The first time, I looked forward to the night feeds. The room was dark, and the only sounds were her small, quick swallows and, now and then, a sigh. She was warm and heavy against me, heavier than the week before, and her head smelled sweet, like milk. That is the half I want to keep. In the other half, my hormones swung by the hour, I was hungrier than I had ever been, and I did not sleep. She wanted to be up at night like a little monster, and spent her days as a peaceful baby.

Painters have shown mothers nursing for centuries. In Europe, many of them painted the Virgin Mary with the baby at her breast. In the Madonna Litta, painted around 1490 and credited to Leonardo da Vinci or his workshop, a mother looks down at the baby she is feeding (Figure 1). Her red dress has a slit sewn over each breast, for nursing. Her face is calm. The baby holds still and looks out at whoever is looking in. The painters kept to the calm, and to one direction: milk goes from the mother into the baby.

Figure 1. Madonna Litta, about 1490, attributed to Leonardo da Vinci. State Hermitage Museum, Saint Petersburg. Public domain, via Wikimedia Commons.

At 2 a.m., in another house, a six-week-old with a cold stops feeding to breathe. A reel on her mother’s phone says the baby’s spit is talking back to the milk. The baby’s nose is blocked, so she lets go with a small wet snort, then latches again. Her forehead is warm against her mother’s arm. The post says the breast learns what the baby has caught. The milk, it says, answers with antibodies made for that germ.

Her mother sends the post to the twelve mothers from her prenatal class before the feed is over, her thumb sticky with milk. Part of the claim was measured. Part of it was a guess.

In 2012, a team in Haifa, Israel, led by the newborn doctor Arieh Riskin, sampled the milk of mothers whose babies were in hospital with a fever. The babies were all three months old or younger. Each mother gave milk while her baby was sick, and again after the baby got better. Across the mothers of 31 sick babies, the milk held a median of about 5,700 white blood cells per milliliter during the illness. After recovery, it held about 2,100. White blood cells are the body’s germ fighters. In the milk of mothers of 20 healthy babies, the counts did not move that way.

The antibodies did not follow. The main antibody in milk did not change much between the sick days and the well ones. Riskin’s team picked mothers by the baby’s illness, so a mother could have been sick too. The study also did not show how the breast would know the baby was sick.

A mother’s own infection is a separate case, and I have had one. Two months after my first daughter was born, the thermometer read 39.1 °C, and I was sure breastfeeding was over. My obstetrician said to keep going. When a mother catches an infection, her body makes antibodies against the germ, and some pass into her milk, antibodies a baby can borrow. Stopping would take those antibodies away.

In 2013, a team in Perth, Australia, led by Foteini Hassiotou, followed 21 mothers. In healthy pairs, white blood cells made up 0 to 2 percent of the cells in milk. When the mother or the baby caught an infection, the share rose, as high as 94 percent. It fell back after recovery. In three of the infections they recorded, the baby alone was sick.

Hassiotou’s team also offered a route. During a feed, milk comes in waves. At the end of each wave, the milk ducts shrink, and some milk flows back into the breast, “likely together with saliva from the baby’s mouth.” The team did not measure that backflow.

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Figure 2. What milk carries and what science has yet to learn about it, from the evolutionary biologist Katie Hinde at TEDWomen 2016. Video and thumbnail: TED, CC BY-NC-ND 4.0.

Say you are one of the twelve. You wake at six to a baby who coughed all night, and the reel is the first thing on your screen. Twelve babies’ next fevers now depend on one post, and none of their mothers can tell which half was measured. Without a baby, the post is a cold remedy a cousin sends to the family chat, with the same two halves. The two-month checkup is a few weeks off. Whichever half you trust by then is the half you act on at the next fever.

The piece before this one, on what the microbes do for a body, left one question open: whether anything travels back the other way, from baby to mother.

A trip back would close a loop: what systems thinking calls a chain of effects that comes back to change where it started. The reel claims a whole one: a baby’s cold reaches the breast, and the milk answers the cold.

A guess like Hassiotou’s can be checked piece by piece. If spit flows back into the breast, bacteria from the baby’s mouth should turn up in the milk. In 2025, Pamela Ferretti, Ran Blekhman and colleagues published a study of 195 mothers and babies in Minneapolis. They went looking for something else: which bacteria live in milk, and which of them join the crowd in a baby’s gut. Mouth bacteria turned up in the milk anyway. Which way they had traveled was a harder question.

What a Pump Can Catch

In Minneapolis, a mother feeds her baby until the baby is full. Two hours later, she switches on a hospital pump, the heavy electric kind. It hums while she empties her right breast until the milk stops. The tubing and the bottle are sterilized. Within twenty minutes, the milk is in a freezer at minus 80 degrees Celsius.

In all, 195 mothers and babies went through some version of this. Mothers gave milk at one month and three months after birth. Babies gave stool, from a diaper, at one month and six months. Ferretti’s team, at the University of Chicago and the University of Minnesota, read those 507 samples.

Milk is hard to search for bacteria. The bacteria counted in milk in part one are real, but next to stool they are few: most of the milk is fat and the mother’s own cells. A pea-sized scoop of stool is packed with the gut’s crowd.

Most earlier milk studies used a method called 16S sequencing. It copies one gene that every bacterium carries, then reads that one gene. The copying starts from a primer, a short single-stranded piece of DNA.

A primer works like a key cut for one lock, the same trouble as a DNA kit that looks for only one key. Bacteria whose gene fits get copied more. A real lock stays shut to the wrong key. A poor fit here still makes some copies, only fewer. The 16S studies mostly found Staphylococcus and Streptococcus, bacteria common on skin and in the mouth.

Ferretti’s team used shotgun sequencing. It breaks all the DNA in a sample into pieces and reads every piece, with no primer aimed at one gene. In their milk, the most common bacterium was Bifidobacterium longum, a gut bacterium of breastfed babies. It turned up in 55 percent of the milk samples and 98 percent of the babies’ stool.

For the gap between the two methods, the team points first to the primer. The common primers were not built to fit Bifidobacterium, so the older method may have missed much of it.

A parent who reads that milk is mostly Staphylococcus may be reading the older method. In the next article about milk, check whether the team read one gene (“16S”) or all the DNA (“shotgun”).

One kind of B. longum is B. infantis, a bacterium that can live on the milk sugars a baby cannot digest. Those sugars are food sent ahead for bacteria. In this study, the milk carried the bacteria too. Food and seed arrived together. Whether the seed takes is a question for the gut.

Who Stays

A gardener tips a rattling packet of mixed seed into one bed. In the packet, a dozen kinds fit side by side. In the soil, they compete for light and water, and one kind can take over.

A baby’s gut works like that bed. In the milk, three kinds of Bifidobacterium often lived side by side, in similar amounts: B. longum, B. breve and B. bifidum. In the babies’ guts, they mostly did not. One of them, or something else entirely, usually took over. The team reads this as “a higher level of competition” in the gut than in the milk. Unlike a garden bed, a baby’s gut is planted by whatever arrives.

The team sorted each stool sample by its most common bacterium. At one month, 68.5 percent were led by bacteria outside Bifidobacterium, mostly two common gut groups, Escherichia coli and Bacteroides. By six months, that share had fallen to 28.1 percent. The share led by B. longum rose from 15.7 to 46.6 percent. In the stool samples that had B. infantis, its average share rose from about 3 percent of the gut bacteria to about 24 percent. Babies whose gut was led by B. longum at both visits had the steadiest gut of all.

Between one and six months, B. longum and B. breve grew in babies fed breast milk alone, and Clostridium perfringens, a cause of food poisoning, shrank. In babies who also had formula, B. longum grew too. That line is for the parent who gives a bottle of formula at night and wonders what it costs the gut.

Across all 195 pairs, the amount of Bifidobacterium in a mother’s milk did not predict the amount in her baby’s gut, though in some pairs it did. Henri Tissier, in 1899, gave the milk the credit for what grew in breastfed babies. Here, how much seed the milk carried did not settle it.

The team names what else might decide: the crowd already in the gut, the baby’s own genes, and what there is to eat. Food is one of the limits a body sets on its microbes, the checks part two described. The study tested none of the three, and which matters most is still unknown.

That is the systems thinker Russell Ackoff’s test of a system: a part’s effect depends on the other parts. One seed lands differently in a different bed.

And the same species name in milk and in stool does not mean the same bacterium.

Which Way the Strains Went

A family walks into a shelter and calls the name of the beagle they lost last week. A dog barks from every pen. The family walks past the shepherds and the terriers to the one beagle, then checks for the torn left ear.

Telling bacteria apart works like that. The species is the dog, and a strain is the beagle with the torn ear. Finding B. longum in a mother’s milk and in her baby’s stool is finding a dog in every pen: almost every baby had it. Finding the same strain in both, down to its torn ear, says much more. One limit: a strain is millions of nearly identical cells, where a dog is one animal.

The team rebuilt the DNA of 77 strains. Sixty-five came from the babies’ stool. Twelve came from milk at one month, since the milk held too little bacterial DNA to rebuild more. The team found twelve cases where one strain turned up in a mother’s milk and in her own baby’s stool. The matches came from six mother-baby pairs and covered ten kinds of bacteria. Every strain they could rebuild from milk turned up in that mother’s baby. So twelve is likely too low: more milk DNA could find more matches.

Figure 3. Six of the twelve matches, in four species. In each tree, an orange dot (a mother’s milk) lands on the same branch as purple dots (her own baby’s stool). Gray boxes mark strains that stayed in one baby from one month to six. From Ferretti et al. (2025), Fig. 3D, CC BY 4.0; cropped, nearby panels removed.

One match was Klebsiella pneumoniae, a gut bacterium that is often harmless. In newborns, it has been linked to sepsis, a dangerous infection of the blood. Klebsiella is the kind of microbe part three called harmful only under the right conditions. None of the babies in the study showed signs of illness, and no mother reported a breast infection.

Two other matches were Streptococcus salivarius and Rothia mucilaginosa. Both usually live in the mouth. They are what a baby’s spit would leave in the milk if Hassiotou’s backflow is real. So the arrow may run both ways. Milk may seed the baby’s gut, and the baby’s mouth may seed the milk. If so, milk is half of a loop.

Which way came first is still unknown. The first milk samples came at one month, too late to see. A mother and a baby also share a home and the people in it, and housemates share strains too. Mother and baby could each have picked up the strain somewhere else.

Strains also come and go between the one-month and six-month visits. Of the strains in a baby’s stool at the first visit, 19 percent were still there at the second. Of the strains shared with the milk, 25 percent were. Babies born vaginally kept more of their strains than babies born by C-section. Antibiotics, and whether the baby still had breast milk alone at six months, made no clear difference.

For the mother who forwarded the reel, the study checks part of the guess: bacteria from a baby’s mouth may reach the milk. Ask the reel what would carry a message about the cold, and who has watched that message travel.

A strain that travels can also carry more than itself.

Who Shares More

At one month, the babies’ stool carried more genes for resisting tetracycline than for any other antibiotic. So did the milk. Doctors avoid tetracycline in pregnancy and in children under eight, because it can stain growing teeth permanently.

These resistance genes let a bacterium survive an antibiotic, and they can pass from one bacterium to another. Two thirds of the babies had taken no antibiotics by six months. Many babies with no antibiotics on record, before, during or after birth, still carried the genes. Babies whose gut was led by Bifidobacterium carried fewer.

Across all the pairs, a mother’s milk and her baby’s stool showed no link in resistance genes. But a pattern across a whole group can hide what happens inside each pair. So the team asked a narrower question: does a baby share more resistance genes with its own mother than with a stranger?

Their test works like a daycare at pickup time with every baby handed to a random mother. Count the genes each baby shares with the mother holding it. Shuffle again, and count again, 1,000 times. That gives the amount of sharing that chance alone produces. Then compare the real pairs. Statisticians call this a permutation test. Unlike a real daycare, the team shuffled the milk samples’ labels on a computer, and no baby left its mother.

The real pairs shared more than the shuffled ones. The shuffle runs on an old logic: write down everything chance could produce, then see how rare the real result is. Here, a result as large as the real one turned up in fewer than 16 of the 1,000 shuffles.

Figure 4. The shuffle, done by hand. The statistician John Rauser asks whether mosquitoes prefer beer drinkers, shuffles the beer and water labels again and again, and finds the real difference out past almost every shuffle. Video: O’Reilly, Strata + Hadoop World 2014, Standard YouTube License.

