish themselves and colonize effectively.

Niche availability and competition

The gut microbiome is a complex ecosystem with limited space and resources. For a probiotic strain to colonize, it needs to find an available niche. This can be challenging because:

• Existing bacteria may already occupy suitable niches.

• Microbes face intense competition for resources.

One study found that a specific strain of Bifidobacterium longum had more success colonizing in individuals who didn't already have native B. longum strains. This suggests that when a niche is already filled by a similar species, it's harder for the probiotic strain to establish itself.

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April 7th, 2020 is a day which will forever live in infamy in my memory. It all began inconspicuously enough in early April. After taking a solitary stroll one afternoon, I developed a sore throat, joint pain in my knees, and weakness in my upper body.

For several weeks prior, I had been experiencing debilitating fatigue and frequent shortness of breath. Initially, I chalked up my symptoms to allergies and possible anemia.

On Good Friday, the breathing trouble escalated drastically to the point where I felt like I was suffocating. My lungs seemed to be ballooning like air bags and then collapsing under the pressure. The heaviness in my lower chest made me feel like my alveolar sacs had been replaced with bags of marbles. I felt as though a giant block of ice had filled the space in my pleural cavity where my lungs used to be.

Saturday was accompanied by the onset of fever and profuse perspiration from my forehead, neck, and back. By Sunday afternoon, my breathing had turned to wheezing, and the unrelenting, excruciating chest pain became unbearable. Tears silently streamed down my face as my breathing continued to shallow. I could feel the air exchange in my lungs becoming more inefficient with each passing breath and seemed to be spiraling into acute respiratory distress.

For so many long haulers like myself, the BC era refers to the time ‘before COVID,’ a simpler time. When the Black Death first ravaged Italy, it spread quickly, but cities soon developed countermeasures and came up with the idea of “quarantine” — the word originally comes from the Medieval Italian word for “forty,” quaranta, because the period of isolation was forty days.

Unfortunately for me, my battle with COVID was not a short one. Well over 10 quaranta would transpire before I regained the slightest sense of stability. On the night of Monday, April 20th, 2020, COVID-19 dealt me another swift, hard blow and reeled me back into cowering submission.

I once again began experiencing a crushing heaviness in my lungs, severe chest pain, nausea, loss of motor control. Within seconds, everything started to go black, and I felt as though I was about to breathe my last. It was like being choked and suffocated at the same time.

With each successive cycle, COVID-19 seemed to reemerge with even greater determination to take me. It was like being knocked to the ground and strangled by an invisible stranger.

I spent the remainder of my days barely breathing. The disease was like huge overlapping waves pushing up against a dam that I was constantly trying to fortify, always threatening to overwhelm my defenses and destroy all of cellular civilization at any given moment.

In accordance with its protean nature, around the five-week mark, COVID-19 began morphing from a primarily pulmonary disease into a neuropsychiatric one as well.

Over the months that followed, I had many complications including lung scarring, dysautonomia, tachycardia, kidney swelling, and GI inflammation that required surgery. COVID also caused a horrible depression, the depths of which is difficult to describe. Oftentimes, I felt as though I was already buried six feet under.

While in the midst of my own seemingly never-ending battle with COVID-19, reports began to emerge of a “long tail” form of the disease, first described by Paul Garner in the British Medical Journal through his own firsthand accounts. Garner has since been involved in efforts to psychologize the condition. A month later, science journalist Ed Yong covered the plight of us “long haulers” in a piece written for The Atlantic:

The route of exposure remained a bit of a mystery. I had been isolating for well over a month when the pneumonia first set in. I hadn’t had any direct contact with healthcare workers, grocery store clerks, or delivery truck drivers.

As the pandemic progressed, we learned that young people were not as protected from experiencing symptoms as had originally been assumed and that patients aged 20 to 44 comprised 20% of those in the ICU. Stories such as those of 25-year-old David Anzarouth, 26-year-old Fiona Lowenstein, 29-year-old Francis Wilson, and 30-year-old Ben Luderer reminded us that no one could be considered safe from this disease.

In the interest of transparency, I have a fairly complicated (a.k.a. unfortunate) medical history. While I have struggled with chronic illness for the past two decades, I don’t suffer from any of the conditions generally thought to predispose an individual to more severe COVID-19 complications, namely diabetes, heart disease, hypertension, cancer, metabolic syndrome, and conditions that affect the lungs such as asthma, emphysema, COPD, and cystic fibrosis.

My pre-existing conditions included Ehlers-Danlos syndrome (a connective tissue disorder that makes me prone to injury), small fiber neuropathy (which feels like system-wide electrocution), chronic cystitis (which causes 24/7 burning bladder pain and urgency), and mast cell activation syndrome (which causes severe reactions to countless food and environmental exposures).

The fireworks sounded like bombs going off outside the large white isolation tent on the eve of July 4th. I had just been triaged and was waiting to see the attending doctor. About fifteen minutes later, a male Indian nurse pulled back the curtain to swab me for SARS-CoV-2. It was the fourth time I had been subjected to the procedure.

After another twenty minutes, the curtain was pulled back once again, and a young blonde doctor entered. She remarked that I didn’t look like I was feeling well. Indeed, I struggled to breathe the entire ride over. She asked me what was going on, and I began to explain my sordid symptoms.

In the pandemic, the divide between the infected and unaffected looms large. Some battle for their lives in intensive care units while others go about their business as usual, almost impervious to the external threat lurking behind every corner looking to claim or at least maim its next victim.

For those afflicted with the long-haul, life looks very different. Will we ever walk without vertigo again? Will our hearts ever beat normally again? Will the brain fog ever clear?

I personally began isolating long before such recommendations became commonplace and nonetheless ended up horribly ill while so many contemporaries seemed to defy social distancing guidelines, downplay the risks, laugh in the face of danger, and still get off scotch-free. It all seemed out of proportion. Nothing made sense, not that it ever did.

If Shakespeare (whoever he was) ever decided to tell my life’s story, he would’ve probably written it as a tragedy — with a heaping teaspoon of humor thrown in for good measure.

Throughout my illness, I struggled with neuropsychiatric symptoms such as hallucinations, depression, and delirium though I dared not admit to these extra-pulmonary manifestations. In my experience, doing so served as grounds for further physical and psychological abuse.

The burden of my pre-existing conditions compounded the pain of my illness. As a young minority female, navigating healthcare had always been tricky. When I experienced any kind of weight loss, I was presumed to have an eating disorder. When I exhibited trouble breathing or rapid heart rate, my distress was dismissed as anxiety. When I had an atonic seizure, I was accused of faking it.

We often speak of our hearts hurting in metaphorical terms, but the myocardial damage from overuse adds another cruel, ironic layer of injury to our pain, like pouring salt and battery acid into an open wound, like a trauma that won’t heal, like a scar that never solidifies or shrinks.

At times, the tachycardia caused a racing pulse of up to 200bpm at rest. At other times, my pulse remained in the low 40s for several weeks. I was too weak to speak and could barely move. I would go to bed, expecting to fall asleep and simply not wake up. I had never been so certain of death and told myself that it was alright, that I had no regrets. I was so sure that I didn’t even cry.

Truthfully, I had lost my will to live. The end seemed more like a welcome reprieve. If I wasn’t able to find healing, maybe I could at least receive some peace. Upon waking in the morning, I distinctly recall the utter disappointment at having to face another day in such excruciating pain.

Each time, the length of time to wear the heart monitor increased: first a week, then fourteen days, then an entire month. The cardiac monitor always smelled as if it had been doused in a liter of pungent perfume, and no amount of rubbing alcohol or hydrogen peroxide could mask the scent.

The continuous hospitalizations and specialist visits offered no resolution to my suffering. Managing my disease had become a full-time job from which I wasn’t allowed to resign. No amount of prescription medications, lifestyle interventions, or n-of-1 experimentation offered relief. The situation seemed hopeless.

