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.

Phascolarctobacterium and Dialister

If you’ve ever unsuccessfully tried dieting to lose weight, your gut bacteria may be to blame. A 2018 study published in the journal Mayo Clinic Proceedings found that an individual’s microbial makeup determined the success of dieting efforts for weight loss.

Purna Kashyap, a gastroenterologist at Mayo Clinic in Rochester, tracked 26 people who were following a low-calorie diet as part of a weight loss program for three months.

“We found that people who lost at least 5 percent of their body weight had a different gut bacteria as compared to those who did not lose 5 percent of their body weight,” Kashyap explains.

Those individuals who achieved positive results on a low-calorie diet had an abundance of a bacterium called Phascolarctobacterium in their guts whereas non-responders were enriched with a bacterium called Dialister.

So how might different kinds of bacteria affect weight loss? A lot of food calories are absorbed courtesy of our microbiota. When we eat whole foods, nutrients are absorbed in the small intestine, and the undigested bits are converted into additional energy by our gut microbiota.

According to Martin Blaser, a professor in the Department of Microbiology at NYU Langone Medical Center,

“Somewhere between 5 to 15 percent of all our calories come from that kind of digestion, where the microbes are providing energy for us, that we couldn’t [otherwise] get.”

In times of food scarcity, the extra energy would be a boon, but in an era where most people want to lose weight, those extra calories are undesirable. “If times were bad, if we were starving, we’d really welcome it,” says Blaser.

Akkermansia

Akkermansia muciniphila, a common human gut symbiont, is over 3,000 times more prevalent in lean mice than in those genetically predisposed to obesity. When transplanted into obese mice, they lose weight and show fewer signs of type 2 diabetes.

The altered abundance of Akkermansia may even account for the success of gastric bypass surgery, an operation that reduces the size of the stomach. People often lose a substantial amount of weight post-surgery, which is normally accredited to their smaller stomachs.

But the procedure also restructures the gut microbiome and leads to a higher abundance of Akkermansia. If you transplant these restructured communities into germ-free mice, those mice start to lose weight.

Supplementing human volunteers who were overweight or obese with live or pasteurized A. muciniphila improved glucose tolerance and reduced fat mass.

Christensenellaceae

Possessing gut bacteria belonging to the Christensenellaceae family is positively correlated with having a healthy weight. While diet typically shapes the gut microbial community more than genetics, Christensenella minuta is an exception, as this species tends to be highly heritable and run in families.

In 2014, Goodrich et al. were the first to observe that Christensenellaceae were significantly enriched in individuals with a normal BMI (18.5–24.9) compared to individuals categorized as obese (BMI ≥ 30). Since then, her finding has been corroborated among many different demographic populations globally.

In fact, Christensenellaceae is associated not only with BMI but also with adiposity as measured by DEXA scans. Consistent with the leanness association, the abundance of Christensenellaceae increases after diet-induced weight loss.

A 2019 review by Jillian Waters and Ruth Ley of the Max Planck Institute for Developmental Biology discussed numerous associated health benefits, including improved metabolic health, lower risk of inflammatory bowel disease, and greater longevity.

A 2021 article published in the journal Cells even described a specific strain of Christensenella minuta that could potentially be used as a live biotherapeutic for obesity!

The Future of Weight Loss Interventions

If microbes can have such a drastic effect on weight and metabolism, is a simple microbiota transplant or probiotic cocktail the cure? Can we throw out our pre-existing knowledge of the importance of diet and lifestyle? Science suggests no.

Our understanding of the microbiome complements but doesn’t completely replace our knowledge of obesity. In 2013, one of Gordon’s graduate students, Vanessa Ridaura, demonstrated the entanglement of diet and the gut microbiota.

She first transferred lean and obese microbial communities into germ-free mice and then proceeded to house both groups in the same cage. Mice frequently engage in coprophagy, the act of consuming each other’s feces, and thereby quickly acquired their neighbor’s microbes.

Ridaura noticed that microbes associated with lean people were able to readily colonize “obese” communities and arrest weight gain, but the reverse wasn’t true. Microbes associated with obesity could never establish in hosts where “lean” microbes were already present.

But the lean microbes didn’t have any distinct advantages over obese ones when it came to taking up residency in the mouse gut. Rather, Ridaura had tipped the balance in their favor by feeding her mice fiber-rich plant chow.

Microbes from lean donors were more enriched for genes that encode for fiber-degrading enzymes and therefore fared well with a plant-based diet. Feeding the mice fatty, low-fiber chow, representative of the standard western diet, swiftly put an end to the lean microbes’ reign.

No longer armed with fiber, the lean microbes were powerless to stop weight gain. A fiber-deprived diet is proverbial kryptonite for your gut microbiota. Residents of a rainforest would fare poorly if dropped into the middle of a desert.

Similarly, gut ecology is just as important as community composition and dictates what kind of microbial inhabitants can take up residence. If the research conducted so far is any indication, providing for our microscopic allies can help guard against obesity and metabolic disease.

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 commercial viability.

Best for: Scientists who want to tackle a specific hard problem with a coordinated team, outside the constraints of academia or traditional startups

What makes them different:

• Multi-year commitments (typically 3-5 years)

• Function as nonprofit start-ups, combining speed and innovation

• Structured as LLCs under a parent 501(c)(3) nonprofit organization

• Focus on tools, platforms, and enabling technologies

Current Opportunities:

• Convergent Research accepts concept proposals on a rolling basis

• Arc Institute supports new research initiatives in biology and biomedicine

• ARIA (UK), the Advanced Research + Invention Agency, focuses on high-risk, high-reward research

• SPRIND (Germany) supports breakthrough innovations in deep tech

• Renaissance Philanthropy focuses on transformative research projects

• Schmidt Sciences Polymath program helps cross-disciplinary teams

Check out the Overedge Catalog for more innovative research organizations!