Two pairs stood out. They shared the most resistance genes, and both were among the six pairs with matching strains. Their samples also gave the most bacterial DNA to read, first and third in the study, and more DNA means more chances to find a match.

The shuffle question works on more than genes. When spit and milk share a strain, or two people in one home share a cough or a claim, the question is whether a stranger would share it too. The mother in the group chat who forwarded the reel is the one to send this to, with that question attached. She can ask it before her next forward, or at the two-month checkup. If no one asks, the reel’s guess travels on beside its measured half.

Spit may reach the milk, then, but none of the studies here watched the spit tell the milk about a cold. At six o’clock the shuffle ends, and each baby goes home in the arms that fed it.

A Closing Invitation. The reel stood for a message from baby back to mother: a guess. The bacteria were real. Milk carries bacteria to a baby, a baby’s mouth may carry them back, and the crowd in the gut decides who stays.

1. Find the second path. This week, when a baby feeds near you, or a toddler hands you a wet, half-eaten cracker, watch the trade both ways. Milk goes in and spit comes back; a spoon goes from one mouth to the other. What just moved, and which way? Which cold last went around your house that way?
2. Split the reel. Before your next forward, or with the last one you sent, read the post aloud and say which half was measured and which a guess. The milk reel: white cells measured, the route guessed. A teething remedy or a sleep tip splits the same way. Which half would you still send?
3. Bring one claim to the exam room. Any visit this month counts, the baby’s or your own. With the paper on the exam table crinkling, ask the doctor about one claim from the group chat: was it measured, and in whom? Would a stranger show it too? One claim checked now is one less guess at the next fever.

At the next 2 a.m. feed, a baby lets go of the breast to breathe, and a little of her spit may slip back with the milk. The milk does not read it. It carries it home.

Worth remembering Save as image

Half a fact can carry a whole guess. Milk can change when a baby is sick, so a post that adds how the breast finds out sounds checked. Before your next forward, ask which half anyone saw happen.

Where This Came From

Ferretti’s study is one of the first to match strains between milk and a baby’s gut. The team found only one earlier metagenomic study that did. Matching strains between a mother’s gut and her baby’s gut is older and better studied, and it finds far more sharing than milk does.

Intellectual Honesty Note. The births, the night feeds and the fever night, with its 39.1 °C reading, are my own, and the reading of the Madonna Litta is this piece’s. The mother at 2 a.m., the reel, its group chat and the twelve mothers are a composite; the reel paraphrases a common claim, not one post. Riskin’s abstract does not report the mothers’ own health. The mother at the pump is drawn from the study’s methods. The key and lock, the seed bed, the beagle and the daycare are illustrations. The formula line reports the study’s comparison, not advice on feeding. The study is observational: it cannot show that milk caused any gut change. Only 25 milk samples were sequenced at three months. The primer explanation is the team’s proposal, not a test. The 16 in 1,000 reads the paper’s bound (p < 0.016, from 1,000 shuffles) as a count.

References

Centers for Disease Control and Prevention. (2025). Influenza (flu) and breastfeeding. https://www.cdc.gov/breastfeeding-special-circumstances/hcp/illnesses-conditions/flu.html

Ferretti, P., Allert, M., Johnson, K. E., Rossi, M., Heisel, T., Gonia, S., Knights, D., Fields, D. A., Albert, F. W., Demerath, E. W., Gale, C. A., & Blekhman, R. (2025). Assembly of the infant gut microbiome and resistome are linked to bacterial strains in mother’s milk. Nature Communications, 16, 11536. https://doi.org/10.1038/s41467-025-66497-y

Harper, D. (n.d.). Antibody. In Online etymology dictionary. Retrieved October 6, 2026, from https://www.etymonline.com/word/antibody

Hassiotou, F., Hepworth, A. R., Metzger, P., Tat Lai, C., Trengove, N., Hartmann, P. E., & Filgueira, L. (2013). Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. Clinical & Translational Immunology, 2(4), e3. https://doi.org/10.1038/cti.2013.1

Hinde, K. (2017, March 28). What we don’t know about mother’s milk [Video]. TED. YouTube. https://www.youtube.com/watch?v=Bo8YN3oB0Cw

Leonardo da Vinci (attributed). (ca. 1490). Madonna Litta [Painting]. State Hermitage Museum, Saint Petersburg. Public domain image via Wikimedia Commons.

National Cancer Institute. (n.d.). Organism strain. In NCI dictionary of cancer terms. Retrieved October 6, 2026, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/organism-strain

National Human Genome Research Institute. (n.d.). Antibody. In Talking glossary of genomic and genetic terms. Retrieved October 6, 2026, from https://www.genome.gov/genetics-glossary/Antibody

National Human Genome Research Institute. (n.d.). Primer. In Talking glossary of genomic and genetic terms. Retrieved October 6, 2026, from https://www.genome.gov/genetics-glossary/Primer

Rauser, J. (2014, October 17). Statistics without the agonizing pain [Video]. O’Reilly. YouTube. https://www.youtube.com/watch?v=5Dnw46eC-0o

Riskin, A., Almog, M., Peri, R., Halasz, K., Srugo, I., & Kessel, A. (2012). Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant. Pediatric Research, 71(2), 220–225. https://doi.org/10.1038/pr.2011.34

Bohnhoff’s team had fed the mice Salmonella, the germ behind food poisoning, to find out. For healthy mice, it took about 100,000 germs to give 5 out of every 10 a gut infection. The mice that took fewer than three had been given one dose of an antibiotic, a drug that kills bacteria, the day before. The drug had killed many of the bacteria living in the mice’s guts. Those bacteria had been keeping the newcomers out, like guards at a door. So the ten-year-old, who asked for one number, gets two. Which one counts depends on who already lives there. That answer leaves open what else the gut’s bacteria were doing.

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Figure 1. The gut’s trillions of microbes and what they do for health, from BBC Global’s Health Decoded (2024), with science journalist Melissa Hogenboom. Video and thumbnail: BBC, Standard YouTube License.

The skin has guards of its own. In 2010, Tadayuki Iwase and colleagues at Jikei University in Tokyo studied Staphylococcus aureus, a bacterium that causes skin and blood infections. They found that some strains of a common skin bacterium make a protein that breaks up the sticky layer S. aureus builds to cling on. Of 88 volunteers, those who carried those strains in their noses rarely carried S. aureus. When the team put such a strain into the noses of volunteers who did, the S. aureus was gone. Bohnhoff took the guards away, and the door opened. Iwase added one, and it shut.

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Figure 2. How the bacteria on skin make it a poor home for invaders, help hold the skin together and train the immune system, from Nature Video (2020). Video and thumbnail: Springer Nature, Standard YouTube License.

Say you stand at the pharmacy counter this month with a prescription for your child’s earache: an antibiotic, twice a day for ten days. The paper bag crinkles as the pharmacist folds it shut. Some ear infections get better without antibiotics. Is this one? The drug cannot tell the germ it was sent for from the crowd in your child’s gut. One dose thinned the gut crowd of Bohnhoff’s mice enough to let three germs in. Ten days leave your child’s gut with fewer guards at its door until the crowd grows back.

Bohnhoff’s mice and Iwase’s volunteers show one idea from a 2024 review by Ziqi Ma and colleagues. The microbes defend the body, and they teach the immune system what to fight. The series’ first two parts followed five of the review’s ideas.

The review names two more. When the body and its microbes stop holding each other in check, the body tips toward illness. And the microbes may help set the targets a body holds steady. Both are loops, the kind systems thinking follows: each side acts on the other, and the other acts back.

A body holds some numbers steady, its temperature among them, the way an oven holds the heat it is set to. In a fever, the brain turns its own dial up by one or two degrees Celsius. The target moves first, and the body shivers until its temperature catches up.

Ma’s team argues that the microbes keep a second hand on the same dial. If ten days of pills can thin the guards in a child’s gut, how much of the turning were those guards doing?

What Keeps the Door Shut

In 1958, surgeons in Denver treated a severe gut infection with a healthy donor’s stool. Four years after Bohnhoff’s mice lost many of their gut bacteria, Ben Eiseman’s team ran the experiment in reverse and gave four patients new ones by enema. The response, they wrote, was “immediate and dramatic.” The idea waited half a century for a proper test.

The infection is now usually traced to Clostridioides difficile, which thrives once antibiotics have thinned its competition. It often comes back after each new course of the drug. In 2013, Els van Nood, Josbert Keller and colleagues in Amsterdam tested a donor’s stool against the standard antibiotic, vancomycin, in 42 patients whose infection kept returning. The stool was passed through a thin tube from the nose into the small intestine. Thirteen of the sixteen patients in the donor group were cured by the first infusion. On vancomycin alone, four of thirteen were. The gap was so wide that the trial was stopped early. It was a small trial, but a stranger’s microbes had taken the space back.

Resident microbes keep newcomers out in several ways. They eat the food a newcomer needs. Some make proteins aimed at rivals, like the one Iwase’s nose strains made against S. aureus. Some change the place itself. In the vagina, Lactobacillus bacteria make lactic acid, which keeps the vagina too acidic for many germs that cause infections.

The microbes also teach. The Amish of Indiana and the Hutterites of South Dakota both came to America from Europe as German-speaking farmers, and their genes are close. They farm differently. Amish families keep dairy cows and work fields with horses, and the barns stand a few steps from the house. Hutterites live on large communal farms run with modern machines. In 2016, Michelle Stein, Carole Ober and colleagues compared the two. About 5 percent of Amish children had asthma, against 21 percent of Hutterite children. The dust in Amish homes held almost seven times as much endotoxin, a molecule from the outer coat of many bacteria.

The team then tested the dust. When they put Amish house dust into the airways of mice, it protected the mice from asthma attacks. Hutterite dust did not. In 60 children, 30 from each group, the Amish children’s immune cells were tuned differently, more toward fighting germs and less toward allergy. Two communities are not a trial. The mouse experiments are what point to the microbes in the dust.

By that definition, the immune system is a system. The three things the systems scientist Donella Meadows said to look for are all there. The cells, tissues and organs are the elements. The substances they make are the interconnections. Fighting infection is the purpose. The Amish dust suggests the microbes belong in the system too, as a part that tunes the immune cells.

Medicine already counts several ways to gain protection after birth. A body can fight off an infection and remember it. A vaccine can teach it. A baby can take antibodies from milk, and whether anything travels back the other way is the last part of this series.

Ma’s team adds the microbes to that list and calls it acquired microbial immunity (Figure 3). It is gained by living among the right microbes, as the Amish children did, or by medicine, as the Amsterdam patients did. Ma’s review counts milk sugars among the ways it is gained, since they feed a baby’s gut bacteria at every meal. It can be lost to one dose of the wrong drug.

Figure 3. Ways to gain protection after birth, with Ma’s addition in the bottom row. Adapted from Ma et al. (2024), Fig. 2, CC BY 4.0; simplified and redrawn, leaving out milk sugars and probiotic products.

That dose often comes home in a paper bag from the pharmacy counter. Anyone handed an antibiotic for a cough, an earache or a sore throat can ask two questions before the first pill. Is this infection caused by bacteria? Antibiotics do nothing against a virus, and most colds are viral. Is there a narrower drug that leaves more of the gut alone? A friend with a toddler and a winter of earaches ahead may want the two questions too. When the first answer is yes, the drug is doing its job. Skipping the questions costs nothing that day. Any cost comes later, in a gut with fewer defenders, like the mice that three germs could infect. Ma’s team claims those microbes also help set the body’s targets, starting with its temperature.

Who Set Normal

In 1868, the German physician Carl Wunderlich published the temperatures of about 25,000 patients. He took them under the arm with a thermometer about a foot long, which needed more than fifteen minutes for each reading. He put normal at 37 °C.

In 2020, Myroslava Protsiv, Julie Parsonnet and colleagues at Stanford checked Wunderlich’s number against the records of about 189,000 people. The records ran from Civil War veterans, through a national health survey in the 1970s, to Stanford patients seen in 2017. Body temperature had fallen about 0.03 °C for every decade of birth. Men born in the early 1800s ran 0.59 °C warmer than men today. Like the fever, the target had moved. This move took two centuries, and the textbooks kept saying 37.

Mice raised without microbes run colder than mice with them. In 2023, Kale Bongers, Robert Dickson and colleagues at the University of Michigan compared about 30 of each. The germ-free mice ran about 0.3 °C colder, and mice whose gut bacteria were wiped out with antibiotics ran colder too. In 116 patients in hospital, the mix of gut bacteria on arrival, read from a rectal swab, predicted how each patient’s temperature would change. A link like that does not prove a cause.