For me, COVID was not a “Netflix and chill” type of illness. It was the type of illness that brought me to my knees, left me in tears, and broke my spirit. It was the type of illness that had me contemplating the end and thinking of all the people I wouldn’t have a chance to say goodbye to. It was the type of illness that left me wondering which breath would be my last.

Breathing distress became my constant companion, my chest ached incessantly, and the burning chronic cystitis pain that I had come to know so well the past decade wouldn’t let me sleep more than an hour at a time. I was so weak that I went weeks without showering.

The violent vomiting and chills began anew any time I tried to reintroduce solid foods. During these episodes, even the weight of my clothes was too much to bear and made my abdominal pain even more excruciating. Paradoxically, the more I ate, the more I lost weight. I spent over 10 months in a state of metabolic acidosis while my hair fell out in clumps.

People often point to my story as a cautionary tale about what can happen if the threat of COVID is not taken seriously. I take issue with this characterization as someone who had been isolating long before the pandemic began. The narrative that medical misfortune is the result of moral deficiency erroneously places the blame on patients for circumstances out of their control.

Too often, our stories are politicized and stripped bare of their humanity, strewn upon the altar of public health warnings and advisories. But behind every story is a human being with hopes and dreams and fears. Behind every story is someone just like us.

Maybe misery really does love company, or maybe we find our common humanity in the sharing of these stories. Maybe through overcoming adversity, we also overcome the distance between us and bridge superficial class divides. After all, no one is immune to the throws of misfortune.

Perhaps that underlies the sentiment that Carl Sagan was trying to convey in Pale Blue Dot, that we all have a responsibility to deal more kindly with one another and preserve and cherish the only home we’ve ever known.

That starts with creating a more inclusive society that acknowledges and accommodates dynamic disabilities and complex chronic illnesses such as long COVID. Until the unaffected are just as enraged as the afflicted, inequality will remain the order of the day.

We needn’t wait for public policy measures to be enacted. Change can start with a simple conversation with a neighbor, friend, or colleague. Change starts with us, the people.

Patient scientists, caregivers, clinicians, disease experts, and drug developers have been making strides towards accelerating research, educating policy makers, and raising awareness of infection-associated chronic conditions, but we still have a long way to go.

Fellow advocates have compiled a guide on how to help someone with long COVID and shared events occurring all around the world to spread more awareness.

A Lifeline to Long COVID Resources

As we continue the fight for better medical care and disability accommodations, I wanted to highlight a resource that I hope will make a difference in the lives of patients worldwide: The Spooniverse.

Created by patients for patients, this comprehensive resource platform brings together hundreds of resources in one accessible hub. On those days when brain fog makes simple tasks feel impossible, you can easily filter by category or directly search for what you need whether that's treatment options, clinical trials, patient communities, or financial assistance.

If you’d like to support this vital community project, here’s how you can help:

• Share this platform far and wide with your support groups, on social media, with healthcare providers who might pass it along to newly diagnosed patients

• Add to the knowledge base by recommending resources you've found helpful that aren't yet included

• Support our mission through a donation if you're able – every contribution helps keep this platform accessible to anyone who needs it

In Conversation with Ryan Prior

A couple years ago, I sat down with journalist Ryan Prior to discuss his book The Long Haul. We discussed long COVID, myalgic encephalomyelitis (ME), patient advocacy, and precision medicine. Here are a few highlights from our interview:

Nita Jain: In your book, you discuss medical gaslighting as a phenomenon whereby patient symptoms are dismissed as imaginary. How can we prevent this from happening to more patients? Does medical school education need to change? Do we need to include more information about the long term effects of SARS-CoV-2? Do we need to start teaching more about chronic fatigue syndrome and myalgic encephalomyelitis? How can we create a more inclusive society that acknowledges and validates patient symptoms?

Ryan Prior: When any person is feeling gaslit, it means that they have a lived experience and then some other authority in their lives tells them that’s not true. So it’s kind of like being systematically lied to. And being dismissed in their own experience, being told that what their five senses are telling them is not correct. When people are sick and that doesn’t appear on diagnostic tests, that can be an issue for doctors who have a certain bandwidth that they’re used to operating in.

They’re limited in their ability to use tools, and that’s where the roots of gaslighting occur because there’s not yet been a single biomarker or specific diagnostic test that is used to describe ME/CFS or long COVID, so it has to be diagnosed on symptoms.

We can go into greater detail, but there’s no shortage of tests that do come back abnormal. I think that’s really important to say that people will have elevated titers for Epstein-Barr virus or herpes virus reactivations. They can have abnormal cortisol levels. They can have low natural killer cell function. They can have T-cell exhaustion. Many have mutations on the MTHFR gene, and we can go down the list of a lot of things. And so that best first step is getting diagnostics right and being able to reckon with complexity.

The second thing is that your doctor’s job is to prescribe medicine. And when they have not been told how to prescribe for this particular diagnosis, they’re powerless from a diagnostic standpoint. And then if they can’t use the levers that they’re used to using, that’s a problem. So it would be easier just to deny the problem exists in the first place than to have the more complex, time-consuming conversation with patients about how to manage the illness and certain drugs that may or may not work.

Nita Jain: You mention how myalgic encephalomyelitis and long COVID can both begin in the aftermath of a viral infection. ME can often start after Epstein-Barr infection, and similar syndromes have been observed after the SARS and MERS pandemics as well.

Long COVID and ME seem to share a lot of overlapping features in terms of reduced blood flow to the brain, GI dysbiosis, mutated mitochondrial DNA, impaired immune cell activity that you had alluded to earlier. In your book, you discuss the overlap of long COVID with conditions like POTS, which is a form of dysautonomia, and mast cell activation syndrome (MCAS).

How close do you think we are to a theory of everything that encompasses these related conditions? And how can we accelerate the pace of research in this area?

Ryan Prior: There’s a chapter later in the book that refers to this as a theory of everything. I think we’re knocking on the door of this new hypothesis about this large swath of human biology that’s covered in this piecemeal fashion and these diseases — mass cell activation syndrome, POTS, Ehlers-Danlos syndrome, myalgic encephalomyelitis, chronic Lyme, fibromyalgia, long COVID, the conditions of dysautonomia, gut dysbiosis, and many more — are part of this complex chronic community.

And so there needs to be an overall systematic approach to treating all of them because I think that they’re all versions of each other, that they’re all — in the words of Dr. Amy Proal — immune-associated chronic diseases.

Nita Jain: I like that you talk about the potential pitfalls of specialization because I do think complexity is something that’s inherent to all disease, not just those that are implicated as having an infection associated with them. To paraphrase John Donne, no man is an island, but neither is any organ, tissue, or cell. All parts of the body are in constant communication with one another and there’s a lot of crosstalk between systems as well.

But how often do you have a neurologist consulting with a GI doctor about their patient’s migraines or memory problems? That doesn’t happen very often. So these pockets of specialties sometimes do more harm than good because we’re not paying attention to the crosstalk that’s happening between systems. And to negate that is leading to a lot of blind spots.

You briefly touched on the infectious origins of Alzheimer’s, and how that ties into the increased risk of dementia observed after COVID. How might solving long COVID also shine light on other conditions?

All diseases have a certain degree of complexity, and looking at a more holistic view of the etiology could be helpful, not just for things like long COVID and ME, but also things like diabetes, Alzheimer’s disease, common conditions that place a very high burden on the healthcare system in America.

Ryan Prior: Yeah, there’s a key part of this is just this our overarching idea of infection theory. So I think Alzheimer’s is a good example of a disease that despite huge amounts of funding and huge amounts of research, there has not been huge amounts of progress, and that could be because of not being able to fully understand the roots of it. If Alzheimer’s or the various forms of dementia have various immune triggers, there could be a decades-long link there about how that led to development of a longer term illness.