2. Scientific Crowdfunding

What it is: Platforms where you can raise funds directly from stakeholders (researchers, patients, enthusiasts) who believe in the work you’re doing.

Best for: Early-stage validation studies, pilot data collection, projects with clear public benefit, building credibility before larger grant applications

Primary Platform:

Experiment.com (Kickstarter for science)

What makes it different:

• You control your timeline and milestones

• Build community and early advocates

• Typical raises: $5K-$50K

• No equity, no debt, just direct support

Success factors:

• Clear, compelling story about why your research matters

• Specific milestones and budget

• Active promotion to your networks

• Regular updates to backers

3. Prize Competitions

What they are: Challenges with cash awards for solving specific problems or achieving defined milestones

Best for: Teams with a working prototype or clear path to demonstrable results

Major Programs:

• XPRIZE ($10M-$100M+ for breakthrough innovations)

• NIH Challenge Grants (various healthcare challenges, $50K-$500K)

• HeroX (multiple biotech and health challenges, $100K-$1M+)

• Luminary Labs competitions (corporate-sponsored health innovation challenges)

What makes them different:

• You only get paid if you win or hit milestones

• But there’s no application fee, no equity given up

• Often comes with visibility, partnerships, pilot opportunities

• Some prizes pay out in stages as you progress

Strategic tip: Many prize competitions are undersubscribed in technical categories. The same innovation that wouldn’t stand out in an SBIR pool might be the only serious entry in a niche prize competition.

4. Sponsored Research Agreements (SRAs)

What they are: Contracts where companies, foundations, or government labs fund your research in exchange for access to results, IP licenses, or first right of refusal

Best for: Research that aligns with a corporate or institutional strategy but doesn’t require you to become an employee or give up core IP

Common Sponsors:

• National Labs (DOE, NASA, etc.)

• Pharmaceutical Companies

  • Johnson & Johnson Innovation: JLABS collaborations, sponsored research

  • Takeda: External innovation partnerships

  • Pfizer: Competitive grants and research collaborations

  • Merck: Research collaborations in specific therapeutic areas

  • Novartis: Biomedical Research Business Development & Licensing

• Research Consortia:

  • TransCelerate BioPharma: Multi-company collaborative research

  • Innovative Medicines Initiative (EU): Public-private partnerships

  • Critical Path Institute: Regulatory science collaborations

What makes them different:

• Negotiable terms (you can often retain IP)

• Larger amounts than typical grants ($100K-$5M+)

• Relationship-based (less competitive than grants)

• Can be structured as milestones or cost-plus

How to pursue them:

• Attend industry conferences in your field

• Reach out to corporate innovation or ventures teams

• Partner with national labs (they often broker SRAs)

• Use platforms like InnoCentive

5. Foundation Mission Grants

What they are: Philanthropic grants from private foundations focused on specific diseases or patient populations, often more flexible and faster-moving than government grants. Many were founded by patients or families affected by the disease.

Best for: Research with clear impact on disease foundation priorities

Major Foundations:

• Chan Zuckerberg Initiative (neuroscience, rare diseases, infectious disease)

• Gates Foundation (global health, infectious disease, vaccine development)

• Pivotal Ventures (Melinda French Gates’ foundation - women’s health, family planning, gender equity in science)

• Amaranth Foundation (longevity research, neuroscience, healthspan extension)

• Wellcome Trust (biomedical research)

• PCORI, the Patient-Centered Outcomes Research Institute (comparative effectiveness research)

What makes them different:

• Often mission-aligned vs. purely scientific merit

• More flexible timelines and budgets than government grants

• Potential for multi-year support

• Some foundations prefer direct reach-out vs. open calls

Making Your Move: A Biotech Founder’s Playbook

While SBIR/STTR works itself out in Congress, you have options. Here’s how to think about deploying these alternatives:

If you need $10K-50K for pilot data: → Scientific crowdfunding (Experiment.com) → Small foundation grants → Early-stage prize competitions

If you need $100K-500K for validation: → Disease foundation grants (CFF, MJFF, ACS) → PCORI pilot funding → Biopharma sponsored research (early collaboration)

If you need $500K-$3M for further development: → Major foundation programs (Gates, Wellcome, CZI) → PCORI large awards → Biopharma sponsored research

If you need $3M+ for a multi-year program: → FROs (Convergent, Arc, Renaissance) → Major foundation partnerships → Consortium funding (IMI, TransCelerate)

The strategic approach:

1. Start small - Use crowdfunding or small foundations for pilot data

2. Build credibility - Use that data for larger foundation grants

3. De-risk commercially - Use foundation funding to attract biopharma SRAs

4. Scale up - Leverage all of the above for FRO funding or major partnerships

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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.

The first Sunday of August marks National Friendship Day in the United States. In his appropriately named treatise on friendship, De Amicitia, Roman statesman and philosopher Cicero begins by discussing how critical friendship is: “Nature loves nothing that is solitary, but always inclines toward some sort of support.”

Similarly, the poet John Donne intoned, “No man is an island.” Even Seneca, one of the great Stoic philosophers, advised his readers to “seek out the company of those with whom they can be their best selves.”

Cicero reminds us that the fruits of our labor are best enjoyed when shared: “There is no meaning in achieving goals, success, fame if you are all alone.”