A body holds its temperature with a balancing loop, a loop that pushes back whenever a reading drifts from its target. The fever’s shivering is that loop at work. Once the brain raises its set point, the temperature the body aims for, the body is for a while colder than its own new target. As on a cold night, it pulls blood away from the skin, and the hands go cold. The thermometer climbs while the person under the blanket feels freezing.

The physiologist Walter Cannon gave this steadiness its name, homeostasis. The loop does the holding. An oven answers to one hand. A body holds many targets at once. In Ma’s view, the microbes are a second hand choosing where the loop holds, a role the team calls homeostatic reprogramming.

Every range printed on a lab report assumes a target the loop is steering toward. The range beside each number comes from many other people. At the next checkup, a useful question is not only “Is this in range?” but “Is this where I usually am?” Last year’s report, held next to this year’s, answers it in a minute. A partner’s reports work the same way. Skip the comparison, and a number can drift for years inside the printed range before anyone looks.

My daughters have had no antibiotics so far. When my first daughter ran a fever at about 18 months, she would not touch her solid food and nursed mostly for comfort. The only medicine she got was acetaminophen. I took her temperature. It moved from 39.4 °C to 37.8 °C. The line the pediatrician’s office gave me was 38 °C, 100.4 °F: no higher. That line is the same for every child. It says nothing about where one child’s own normal sits.

If the microbes help choose where the loop holds, could thinner gut communities explain part of the drop since Wunderlich?

Ma’s team offers the idea as a hypothesis. Protsiv’s team pointed to fewer chronic infections. Both explanations run through microbes, and neither team tested the other’s.

Allan Konopka, who studies microbial communities, warns that biologists tend to expect a “balance of nature,” a steady state every system returns to. A normal that drifts over two centuries is easy to miss. So is a normal that two sides hold at once, like the low-oxygen layer by the gut wall in part two. That layer shifts with every meal.

How Health Tips

Some gut bacteria turn part of a meal of eggs into a gas that smells like fish. The smell is the mild part. The part those bacteria use is choline, a nutrient in the yolk. The liver turns that gas into TMAO, a molecule the blood then carries. In 2016, Weifei Zhu, Stanley Hazen and colleagues at the Cleveland Clinic followed more than 4,000 heart patients. Patients in the top quarter for TMAO had 1.64 times the risk of a heart attack or stroke.

The comparison is with the bottom quarter over three years, after allowing for other risk factors. In the lab, TMAO made platelets, the blood cells that start a clot, quicker to react. The study measured TMAO in the blood and did not track diet, so it does not by itself make a case against eggs.

A bowl of oats or beans carries fiber for the gut’s bacteria. Some of that fiber ends as butyrate, the fatty acid the cells of the colon wall run on. One gut can run both routes at once. Which one wins depends on the meal and on which bacteria are there to meet it.

Ma’s team puts the last idea of the framework into one model of health and illness. The body needs four things from its microbes, and each can fail (Figure 4). First, the body needs enough contact with microbes, kept in check. Too little, at the extreme, is what Ma’s team calls germ-free syndrome: the faults of animals raised with no microbes at all. Too much is overgrowth, such as bacteria spreading up into the small intestine, where they cause bloating and pain. Second, a gut wall that holds, so that bacteria and their parts stay out of the blood. Third, more helpful products than harmful ones, butyrate on one side and TMAO on the other. And fourth, steady control as the microbes change, because bacteria mutate.

Figure 4. Four things the body needs from its microbes, and how each one fails. Adapted from Ma et al. (2024), Fig. 7, CC BY 4.0; simplified and redrawn.

In 2022, Yi Yang, Noah Palm and colleagues at Yale put one strain of Enterococcus gallinarum, a gut bacterium, into eight germ-free mice. Three months later, it had picked up 159 new mutations. It had also split into two lines. One kept to the open gut. The other adapted to the gut lining, slipped past the immune system, and spread to the lymph nodes and the liver. There it caused more inflammation. A person’s gut is crowded with rivals; these mice had none. Ma’s team rules out any simple list of good and bad bacteria. “In a rigorous sense, all human microbes exhibit conditional pathogenicity,” they write. Any of them can cause harm under the right conditions. What a microbe does depends on what it is connected to.

When all four needs hold, the body stays in charge, and the microbes’ hand on the dial helps it. When they fail, the microbes take over, and the body drifts toward illness. The model leaves open which side pushed first.

In an ordinary week, an antibiotic course thins the contact. A week of white bread and no beans leaves the butyrate makers hungry, and the wall’s cells with them. The question at the next grocery run is which meals feed the bacteria that feed the wall. The snack within reach right now has a fiber line on its label. A pot of lentils simmering on a weeknight stove feeds everyone at the table, and the bacteria that feed the wall.

A Closing Invitation. Three germs could infect Bohnhoff’s mice because the door their microbes held had been opened. Their hand is on the body’s dial too: helping set a temperature, and deciding which way a meal runs.

1. Find your own normal. Tomorrow morning, before coffee, start a sticky note inside the medicine cabinet door with your temperature and a partner’s or child’s. The cool tip goes under the tongue, then the beep. Is it 37, or lower, like most people’s now? Was the last fever in your house read against 37?
2. Check the cart. At the next grocery run, before the checkout belt starts to move, look over what you picked: beans, oats, lentils, a whole-grain loaf? Which dinner this week has no fiber in it at all? Which can or bag could you add for that night?
3. Ask what number means call. Send the doctor’s office a short message from your phone now, or ask at the next checkup: which temperature means call? If your normal runs below 37, does the line move with it? Then the next shivering night can be what it is: a body chasing a target it moved.

At the counter, ask the ten-year-old’s question the other way round: how many guards will ten days of pills leave? The label on the bag names one germ, not the crowd that helps hold the door and the dial.

Worth remembering Save as image

Your next antibiotic cannot tell the burglar from the guards. It also kills gut bacteria that keep germs out. In mice, one dose cut the germs needed to infect half from about 100,000 to fewer than three.

Where This Came From

Ma’s homeostatic reprogramming builds on Claude Bernard, who wrote in the 1800s of the milieu intérieur, the inner fluid a body keeps steady around its cells. Ma’s team adds the microbes as a fourth force beside the nervous, immune and metabolic systems, and asks whether “steady” was ever the right word.

Intellectual Honesty Note. The ten-year-old in the opening and the pharmacy counter scene are hypotheticals. My first daughter’s fever and the 38 °C line are my own. The fall in average body temperature is read here as a lower target; Protsiv’s team measured temperatures, not set points. Acquired microbial immunity, homeostatic reprogramming and the four needs are proposals in Ma’s review; the team calls the second a hypothesis. The hand on the dial and the oven are devices: a body’s set points are held by loops of nerves, hormones and cells, not turned by a hand. Bohnhoff’s team used a Salmonella strain resistant to streptomycin; Ma dates the study 1967, and the 1954 paper is the original.

References

Bohnhoff, M., Drake, B. L., & Miller, C. P. (1954). Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proceedings of the Society for Experimental Biology and Medicine, 86(1), 132–137.

Bongers, K. S., Chanderraj, R., Woods, R. J., McDonald, R. A., Adame, M. D., Falkowski, N. R., Brown, C. A., Baker, J. M., Winner, K. M., Fergle, D. J., Hinkle, K. J., Standke, A. K., Vendrov, K. C., Young, V. B., Stringer, K. A., Sjoding, M. W., & Dickson, R. P. (2023). The gut microbiome modulates body temperature both in sepsis and health. American Journal of Respiratory and Critical Care Medicine, 207(8), 1030–1041.

Bryce, E. (2018, January 8). How does your immune system work? [Video]. TED-Ed. YouTube. https://www.youtube.com/watch?v=PSRJfaAYkW4

Cannon, W. B. (1929). Organization for physiological homeostasis. Physiological Reviews, 9(3), 399–431.

Centers for Disease Control and Prevention. (2025). Healthy habits: Antibiotic do’s and don’ts. https://www.cdc.gov/antibiotic-use/about/index.html

Eiseman, B., Silen, W., Bascom, G. S., & Kauvar, A. J. (1958). Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery, 44(5), 854–859.

Hogenboom, M. (2024, October 8). How your gut microbes shape your health [Video]. BBC Global. YouTube. https://www.youtube.com/watch?v=aEhrcIZE1ZM

Iwase, T., Uehara, Y., Shinji, H., Tajima, A., Seo, H., Takada, K., Agata, T., & Mizunoe, Y. (2010). Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature, 465(7296), 346–349. https://doi.org/10.1038/nature09074

Konopka, A. (2026, May 6). Systems thinking [Substack post]. https://thinkmicrobe.substack.com/p/systems-thinking

Ma, Z., Zuo, T., Frey, N., & Rangrez, A. Y. (2024). A systematic framework for understanding the microbiome in human health and disease: From basic principles to clinical translation. Signal Transduction and Targeted Therapy, 9, 237. https://doi.org/10.1038/s41392-024-01946-6

Meadows, D. H. (2008). Thinking in systems: A primer (D. Wright, Ed.). Chelsea Green.

National Cancer Institute. (n.d.-a). Homeostasis. In NCI dictionary of cancer terms. Retrieved October 6, 2026, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/homeostasis

National Cancer Institute. (n.d.-b). Immune system. In NCI dictionary of cancer terms. Retrieved October 6, 2026, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-system

Nature Video. (2020, December 16). The skin microbiome: A healthy bacterial balance [Video]. YouTube. https://www.youtube.com/watch?v=MWE3U3FItlc

Protsiv, M., Ley, C., Lankester, J., Hastie, T., & Parsonnet, J. (2020). Decreasing human body temperature in the United States since the Industrial Revolution. eLife, 9, e49555.

Stein, M. M., Hrusch, C. L., Gozdz, J., Igartua, C., Pivniouk, V., Murray, S. E., Ledford, J. G., Marques dos Santos, M., Anderson, R. L., Metwali, N., Neilson, J. W., Maier, R. M., Gilbert, J. A., Holbreich, M., Thorne, P. S., Martinez, F. D., von Mutius, E., Vercelli, D., Ober, C., & Sperling, A. I. (2016). Innate immunity and asthma risk in Amish and Hutterite farm children. New England Journal of Medicine, 375(5), 411–421.

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He meant to be the one who stayed well. In Berlin, Robert Koch had found the comma bacillus in cholera patients and said the germ was the cause. Pettenkofer thought a germ needed help: from the soil, the season and the person it entered. Within days he had colic and loose stools, and they lasted until 15 October. His stool was “swarming with comma bacilli.” Cholera itself never came, and he took that as proof.

He was wrong about the germ. Vibrio cholerae does cause cholera. His question was better than his answer: why does one person swallow a germ and stay well?

In 2018, Firas Midani, Regina LaRocque and colleagues asked it again in Dhaka, Bangladesh. They followed 76 people who lived under one roof with a cholera patient, for 30 days. Twenty-two caught the germ, and 54 did not. Swabs from each person’s gut, taken when they joined the study, told the two groups apart better than chance. The pattern lay in the crowd of gut bacteria, about 100 kinds. Those who got infected carried fewer of one large group, the Bacteroidetes. The swabs show who was more likely to catch the germ, not why.

In my house, no one is skipped. A cold comes home with my older daughter and goes through everyone, one at a time, until it has passed around the whole family. A cold is not cholera, and a house is not a study. Still, under my roof the germ wins every time, and in Dhaka most of the household never caught it.

Say an email goes round the office on a Monday: a stomach bug has hit the third floor. By Wednesday, half the desks on your row are empty. You ate the sandwiches at Monday’s meeting and filled your cup beside the people now home sick, and you stay well. You still cancel Saturday’s drive to your parents’, two hours each way, because you cannot tell why the bug passed you, or whether it will come back.

If the same germ reaches everyone under one roof and fewer than one in three catch it, what does the one who stays well carry that the others do not? The next cold that comes home is a chance to ask who it skips, and why.

Ziqi Ma and three colleagues gave one answer in 2024, in a review of the body’s microbes and human health. The first part of this series took two of their ideas: a person carries a second set of genes in their microbes, and a body without them has missing parts. Their next idea is about the host a germ meets, and that host is more than the person alone.

Who the Host Is

People who share a home also share some of their gut bacteria. With the bacteria comes part of the second set of genes, the adaptive genome. In 2023, Mireia Valles-Colomer and colleagues traced bacterial strains, the kinds within one species, across more than 9,700 samples from around the world. People in one home shared about 12 percent of their gut strains and 32 percent of their mouth strains. The longer they had lived together, the more mouth strains they shared.