Nita Jain: I love the idea of genomics making it to clinical prime time because in your book you talk about how Alzheimer’s risk is better predicted by two factors in conjunction than either alone, that being the presence of an APOE4 gene mutation as well as an infection that crosses the blood-brain barrier. What are some other examples where having that genetic information could really inform healthcare decisions?

Ryan Prior: One easy one off the top of my head is the MTHFR gene present in a number of chronic illnesses, which is a piece of the methylation cycle, so ways in which cells create energy. Supplementing with B12 or methylated B12 is one way to get around it. And low-hanging fruit in the form of an over-the-counter supplement that could be accessed in any corner drugstore can have a pretty significant benefit in a good number of chronic illness patients. When you’re looking for ways to improve your health, 10 percent, 15 percent, 20 percent, you wanna have some small wins along the way.

Nita Jain: I want to take a minute to talk about economic prospects for long haulers. The United States is just one of a handful of countries that doesn’t have any paid annual leave. And I’ve personally observed a lot of spoonies turn towards entrepreneurship as a way to cope with the fact that standard 9-to-5 jobs don’t really accommodate their specific health needs.

You published an opinion piece in The Guardian along with Fiona Lowenstein, founder of the Body Politic, about how long COVID could be responsible for up to one third of the current labor shortage in the US.

You conclude, “Fixing the labor shortage means treating, accommodating, and mitigating long COVID. It requires building a society in which disabled people can participate.” What does an inclusive society look like? And how do we ensure that disabled and chronically sick people are able to participate in our economy?

Ryan Prior: 1 in 4 people has a disability. So, chronic illness, long COVID all reports up on this larger disability access question. And there’s real strength in numbers here. The Americans with Disabilities Act was passed in 1990, and there needs to be a second. People think about disability, but they’re thinking about wheelchair ramps and curbs, but there are other areas where disability protections can save lives by giving access to Medicaid and making accommodations.

The largest number of newly disabled people in our generation are COVID long haulers. So long COVID or complex chronic illness is the biggest category of where disability policy needs to be updated. The most basic thing I’ll say is that people with complex or intermittent disabilities with brain fog and fatigue benefit from being able to work remotely.

If they waste all their energy getting to the office, don’t make them go to the office. Also, they’re probably immunocompromised. Don’t make them go to the office. You’re going to increase disabled workforce participation in conjunction with cases where remote work is available. And there was an increase in disabled workforce participation in 2020 because that was the greatest amount of remote work options also being available.

Nita Jain: Absolutely. And not only remote work but having flexible hours because with a lot of chronic illness, you sometimes need some time to recharge in the middle of the day because of fatigue or flareups or brain fog interfering. So I think being able to set your own hours is also really important for people who are dealing with complex immune related issues.

Ryan Prior: Rest is the most helpful prescription for people with post-viral conditions, so we need labor policies to reflect the need to rest. It’s really that simple. A lot of our advocacy through the Century Foundation is just helping explain that to the Department of Labor. And we hope we’ll be further empowered to issue guidelines for employers and schools and universities to advocate for people with these conditions. But rest is the basic principle.

A recent longitudinal study examined how glucose levels in early adulthood impact the risk of developing Alzheimer’s later in life.

Data from nearly 5000 participants (35–50 years old) over the course of 38 years were analyzed to determine correlations between metabolic markers and Alzheimer’s disease.

Individuals with higher blood glucose levels during middle adulthood had a 14.5% higher risk of developing Alzheimer’s disease later in life. But why might we observe this association between impaired glucose metabolism and deterioration of brain function?

How Can Defects in Glucose Metabolism Impair Brain Function?

The brain uses glucose as its primary energy source but can also use ketones under fasting conditions. High blood sugar coincides with a reduced ability to uptake glucose into the brain, making diabetes and obesity major risk factors for dementia.

ApoE4 is a gene that is strongly associated with an increased risk of developing Alzheimer’s later in life. Having one mutated copy doubles your risk, and having two mutated copies increases risk 10-fold.

Young adults who carry one copy of the implicated ApoE4 variant have abnormally low levels of glucose in regions of the brain that are affected by Alzheimer’s disease — namely the posterior cingulate, parietal, temporal, and prefrontal cortex.

How Do Our Bodies Regulate Insulin Secretion?

Evidence for insulin resistance in the brain is where Alzheimer’s disease sometimes gets its moniker of “type 3 diabetes.” A paper published last year by researchers in Japan offers yet another piece to the puzzle. Amyloid beta (Aβ), a protein often implicated in neurodegeneration, may play a role in regulating insulin secretion.

While plasma Aβ levels are traditionally thought to reflect brain pathology, the researchers demonstrated that glucose- and insulin-sensitive tissues like the pancreas, adipose tissue, skeletal muscles, and liver also secrete Aβ, which in turn inhibits insulin secretion by β-cells in the pancreas.

As our blood glucose levels rise after a meal, the pancreas secretes insulin, which stimulates glucose uptake by insulin sensitive tissues, thereby decreasing blood glucose. But there’s more to the story: the pancreas also secretes Aβ when stimulated by glucose.

Researchers refer to this glucose-dependent secretion of Aβ as “primary secretion.” Insulin circulates and binds to peripheral target tissues, triggering muscle, liver, and fat tissue to then secrete Aβ in an insulin-mediated manner, what the researchers call “secondary secretion.”

While glucose is the main driver of insulin secretion, plasma Aβ may help fine tune it. Aβ secreted from islet β-cells in the pancreas adjusts insulin secretion in an autocrine manner and Aβ secreted from insulin-targeted organs suppresses insulin secretion in an endocrine manner. This two-step regulation of insulin helps keep blood sugar levels stable.

Aβ secreted from peripheral tissues likely functions as an organokine, an endocrine factor that is involved in crosstalk between organ systems and contributes to glucose and insulin homeostasis. In response to insulin, muscle, liver, and fat tissue release their own organokines, known as myokines, hepatokines, and adipokines, respectively.

Over ten years ago, another research group identified APP as a top candidate gene that regulates insulin secretion from pancreatic islets and reported that loss of APP in mice leads to increased insulin secretion from islets in response to glucose, but the mechanism for why this occurred was previously unknown.

We now know that APP knockout mice exhibit upregulated insulin secretion because APP-derived Aβ negatively regulates insulin secretion. This relationship suggests a connection between Alzheimer’s disease and diabetes. A couple other mechanisms might also explain the connection:

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CRISPR-Cas9 borrows a concept from bacterial immunity to edit human genes.

CRISPR-Cas9 takes advantage of the bacterial equivalent of adaptive immunity. CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is an RNA mediated bacterial defense against viral or plasmid DNA.

When a bacterium is exposed to a pathogen such as a bacteriophage, it stores some viral DNA in its own genome in “spacers,” which serve as excerpts from sequences of past enemies that have attacked the bacterium or its ancestors.

The spacers essentially function as genetic mug shots, allowing the bacterium to remember pathogens in case of future invasions. When required, the CRISPR defense system will slice up any DNA matching these genetic fingerprints.

In 2012, Jennifer Doudna and Emmanuelle Charpentier demonstrated how CRISPR could be used to slice any DNA sequence of choice. The CRISPR-Cas9 system allows researchers to not only recognize and remove DNA sequences but also modify them.

The completion of the Human Genome Project in 2003 provided a copy of the genetic book of life; CRISPR offers a way to erase and “correct” certain words in that book. Treating blood disorders, such as sickle cell anemia, which is caused by a single point mutation, could be possible.

Of course, this newfound power raises several ethical concerns. The major worry among scientists revolves around the long-term consequences of germline modification, meaning genetic changes made in a human egg, sperm, or embryo.