Indeed, an NIH-funded 80-year longitudinal study found that close relationships kept people happy and healthy throughout their lives more than money, fame, social class, IQ, or genes. But what does it really mean to be a friend?

On Bearing Witness

An ineffable boon of friendship is bearing witness to moments both great and small. The word for hello in Zulu, the most spoken native language in South Africa, is “sawubona.” More than a mere greeting, sawubona literally means “I see you” and conveys:

I see the whole of you — your experiences, your passions, your pain, your strengths and weaknesses, and your future. You are valuable to me.

As the English poet David Whyte beautifully described in a word meditation,

The ultimate touchstone of friendship is not improvement, neither of the other nor of the self. The ultimate touchstone is witness, the privilege of having been seen by someone and the equal privilege of being granted the sight of the essence of another, to have walked with them and to have believed in them, and sometimes just to have accompanied them for however brief a span, on a journey impossible to accomplish alone.

In a pivotal scene from the movie Shall We Dance, when asked why she wants to be married, Susan Sarandon’s character remarks that we all just want someone to bear witness:

We need a witness to our lives. There are 8 billion people on the planet … I mean, what does any one life really mean? But in a marriage, you’re promising to care about everything — the good things, the bad things, the terrible things, the mundane things … all of it, all the time, every day. You’re saying, ‘Your life will not go unnoticed because I will notice it. Your life will not go un-witnessed because I will be your witness.’

Bearing witness is not for the faint of heart and often functions as a litmus test of sorts, as true friends will remain a part of your life regardless of how rough the waters get.

On Being Bound

By its very virtue, bearing witness leads to the development of empathetic bonds that cause us to revel in our friends’ triumphs and successes as well as feel pain when they’re suffering.

In a scene from the movie A Beautiful Day in the Neighborhood, based on a true story, the character of Mr. Rogers demonstrates the word for friend in sign language using interlocking index fingers.

The connotation is obvious: friends are inextricably bound, their journeys irrevocably intertwined. Similarly, in “Any Human to Another,” the poetess Countee Cullen wrote:

Your grief and mine
Must intertwine
Like sea and river
Be fused and mingle
Diverse yet single
Forever and forever

Cullen emphasizes that we each have a responsibility to carry one another’s burdens and share in each other’s pains and sorrows, and this responsibility is an important act of self-sacrifice.

Speakers of several Indian languages including Sanskrit, Hindi, Marathi, and Kannada know that the word “mitra” means friend. The heart’s mitral valve is named for its resemblance to a bishop’s miter cap whose name comes from the Greek word mitra (belt), which comes from a proto-Indo-European root meaning “to bind.”

Thus, we once again arrive at the image of friends being bound together. Critically, Cicero warns that true friendship can’t exist except between good people, for “friendship (amicitia) is derived from the word love (amor) and leads to the establishing of goodwill.”

He expounds, “Friends show proof of loyalty, uprightness, fairness and generosity; they are free from caprice, and passion and insolence, and have great strength of character…If you remove goodwill from friendship, the very name of friendship is gone.”

On Dynamic Boundaries

In her piece on friendship in the age of the internet, Bev Potter explains the changing landscape of friendship now that physical proximity is no longer a requirement. The word “friend” is used much more liberally nowadays and without qualification.

In his book, Friends: Understanding the Power of Our Most Important Relationships, Oxford evolutionary psychologist Robin Dunbar posits that friendships can be accurately illustrated as a series of concentric circles representing different levels of friendship.

While Dunbar’s number of 150 is frequently cited as the maximum number of relationships one can maintain, considerably less attention is given to the number of close core friendships one can maintain.

Distribution of Dunbar’s survey data on personal friendships formed a series of layers with each successive layer being three times larger than the layer preceding it. The innermost layer of 1.5 includes our life partners. Of note, Cicero once wrote, “The bonds of affection always unite two persons only, or at most, a few.”

The next layer of five close friends includes people who will drop everything in order to support us in times of distress. A study by Jeffrey Hall concluded that it takes an average time investment of 200 hours for someone to go from an acquaintance to a best friend. Hall explains,

It is possible to know someone for years, but not develop a friendship, and to know someone for 6 weeks and become best friends…the amount of time that has passed since meeting provides insufficient information about friendship development.

The size of each layer is generally fixed but may depend on certain personality characteristics. For example, extroverts tend to have more friends in each layer than introverts who typically prefer to have fewer friendships and invest more time in each.

In an amusing scene from The Big Bang Theory, Sheldon decides to kick Raj out of his immediate circle to avoid the “herculean task” of maintaining five close friendships.

On Common Ground

Dunbar lends credence to the old adage “birds of a feather flock together” with his seven pillars of friendship, which may be used to predict the likelihood that two people will become friends. These dimensions of homophily are:

1. Growing up in the same place, especially during core teenage years

2. Speaking the same language

3. Having similar educational or career trajectories

4. Enjoying similar hobbies and interests

5. Sharing religious, moral, or political views

6. Having the same sense of humor

7. Sharing similar musical tastes

Notably, Dunbar says these pillars are interchangeable. None is more important than any other. The more of these pillars friends have in common, the closer they tend to be. We typically share 6–7 pillars with friends in the innermost circle, but only 1–2 pillars with friends in the outer circle.

Not only do we share more interests with our closest friends, but we also appear to share more genes than we do with strangers. In fact, friends seem to be as closely related as fourth cousins. While we tend to share genes relating to smell, we tend to have very different genes relating to immune activity, a finding also observed among spouses.