That sharing begins on the day someone new moves under one roof: a new baby, a new partner, a new roommate. The question for a household is who brought what in, and the samples cannot answer it. They show who shares strains, not who passed them to whom.

In South Africa, Christina Gosmann and Douglas Kwon’s team tracked one germ, HIV, in 236 young women. They tested the women again and again. None had it at the start, and all were 18 to 23. Thirty-one became infected during the study.

The team had also sampled the bacteria in each woman’s vagina. Some women had a mixed community, with many kinds of bacteria and few Lactobacillus. Others had a community dominated by one species, Lactobacillus crispatus. The mixed group was more than four times as likely to become infected. Not one of the women dominated by L. crispatus became infected. The mixed communities came with more of the activated immune cells that HIV infects. A study that follows people cannot settle what caused what, though. The women with mixed communities may have differed in other ways too, and the bacteria could be a marker as much as a cause.

Animals can be tested more directly. In 1955, Bruce Phillips of the US Public Health Service and colleagues placed Entamoeba histolytica, an amoeba that causes dysentery, into the guts of germ-free guinea pigs. The amoeba did no harm. When the guinea pigs got one kind of common gut bacterium first, the amoeba damaged the gut wall.

Scott O’Neill’s team at Monash University ran a cleaner test, on a mosquito. Aedes aegypti carries dengue, a virus that brings fever, crushing joint pain and, in the worst cases, bleeding. Many insects carry a bacterium called Wolbachia inside their cells, but this mosquito normally does not. The team moved a strain of Wolbachia from fruit flies into Aedes aegypti. Inside the mosquitoes that carried it, the virus grew poorly. Like the aphid’s bacteria in part one, Wolbachia passes from mother to eggs, so it can spread through a wild population on its own.

From 2017 to 2020, Adi Utarini and colleagues at Gadjah Mada University tested those mosquitoes in Yogyakarta, Indonesia. They split a part of the city, home to about 313,000 people, into 24 areas and released Wolbachia mosquitoes in half of them, chosen at random. Volunteers left buckets of water and mosquito eggs around the neighborhoods, and the eggs hatched into mosquitoes carrying the bacterium. In the areas that got them, dengue fell by 77 percent, and hospital stays for dengue by 86 percent. It was one trial, in one city. With the same mosquito and the same virus, the bacteria living inside the mosquito changed how often it passed the virus on.

Whether a germ makes someone sick depends on the germ, on the person’s own genes and on the microbes already there. Ma calls the person and their microbes together a meta-host. Doctors have long asked why one germ makes one patient very sick and leaves another well, and why one transplant takes while another fails. Ma’s team points to the meta-host as part of the answer. Pettenkofer’s cup asked the same thing in 1892, and the Dhaka swabs asked it again in 2018. The germ was Koch’s. The host was Pettenkofer and everything living in his gut.

When a stomach bug goes through a home of four and skips one person, that person is a different meta-host from the other three. The crowd that person carries is one of three places to look for why. The host had always been a crowd, and part of that crowd lives in every human mouth.

What the Body Keeps in Check

On 17 September 1683, Antonie van Leeuwenhoek wrote to the Royal Society about the white paste on his teeth. He was a cloth merchant in Delft who ground his own lenses. He scraped some of the paste from between his teeth, thick as wet flour, and looked at it through one of his lenses. It was alive.

Some of the tiny animals darted through it “as a Jack or Pike does thro the water.” Others “spun about like a Top.” He kept his teeth “usually very clean,” he wrote, and still the animals were there. He looked at the teeth of two old men, one who lived soberly and one who drank brandy and wine every day, and found animals there too.

Three centuries later, scientists still argue about what to call them. In 1992, the immunologist Velio Bocci, at the University of Siena in Italy, called the gut’s bacteria “the neglected organ,” and the label spread. In 2022, Alessandro Fucarino, Francesco Cappello and colleagues at the University of Palermo answered that the label does not fit. An organ is built from tissues that grow from the embryo, and microbes arrive from outside. In a 2026 essay, the microbial ecologist Allan Konopka points out that the right picture depends on the level someone looks from.

In their 2024 review, Ma’s team looks from the level of tissues. Next to the four kinds in biology textbooks, epithelial (the body’s linings), connective, muscle and nervous, they propose a fifth. They call it a “slave tissue,” a term borrowed from sociology, to say the body is in charge. This piece calls it a managed tissue.

The managing never stops, because bacteria left alone keep multiplying. More cells make more cells, a reinforcing loop that slows only when the food runs out. So the body sets limits of its own, and one of them can be seen under a microscope.

In 2008, Malin Johansson, Gunnar Hansson and colleagues at the University of Gothenburg, in Sweden, looked at the lining of the colon in five mice. It wore two coats of mucus, together about as thick as two human hairs. The outer coat was loose and full of bacteria. The inner coat, packed tight and stuck to the wall, held none. In mice bred without the main mucus protein, bacteria lay against the cells of the wall, and the colon became inflamed.

Mucus is one limit among several. Antibodies released into the gut keep microbes in their places. Proteins in the gut and in milk lock away iron and zinc that bacteria need to grow. Stomach acid kills many germs before they reach the gut, which is why Pettenkofer drank his baking soda first. Leeuwenhoek’s tooth cleaning in Delft belongs on that list. So do the milk sugars that opened this series. Only some bacteria can eat them, so a mother’s milk helps choose which ones grow in her baby’s gut. What the one who stays well carries is a crowd, and the crowd helps only while the body keeps it in check.

The same managing reaches the dinner plate. Onions, apples and whole-grain bread carry fiber, food the body cannot digest and many gut bacteria can. When fiber runs short, some of those bacteria turn to the mucus coat instead (Figure 1). What goes on the plate at this week’s seven dinners helps decide what the colon’s bacteria eat.

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Figure 1. Fiber as food for gut bacteria, and what hungry bacteria do to the mucus lining, from TED-Ed (2017): lesson by Shilpa Ravella, animation by Andrew Foerster. CC BY-NC-ND 4.0.

By the sink, a toothbrush with splayed bristles has been doing the managing twice a day. No brush reaches the gut wall.

Where the Oxygen Goes

Right next to the gut wall, there is almost no oxygen, and the body’s own cells keep it that way. The cells that line the colon run mostly on butyrate, made by gut bacteria from fiber like the onion’s and the apple’s. Butyrate is the molecule that sealed a leaky brain barrier in part one. Its name comes from butter, and its acid gives rancid butter its sour smell.

Burning butyrate takes oxygen, and the cells take that oxygen from the edge of the gut. That suits the bacteria that make butyrate, because most of them cannot live where there is oxygen. The layer by the wall works like a shared room. The bacteria feed the cells, and the cells keep the room low on oxygen. The room runs on a reinforcing loop: each side keeps the other going.

In 2017, Mariana Byndloss, Andreas Bäumler and colleagues at the University of California, Davis, broke the loop with antibiotics in mice. The drugs killed the butyrate makers. Without butyrate, the colon cells switched to burning sugar, which uses less oxygen, and more oxygen reached the gut. E. coli and Salmonella, a germ behind food poisoning, can breathe that oxygen, and they multiplied. In Ma’s review, the life that gut cells and microbes share has a name: cell-microbe co-ecology. In that co-ecology, when one side shifts, the room shifts, and the room decides who can live in it. A germ that the room kept out yesterday can move in today. The one who stayed well last month can fall sick this month, with nothing changed in the germ.

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Figure 2. Salmonella, one of the germs that move in when oxygen reaches the gut, from The Washington Post (2018). Video and thumbnail: The Washington Post, Standard YouTube License.

The Davis work was done in mice, but an antibiotic course in a person can thin the butyrate makers too. The risk outlasts the pills. In the month after an antibiotic, a person is up to 10 times more likely to catch Clostridioides difficile, a gut germ that multiplies when antibiotics clear out its rivals. Age over 65 and a stay in a hospital or nursing home raise the risk again, and in older patients, C. difficile can be life-threatening.

In the days after the pills, loose stools are one sign the room has shifted. The CDC’s rule is short: diarrhea during an antibiotic course, or after it, is a reason to contact a doctor. A grandparent in a nursing home, just through a course, is the person most worth reminding of that rule. The germ may be the same as last month’s. The room it reaches has changed.

A Closing Reflection. Pettenkofer’s cup stood for an old question: why one germ takes one person and passes another. Part of the answer is the crowd each person carries, and the body that keeps it in check. Three ways to see yours.

1. Map who shares. From where you sit, find one thing your home or office passes around: the mug by your hand, the toothbrush cup, the shared towel, the spoon at dinner. Who has lived or worked beside you longest, and what crowd do you two now carry in common?
2. Trace the last bug. When the next cold reaches your home, think back, alone or with a sister or housemate, to the last stomach bug that went round. Who caught it first, who caught it last, and who was skipped? The same germ had its chance at each of you. What might the one who stayed well have been carrying?
3. Feed the second crowd. At dinner tonight, slice an apple or an onion onto your plate and hear the knife crunch through. Which dish fed only you, and which fed your crowd too, so fewer of its bacteria turned to the mucus coat?

Tracing a bug through your house asks Pettenkofer’s question of everyone at once. When it has gone round, one bed still has its sheets on. The germ reached that bed too, and met a different crowd there.

Worth remembering Save as image

Every germ arrives late. Each body’s gut bacteria got there first, so one stomach bug can go through a whole house and leave one person well.

Where This Came From

Of Ma’s eight ideas, this part takes three; the one on how resident microbes keep germs out and teach the immune system opens part three. Ma’s review gives cell-microbe co-ecology no section of its own; it gets one here. Pettenkofer’s side of the 1892 argument held that a germ needs the right soil, in the ground and in the person. The ground half did not hold up. The person half is the one this piece follows.

Intellectual Honesty Note. Pettenkofer’s dose, the baking soda, his symptoms and the “swarming” line come from the 1892 English report of his experiment, as quoted by Cabinet; the German original was not opened. “Stayed well” means he never had cholera; he had colic and loose stools for about a week. The office in the stakes paragraph is hypothetical. The Dhaka swabs were rectal swabs. The meta-host, the managed tissue and cell-microbe co-ecology are Ma’s proposals, not tested models. The mucus result is from five mice, not people. “Two human hairs” is this piece’s gloss of the mucus coats’ 150 micrometers. The Entamoeba result is reported from summaries of the paper, which was not opened. Leeuwenhoek’s words are from the Royal Society’s English abstract of his letter, printed in 1684.

References

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Byndloss, M. X., Olsan, E. E., Rivera-Chávez, F., Tiffany, C. R., Cevallos, S. A., Lokken, K. L., Torres, T. P., Byndloss, A. J., Faber, F., Gao, Y., Litvak, Y., Lopez, C. A., Xu, G., Napoli, E., Giulivi, C., Tsolis, R. M., Revzin, A., Lebrilla, C. B., & Bäumler, A. J. (2017). Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science, 357(6351), 570–575.

Centers for Disease Control and Prevention. (2026). About C. diff. https://www.cdc.gov/c-diff/about/index.html

Fucarino, A., Burgio, S., Paladino, L., Caruso Bavisotto, C., Pitruzzella, A., Bucchieri, F., & Cappello, F. (2022). The microbiota is not an organ: Introducing the muco-microbiotic layer as a novel morphofunctional entity. Anatomia, 1, 186–203.

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Indriani, C., Tanamas, S. K., Khasanah, U., Ansari, M. R., Rubangi, Tantowijoyo, W., et al. (2023). Impact of randomised wMel Wolbachia deployments on notified dengue cases and insecticide fogging for dengue control in Yogyakarta City. Global Health Action, 16(1), 2166650. https://doi.org/10.1080/16549716.2023.2166650

Johansson, M. E. V., Phillipson, M., Petersson, J., Velcich, A., Holm, L., & Hansson, G. C. (2008). The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences, 105(39), 15064–15069. https://doi.org/10.1073/pnas.0803124105

Konopka, A. (2026, May 6). Systems thinking [Substack post]. https://thinkmicrobe.substack.com/p/systems-thinking

Leeuwenhoek, A. van. (1684). An abstract of a letter from Mr. Anthony Leevvenhoeck at Delft, dated Sep. 17. 1683, containing some microscopical observations, about animals in the scurf of the teeth. Philosophical Transactions of the Royal Society of London, 14(159), 568–574. https://doi.org/10.1098/rstl.1684.0030

Ma, Z., Zuo, T., Frey, N., & Rangrez, A. Y. (2024). A systematic framework for understanding the microbiome in human health and disease: From basic principles to clinical translation. Signal Transduction and Targeted Therapy, 9, 237. https://doi.org/10.1038/s41392-024-01946-6

Midani, F. S., Weil, A. A., Chowdhury, F., Begum, Y. A., Khan, A. I., Debela, M. D., et al. (2018). Human gut microbiota predicts susceptibility to Vibrio cholerae infection. Journal of Infectious Diseases, 218(4), 645–653. https://doi.org/10.1093/infdis/jiy192

Phillips, B. P., Wolfe, P. A., Rees, C. W., Gordon, H. A., Wright, W. H., & Reyniers, J. A. (1955). Studies on the ameba-bacteria relationship in amebiasis: Comparative results of the intracecal inoculation of germfree, monocontaminated, and conventional guinea pigs with Entamoeba histolytica. American Journal of Tropical Medicine and Hygiene, 4(4), 675–692.