Edits made in the germline will affect every cell in an organism and will also be passed on to any offspring. If a mistake is made in the process and a new disease inadvertently introduced, these changes will persist for generations to come. Germline edits are essentially forever.

Human germline modification can also open the door to designer babies, allowing not only for the cure of genetic diseases but also the installation of genes to offer protection against infection, Alzheimer’s, and even aging.

For many, the thought of controlling our own genetic destinies seems to be a very slippery slope, conjuring up dystopian images of Frankenstein or Brave New World. In 2015, Doudna and other scientists proposed a moratorium on the use of CRISPR-Cas9 for human genome editing until safety and efficacy issues could be more thoroughly addressed.

CRISPR-Cas9 gene editing technology may have unintended consequences.

CRISPR is currently being used in clinical trials for cancers and blood disorders; since these interventions won’t lead to heritable DNA changes, these trials don’t face the same ethical dilemmas as Dr. He’s experiment but may nevertheless carry risks.

Doubts persist about the safety and efficacy of the CRISPR gene editing system, as many other initially promising technologies have failed. Conventional gene therapies, which attempt to insert healthy copies of genes into cells using viruses, faced many early setbacks, including the tragic death of 18-year-old Jesse Gelsinger in 1999 during a gene therapy trial for ornithine transcarbamylase deficiency.

While more precise than traditional gene therapy, CRISPR nonetheless sometimes results in unintended edits. But even precise cuts can have unexpected consequences.

Two separate 2018 studies published in Nature Medicine, one conducted by the Karolinska Institute in Sweden and the other by Novartis Institutes for Biomedical Research, concluded that CRISPR edits might increase the risk of cancer via inhibition of a tumor suppressor gene called P53, which has been described as “the guardian of the genome” due to its crucial role in maintaining genomic stability.

Double-stranded DNA breaks made by CRISPR activate repair mechanisms encoded by P53 that instruct the cell to either mend the damage or self-destruct. Making these types of edits successfully would therefore require inhibition of P53; however, cells could become more vulnerable the development of cancer as a result.

CRISPR-Cas9 genome editing can also trigger a phenomenon called chromothripsis, a catastrophic event where a chromosome shatters and reassembles incorrectly. A 2021 study published in Nature Genetics found that CRISPR-Cas9 editing can cause extensive chromosomal rearrangements, including large deletions and complex genomic alterations at the target site.

These on-target consequences occur when the DNA repair machinery attempts to fix the Cas9-induced break but does so imprecisely, leading to the loss of tumor suppressor genes or activation of oncogenes.

“We don’t always fully understand the changes we’re making,” says Alan Regenberg, a bioethicist at Johns Hopkins Berman Institute of Bioethics. “Even if we do make the changes we want to make, there’s still question about whether it will do what we want and not do things we don’t want.”

But even if genetic editing technology like CRISPR-Cas9 could be made sufficiently accurate and precise, the idea that certain genes can be categorized as either advantageous or deleterious is fundamentally flawed.

Genetic strength or weakness is relative, as perceived imperfections may actually confer resilience in a changing environment.

It is an error to imagine that evolution signifies a constant tendency to increased perfection. That process undoubtedly involves a constant remodeling of the organism in adaptation to new conditions; but it depends on the nature of those conditions whether the direction of the modifications effected shall be upward or downward. Retrogressive is as practicable as progressive metamorphosis.

— English Biologist Thomas Henry Huxley, 1888

In biology, those organisms that are most suited to their environment exhibit the highest fitness, a measure that accounts for both survival and reproduction. The accumulation of mutations over time is thought to contribute to many disease processes, but genetic diversity can also be beneficial for an organism when faced with a changing environment or unanticipated stress, such as drought or illness.

Discussions on rigid natural selection should give way to more nuanced conversations on “balancing selection, the evolutionary process that favors genetic diversification rather than the fixation of a single ‘best’ variant,” as described by Professor Maynard V. Olson at the University of Washington.

Evolution has allowed many potentially deleterious genes to remain in the gene pool due to their ability to impart a selective advantage to individuals with carrier status, a phenomenon referred to as heterozygote advantage.

Sickle cell anemia is a disease inherited in an autosomal recessive pattern — two copies of the problematic gene variant are necessary for disease expression. However, having just one copy of that variant confers resistance to malaria, which may explain the increased prevalence of sickle cell anemia in areas where malaria is more common, namely India and many countries in Africa.

In other words, malaria acts as a selective evolutionary pressure maintaining the occurrence of the sickle cell variant in the gene pool.

To further examine the utility of genetic diversity, consider the fact that over half of all hepatocytes (liver cells) in humans exhibit polyploidy, meaning that instead of having two copies of each chromosome, they have four, eight, or even 16.

Cells that contain an abnormal copy number of chromosomes are often seen as aberrant, but considering the liver’s role as a waste-processing plant, this type of built-in redundancy likely comes in handy upon exposure to DNA-denaturing substances. If a toxic substance damages a gene on one chromosome in a liver cell, the backup copies of that chromosome can ensure the gene will still function properly.

Harvard geneticist George Church offers some anecdotal evidence supporting the maintenance of neurodiversity in the gene pool, explaining that people with autism have historically been described as intellectually disabled. But very often, if they can become high-functioning, they’re the opposite. They actually contribute things to society that nobody else sees. Church himself has narcolepsy and struggled with dyslexia as a child, differences that he feels have contributed to his creative abilities.

The Yale Center for Dyslexia & Creativity says dyslexia affects 20 percent of the U.S. population and accounts for 80–90 percent of all individuals with learning disabilities. A study conducted by London’s Cass Business School found that dyslexia is much more common in entrepreneurs than in the general population, as 35 percent of U.S. entrepreneurs that were studied exhibited dyslexic traits. Researchers also determined that compensatory strategies, such as ability to delegate and enhanced oral communication skills, likely contributed to success in the business arena.

Shark Tank investor Barbara Corcoran credits dyslexia for helping her develop empathy and making her “more creative, more social and more competitive.” Similarly, Richard Branson, Charles Schwab, and Ikea founder Ingvar Kamprad have spoken about how dyslexia fostered innovation and helped shape their unique worldviews. Considering the countless advantages of a perceived disability, any ill-conceived efforts to normalize the genetic bell curve could mean missing out on the incredible potential of genetic neurodiversity.

Speculation surrounding “designer babies” is based more in science fiction than scientific fact.

Man is a maker and a selector and a designer, and the more rationally contrived and deliberate anything is, the more human it is.

— Joseph Fletcher, one of the founders of bioethics, 1971

Basic research on gene editing and the use of somatic gene editing to heal individuals who are sick are generally widely accepted among the public. The waters become murkier when we consider germline editing and the possibility of preventing disease or altering traits unrelated to health needs.

In the 1970s, scientists first began to establish distinctions between somatic and germline genome modifications; somatic edits only affect a single individual while germline edits can be passed down over generations.

By the mid-1980s, bioethicists began to argue that the morally relevant line was between disease and enhancement rather than somatic and germline. Discussions of heritable enhancements in particular raise fears of a possible return to eugenics.

Designer babies is a term commonly used in the vernacular to refer to babies with genetic enhancements. John Fletcher, former head of bioethics at the National Institutes of Health (NIH), once wrote,

The most relevant moral distinction is between uses that may relieve real suffering and those that alter characteristics that have little or nothing to do with disease.

Many scientists today share the sentiment that treatment and prevention of “disease” constitute acceptable uses of CRISPR technologies while “enhancement” applications should be discouraged, but the boundary between the two is riddled with semantic discord.

Pharmaceutical companies frequently invent new medical diseases in a process known as medicalization. Neither can the medical profession be relied upon to make the distinction, as many plastic surgery practitioners conduct procedures that can more aptly be described as enhancement. Moreover, the line delineating disability and disease is often blurred, and many perceived shortcomings may in fact represent normal variation on the phenotypic spectrum.