James Fowler, a professor of political science and medical genetics at the University of California, San Diego, explains:

One of the reasons why we think this is true is because it gives us extra protection. If our spouses have an immune system that fights off a disease that we’re susceptible to, they’ll never get it, and then we’ll never get it. And so it gives us an extra layer of protection.

On Romantic Love and Friendship

Earlier during the pandemic, headlines covering a study published in the Journal of Personality and Social Psychology suggested that we may be happier with friends than our children or romantic partners, but lead author and Southern Methodist University professor Nathan Hudson cautioned,

Our study suggests that this doesn’t have to do with the fundamental nature of kith versus kin relationships. When we statistically controlled for activities, the ‘mere presence’ of children, romantic partners, and friends predicted similar levels of happiness. Thus, this paper provides an optimistic view of family and suggests that people genuinely enjoy their romantic partners and children.

In other words, what we do with our loved ones may be a bigger predictor of happiness than whom we spend time with. Regardless, Dunbar suggests that the time and energy invested in long-term romantic relationships requires the sacrifice of two people. He writes, “Falling in love will cost you two friendships.”

Two people will move from your circle of close friends to your circle of best friends, and two people from that circle will move into good friend territory, essentially producing a domino effect. If you were to have asked 16th century philosopher Michel de Montaigne, he might’ve said the sacrifice isn’t worth it.

While some of his ideas read as misogynistic by modern standards, Montaigne was ahead of his time in several respects. In his newsletter The Introverted Thinker, Julian Bašić discusses Montaigne’s seminal essay, On Friendship:

[Montaigne] explores the importance of friendship and how strong a bond can be between two friends, as opposed to the false lustful passion in a relationship. It really opens your eyes to how valuable a true friendship is, where each friend is always there for the other.

It really makes you wonder about the temporary and damaging nature of most relationships, and how we push away genuine friends for a temporary fiery burst of love. Montaigne is clear that we should prioritize friendships over romantic relationships.

Bašić writes that the following quote from Montaigne struck a chord:
“The love of friends is a general universal warmth, temperate moreover and smooth, a warmth which is constant and at rest, all gentleness and evenness, having nothing sharp nor keen.”

Unsurprisingly, Montaigne also believed, “If there is such a thing as a good marriage, it is because it resembles friendship rather than [romantic] love.” Along a similar vein, Nietzsche said, “It is not a lack of love, but a lack of friendship that makes unhappy marriages.”

“Marry your best friend,” advises American psychologist, therapist, and researcher John Gottman. “The simple truth is that happy marriages are based on a deep friendship. By this, I mean a mutual respect for, and enjoyment of, each other’s company.”

Real-world data seems to back up that advice, as a study conducted by the National Bureau of Economic Research found that people who consider their spouse to be their best friend experience much higher levels of life satisfaction than people that don’t.

Researchers reported that “the well-being benefits of marriage are on average about twice as large for those (about half of the sample) whose spouse is also their best friend.” Inc. columnist Melanie Curtin expounds,

When deciding on a mate for life, we can place a lot of emphasis on a wide variety of factors: [Are they] educated enough? Do [they] make enough money? Do we have similar values? Do I get along with [their] parents? Do we know how to fight well? Do [they] make me laugh? [Are they] reliable?

This science suggests that if you want a fulfilling partnership and satisfying life, there’s one question to add to the list that should arguably be put at the top:

Is she/he/[they] my best friend?

A best friend has your back. A best friend supports your dreams. A best friend is someone you can call anytime, anywhere, without feeling like they’ll resent you for it. They’re the person you put as an emergency contact and the first person you think about when something wonderful happens at work. They know all your quirks (and love you anyway). They can challenge you in deep ways because they know the ins and outs of your psyche (and love you anyway). They’re the kind of person who’ll make soup and draw you a bath when you’re sick, even if they’re busy, because they genuinely want you to feel better.

If you’re looking for a way to examine the status of your current or future romantic relationship, it’s probably wise to keep this in mind.

On Renewing Friendship

Wall Street Journal columnist Elizabeth Bernstein explains that reconnecting with friends in person post-pandemic may be a tricky road to navigate. One or both parties may feel hurt or abandoned, as it’s been a difficult time for everyone. Respectfully addressing these feelings through “active repair” and then focusing on reconnecting may be the best path forward.

Sometimes we may unintentionally gaslight our friends or partners by sweeping conflict under the rug or dismissing it as “water under the bridge.” Gaslighting occurs when certain behaviors make other people question their version of reality.

While glossing over a spat may seem like a positive way to avoid further conflict, failure to acknowledge hurt feelings and the events that transpired can be a form of gaslighting. Unsurprisingly, avoidance strategies usually lead to negative relationship outcomes.

Dr. Claire Jack, a therapist and anthropologist explains, “Disregarding someone else’s emotional and processing needs in this way, over time, has the effect of silencing them. What point is there in discussing things with you if you deny the significance of what happened before?”

Avoidance strategies often end up condoning bad behavior and trivializing the damage caused as a result. Active repair strategies, on the other hand, involve active listening, apologizing, talking things through, arriving at a compromise, and displays of affection, all of which have the potential to bring people even closer together than before.

Most importantly, active repair involves acknowledging what happened and validating a person’s feelings by understanding where they are coming from. Friendship requires both parties to be open to difficult conversations and receptive to change. While some of the great philosophers insist on the constancy of friendship, friendship can change over time and even grow into something better akin to a fine wine.

Considering our frailties and shared vulnerability to misfortune, perhaps there is no sweeter panacea than that offered by friendship, in whichever form we’re fortunate enough to experience it.

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/

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.