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The count held as later milk came in. At about 800 milliliters a day, a little over three cups, a baby takes in ten million to a hundred million bacterial cells. Older counts, which grew the bacteria on lab dishes, found about a hundred times fewer. The cells in each feed are a baby’s first share of the microbes NPR called an invisible universe (Figure 1).

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Figure 1. A tour of the microbes on and in a body. Drawn by Ben Arthur for NPR (2013). The video repeats an old estimate of ten microbial cells for every human cell; a 2016 recount by Ron Sender, Shai Fuchs and Ron Milo put it closer to one to one. Video and thumbnail: NPR, Standard YouTube License.

Which bacteria end up in a gut is not random. In 1899, Henri Tissier, a children’s doctor at the Pasteur Institute in Paris, looked at babies’ stool under a microscope. In breastfed babies, one bacterium crowded out almost all the rest. Its rods often split at one end into a Y, so he named it bifidus, Latin for “split in two.” Today it is called Bifidobacterium. In bottle-fed babies, and in babies sick with diarrhea, it was far scarcer, and a mixed crowd took its place. The milk seemed to pick the winner.

Food is part of the answer. Human milk also carries a family of sugars the baby cannot digest. Most of them reach the colon, the last stretch of the gut, untouched. In 2006, Robert Ward, Bruce German and colleagues at the University of California, Davis, purified those sugars. They fed the sugars to bacteria as the only food. One common gut bacterium could not live on them. Bifidobacterium infantis, one of Tissier’s Y-shaped bacteria, could. A year later, the team tested five kinds of Bifidobacterium, and infantis grew three times as dense as the rest. Every feed has two eaters: the baby, and the baby’s bacteria.

I have fed babies both ways. My first daughter had only breast milk. My second weighed more than 10 pounds at birth and was hungry before my milk arrived, so I breastfed her and we topped her up with formula. Her sister’s diapers had been mustard yellow. Hers were light brown, and they differed in texture, smell and how often they came. Tissier would have put both diapers under his microscope and counted the Y-shaped rods.

From birth on, bacteria settle wherever a baby’s body meets the outside world: in the gut, on the skin, in the mouth and nose, in the vagina. Each place grows its own crowd. Count every crowd, with the fungi and viruses beside them, and the whole is called the human microbiome.

Say you stand in the dairy aisle this week with a probiotic yogurt in one hand and a plain tub in the other. The probiotic costs twice as much. Its label promises billions of live bacteria for your gut, and the foil lid is cold under your thumb. Into the cart it goes, with a second for your mother, this week and most weeks after: fifty-two tubs a year each. The label counts what goes in. How many of those bacteria stay, and what crowd already lives in each gut to meet them? The label does not say, so both of you pay double for a count of arrivals.

Milk feeds a baby’s bacteria at every meal, and a grocery aisle sells adults more. If bacteria keep arriving from the first swallow to the fifty-second tub, what are they to the body? Systems thinking answers a question like that by asking what else each part is connected to. Biology now counts microbes the way it counts genes, all at once from one sample. A list of their names, though, does not say who feeds whom. In a gut, each kind of bacterium is fed, held back or crowded out by the others and by the body it lives in.

In 2024, Ziqi Ma and three colleagues, at Heidelberg University Hospital and Sun Yat-sen University, drew on more than 700 papers to answer what microbes are to a body. Their review sets out eight ideas for how microbes and a body fit together. Two of them are here: whose genes make up a person, and what a body lacks without its microbes. The next three are in a second part, on why one person stays well when a germ goes around. The last three are in a third, on how the microbes work for health and why a body needs them.

Where the Crowds Live

In 2009, the Human Microbiome Project sorted the bacteria it studied by body part, in a pie chart. Ma’s review puts the pie’s shares on a drawing of a human body. The gut gets 29 percent and the mouth 26, close behind. The skin, the airways and the urogenital tract, the urinary and genital organs, share the rest. The review calls the gut the most densely populated of the five.

I traced Ma’s numbers back to that pie, then tried to replicate it. The project’s website listed every bacterium it had sequenced (its DNA read) or queued for sequencing, with the body site each came from. The Internet Archive saved two earlier copies of that list, from March and April 2009. I counted both by the pie’s own rule: one strain, one count, sorted by body site. A strain is one line within a species, the way a beagle is one breed of dog.

Neither copy matched the pie, and the two did not match each other. In March, the gut held 58 percent of the list. By April it held 42, and in the pie, 29 (Figure 2). The list grew, and the shares moved with it. The shares measure what the project chose to sequence. When a probiotic label or a headline next quotes a share of the microbiome, the question to ask is what was counted. Without that question, a list of what a project sequenced reads as a count of what lives in a gut.

Figure 2. The five percentages in Ma et al.’s 2024 review (squares), beside my recount of two earlier versions of the same list (circles and diamonds). Each marker is a share of the strains the Human Microbiome Project (HMP) had sequenced or queued for sequencing from that place, not a share of the bacteria living there. Squares from NIH HMP Working Group (2009), Fig. 3, as reprinted in Ma et al. (2024), Fig. 1; circles and diamonds counted for this piece from the project’s online strain lists, as saved by the Internet Archive. Chart drawn for this piece.

Where bacteria live takes a different count. Ma’s five shares look close to even. By cell count, they are far from it. Most of a body’s bacteria live in the colon. A single gram of stool, about the weight of a paper clip, holds some 90 billion bacteria. That is eleven times the number of people on Earth. Each of those cells carries genes of its own.

Whose Genes Count

On a rosebush, an aphid that lacks the genes to feed itself presses its mouthparts into a stem and drinks. Sap is mostly sugar water. It holds too few of the amino acids an animal needs to build proteins, and the aphid cannot make them.

Bacteria called Buchnera live inside special cells in the aphid’s body and make the missing amino acids for it. The bacteria have lost so many of their own genes that they cannot live anywhere else, and the aphid cannot live without them. A mother aphid passes them straight into her eggs. Almost every aphid starts life with its bacteria in place.

People start differently. By most evidence, a human baby grows in the womb without live microbes. The first ones arrive at birth, from the mother’s skin, gut and birth canal. More microbes come with every feed, as in the opening’s first drops, and from everyone who holds the baby, and they keep arriving for life. By about age three, a child’s gut community settles into something close to an adult’s.

The bet on how many genes a person carries ended near 20,000. The crowd in one gut carries far more. In 2010, the European MetaHIT team sequenced stool from 124 people. They counted 3.3 million distinct microbial genes, about 150 times the human count. Any two people differ in only about 0.1 percent of their own DNA, Ma’s team notes. The microbes may explain more of what sets one person apart. How much more, no one knows yet.

Ma and colleagues split a person’s genes into two sets. The first comes from egg and sperm.

The innate genome is inherited by fixed rules and stays largely the same for life. The second set is the genes the microbes carry.

The adaptive genome is picked up over a lifetime. It changes with what a person eats, the drugs they take, where they live and who they live with. The innate genome changes over many generations. The adaptive genome can change in days (Figure 3). A probiotic tub from the dairy aisle can reach only the second set; no yogurt has yet edited the first.

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Figure 3. About 20,000 human genes against millions of microbial ones, and why food can change the second set but not the first, from The Washington Post (2021), with food and mental health reporter Mary Beth Albright. The mouse and fly studies it cites are early work. Video and thumbnail: The Washington Post, Standard YouTube License.

A newborn’s second set starts near empty. To learn what that set does for a body, the plainest test is a body that grows up without it from birth.

What Goes Missing

Doctors in Houston placed David Vetter inside a plastic bubble within seconds of his birth, in September 1971. He had severe combined immunodeficiency, an inherited disease that leaves the body almost no immune defense. His older brother had died of it as a baby.

Everything that went into the bubble was sterilized first: food, water, clothes, toys. Filtered air flowed in without stopping. His parents touched him through rubber gloves set into the plastic wall. In 1983, doctors gave him bone marrow from his sister, hoping it would build him an immune system. The marrow carried a virus no test had found. He died of a cancer it caused in February 1984, at twelve.

David is the closest thing to a germ-free person in the medical record, and he says little about what germs do for a body. His immune system had failed from birth, so any difference in him could come from the disease. For a cleaner answer, scientists turned to animals.

At the Lobund Laboratory at the University of Notre Dame, rats were delivered by cesarean section into sealed steel tanks and raised there on sterilized food, generation after generation. In 1963, Helmut Gordon, Bernard Wostmann and Edith Bruckner-Kardoss compared the colony’s rats with ordinary rats of the same stock. They had ten germ-free rats and twelve ordinary ones. The two groups weighed the same. The germ-free hearts pumped about 30 percent less blood per minute for their weight, and not one germ-free rat reached the ordinary range. In a second set of rats, the germ-free ones also carried about a fifth less blood.

Later studies, gathered in Ma’s review, added to the list. Germ-free animals have a swollen cecum, the pouch where the small intestine meets the large one, about twice its usual size in rats. They have a smaller thymus, the gland that trains immune cells, and fewer immune cells in the gut wall.

The changes reach the brain. A tight seal of cells, the blood-brain barrier, keeps most of what travels in the blood out of the brain. In 2014, Viorica Braniste, Sven Pettersson and colleagues at the Karolinska Institute in Stockholm injected a blue dye into the blood of mice, three to a group. In ordinary mice, the dye stayed inside the blood vessels. In germ-free mice, it leaked into the brain itself. The leak starts before birth and lasts into adulthood. When the team gave adult germ-free mice the gut bacteria of ordinary mice, the seal tightened. Butyrate alone, a fatty acid that gut bacteria make from fiber, tightened it as far as in ordinary mice. Three mice to a group make a fragile test, and a mouse brain is not a human one.

Ma’s team gathers these findings under one name: germ-free syndrome. Taking the microbes away does not leave a clean body. It leaves a body with missing parts. “A gut devoid of microorganisms,” they write, “cannot be considered a complete intestine.”

Germ-free syndrome is Ackoff’s definition of a system, run as an experiment. Each part can change how the whole behaves, but never alone. The mice lost the microbes in their gut, and the seal around their brains changed.

Anyone who has finished a course of antibiotics has run a small, short version of this experiment. In a Danish study, twelve healthy men took a mix of strong antibiotics for four days. Their gut bacteria took about six weeks to come back close to where they had been. Six months later, nine common species were still gone from most of the men. The study was small, and its three drugs are usually kept for the hardest infections.

In the weeks after a course, the question is what changed besides the infection it treated: digestion, appetite, a rash. A friend who starts a course of pills this week is one person to pass the Danish study to, in a one-line text. On a kitchen counter, the last few pills rattle in their bottle, and the gut they passed through is still counting its losses.

A Closing Invitation. The milk in the opening fed two eaters at once. So does every meal and every dose: whatever reaches a body reaches its microbes too. Three ways to watch for the second eater.

1. Count the last course. From where you sit, think of the last antibiotics in your home, yours or a child’s: the pink bottle in the fridge door, the blister pack in a drawer. How many days did the course run? In the six weeks after, what changed besides the infection: digestion, appetite, a rash?
2. Turn the tub over. At the store this week, pick up one probiotic yogurt or capsule box and read the back, the plastic cold in your hand. What does it count: bacteria made, bacteria alive, or bacteria that stay? Which crowd is already in your gut to meet them? Is that count worth twice the price of a plain tub?
3. Tell the next one. When a coworker or a parent mentions this month that they have started antibiotics, tell them about the twelve Danish men: four days of pills, and about six weeks for most gut bacteria to come back. Nine species were still missing at six months. Which weeks after the empty bottle might feel different to them?