The discussion of whether we can or should modify human characteristics may be a moot point since our knowledge of which genes affect complex traits such as height, intelligence, and eye color is still limited. Additionally, most traits are influenced not only by genetics but also environmental factors, and monozygotic twin studies demonstrate that genes alone cannot predict whether physical traits will be expressed.

Furthermore, genes that encode for physical traits may also impart increased vulnerability to certain diseases. For example, variations in the MC1R gene responsible for red hair color may also increase the risk of developing skin cancer.

The efforts of Dr. He Jiankui to confer HIV resistance to twins Lulu and Nana may have also resulted in increased susceptibility to infection by West Nile virus or influenza. As always, trade-offs exist, and the idea of the “perfect specimen” is a fallacy. Any efforts to gain genetic advantages will always be subject to the limitations of biology.

Our understanding of gene-disease links is based on limited data and is therefore incomplete. The singular “wild-type” does not exist.

How do we define a mutation? The simple answer is a genetic sequence that differs from the agreed-upon consensus or “wild-type” sequence. After the completion of the Human Genome Project in 2003, the arduous process of genome annotation began. Genome-wide association studies, or GWAS, began examining population data over time to look for possible associations between genetic variants, or genotypes, and physical traits and diseases, or phenotypes.

Unfortunately, these studies often fail to employ random sampling, and 96 percent of subjects included in GWAS have been people of European descent. In fact, scientific disciplines frequently disproportionately sample from WEIRD (western, education, industrialized, rich, democratic) populations, whether studying genetic diseases or human gut microbiota.

Given the sources of genetic information used to determine “wild-type” sequences, we may be using information that is relevant to one demographic but not another. According to Maynard Olson, one of the founders of the Human Genome Project, the wild-type human simply doesn’t exist, and

genetics is unlikely to revolutionize medicine until we develop a better understanding of normal phenotypic variation.

These words seem to have fallen on deaf ears, however, as evidenced by the burgeoning numbers of genome-wide association studies conducted over the last 12 years. Most of the associations discovered thus far are only correlative, and few studies have been conducted to determine whether observed associations are indeed causal.

But the majority of afflictions commonly affecting the general population, such as type 2 diabetes, cardiovascular disease, cancer, Alzheimer’s, and Parkinson’s are not caused solely by mutations.

Disease seldom arises as the result of genetic mutation alone.

The critical take-home medicine here — one that needs to be reinforced over and over — is that as we enter the age of genomic medicine, simply having a mutation in a disease gene does not mean you have the disease or will get the disease.

— Harvard geneticist Robert Green, 2012

Chronic diseases are the result of a complex interplay between host genetics and the environment. A study conducted by the Wellcome Trust Sanger Institute in Cambridge, England analyzed DNA sequencing data from 179 people of African, European, or East Asian origin as part of the 1000 Genomes Pilot Project and discovered that healthy individuals carried an average of 400 mutations in their genes, including around 100 loss-of-function variants that result in the complete inactivation of about 20 genes that encode for proteins. These findings indicate that deleterious mutations, even those that lead to protein damage, do not invariably give rise to disease.

As Professor James Evans from the University of North Carolina, who was not involved in the study, summarized in an NPR health blog:

We’re all mutants. The good news is that most of those mutations do not overtly cause disease, and we appear to have all kinds of redundancy and backup mechanisms to take care of that.

The authors hypothesize that healthy individuals can carry disadvantageous mutations without showing ill effects for a number of possible reasons: an individual may carry just one copy of a gene mutation for a recessive disorder that requires two mutations in order to manifest the disease, the disease may exhibit delayed onset or require additional environmental factors for expression, or the reference catalogs used to identify gene-disease links may be inaccurate. An analysis conducted by the National Center for Genome Resources found that 27 percent of database entries cited in the literature were incorrectly identified.

To account for the discrepancy between genetic predisposition and disease manifestation, in 2005, cancer epidemiologist Dr. Christopher Wild proposed the concept of the exposome, which encompasses “life-course environmental exposures (including lifestyle factors) from the prenatal period onwards” and accounts for factors such as socioeconomic status, chemical contaminants, and gut microflora.

The risk of developing a chronic disease during one’s lifetime may be modeled by G×E: the interaction between a person’s genetics (G) and lifetime exposures (the exposome, E). Identical twin studies reveal that genotype alone cannot determine whether a given phenotype will be expressed, and the interaction between genes and the environment needs to be taken into account.

In fact, the “genes load the gun, environment pulls the trigger” paradigm may be overly simplistic, as Dr. Alessio Fasano at Harvard Medical School has shown that loss of intestinal barrier function is likely also necessary for the development of chronic inflammation, autoimmunity, and cancer.

Two particular gene markers, HLA-DQ2 and HLA-DQ8, are observed in the vast majority of celiac disease cases. While over 30 percent of the U.S. population carries one or both of the necessary genes, only around one percent of Americans have celiac disease.

These data suggest that exposure to gluten through ingestion of wheat, barley, or rye is not sufficient to trigger the development of celiac disease even in individuals with a genetic predisposition. Without the additional loss of intestinal tight junction function, celiac disease is not made manifest. Thus, factors besides genetics are necessary for the development of chronic disease.

Before jumping onto the gene editing bandwagon, we should perhaps investigate the untapped potential in safer treatment methods, such as modifying the diet, restoring mitochondrial function, manipulating the microbiome, and resetting circadian clocks. Attempting to restore normal physiology using more expedient methods prior to making drastic and irreversible genetic changes would serve us well.

Decades before such chronic medical conditions reached epidemic proportions, a microbiologist named René J. Dubos (1901–1982) had already begun cautioning against impending urbanization, loss of biodiversity, and technological shifts borne out of convenience rather than necessity.

Dubos initially gained fame after discovering the first clinically tested antibiotic, gramicidin, in 1939. His discovery revived interest in Alexander Fleming’s discovery of penicillin and launched the era of antibiotics.

Dubos would go on to pioneer the field that is now known as the developmental origins of health and disease (DOHaD). Ironically, Dubos’ discovery may have galvanized the very forces he warned against. In his discussions on biodiversity, Dubos intoned:

“Man himself has emerged from a line descent that began with microbial life, a line common to all plant and animal species…[he] is dependent not only on other human beings and on the physical world but also on other creatures — animals, plants, microbes — that have evolved together with him. Man will ultimately destroy himself if he thoughtlessly eliminates the organisms that constitute essential links in the complex and delicate web of life of which he is a part.”

Honor Thy Gut Symbionts

A study published in The BMJ discovered that as many as one in four antibiotic prescriptions were not medically justified, according to data on outpatient antibiotic prescription fills from 2016.

Lead author Kao-Ping Chua, a researcher and pediatrician an University of Michigan C.S. Mott Children’s Hospital, commented that the actual percentage of unnecessary prescriptions may be much higher than the numbers suggest, as many additional prescriptions were either not associated with a documented diagnosis or only considered potentially appropriate.

While antibiotics hold the potential to save lives when used judiciously, the unrestricted use of these drugs can be problematic in a number of ways.

Indiscriminate antibiotic use for the purposes of fattening livestock has a number of harmful downstream effects, such as the spread of antibiotic-resistant microorganisms including methicillin-resistant Staphylococcus aureus (MRSA), pathogenic species of Salmonella, and antibiotic-resistant E. coli strains that can contribute to the development of drug-resistant urinary tract infections in consumers.

Apart from the well-documented issue of life-threatening infections associated with the development of antibiotic resistance, over-prescription of antibiotics is also contributing to a substantial loss of human gut microbiota biodiversity in Westernized societies.

Diet- and antibiotic-driven gut microbial extinction events, especially during early development, can have long-term health consequences and predispose individuals to allergies, asthma, autoimmunity, and metabolic disorders later in life.