Listen to this episode on Apple, Spotify, and YouTube.

Expectation vs. Reality

At first glance, EHRs seem like the perfect solution—a master digital library where all patient information is neatly organized and accessible at the touch of a button. While this concept is appealing, its execution is fraught with challenges. EHRs often contain data that is incomplete, inconsistent, or even inaccurate. This digital goldmine that promises to enhance healthcare can sometimes do quite the opposite.

EHRs Are a Little Bit Racist

One of the most significant problems plaguing EHRs is the presence of systemic biases that are often entrenched within the healthcare system.

• Gender Bias: Studies indicate that women's pain is often underestimated compared to men's.

• Racial Bias: Black patients are systematically undertreated for pain when compared to white patients, with some healthcare providers endorsing false beliefs about racial differences in pain perception.

• Obesity Bias: Frequently, physicians attribute a wide array of health conditions to a patient's weight, which can result in overlooked or delayed diagnoses for conditions unrelated to obesity.

These biases significantly affect the data recorded in EHRs, skewing the representation of patient populations and impacting the quality of healthcare delivered.

The Domino Effect of Distorted Data

The biases inherent in EHRs do more than just affect individual patient care; they also warp the larger data landscape. This results in underrepresentation, where certain groups, like rural communities with limited healthcare access, are absent from the data, leading to skewed depictions dominated by urban populationsa.

Distorted associations are another issue. EHRs might misleadingly present a strong connection between particular medications and improved heart health. However, this observation might overlook confounding socioeconomic factors—such as the correlation between the medication's cost, patient insurance coverage, and better health outcomes—resulting in potentially inaccurate prevalence estimates.

Tipping the Scales Towards Data Equity

With these issues in mind, a critical approach to EHR data is essential. Understanding these limitations enables researchers and healthcare professionals to harness the full potential of EHRs while navigating their pitfalls. The goal is to improve healthcare for everyone, especially those underrepresented or misrepresented in data.

Behind every EHR data point lies a real person whose health and well-being might hinge on its accuracy. The biases and inaccuracies woven into these records require us to remain vigilant, asking critical questions about what might be missing or misrepresented. By keeping these limitations in mind, we can better use EHRs to improve healthcare for everyone, ensuring that no patient is left behind.

Meet Rand Hindi, CEO of Zama and an investor in multiple tech sectors, including privacy, AI, blockchain, medtech, and psychedelics. In this episode, Hindi discusses the future of privacy through homomorphic encryption, the concept of ubiquitous computing, and the future of AI-driven automation.

He delves into recent advancements in computational biology, including AlphaFold's progress on protein structures, and explores the implications for drug design. Hindi also examines the merging of technology and biology and the transformative potential of precision psychedelics for mental health.

He shares his thoughts on transhumanism and the ethical responsibilities of developers in shaping the future of technology.

This interview was filmed November 2022.

Listen now on Apple, Spotify, and YouTube.

The Journey to Privacy Advocacy

Hindi's journey into privacy advocacy begins with a personal story from his teenage years. While developing a social network, a bullying incident led him to uncover the importance of privacy.

Despite resolving his situation by accessing private messages, the experience left a lasting impression on him. He realized that even as a creator, he did not have the right to violate users' privacy, motivating him to ensure that digital platforms respect it by design.

Hindi envisions a future where privacy is built into the very fabric of the internet through homomorphic encryption, a method to process encrypted data without decrypting it. Hindi envisions a future where HTTPZ, the next evolution of encrypted internet protocols, ensures end-to-end encryption, making data privacy a reality by default.

This advancement holds the potential to revolutionize diverse sectors ranging from smart contracts to targeted advertising to healthcare, allowing for data analysis without exposing users’ personal information.

Bioinformatics & Personalized Medicine

Homomorphic encryption would enable secure sharing of medical data for research without compromising individual privacy. In a world where data leaks pose significant risks, this technology stands as a safeguard against unauthorized data exposure, fostering trust and innovation in medical research.

Drawing upon his bioinformatics background, Hindi describes the potential for AlphaFold's protein structure databases to revolutionize drug design and disease prevention.

Hindi's investments in technologies like portable MRIs and precision psychedelics reflect his commitment to innovative healthcare solutions. He highlights both the ancient wisdom and recent scientific validation of psychedelics for enhancing creativity and treating mental health conditions.

Implications for Work and Society

On the future of work, Hindi envisions automation replacing repetitive tasks, empowering professionals to focus on more fulfilling roles. His outlook suggests a transformation in career paths, characterized by serial specialists, individuals continually adapting and mastering new skills throughout their lives.

As an Ethereum optimist, Hindi highlights the role of developers in defining the evolution of ethical technology and praises the Ethereum community for valuing privacy and governance, reminiscent of the early days of the internet.

Hindi foresees a world where artificial intelligence becomes unobtrusive through ubiquitous computing. By reducing the friction of constant notifications and making technology seamlessly blend into the background—similar to electricity today, AI will enable a new era akin to the singularity where humans and technology become indistinguishable.

Thoughts on Transhumanism

Hindi posits that we are all inherently transhumanists with a rich and storied history of fashioning tools to transcend biological limitations. From prosthetics to wearable tech, the integration of technology into the human experience is inevitable. However, he emphasizes the importance of ensuring technology remains safe and trustworthy, especially as it becomes inseparable from our physical and mental well-being.

Hindi advocates for innovations that address vulnerabilities like climate change and chronic diseases, prioritizing investment in science to safeguard our future. Whether through homomorphic encryption, ubiquitous computing, or the integration of AI into our lives, the future holds boundless possibilities if advancements remain aligned with ethical principles for the betterment of society.