Tonight, somewhere, a baby feeds. Each swallow carries bacteria in, and sugars that only some of them can eat. Both eaters grow at every feed, and a scale weighs only one of them.

Worth remembering Save as image

You never eat alone. Every bite and every pill also reaches the bacteria in your gut. So four days of strong antibiotics can leave some gut species gone six months later.

Where This Came From

The milk thread is older than Ma’s review: Tissier saw his split rods in 1899, more than a century before Ward and German grew one of them on milk’s own sugars. The genes idea has a lineage too, which Ma’s review traces. Lynn Margulis called a host with its microbes a holobiont in 1991, and Richard Jefferson later named their combined genes the hologenome. The aphid fits that word well. Ma’s team argues that people do not, because contact is not inheritance, and so they split a person’s genes in two. The two ideas here are the first and second of Ma’s eight; the order is this piece’s own.

Intellectual Honesty Note. This piece describes what milk carries, not how anyone should feed a baby. The two daughters and their feeds are my own. The dairy aisle in the stakes paragraph is hypothetical. Ma’s text reads the 2009 pie’s shares as density, and it drops the pie’s blood (1 percent) and eye (0 percent) slices, so its five places add up to 99 percent. My recount (lists saved March 6 and April 10, 2009) groups body sites by name: gut and stomach under GI tract, vagina and urine under urogenital. Strains listed with no site, 1 and 4 percent, count in the totals but get no marker. No later copy of the list was saved, so the pie itself could not be recounted. Ma et al. (2024) is a narrative review, and its ideas are proposals, not settled findings. Tissier’s findings are reported from later accounts; his 1900 thesis was not opened.

References

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Alice is wrong: at every size she is still Alice, and nearly every change came from something she ate or drank. Carroll never says what the cake or the bottle changed inside her.

Figure 1. Left: Alice holds up the “DRINK ME” bottle. Right: after the “EAT ME” cake, “opening out like the largest telescope that ever was.” Illustrations by John Tenniel (1865), public domain, via Wikimedia Commons (left, right).

Real bodies change with what they eat, too. Feed a bee larva royal jelly and it grows into a queen instead of a worker, on the same DNA it started with. A cell reads whatever letters it is handed, and the jelly does not hand it new ones. The jelly changes which of them get read.

It is your next checkup, at a new clinic. Your pen stalls over the intake form’s family history: a list of diseases, each with a box to tick for any relative who had it. The line you are stuck on is diabetes. If your parents moved countries, or you did, your DNA made the trip unchanged. Your odds of getting Type 2 Diabetes may not have. If your family is Asian American, the American Diabetes Association says to consider a blood sugar test at a body mass index of 23, not 25. From age thirty-five, it says to test at any weight. For a woman 160 centimeters tall, 23 is about 59 kilograms. Nearly one in four American adults with diabetes does not know they have it. If your mother is one of them, you leave the box blank, and your doctor loses one reason to test you.

A blank box costs one reason to be tested, but why would a move change the odds and leave the DNA alone? That gap is what a paper I worked on is about. Close to midnight, seven years ago, a dozen drafts into the manuscript, I have been stuck on one paragraph for twenty minutes.

The paragraph makes the jelly’s claim about people: two groups who share an ancestry, and with it most of their DNA. One group moved across an ocean and one stayed home. People with diabetes carry different chemical tags on a gene called TXNIP than people without it. The ones who moved carry a few differences of their own. I cannot vouch for the paragraph’s statistics, because I cannot picture what a tag does to a gene whose letters never changed.

On this paper, mine is the tenth of sixteen names: the statistician. I checked the analysis with Dominic, the lead author, sorting real differences from chance. Tonight my whole job is one comment in the margin, on whether the statistics hold.

I know the basics of the double helix. What I do not have is the vocabulary everyone else on this list uses every day, starting with what a promoter region does.

The little I have picked up from this list says chemical tags sit near the front of a gene and turn it down. The paragraph on my screen puts the tags inside the gene, near the gene’s far end, and I cannot see what a tag would be doing there. I have read the paragraph so many times tonight, the words have started to come apart. My eyes go a little heavier each time I reach “differentially methylated.”

I do not remember deciding to close them.

Someone is already waiting when I open them again. This is not my desk. It takes me a moment to place why it feels so much like Wonderland. The Hatter is there, in a hat two sizes too large, tipped over one eye. He holds a full teacup, though I never once see it get poured or emptied.

His voice, when it comes, is David Attenborough’s, hushed and marveling.

“You will want to know the one rule before you go any further,” he says, not quite looking at me. “Size. Nothing about how large or small you are stays fixed here, only your curiosity does. Stand back far enough and you get an entire field at once. Stand close and you are shoulder to shoulder with something small enough to carry a single bead against its own chest.”

I do not ask how he seems to know what I am going to need.

Who Keeps the Caps

Six billion tiny sprites, no bigger than a thumb, hold hands in two long lines across a field. The lines twist around each other the whole length of the field. Each sprite presses a bead to its chest, stamped with one of four letters, T, C, G or A. Their eyes glow a deep amber, like drops of honey.

A second field lies beside it. Same six billion sprites, matching order, letter for letter, first bead to last.

The Hatter: Every cell in a human body, with only a few exceptions, carries an identical copy of the genome. A neuron and a liver cell do not look alike and do not do similar work, on identical instructions. If the code is not the difference, something else is deciding which parts of it get followed. A verse, here, means one gene, the stretch a courier stops to copy: long enough to be worth reading as a single instruction, not the whole endless line. That is why a DNA kit can read a person’s genes from a cheek swab, and why the swab cannot say which of them that person’s liver is using.

Back among the sprites, something small is going from sprite to sprite with a satchel. I shrink down until the double line towers on both sides of me. Up close, it is an imp, smaller than the courier imps that pass through here to copy a verse onto a thread of their own, and far quieter. This one goes by Hush, the keeper of the caps.

Hush does not carry beads, and Hush does not thread anything. Hush carries a satchel of tiny knitted nightcaps, soft and pointed, with a little tassel on the end, the kind that shows up in bedtime picture books. It does not cap just any sprite. It caps only the C sprites, and only a C with a G sprite standing next in line. One by one, it is choosing which of those get to keep working today and which ones get to go to sleep.

A nightcap does not unlink a sprite’s hands. T still finds A, and C still finds G: the cap rides on top, out of the partners’ way. Hush just tugs it gently down over a sprite’s eyes and ears, and the sprite yawns once, settles, and drifts off right there, mid-chain, still holding on with both hands.

The caps that put a verse to sleep go on its flag, the short run of sprites just before the verse that tells a courier where to start reading. When one of the courier imps comes flying past later, looking for that flag, it finds the flag’s sprites asleep. A sleeping sprite still holds its bead, but it gives a courier no sign to stop. With no flag to see, the courier never stops, and the verse goes unread.

The Hatter: The flag has a name: a gene’s promoter. A courier builds its thread in one direction only, starting at the end biologists call 5’ and heading toward the end called 3’. So the flag sits upstream, on the 5’ side of its verse. Caps on a promoter keep the reading machinery from starting there, and that is how they silence the gene.

Hush caps the same flags every time it visits this line, one handful of verses put to sleep, the rest left wide awake, night after night, cell after cell. Most of Hush’s caps go everywhere else, along the long stretches between verses and down the middle of the verses left awake. The caps inside a verse stop a courier from starting partway down it. A courier already reading the verse runs straight over them.

The Hatter: This is called methylation. Hush stands for an enzyme, as every imp here does: a DNA methyltransferase, the one that lays the caps. The nightcap is a methyl group, a small chemical tag that attaches directly to DNA. In people, it lands almost always on a C followed by a G. Nothing about the underlying sequence changes. Only whether it gets read does.

Hush works from what is happening in the body. In a growing embryo, its caps help decide which verses a liver cell will read and which a neuron will. After that, other signals move them: a nutrient the body was shorted before birth, a hormone running high for years, a long stretch of chronic inflammation. Each one changes which caps Hush lays, as royal jelly does in a bee larva.

epigenetics, n.

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“The study of how DNA interacts with the multitude of smaller molecules found within cells, which can activate and deactivate genes.”

The Hatter: Some marks come from outside the body. In a smoker’s blood, a site on a gene called AHRR loses its caps. After the last cigarette, most smoking-linked sites drift back within about five years, and a few still lack their caps decades later. For someone who has quit, the number to count is the years since the last cigarette.

Figure 2. Same DNA, different caps. Two genetically identical agouti mice: in the brown one, methylation keeps the agouti gene quiet; in the yellow one, it does not, and the mouse grows fat and prone to diabetes. Mouse photo by Randy Jirtle and Dana Dolinoy (2007), CC BY 3.0, via Wikimedia Commons.

I pull back until both double lines fit in view at once. Same six billion sprites in each, in the same order. In one, a verse lies wide open, read on request. In the other, the same verse sleeps under one of Hush’s caps and gets passed over.

A verse asleep with every letter in place: that is the first thing the two fields were hiding. The sprites’ amber eyes blink out before I can see what a move across an ocean would change.

Where the Caps Came Off

At one in the morning, I wake at my own desk, the cursor blinking in the empty comment box. My cheek carries the print of the keyboard’s edge. The paragraph that stopped me is still there, unchanged. But now I can picture it.

There are two cohorts behind this paper, an ocean apart. In the Philippines, in the heat, blood is drawn from 198 adults born there and still living there. In the United States, blood is drawn from a second cohort: 167 Filipinos who moved there. The two groups share an ancestry. Their lives since have split. Blood from both cohorts is read on a chip that checks about 850,000 sites at once.

Researchers call this design a natural experiment: a real-world split that works like a controlled study, though nobody assigned anyone to a group. Migration did the assigning here. Since ancestry is held steady, whatever differs afterward in methylation becomes a candidate for something the years apart did. The design cannot hold steady everything else that moved with the families: food, work, income, a different health system, a different winter. It can point to the years apart, but not to any one thing in them.

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Figure 3. The Dutch Hunger Winter of 1944–45, the best-known natural experiment in epigenetics, from MinuteEarth (2015), YouTube embed. The frightened mice belong to the video’s later, still-debated claim: marks passed from parents to offspring.

Type 2 Diabetes is a good disease to test this way. Genes explain only part of who develops it, and the risk often climbs after people move to a new country. Among Filipinos, diabetes is more common in those who moved to the United States.

After quality checks, about 716,000 of the chip’s sites were tested. By my own arithmetic, at the usual one-in-twenty bar, about 36,000 of them would look like finds by chance alone. My part was the correction that keeps chance hits to a small share of what gets called real. After the correction, 177 of those 716,000 sites were left standing as tied to diabetes. The shifts were small: a site gained or lost about one cap in twenty in people with diabetes.

Three of the 177 fall on TXNIP, the gene from the paragraph I was stuck on. Earlier studies of diabetes had flagged it too. Rising blood sugar pushes TXNIP to make more of its protein, and too much of that protein damages the cells that make insulin. Whether the changes at those three sites come before the diabetes or after it, a single blood draw cannot say, and the paper leaves that order open.

The three sites lie inside the TXNIP verse, near its far end, right where the paragraph had put them, and in the people with diabetes they had lost their caps. They were the caps Hush lays along the middle of an awake verse. Where the caps came off, the paper saw more copying of the verse’s tail, as if a courier had found a flag where none belonged and started reading partway through. The paper’s title calls this spurious transcription initiation. That false start is the part my coauthors understood long before I did, the part I needed six billion sprites and an imp named Hush to finally hold onto.

On the intake form’s family history, I tick yes beside diabetes. My mother’s whole family has diabetes, except her. My grandfather on her side died of it. So did one of her sisters, from complications. She was on dialysis. Each time I got pregnant, the first time and the second, my doctors checked that history. It puts me at risk for gestational diabetes, the kind that starts during pregnancy. I had a stake in this before the paper, and after it. I also made the same move as the paper’s second cohort, from the Philippines to the United States. The paper says the move can count too.

This is the second thing the two fields were hiding: one for the cohort that stayed, one for the cohort that left. Real people do not match letter for letter the way the fields do. But the two cohorts share an ancestry, and their caps landed in different places. Where diabetes and the move overlapped, the analysis found three more sites, near genes called MAP2K7, PRMT1 and ADM5. Their cells were handed the same letters and still read them differently.

The cohort that left is the part of this story to send a brother or cousin who moved too and has never had a blood sugar test. One call this week can ask the family one question: has anyone been told they have diabetes? A yes goes in the diabetes box before the next checkup. Left blank, the box costs that brother or cousin the same lost reason to be tested.