However, when seeking solutions to our modern microbial extinctions, we must take care not to simply artificially restore our microbes while the mechanisms that first led to dysbiotic shifts remain in place.

Enthusiasm for microbial restoration therapies and other pharmacological interventions should be checked by a comparable consideration of ecological solutions. Similarly, public health programs targeting vaccination should not neglect proper nutrition, hygiene, and access to clean drinking water as other crucial factors necessary for host immunity and prevention of infectious diseases.

Burning the Midnight Oil

In addition to pharmacological agents, lifestyle changes have also had dramatic impacts on our patterns of activity and rest. Our ancestors rose and set with the sun. We are presently exposed to numerous sources of bright light from lamps and light fixtures, television and computer screens, and other light-emitting devices while our daytime exposure to sunlight has considerably diminished.

Additionally, 15–20 percent of western populations regularly work at night in illuminated surroundings. The advent of light bulbs and artificial lighting at the end of the 19th century was undoubtedly a technological wonder but also contributed to disruption of natural circadian rhythms, which is associated with metabolic dysregulation, reduced insulin sensitivity, and risk of obesity. On light, Dubos wrote:

“Until the last century, man lived in the dark for long hours…modern man, in contrast, is exposed to bright light for 16 hours a day. In view of the fact that light rays can affect several hormonal activities, and that many, if not most, physiological functions are linked to circadian and seasonal cycles, it seems possible that this change in the ways of life will have long-range consequences for the human species.”

Robust circadian rhythms are established by the alignment of the central and peripheral clocks. The central circadian clock, located in the suprachiasmatic nucleus (SCN), is dictated by light-dark cycles while the peripheral clocks in tissues such as the liver, muscle, and pancreas are governed by feeding and fasting patterns. Synchronizing these clocks is associated with various health benefits, including improved insulin sensitivity, better sleep quality, and reduced risk of metabolic syndrome.

The availability of artificial lighting not only impacts our sleep-wake cycle but our feeding-fasting cycles as well, as most of us commonly consume food after sundown. This seemingly innocuous habit might have more insidious health effects than initially realized, as late-night eating drives circadian misalignment, microbial dysbiosis, and the development of metabolic disease.

Carbohydrate consumption, in particular, after sundown can lead to hyperglycemia since melatonin inhibits insulin secretion by the pancreas, an evolutionary adaptation designed to prevent blood sugar from crashing in the middle of the night when food was typically scarce.

Conversely, consumption of a larger proportion of our daily energy requirements early in the day promotes circadian alignment and produces metabolic benefits since glucose tolerance and diet-induced thermogenesis are higher in the morning than in the evening.

Circadian misalignment also affects our microbial inhabitants, as the gut microbiota display diurnal variations related to timing of food consumption, overnight fast duration, and frequency of light exposure.

A study published in Frontiers in Microbiology conducted in a mice model discovered that, in contrast to 12 hours of artificial light exposure per day, constant exposure to artificial light resulted in an increased abundance of Ruminococcus torques, a bacterial species associated with gut barrier degradation, and a decreased abundance of Lactobacillus johnsonii, a species known maintain the integrity of the intestinal epithelial layer.

These findings may provide a possible mechanism by which disruption of normal circadian rhythms can damage the gastrointestinal lining and lead to other subsequent effects.

Ain’t No Sunshine

Increased exposure to artificial lighting in modern times has also typically been accompanied by reduced exposure to solar ultraviolet radiation, which is in turn associated with a number of physiological consequences. Until the Industrial Revolution, our ancestors mainly held outdoor occupations whereas the majority of the population in developed countries now works indoors.

Since the Second World War, developments such as automobiles, television, computers, video games, and other technological devices promoted indoor activities over outdoor pursuits.

In the millennia before these technological advancements, the skin pigment of a population reflected the ideal balance between the positive and deleterious effects of sun exposure in a given climate.

Darker skin is hypothesized to protect against sunburn and possibly folate deficiency while lighter skin is thought to allow sufficient biosynthesis of vitamin D and other compounds in areas with less ambient ultraviolet radiation.

However, lifestyle changes and the migration of light skinned people to tropical climates have resulted in a more intermittent pattern of sunlight exposure. The recent rise in skin cancer is often considered a result of evolutionary mismatch between skin type and geography. Richard Weller, a dermatologist at the University of Edinburgh, explains,

“Homo sapiens have been around for 200,000 years. Until the industrial revolution, we lived outside. How did we get through the Neolithic Era without sunscreen? Actually, perfectly well. What’s counterintuitive is that dermatologists run around saying, ‘Don’t go outside, you might die.’”

An estimated one billion people worldwide suffer vitamin D deficiency or insufficiency. Inadequate amounts of non-burning sun exposure and resulting vitamin D deficiency carry increased risks of all-cause mortality, hypertension, cardiovascular disease, metabolic syndrome, diabetes, obesity, Alzheimer’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, non-alcoholic fatty liver disease, macular degeneration, and myopia as well as increased risks of colorectal, breast, prostate, and pancreatic cancers.

So far, the only identified risk associated with the amount of non-burning sun exposure required to achieve serum vitamin D levels of 30 ng/mL is a possible increased risk of non-melanoma skin cancers such as basal and squamous cell carcinomas, which are seldom fatal. Moreover, sun exposure is associated with a relatively favorable prognosis and increased survival rate in malignant melanoma. According to Weller,

“The risk factor for melanoma appears to be intermittent sunshine and sunburn, especially when you’re young. But there’s evidence that long-term sun exposure associates with less melanoma.”

The benefits of sun exposure extend far beyond those conferred by adequate levels of vitamin D. Sunlight also triggers the release of various other important compounds in the body, including serotonin, endorphins, and melatonin.

Additionally, sun exposure induces skin to release nitric oxide, which dilates blood vessels and lowers blood pressure, into systemic circulation to exert cardioprotective and antihypertensive effects. A 2014 study found that nitric oxide-mediated effects of ultraviolet radiation suppressed obesity and symptoms of metabolic syndrome independently of vitamin D.

Furthermore, exposure to both UVA and UVB radiation can help prevent autoimmune disease through upregulation of cytokines (TNF-α and IL-10) and increased activity of regulatory T cells that remove self-reactive T cells.

Calcitonin gene-related peptide (CGRP) is also released in response to both UVA and UVB light and inhibits mast cell degranulation, which may explain sunlight’s efficacy in treating skin disorders such as psoriasis.

With the preponderance of evidence suggesting numerous health benefits associated with diet and lifestyle changes, we would be remiss not to take advantage of the opportunity to improve our health using the most accessible of means, which may include the use of restricted feeding windows, regular sleeping schedules, and sensible sun exposure.

We are not individuals but walking, talking ecosystems that require feedback from our microbial symbionts and the outside world in order to regulate inflammation, train immune tolerance, maintain homeostasis. Forging ties with our microbial symbionts has allowed us to achieve what we never could in isolation.

Our human chromosomes provide an incomplete picture of the genetic information we carry and neglects the bacterial, archaeal, fungal, protistan, and viral genetic information that is equally integral to human identity if not more so.

Transposable elements or transposons, often referred to as “jumping genes,” are remnants of ancestral viral and parasitic infections that subsequently became integrated into the human genome in a manner similar to the CRISPR defense system in bacteria. More than 45 percent of the human genome is derived from transposons, whereas coding regions called exons comprise less than two percent.

The Missing Link in the Evolutionary Record

Evolution has occurred at a pace much too quick to be explained by random mutation alone. To compensate, biologists have also introduced additional mechanisms such as genetic drift, gene migration, gene flow, and epistasis. However, even these mechanisms cannot sufficiently explain the quantum leaps by which evolution has taken place.