Connect with Rand Hindi

If you’d like to get in touch with Hindi or follow his work, you can connect with him on LinkedIn or subscribe to his newsletter below:

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By Rand Hindi

Soon a series of regular quantified self meetups began to spring up, first in the Bay Area but eventually all over the world. Worldwide conferences attracted thousands of like-minded individuals and spawned the development of dozens of successful products such as Fitbit and Oura Ring.

The Quantified Self is an international community of people who use self-tracking tools and share an interest in “self-knowledge through numbers.” Quantified self experiments can track many different types of health data such as mood, sleep, weight, step count, blood sugar, cholesterol levels, symptom severity, heart rate variability, and microbiome composition.

While the quantified self movement began with a focus on optimizing performance and general wellness, it has evolved to become particularly valuable for patients with complex chronic conditions. This evolution represents a shift from fitness tracking to illness monitoring and management.

Getting Started

The basic approach to quantified self experiments provides a powerful framework for chronic illness management:

1. Decide what you want to observe. For chronic illness, this means identifying not just primary symptoms but also potential triggers, treatments, and quality-of-life factors that fluctuate with your condition.

2. Make sure your observations are relevant, consistent, & trustworthy. With chronic illness, consistency becomes crucial. Logging at similar times each day, using clear rating scales, and being honest about activities all contribute to more useful data.

3. Collect data and record observations. Apps like Visible and Bearable can significantly reduce the burden of this step, making it possible to track even on difficult days when symptoms are flaring.

4. Consolidate your insights. The true power of self-tracking emerges here, as patterns reveal themselves over time, empowering more informed decisions about activities, treatments, and lifestyle changes.

Symptom Pattern Recognition

For patients with complex conditions, identifying symptom patterns can be challenging due to the multifaceted and protean nature of our illnesses. Health tracking applications help overcome this challenge by:

1. Enabling comprehensive tracking: Apps like Bearable allow users to track symptoms, treatments, and environmental factors that might affect their health.

2. Visualizing correlations: These tools generate reports that reveal relationships between symptoms and potential triggers that might otherwise go unnoticed.

3. Reducing cognitive burden: By providing a structured framework for data collection, digital health tools reduce the mental load associated with remembering and connecting experiences over time.

Pacing and Energy Management

Many chronic conditions involve limited energy reserves and post-exertional flares. Health tracking tools help patients optimize their energy expenditure through:

1. Real-time monitoring: Apps like Visible use wearable technology to provide immediate feedback on physical exertion levels, helping users stay within their safe zone.

2. Establishing baselines: By collecting consistent data over time, patients can establish their personal thresholds and recognize early warning signs of overexertion.

3. Proactive pacing strategies: With better understanding of energy patterns, patients can implement preventative pacing rather than reactive rest.

Medical Collaboration and Diagnosis

Health tracking tools bridge the gap between episodic medical appointments by providing objective data that can enhance clinical decision-making:

1. Enhanced communication: Patients can share detailed health reports with providers, offering a more comprehensive view than basic symptom recall.

2. Diagnostic insights: Patterns revealed through consistent tracking can provide clues for diagnosis, especially for conditions with subtle or fluctuating symptoms like dysautonomia, which affects heart rate, blood pressure, and digestion.

3. Treatment evaluation: Systematic tracking before and after interventions like ivabradine provides objective measures of treatment efficacy.

Honor Your Limitations

The goal of self-tracking is to improve quality of life, not become another burden. Adapt your approach to accommodate fluctuating abilities:

• During periods of remission, you might track more detailed metrics

• During flares, focus only on essential data points

• Use voice memos or simplified logging methods when energy is limited

• Remember that imperfect data is still valuable, and consistency matters more than perfection

If you’d like to learn more about different health tracking tools, check out the Digital Health/Symptom Tracking section of the The Spooniverse!

Contrary to what you may hear, it's not a matter of concentration.

1️⃣ 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.

2️⃣ 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.

3️⃣ The "like will to like" principle: This principle states that probiotic strains have a better chance of colonizing when there are already related species present in the gut microbiome. This might seem contradictory to the previous point, but it suggests that:

🎯 A similar microbial environment may be more hospitable to the incoming probiotic strain.

🎯 The presence of related species might indicate that the gut environment is suitable for a particular type of microbe.

In this episode of Evolving, I had the opportunity to chat with Richard Sprague, a software engineer, quantified self enthusiast, and co-founder of personal health tracking startups. Sprague discusses the complexities of the microbiome, the limitations of single-point microbiome testing, and the importance of longitudinal sampling.

He shares insights from his extensive self-experimentation data collection, discussing fasting, probiotics, and the impact of alcohol on glucose levels. Sprague also touches on how personal science can empower individuals to optimize their health by tailoring approaches to fit their unique biological responses.

Listen now on Apple, Spotify, Amazon Music, and YouTube.

When Big Tech Meets Tiny Microbes

Our bodies contain multitudes. Trillions of microbes live in and on us, forming a complex ecosystem that influences everything from digestion to mood. Understanding this ecosystem presents an exciting frontier for health optimization, one that Richard Sprague has been exploring with the methodical approach of an engineer.

As a former tech executive at Microsoft and Apple, Sprague sees patterns where others might see chaos. He started using personal computers during the early days of the revolution and saw the democratizing potential of technology. This perspective led him to view the body as hardware that could be optimized through the right inputs.

But the microbiome quickly revealed itself as far more complex than any computer system. The body isn't just a machine running code but a dynamic ecosystem constantly responding to countless stimuli.