I did not know that night whether the comment I left would be any good. I know now. The paper published at the end of 2019. TXNIP made it past every round of review, and the sentence that stopped me that night has been in print ever since. The dream went fuzzy by morning, and I did not think about it again for a long time.

Seven years later, it is the field that came back, not the paragraph, not the comment, not even the paper.

A Closing Invitation. Like Alice at every size, the same words can land differently, and the same DNA can be read differently. Right now, say this out loud three times, landing on a different word each time:

I never said she stole my money. (Someone else did.)
I never said she stole my money. (I only implied it.)
I never said she stole my money. (She borrowed it.)

Which version would you least want your best friend to hear?

1. Look past the same letters. The next time someone at a family dinner says “diabetes runs in our family,” notice what else the family shares besides its DNA: one rice pot, long workdays, a move across an ocean. Which of those could change how that DNA gets read?
2. Get ahead of the blank box. This month, ask your clinic for a blood sugar test if you are thirty-five or older, or Asian American with a body mass index of 23 or more. A ticked diabetes box adds a reason. Found early, high blood sugar has less time to do harm. Which sibling or cousin who moved too could book theirs the same week?

Hush never deletes a gene, only caps it. Each cap puts one sprite to sleep, still holding hands.

Worth remembering Save as image

Silence is not deletion. A cell can stop using a gene without changing a letter, and food, smoking or a move abroad can choose which ones.

Where This Practice Came From

Waddington’s 1942 paper, three pages in Endeavour, is where the word epigenetics starts. The field, the sprites, and the courier imps first appeared in the walkthrough of the double helix, transcription, and translation.

Intellectual Honesty Note. The sprites, the imps, the field, the nightcaps and the rest of the staging are invented, built to make old, well-tested science easier to hold onto, never to replace it. So are the dream, the Hatter and his David Attenborough voice, and the night at the desk is dramatized. Each mechanism the sprites act out is textbook biology, and the Hatter’s asides name it plainly so the metaphor never carries it alone. The video in Figure 3 goes further than this piece, into marks said to pass from parents to children and grandchildren, which is still debated; this piece leans only on its account of the Dutch famine as a natural experiment. The false start at TXNIP is the paper’s reading of the marks around those sites, not a courier caught in the act.

References

Albao, D.S., Cutiongco-de la Paz, E.M., Mercado, M.E., Lirio, A., Mariano, M., Kim, S., Yangco, A., Melegrito, J., Wad-asen, K., Gauran, I.I., Francisco, M.A., Santos-Acuin, C., David-Padilla, C., Murphy, E.J., Paz-Pacheco, E. and Seielstad, M., 2019. Methylation changes in the peripheral blood of Filipinos with Type 2 diabetes suggest spurious transcription initiation at TXNIP. Human Molecular Genetics, 28(24), pp.4208-4218.

Alberts, B., Heald, R., Johnson, A., Morgan, D., Raff, M., Roberts, K., & Walter, P. (2022). Molecular Biology of the Cell (7th ed.). W. W. Norton.

American Diabetes Association Professional Practice Committee. (2022). 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes, 2022. Diabetes Care, 45(Suppl. 1), S17–S38.

Carroll, L. (1865). Alice’s Adventures in Wonderland. Macmillan.

Centers for Disease Control and Prevention. (2023). National Diabetes Statistics Report. https://www.cdc.gov/diabetes/data/statistics-report/index.html

Guerrero-Bosagna, C. (2016, June 27). What is epigenetics? [Video]. TED-Ed. YouTube. https://www.youtube.com/watch?v=_aAhcNjmvhc

Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S., et al. (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences, 105(44), 17046–17049.

Holliday, R. (2006). Epigenetics: a Historical Overview. Epigenetics, 1(2), 76-80.

Jirtle, R., & Dolinoy, D. (2007). Agouti mice [Photograph]. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Agouti_Mice.jpg

Joehanes, R., Just, A. C., Marioni, R. E., Pilling, L. C., Reynolds, L. M., Mandaviya, P. R., et al. (2016). Epigenetic signatures of cigarette smoking. Circulation: Cardiovascular Genetics, 9(5), 436–447.

Kucharski, R., Maleszka, J., Foret, S., & Maleszka, R. (2008). Nutritional control of reproductive status in honeybees via DNA methylation. Science, 319(5871), 1827–1830.

MinuteEarth. (2015, November 18). Epigenetics: Why inheritance is weirder than we thought [Video]. YouTube. https://www.youtube.com/watch?v=AvB0q3mg4sQ

Neri, F., Rapelli, S., Krepelova, A., Incarnato, D., Parlato, C., Basile, G., et al. (2017). Intragenic DNA methylation prevents spurious transcription initiation. Nature, 543(7643), 72–77.

Tenniel, J. (1865). [Illustrations]. In L. Carroll, Alice’s Adventures in Wonderland. Macmillan.

Waddington, C. H. (1942). The Epigenotype. Endeavour, 1, 18–20.

Waterland, R. A., & Jirtle, R. L. (2003). Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology, 23(15), 5293–5300.

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Figure 1. Mr. DNA’s lesson from Jurassic Park (Spielberg, 1993, Universal Pictures): the mosquito, the amber, and the frog DNA that filled the holes. Still from the film, YouTube embed.

Later in the film, the fossil hunter Alan Grant crouches in the grass and turns a piece of eggshell over in his hand. It is hatched, and empty. The park’s scientists made every dinosaur female, so the animals should not be able to breed. “Life found a way,” Grant says. The frog DNA brought frog instructions with it. One of them let an animal switch from female to male. The dinosaurs’ cells could not tell which parts of their DNA came from a frog. They read all of it and followed all of it.

Some of the cartoon is true. DNA is a code, and a living thing is built by reading it. Insects do get trapped in amber, wings and legs and hairs kept whole for millions of years. In 2013, scientists described a mosquito, 46 million years old, with traces of blood still in its belly. The mosquito was pressed in shale, a flat, flaky stone, not amber, and it held no DNA.

Real DNA would not have lasted. Moa were giant flightless birds in New Zealand. In their bones, a short stretch of DNA has a half-life of about 521 years: after that long, half of it has broken apart. After another 521 years, half of the rest is gone. The oldest DNA recovered so far is about two million years old, from ancient sediment in northern Greenland. The last dinosaurs died sixty-six million years ago.

Living DNA has no frog in it, but it does have a backup. Every letter is stored twice, once as itself and once as its partner on the facing strand: T always across from A, C always across from G. When a letter on one side is damaged, the cell reads the partner across and puts the right one back.

Mr. DNA never said who does the reading. In a living cell, three kinds of enzymes do it, far too small to see, and they work like a crew with three jobs. One checks the letters. One carries a copy of them away. One builds from the copy.

The checker has plenty to do. About 330 billion cells in a human body are replaced every day. Most are blood cells, made deep in the bones by marrow cells that copy all of their DNA every time they divide. Each copy is checked as it is made and ends up with about one wrong letter in a billion. That checker is a handful of proteins, built from genes like any other. In some families, one of those genes is broken from birth, wrong letters slip through, and colon cancer can come years early. The condition is called Lynch syndrome. About one person in three hundred carries it, most without knowing.

At your next checkup, the clipboard form will ask about family history. Each disease gets a box to tick and a line for the relative’s age. Watch for three relatives with colon or uterine cancer, across two generations, one of them before fifty. That pattern points to Lynch syndrome, and a genetic test can find it. For a carrier, that test can move the first colonoscopy a decade or more earlier, so why do a few extra wrong letters matter that much? The box matters even without Lynch. Someone I know learned she had rectal cancer in her late forties. Her son had his first colonoscopy at thirty-six, nine years before most Americans start. The rule is short enough to check tonight. When a parent, brother, sister or child had colon or rectal cancer before sixty, screening starts at forty, or ten years before their age at diagnosis if that is earlier.

The Inspector

The camera sweeps in low over an empty football field, grass catching early light. This is a second film, about real DNA and the checkers that catch wrong letters before they settle in. Nothing moves yet, and there is not a sound. Imagine the voice that follows as something like Morgan Freeman’s, calm and certain, the voice that says what is real.

Narrator: What does DNA look like? It is a chain of small repeating units called nucleotides. Each one carries a single base, one of four, written T, C, G or A. In this story, each nucleotide is a sprite.

The grass at the edges of the frame blurs. Its color deepens and its outlines sharpen, until the picture looks hand drawn. The film has tipped from real into imagined.

The sprites appear first: thumb-sized wingless creatures with a faint shimmer across their skin, pastel one second and rainbow-bright the next. The eyes of these sprites burn with a rich, liquid amber, capturing the warmth of trapped sunlight. Each one holds a single glowing, magnetic bead pressed close to its chest, stamped with one of four letters: T, C, G or A.

Figure 2. The four kinds of sprite, one for each letter: T, C, G and A, each holding its bead. Drawn for this piece, using a sprite illustration from Reverso Dictionary only as a reference: no wings, new colors, and the beads added.

The field is full of six billion sprites: a single copy of human DNA holds about three billion pairs of letters, and every pair takes a sprite from each strand.

Picture each sprite holding hands with the sprite to the left and to the right of it, stretching the length of the field. Then picture two strands of these sprites leaning into each other and twisting over and over. They wrap around each other the way two vines climb together, with nothing solid at the center. That twist, seen from above, is the one biology textbooks draw: the double helix. Each sprite also holds hands with one partner across the twist, the same pairs as the backup: T with A, C with G. So the two strands hold together, rung after rung, end to end.

Watching over the sprites is an imp, and it looks nothing like them. It is low to the ground and broad-shouldered, its face dominated by a nose too big for it. The nose twitches constantly, the one part of the imp that never stays still. It walks on its own two feet, head low, sniffing. An imp is not a nucleotide and never was. It stands for something else entirely: an enzyme, a piece of the cell’s machinery that acts on the code rather than being part of it.

The imp lifts a tiny megaphone anyway, out of habit, and calls down the field, “INSPECTION!”

This happens every time a cell copies its DNA, so one of the two strands on the field is brand new, copied from the other a moment ago. Most of the walk is uneventful: T holding A, C holding G, pair after pair, nothing for the imp to do but keep walking. Then, somewhere past midfield, the imp’s nose twitches harder and stops.

A T has ended up paired with a C. The copying makes slips like this now and then, far more often than the finished strand shows, because most of them get fixed. A wrong pair like this one gives off a smell, faint but unmistakable: a skunk that got too close. In a cartoon it would earn its own wavy green cloud. The imp follows its nose straight to it.

It pries the mismatched pair apart. The two beads do not resist. They were never locked, only resting uneasily against each other: no click, no jolt, nothing holding them there but bad luck. The imp waits, and within moments the real partner drifts into place, the A the T should have had all along. This time there is a click, sharp as a snap, and a jolt runs through the imp’s fingers as the right bead seats home. The imp moves on, nose twitching, for the next few billion yards.

Narrator: Real pairs are held together by hydrogen bonds, weak pulls between the bases, a little like the pull of the beads’ magnets. A T and a C fit badly and hold weakly, so a pair like that one stays loose. The smell is invented. The repair is not. Real cells run mismatch repair enzymes that follow the copying machinery, scan the new strand for loose pairs like this one, and fix them.

Narrator: These are the enzymes Lynch syndrome breaks. A carrier is born with one broken copy of one of these genes and one working copy. In any cell that loses the working copy too, the inspector stops catching slips, and they pile up. That is why carriers are usually advised to start colonoscopies in their twenties or early thirties, depending on the gene. They repeat them every year or two; for everyone else, screening now starts at forty-five. A carrier who never finds out may wait for forty-five like everyone else. A positive test is news for a brother, a sister or a grown child, who may carry the same broken copy. A slip the inspector misses stays put like any other letter, waiting to be read.

The Courier

A second imp has been waiting at the sideline the whole time, and it never fixes anything. It is smaller and quicker, restless in a way the bead-carrying sprites are not, and more interested in reading than in landing anywhere for good. This one goes by Quill. Imps like Quill do not carry a bead of their own to keep. They carry an empty thread, waiting for something worth copying onto it.

The double line rests, twisted and still. Somewhere inside it is the wing-shimmer verse: a stretch of letters that holds the recipe for the shimmer on a wing. It runs about a thousand sprites from end to end, sometimes several times that, and does nothing until it is needed. Just before the verse begins, a short handful of beads, no more than a few dozen sprites long, forms a pattern unlike anything nearby. This pattern is a flag. It marks where reading starts and carries no recipe of its own. Every courier knows that pattern on sight, the way the inspector knows a smell. The moment a courier passes over the flag, it knows that everything past it is worth reading.