To isolate the genes of an individual as the sole drivers of evolution is to ignore the contributions of billions of years of symbiotic coexistence, at a dangerous cost. We must unite Neo-Darwinist and Lamarckian views of evolution, akin to the attempt to unite gravity and quantum mechanics in physics. To understand evolution at the macroscopic scale, we need to examine evolution at the microscopic scale as well. Enter the hologenome.

“[The hologenome concept] embraces a vibrant and more satisfying view of the nature of biology, namely that the microbiome is as essential as the genome in defining what an animal or plant is and is not.”

— Neuroscientist Roman M. Stilling

The hologenome accounts for the genetic material of a host, or holobiont, plus all its symbiont microbiota. Many bacteria that live in and on our bodies multiply rapidly enough to go through several generations of offspring within the span of 24 hours, accounting for why antibiotic resistance evolves so rapidly.

Bacteria reproduce, mutate, and therefore evolve very quickly. In this manner, the hologenome can evolve at a much more rapid pace than the human genome. As science writer Ed Yong expounds in I Contain Multitudes,

“By partnering with microbes, we can quicken the slow, deliberate adagio of our evolutionary music to the brisk, lively allegro of theirs.”

The human body has 10 times as many microbial cells as DNA-bearing human cells. A 2016 study challenged the commonly quoted 10:1 ratio of microbial cells to human cells and estimated that a human body contains ~30 trillion human cells and ~40 trillion microbes, proposing a microbe to human cell ratio of about 1.3.

However, if we are solely interested in cells bearing genetic contents and therefore ignore the non-nucleated red blood cells and platelets, we again obtain a microbial/human result of about 10:1.

Keep in mind that this ratio does not account for mitochondrial DNA, which is also hypothesized to be microbial in origin. Mitochondria are organelles responsible for cellular energy production in animals, and chloroplasts are responsible for photosynthesis in plants. Microbiologist Eugene Rosenberg, who first posited the concept of the hologenome, explains,

“Mitochondria and chloroplasts can be considered ‘extreme symbionts’ because they were derived from alphaproteobacteria and cyanobacteria, respectively.”

The human microbiome consists of 3.3 million unique genes, a set 150 times larger than our own genome. However, examining the microbiome from a purely quantitative standpoint belies the real-world utility of microbial genetic diversity.

Generally, reduction in gut microbiota diversity, such as that induced by antibiotics, leaves the host vulnerable to infection, C. difficile infection being the most well-characterized example of this phenomenon.

Loss of microbial gene diversity is observed in many diseases, and fecal microbiota transplantation, a procedure designed to restore gut microbial diversity, has been shown to be beneficial for not only gastrointestinal conditions such as C. difficile infection, inflammatory bowel disease, and irritable bowel syndrome but also autism, allergies, autoimmunity, skin conditions, chronic fatigue syndrome, depression, diabetes, obesity, and neurological disorders.

The Microbiome Compensates for Host Defects

The predictive power of the microbiome may exceed that of genome-wide association studies when it comes to understanding complex human diseases. Microbial genes provides the crucial complement to features missing in the host’s core genome.

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Countless others present opportunities to shift the microbial balance in one’s favor through the use of probiotics, prebiotics, synbiotics, phages, helminths, quorum sensing inhibitors, immune modulators, skin creams, body washes, vaginal suppositories, and more. However, our enthusiasm to learn and tweak our microbial communities should be tempered with caution and humility regarding how much remains unknown.

The compositions of gut microbial communities are highly variable across populations

When it comes to composition, there is no singular healthy reference human microbiome. Which bacteria live in your gut depends on host genetics, ancestry, sex, diet, geographical considerations (sunlight exposure, climate), and many other factors. On average, any given two people share 99.9% of their genome but only about one third of their gut microbiome (by composition).

The latter finding generally holds true even for identical twins (37% vs 35% for unrelated individuals). The remaining two-thirds may be influenced by mode of birth delivery, breastfeeding history, age, stress, medication use, variability in sleep patterns, circadian rhythms, exercise, and other environmental factors.

Before the advent of large-scale microbiome sequencing efforts, researchers assumed the existence of a common “core” of microbes shared among human populations, as culture-based studies seemed to suggest that most adults harbored certain bacterial species such as Escherichia coli.

This expectation of a core microbiota was swiftly upended by the results of non-culture sequencing studies, which repeatedly demonstrated vast microbial diversity that is both highly variable over time and across human populations!

Moreover, since most microbiome studies disproportionately sample from WEIRD (Western, Education, Industrialized, Rich, Democratic) populations, we may still only be seeing the tip of the iceberg in terms of extant global microbial diversity.

Even though two individuals may not share any of the same gut bacterial species, the types of bacteria able to successfully colonize the human gut belong to just a handful of taxonomic groups called phyla.

In this manner, the gut microbiota display phylogenetic underdispersion. In other words, out of the hundreds of bacterial phyla found in natural environments, the human gut is characterized by only 5–7 distinct phyla. However, the relative proportions of these phyla can vary considerably among individuals.

The composition of microbial communities may change, but function remains the same

Although individuals exhibit a great deal of microbial variation at the compositional level, the functional profile of gut microbial communities remains fairly stable. In other words, while we may harbor markedly different microbes, the activities those microbes carry out are remarkably similar.

A 2012 study conducted by the Human Microbiome Project Consortium reported that genes representing metabolic pathways were stable among individuals despite variation in community structure. The Turnbaugh lab similarly described how microbial genes shared among individuals comprise “an extensive, identifiable ‘core microbiome’ at the gene, rather than at the organismal lineage, level.”

Overall, the metabolic capabilities of gut microbiomes seem relatively conserved among healthy adult individuals, and deviations from this core microbiome at the gene level are associated with obesity and other disease conditions. As Dr. Rob Knight of the American Gut Project summarizes,

“The common core is at the level of functions, not members.”

Tied to the overall conservation of functional genes is the concept of functional redundancy, a backup system in which many types of bacteria are capable of carrying out the same metabolic processes. As a result, a healthy gut microbiome can be assembled in a number of different ways.

For example, Oxalobacter formigenes is the most well-characterized oxalate-degrading microbe in the colon, and its presence has been associated with a reduced risk of developing kidney stones.

But certain strains of Lactobacillus and Bifidobacterium have also been shown to carry the same oxc and frc genes responsible for oxalate degradation as O. formigenes, and Eubacterium lentum and Enterococcus faecalis can consume oxalate as well.

Similarly, Roseburia intestinalis, Faecalibacterium prausnitzii, Butyricicoccus pullicaecorum, Eubacterium hallii, Anaerostipes caccae, and several other species are capable of synthesizing butyrate, a short-chain fatty acid.

This built-in redundancy ensures that the loss of one particular strain or species doesn’t spell metabolic doom for the host. Accordingly, testing services reporting that certain bacterial species are outside a specified abundance range should be interpreted with caution.

Functional redundancy confers stability and negates the need for keystone species, defined as those species that have a disproportionately large effect on community structure relative to their abundance.

Potential keystone species such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Roseburia intestinalis, Christensenella minuta, and Bacteroides uniformis have been proposed, yet none can be generalized as fundamental across all human gut populations. The Hadza hunter-gatherers of Tanzania, for instance, do not harbor any Bifidobacterium but still have very low rates of chronic disease.

Variations in gut metabolism outside the core microbiome can result in individualized responses to food and drugs

While essential pathways, such as those responsible for the breakdown of carbohydrates and protein, may be conserved in the common core metagenome, or collective genetic material present among the microbiota, not all metabolic pathways are represented in the core. Differences in these variable pathways can affect individual responses to diet, medication, and other therapeutic interventions.

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A few years ago, I heard a TED Talk given by Dr. Shamini Jain and strongly identified with many of the experiences she was describing. Like her, I have seen many scientific paradigms upended during my lifetime, such as the still widely circulated myth that neurogenesis doesn’t occur after childhood or the assumption that lymph nodes don’t exist in the brain.