The Snapshot Fallacy: Why One Test Isn't Enough

One of the most important lessons from Sprague's exploration is that microbiome testing requires multiple samples over time. Our gut bacteria undergo significant shifts even within a 24-hour period, making single-sample testing misleading.

A one-time gut check might capture an unusual day rather than represent an average of your typical microbial makeup. This temporal variance means that meaningful microbiome understanding requires tracking changes over time rather than fixating on a single snapshot. For accurate assessment, longitudinal sampling is essential.

When interpreting microbiome test results, be aware of the "compositional problem." When you take a subset of an environment, you're assuming it's evenly distributed and representative, an assumption that isn't always accurate.

Most microbiome tests report results as percentages (scaled to 100%). This creates a potentially misleading picture where proportion is conflated with abundance. If your test shows 5% Lactobacillus one day and 10% the next, this doesn't mean the bacterial population doubled because the context of the entire ecosystem matters.

The Quantified Gut: Finding Signal in the Noise

Different testing companies use different methods, making direct comparisons tricky. The American Gut project uses filtering techniques that differ from commercial testing services. Even the sampling technique matters. Beneficial bacteria like Akkermansia tend to concentrate near the outer surface of stool where they interact with the intestinal mucosa.

Sprague's advice? If you're tracking your microbiome over time, stick with the same testing laboratory rather than switching between companies. The consistency of methodology matters more than finding the ideal test.

When Sprague interprets microbiome results, he pays special attention to the number of sequencing reads obtained. Low read counts can produce misleading results through undersampling, a bit like trying to understand a forest by looking at just a handful of trees.

N-of-1: Power of Personalized Experimentation

Standard health recommendations often miss the mark because they're based on population averages that may not apply to your unique biology. What works wonderfully for one person might do nothing or even cause problems for another.

This is where self-experimentation becomes valuable. By tracking your responses to specific foods, supplements, or lifestyle changes, you can identify patterns unique to your body. These personalized insights often reveal surprising connections that general studies wouldn’t be able to predict.

Sprague has found that structured tracking reveals counterintuitive findings. Some "healthy" foods might trigger inflammatory responses in certain individuals. Interventions widely considered beneficial might produce unexpected effects given someone's unique physiology.

Geographic Imprints: How Living Abroad Reshaped Sprague’s Microbiome

Your surroundings profoundly influence your microbiome. After living in Japan for a decade, Sprague discovered he had acquired bacteria that could break down polysaccharides in seaweed, microbes typically only found in Japanese populations. This microbial transfer gave him digestive capabilities that most Westerners lack.

The Japanese diet, with its emphasis on fermented foods like miso, natto, and kimchi, supplies beneficial bacteria absent from typical Western diets. These nutritional differences create measurable changes in the microbiome with real health implications.

Cross-cultural studies reveal surprising patterns. Hunter-gatherer populations like the Hadza have drastically different gut bacteria than Western subjects. Notably, they completely lack Bifidobacterium, a genus many probiotic companies tout as essential to good health. These variations across global populations challenge our assumptions about what a "healthy microbiome” should contain.

Microbial Redesign: Diet and Fasting as Tools

The microbiome responds rapidly to dietary changes. Fasting causes shifts that reduce food-dependent bacteria while allowing hardier species to flourish. This microbial reset triggers broader effects including cellular cleanup processes and metabolic changes.

Antibiotics represent powerful but blunt tools for altering the microbiome. Their action affects beneficial microbes alongside harmful ones, often with lasting consequences. After antibiotics, your microbiome may establish a new baseline that is significantly different from the one you had before.

Different foods selectively feed certain bacterial species. Fibers preferentially nourish specific butyrate-producing bacteria while fermented foods introduce transient microbes that, even without permanent colonization, can positively influence immune function during their passage through your system.

Gut-Brain Axis & Glymphatic System

Our understanding of body systems constantly evolves. Absence of evidence is not evidence of absence, a principle perfectly illustrated by the discovery of the glymphatic system, the immune component that exists in the brain, in 2015. Because scientists were previously unable to visualize lymph nodes in the brain, they assumed they simply didn’t exist.

This discovery has profound implications for how we think about brain health. Some researchers suspect connections between the microbiome and neurodegenerative conditions. For instance, loss of smell is an early symptom of Alzheimer's disease, which could indicate disruptions in the nasal microbiome.

These findings remind us to approach the microbiome with humility. As Sprague emphasizes, our health emerges from complex networks involving microbes, genes, diet, and environment — not isolated components operating independently.

Data-Driven Discoveries: Personal Health Tracking Reveals Hidden Patterns

Modern technology lets us measure what was previously invisible. Continuous glucose monitoring (CGM) gives you a readout of how your body responds to specific foods, enabling personalized dietary choices beyond generic recommendations.

When combined with microbiome data, these measurements reveal connections between gut bacteria and whole-body responses. Patterns emerge showing how specific microbes influence everything from inflammation markers to mood regulation. This transforms vague notions about listening to your body into precise, measurable feedback.

The most valuable insights come from thoughtful self-experimentation. By systematically varying inputs while measuring outcomes, you can uncover cause-and-effect relationships unique to your biology. Sprague discovered that, contrary to expectations, alcohol actually lowered his blood glucose levels.

Connect with Richard Sprague

If you'd like help interpreting your microbiome results or gaining deeper health insights, Sprague welcomes your questions. You can follow his work through Twitter, his Substack newsletter below, or his personal website where he shares ongoing experiments and invites others to engage with him.

Personal Science

Science for personal, not professional use. Published every Thursday.