As was the case for her, my scientific background also initially left me skeptical of complementary and alternative medicine. As I grew older, I tried to make sense of the various approaches espoused by different medicinal camps. Jain’s discussion of the divide between allopathic and alternative medicine got me thinking about how the use of these terms is problematic at a much larger level.

The Appropriation of Ancient Wisdom

Is progress the consequence of cutting-edge novelty or is it the result of returning to our roots? Is it somewhere in between? Modern medicine prides itself on constant innovation, yet some of its most significant breakthroughs represent rediscovery rather than revolution. What we call progress often represents devolution, or at best, a belated recognition of forgotten knowledge.

When MIT researcher Otto Scharmer described organizational evolution as a progression of "operating systems," he perpetuated the problematic narrative of a linear timeline whereby the past is inherently less evolved, innovative, and progressive than what lies ahead in the future.

In Scharmer’s estimation, organizations evolve from being authority-driven and input-focused, to prioritizing efficiency and outputs, to emphasizing customer outcomes, and finally to adopting ecosystem-oriented approaches.

This framework is particularly disingenuous in the case of medicine, where salutogenesis, a “4.0 operating system,” actually represents our earliest understanding of health. Traditional Chinese Medicine, Ayurveda, and indigenous healing practices have always exploited natural ingredients to restore wellness.

Yet for centuries, ancient wisdom has been suppressed and systematically appropriated, only gaining legitimacy once discovered and validated by western institutions. When indigenous peoples and marginalized groups are the stewards of knowledge, their practices are dismissed as folklore until repackaged and imbued with profitable meaning by medical institutions and insurance overlords, the self-appointed arbiters of truth.

Even worse, this system of scientific colonialism implies that knowledge from cultures without access to state-of-the-art instruments, such as hunter-gatherer tribes, cannot be validated without encroachment from more “civilized” peoples.

This institutional isolationism perpetuates cycles of suffering by denying patients access to effective treatments that fall outside the dominant medical paradigm. Even if an alternative therapy emerges as a more effective treatment than the prevailing standard of care, a substantial window of time typically elapses before that alternative treatment migrates to default status, if it ever does.

Mind Your Microbes

Fecal microbiota transplantation (FMT) is a procedure that involves transplanting bacteria from the stool of a healthy donor into a patient with a disrupted gut microbiome. The first documented use of FMT was in 4th century China when Ge Hong used a fecal slurry to treat patients with severe food poisoning and diarrhea.

Long considered an experimental therapy, FMT has gradually become part of the standard of care for the treatment of C. difficile colitis. Clostridioides difficile is best characterized as a pathobiont, a microorganism that is usually a part of the host microbiome but can become harmful when the host’s immune status or native microflora are altered.

Antibiotics are a known risk factor for the development of recurrent Clostridioides difficile infection (rCDI) because they induce the type of dysbiosis, or microbial imbalance, that allows C. difficile to gain a foothold. By killing both pathogens as well as friendly commensals indiscriminately, antibiotics eliminate the very microbes that keep pathobionts like C. difficile in check.

The evidence supporting FMT's superiority is compelling. A large cohort study involving almost 300 patients demonstrated that FMT outperformed antibiotics when evaluating several different outcomes in patients with rCDI.

These findings were further validated by a 2023 review of six randomized clinical trials (RCTs), which found that FMT not only resolved symptoms better but also resulted in fewer adverse events and overall mortality compared to antibiotic therapy.

But first-line therapy for rCDI still consists of antibiotics while fecal microbiota transplantation (FMT)—despite being safer and more effective— is considered an appropriate course of action only if the patient fails to respond to antibiotics.

Repeated antibiotic treatments for rCDI will lead to more recurrences. Modern medicine has managed to market the cause as the cure. To treat rCDI with antibiotics is to knowingly perpetuate patient suffering. FMT offers a way to break the cycle.

Pathology vs Ecology

Antibiotics and FMT represent two fundamentally different approaches to infectious disease and the practice of medicine more generally: one is an elimination-based approach that seeks to eradicate, and the other is an ecological approach that seeks to restore equilibrium.

Antibiotics aim to annihilate any potentially pathogenic agents, but nature abhors a vacuum. Every single millimeter of your body is colonized, and microbes will always find a way to reclaim the void left behind. FMT at least offers some agency as to which microbes will occupy that niche.

Rather than trying to kill the enemy and select for resistance in the process, FMT addresses the ecological disturbance. Disease is about diplomacy.

These drastically differing perspectives underlie the discrepancy between sterilizing immunity and microbiota-nourishing immunity. Sterilizing immunity represents our scorched-earth defense system, designed to detect and destroy invaders at all costs. In contrast, microbiota-nourishing immunity operates more like ecological diplomacy, cultivating strategic alliances that guard against threats through collectivism.

The human body balances this duality through mechanisms that support both defensive elimination and ecological restoration. But the vast majority of western medicine, to the detriment of patients, focuses almost exclusively on the former.

Many establishment scientists will be quick to falsely characterize the ecological perspective as an endorsement of the appeal to nature fallacy, a rhetorical technique whereby what is natural is considered good. The ecological perspective focuses on systems dynamics rather than arbitrary delineations of “natural” and “artificial.”

FMT works not because it’s natural but because it restores disrupted microbial ecosystems, as validated by robust clinical outcomes. The case of C. difficile infection treatment exemplifies how modern medicine sometimes perpetuates cycles of intervention that may harm rather than heal.

The preferential use of antibiotics over FMT, despite evidence supporting the latter's superiority, demonstrates our healthcare system's attachment to reductionist approaches over restorative ecological ones. This bias persists even when ecological approaches prove more effective.

These attitudes even pervade approaches to mental health. Whereas western approaches have traditionally sought to avoid and pathologize negative emotions in a frenzied quest for hyperoptimization, eastern perspectives recognize the wisdom of flowing through rather than against our emotional undercurrents.

Like water adapting to its container, this flexibility allows us to observe and move through emotional states without resistance or judgment, an approach western psychology is only now beginning to embrace. It is indeed okay to not be okay.

Personalized vs Population-Based

The chasm between western and eastern perspectives isn’t just philosophical; it manifests in tangible effects on patient outcomes. Western medicine's devotion to standardization, while crucial for reproducibility and large-scale studies, can inadvertently mask clinically significant individual variation.

A recent Nature study of over 12,000 patients highlights how our reliance on population-based reference ranges for laboratory tests may obscure meaningful changes at the individual level.

The research examined nine key blood count indices over a 20-year period and found that each person’s metrics remained remarkably stable, and their unique setpoints were as distinctive as a fingerprint or what researchers called an “index of individuality,” differing from 98% of other healthy adults.

Individual setpoints far outperformed population-based references in predicting mortality risk and also revealed unexpected associations with specific diseases—from atrial fibrillation to diabetes to blood cancers—often before traditional diagnostic criteria would raise concerns.

We can’t ignore the potential implications. When we compare a patient's lab values to broad population averages rather than their personal baseline, we risk missing early warning signs of disease or misinterpreting normal individual variation as pathological. Among the 500 million complete blood counts performed annually in the United States alone, how much vital information are we missing by ignoring individual variation?

A drop in hemoglobin that falls within "normal" population ranges might actually signal iron deficiency for a specific patient. A platelet count considered unremarkable by standard measures could indicate nine-fold higher risk of blood cancer-associated mutations when compared to that individual's baseline.

Transforming medicine doesn’t mean abandoning population-based standards but enriching them with individual context. The future of healthcare depends on hybrid systems that can integrate both personal baselines and population insights akin to how gut-immune crosstalk balances both targeted elimination and ecological restoration. Progress lies not in choosing between these perspectives but in building frameworks sophisticated enough to examine multiple levels simultaneously.

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.

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.