By Richard Sprague

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 60 days 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:

How Does Amyloid Beta Build Up in the Brain?

In the body, Aβ can be found in the brain and in plasma. In order to be transported into circulation, Aβ in the brain must cross the blood-brain barrier (BBB) through a receptor known as low density lipoprotein receptor-related protein 1 (LRP1).

Transport of Aβ from circulation into the brain is mediated by the receptor for advanced glycation end products (RAGE). High blood glucose and insulin levels, or hyperglycemia and hyperinsulinemia, can cause prolonged production of Aβ in plasma, which can negatively alter the equilibrium between brain Aβ and peripheral Aβ by suppressing Aβ efflux from the brain.

In other words, chronically elevated Aβ levels in circulation may impair transport of Aβ out of the brain. At the same time, high levels of circulating insulin can cross the blood-brain barrier and prevent the breakdown of Aβ in the brain by competing for insulin-degrading enzyme.

As a result, Aβ becomes abundant in the brain because of reduced excretion into the circulation and insufficient enzymatic degradation. The enriched Aβ may start to clump together into soluble oligomers, triggering cognitive dysfunction and the resulting cascade of events that leads to Alzheimer’s disease.

The authors also note that plasma Aβ levels can be used as a diagnostic biomarker of AD but only in the fasting state since plasma Aβ levels change rapidly with food intake.

How Are Diabetes & Alzheimer’s Disease Connected?

However, several previous studies have observed different results. In humans, diabetes is associated with cerebrovascular lesions, neurodegeneration, and cognitive dysfunction, but not brain amyloid accumulation, as measured by amyloid PET imaging. But it’s important to note that soluble Aβ oligomers can’t be visualized using amyloid PET.

Similarly, a mouse model of Alzheimer’s and diabetes demonstrated accelerated cerebrovascular amyloid deposition and worsening cognitive dysfunction without an increase in brain Aβ levels, so different pathways may be at play.

One alternative theory is that diabetes-induced Aβ transport into the brain encourages amyloid deposition at the vascular wall, damaging the ability of the glymphatic system, responsible for housekeeping and waste clearance, to discharge brain Aβ into circulation.

Diabetes may affect brain Aβ levels differently depending on disease status with enhanced Aβ deposition near blood vessels observed early on and brain tissue damage observed later. More research is needed to determine whether brain Aβ levels increase in diabetes.

For now, what we can say is that maintaining healthy insulin sensitivity may substantially reduce the risk of Alzheimer’s disease later in life.

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.

Consider the case of lactose intolerance. Tolerance to lactose is usually assessed based on the activity of the human lactase enzyme. The lactase enzyme breaks down lactose into its monosaccharide constituents, glucose and galactose.

In the majority of humans, the gene that encodes for the lactase enzyme shuts off shortly after weaning, making lactase persistence rare and lactose intolerance the default status. However, many bacteria belonging to the genus Lactobacilli also have genes that encode for the lactase enzyme.

Therefore, if an individual did not have a functioning human lactase gene but nonetheless carried enough lactose-degrading symbionts, he would nonetheless be able to tolerate some amount of lactose, depending upon the activity of his fellow inhabitants’ lactase enzymes.

In addition to metabolism, microbial genes augment host fitness through major roles in detoxification, protection against pathogens, and nervous system development. In fact, the gut microbiota can exert epigenetic effects by fermenting fiber to produce metabolites such as butyrate, a short-chain fatty acid that exerts a wide range of anti-inflammatory effects.

Not only does butyrate serve as the primary energy source for cells in the colon, but butyrate is also a potent inhibitor of a class of enzymes known as histone deacetylases (HDACs), which promote the expression of genes that facilitate memory consolidation, neurogenesis, and neuroprotection.

Due to its role in HDAC inhibition, butyrate is considered an anticancer agent and shows promise for the treatment of many diseases. Sodium butyrate, the salt form of butyrate commonly used in pharmacological studies, has been shown to improve brain function in animal models of Huntington’s disease, Parkinson’s disease, and advanced stage Alzheimer’s disease.

By influencing the expression of tight junction proteins, butyrate also regulates permeability of the blood-brain barrier and the gut epithelial barrier, both of which are altered in autism spectrum disorders.

Invictus, Revisited

Critics of the hologenome theory question whether the microbiome can be transmitted with sufficient fidelity across generations to be considered a unit of selection in evolution. However, another school of thought argues that transmission of specific species is irrelevant as long as the metabolic processes enabled by the microbiome are conserved.

In other words, while humans harbor taxonomically unique microbial communities, the functions those communities carry out do not exhibit much variability. Evolutionary biologist W. Ford Doolittle expressed this idea in a 2017 article entitled, “It’s the song, not the singer,” an inversion of a popular Rolling Stones song.

Revisiting the question of who is really in charge, researchers at Cornell University tracked the changes in the gut microbiome of a newborn for over two years and made a tantalizing discovery.

Metagenomic analyses revealed that polysaccharide-digesting functional genes appeared in the gut microbiome while the baby was still exclusively consuming breast milk, several weeks prior to the introduction of polysaccharide-containing solid food in the diet, suggesting a microbial priming of the infant gut in preparation for an adult diet.

This metabolic preprogramming implies that perhaps our microbes are the ones pulling the puppet strings, a humbling insight in the context of our anthropocentric view of the world.

Through our partnerships with our resident microbes, we have transformed so quickly as to become unrecognizable to our former selves. Though we may have spent most of our lives blind to the microscopic bonds we have formed, the interactions have nevertheless left indelible imprints on our lineage.