Narrator: A verse like this one has a real name: a gene. Most DNA codes for no protein at all, only long stretches of sprites holding hands. A gene is the stretch that gets read and built into something real: a protein, a working part of the body. Genes turn into things a person can see, feel or measure, like the enzyme that lets a body digest food, or the protein that keeps a heart beating. The flag is real too. A short marker just before each gene, called a promoter, tells the reading machinery where to start. Whether a courier ever sees that flag is decided elsewhere, by nightcaps that put a verse to sleep.

Quill peels off from the sideline and flies straight for the flag. It leaves alone the hands each sprite holds along its own strand. Instead it slips in sideways between the two strands and pries the partners across apart, one pair at a time. It works like unzipping a jacket: the teeth open only where the pull has passed. Here the zip closes again right behind Quill, so only a few pairs are ever open at once.

With the two sides briefly open, Quill reads down one of them, letter by letter, and threads a single new strand as it goes, matching each letter to its partner. An A on the open strand pulls in a paler, imp-only bead standing in for T. A T pulls in a plain A, a C pulls in a G, and a G pulls in a C. Quill’s beads are a shade paler than the sprites’ beads, a little cooler under light. Unlike the double line it came from, the new thread gets no partner of its own. If the sprites hold beads labeled A-T-C-G, Quill writes them as U-A-G-C, with U for its pale bead. Thousand-some beads later, Quill reaches the end of the verse and snaps free, and the two strands fall back together, sealed.

Narrator: RNA uses a related letter, uracil (U), wherever DNA would use T: Quill’s paler bead. Messenger RNA is not built to last. A typical one survives long enough for the builders to read it, often hundreds or thousands of times, before the cell’s enzymes break it down.

Narrator: That is also why an mRNA vaccine cannot rewrite a person’s DNA. The vaccine is a courier’s thread delivered from outside. The body’s builders read it for a few days, the cell breaks it down, and it never goes back into the double line. So the courier is the part of this story to send a friend who worried at dinner that the shot changes their genes. The better question is what the builders make from the thread.

The Builder

Quill touches down at a cluster of stockier imps, the builders, round-shouldered and built for handling. Quill hands its thread over and lifts off again. The builders are stationed where they are needed, this time at the base of a flat, colorless pair of wings. The wings belong to no sprite on this field. They belong to the much larger creature this field lives inside: the whole field is the DNA in one of its cells.

The builders read Quill’s thread three beads at a stretch, always three. Each triplet acts like a single word rather than three separate letters.

A builder reads the first triplet and reaches into a supply shelf stocked with tiny colored droplets. It pulls out the one droplet that triplet calls for, clips it onto a growing chain, and moves on to the next three beads. Another triplet, another droplet, clipped on right after the first. Each triplet calls for one droplet and no other. A wrong droplet does not fit the call and will not clip on, the same exact-match rule that decided which beads could pair.

If the inspector had missed that T and C back on the field, the builders would never know. The wrong letter would be copied into the thread like any other. Its triplet could call for a different droplet, and the builders would clip it on without a pause. Like the dinosaurs’ cells with the frog letters, they read all of it and follow all of it.

Narrator: In Lynch syndrome, this is how the cancer starts. Slips the inspector would have caught land in genes that tell a cell when to stop dividing, and the builders make those proteins wrong. The early colonoscopies are the step against it: they find growths while they are small enough to remove. Not every carrier gets cancer, and why some do young and others never do is still being studied.

Eventually a triplet arrives that calls for no droplet at all. The nearest builder reaches for the shelf, comes back empty-handed, and shrugs. This is the stop signal: the work here is finished. The builders let go of the chain: a long, straight row of droplets with no shine to it yet, waiting to become something more.

Narrator: The builders are ribosomes, and the droplets are amino acids. Each three-bead word is a codon, and each codon calls in one amino acid. The stop signal is real too: a stop codon tells the ribosome to let the chain go.

Then the chain curls, almost too fast to watch, like a ribbon pulled once across a scissor blade. It folds in on itself, droplet finding droplet, until it locks into one fold and stays there. The fold catches light, thin and blue on one side, warm and gold on the other, the instant it settles against the wing.

Figure 3. One short verse read through: the strand Quill reads, the thread Quill makes, and the droplet the builders clip on for each three-bead word. The verse is invented; the matching and the codon readings are real.

Narrator: The shimmer is not invented either. Its closest real version swims in the ocean. Squid make proteins called reflectins, each one a gene’s worth of droplets, folded like any other. Inside the squid’s skin, reflectins pack into thin stacked plates, and the gaps between those plates set the color the squid reflects. When a nerve signal arrives, the reflectins clump tighter and water squeezes out. The plates thin, and the shimmer slides from red toward blue while a diver watches. Gene, protein, fold, stack, shimmer: that is the builder imps’ chain, plus the stacking step the story leaves out.

Figure 4. A Caribbean reef squid at Bari Reef, Bonaire, its skin shimmering with structural color. Photo by Betty Wills (2005), CC BY-SA 4.0, via Wikimedia Commons.

Narrator: Many antibiotics work by jamming the builders inside bacteria. Bacterial builders differ from human ones, so the drug stops theirs and leaves the body’s own mostly alone. A cold is a virus, and a virus has no builders of its own. When a visit for a sore throat turns to talk of a prescription, one question decides it: is this infection bacterial? A cold usually clears in less than a week, and an antibiotic finds nothing in it to jam. The virus has handed its thread to the body’s own builders, and they read it like any other.

A Closing Invitation. The dinosaurs followed the frog letters because cells read whatever they are handed, right or wrong. The inspector, the courier and the builders each come back here as one small check on what your cells get handed.

1. Settle the dinner worry. Think of the last time mRNA vaccines came up, at a pharmacy counter or across a dinner table, and kept someone up worrying that night. Picture the courier’s thread: read for a few days, broken down, never written into the double line. Which worry is left for the next time, once the gene worry is gone?
2. Find the broken inspector. This weekend, before your next checkup, call one relative and ask who had colon or uterine cancer, and at what age. Start with the one who always knows who married whom. Two names and two ages can move your first screening years earlier. Could the answers point to a broken inspector, and who else needs to hear them?
3. Check for builders to jam. The next cold or flu will bring a scratchy throat and the pull to ask for antibiotics. Before you ask for the prescription, ask the builders’ question: is this one bacterial? Which of your last few prescriptions would pass it?

T always finds A because an inspector walks every new strand and sets wrong letters right. In some families, that inspector is broken from birth. The phone in your hand can find a broken one while T still finds A.

Worth remembering Save as image

Your cells follow a typo as faithfully as the truth. One call to ask which relatives had colon cancer, and how young, can move your first colonoscopy years earlier.

Where This Practice Came From

In 1895, a local seamstress told the Michigan pathologist Aldred Warthin that she would die of cancer, because so many in her family had. She did, of cancer of the uterus. Warthin traced her relatives and in 1913 published them as “Family G,” arguing that a weakness for cancer could be inherited. In the 1960s, Henry Lynch found the family again: more than 650 members, 95 of them with cancer. The pattern now carries his name. The pairing rule the sprites act out comes from Watson and Crick’s 1953 paper. It ends on a line pointing at the copying the inspector checks: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” How cells check that copying was worked out later. Paul Modrich showed how cells repair mismatched pairs after copying, and shared the 2015 Nobel Prize in Chemistry for it.

Intellectual Honesty Note. Every mechanism the sprites act out is standard molecular biology, confirmed at each step through the Narrator’s asides. The sprites, the imps, the football field and the snap are invented staging. Real mismatch repair does not swap a single bead: it cuts out a stretch of the new strand and copies it again. The shimmer as one folded protein is also a simplification; real structural color needs many molecules stacked in layers. The field holds one copy of the genome; a real cell holds two, one from each parent. The intro’s three-relatives rule is a short form of the clinical checklist, which also asks that the relatives be closely related and counts other Lynch cancers. Wrong pairs and wrong droplets are rare, not impossible: a T and a C can hold weakly, and builders do now and then clip on a wrong droplet. The Jurassic Park science is the film’s own: only a few frog species, some reed frogs among them, have been reported to change sex.

References

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Near the edge of the frame, a few cells hang straight down, long and bumpy, like peanut shells made of wax. In each one, a larva floats on a pool of thick white jelly, far more than it can eat.

Any female larva in the hive can grow into a queen or a worker. Her genes do not decide which. The larvae in the hanging cells become queens. A queen lives for years and can lay more than a thousand eggs a day. A worker lives a few weeks in summer and usually lays none.

Food decides which. The white jelly is royal jelly, a rich food made in glands in the workers’ heads. The workers feed it to a few larvae for as long as they are larvae. The rest get a plainer mix with pollen and honey in it, and become workers. Food cannot rewrite a gene. So what does it change?

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Figure 1. How royal jelly makes a queen, from SciShow (2015), YouTube embed. The video credits one jelly protein, royalactin. A later team could not reproduce that result.

In 2008, a team at the Australian National University, in Canberra, tested one answer. Cells can stick small chemical marks onto some of their genes. Biologists call these methylation marks. They help decide which genes the cell reads and which it skips. The marks work like punctuation: add a comma or a period, and the same words read differently.

The team switched off one gene in newly hatched larvae: the gene for an enzyme that lays down those marks. Then they fed the larvae a worker’s diet. Most of them came out as queens, with full ovaries. The team called it “a royal jelly-like effect.” Each larva kept the genes it was born with. What changed was which of them got read.

The bee each larva became depended on what its genes were connected to: the marks, the food, and the workers who chose which larvae to feed.

Say you mail a spit sample to a DNA testing company, and the report comes back: you probably cannot digest milk as an adult. You start drinking your coffee black, bitter at the first sip. You stop buying cheese, pay extra for lactose-free milk and read every label in the shop. Your partner switches to oat milk so the fridge needs only one carton. By your next checkup, you have gone months without an easy source of calcium.

Here is how such a report could be wrong. For most people in the world, the body stops digesting milk after childhood, like a door that locks. Some people carry a key that keeps the door open. In Europe, most people who have a key share one version of it. Many families who kept cattle in East Africa carry a different key that opens the same door. Say the test looks only for the European key. A person who carries the East African one gets a report that finds nothing it knows and says the door is locked. That person gave up milk for nothing. The test was right about the European key. It never asked where the family came from. Systems thinking has a question for any test result that costs someone milk, cheese and calcium: what else is that result connected to?

Which Genes Get Read

Counting human genes started as a bet. In May 2000, at Cold Spring Harbor, the geneticist Ewan Birney opened a pool on how many genes the human genome would turn out to hold. Biology was about to get its first full parts list for a person: the genes, each one a recipe for a molecule the body uses. The guesses ran from about 20,000 to more than 200,000. In 2003, the count came in at 24,847. The closest guess, 25,947, belonged to Lee Rowen, who worked at the Institute for Systems Biology. She won $600 and a signed copy of The Double Helix.

Later counts settled lower, near 20,000. The worm C. elegans, about a millimeter long, has a little over 20,000 genes of its own. So the number of parts could not be what makes a person a person. In Donella Meadows’ definition of a system, the parts matter less than the rules that connect them. A count of genes is like a count of cards: fifty-two cards can deal poker or solitaire, and the rules make the game. The difference between a person and a worm lives in the rules: how the genes get used, and what they connect to.

A full gene count is one example of omics: measuring one layer of a living thing all at once. Each layer takes the suffix -ome. Two of them explain the bees.

The genome is the layer the walkthrough of DNA, transcription, and translation takes apart. The epigenome is the layer the natural experiment on methylation follows.

The bees showed the epigenome at work: the food changed the marks, not the genes. And what a cell reads can turn around and change what it reads next.

How the Layers Loop

E. coli, a bacterium in the gut, leaves one of its genes unread until milk shows up. The gene makes an enzyme that digests lactose, the sugar in milk. In 1961, at the Pasteur Institute in Paris, François Jacob and Jacques Monod worked out how the cell decides. A protein called a repressor sits on the gene and keeps it switched off. When lactose arrives, it pulls the repressor off, and the cell makes the enzyme. The enzyme breaks the lactose down. When the lactose runs out, the repressor settles back, and the gene switches off again.

In Meadows’ terms for feedback, that is a balancing loop: a change that comes back around and undoes itself. The gene answers to the sugar, and the sugar answers to the gene.

A loop can also cross layers. In 2012, Romain Barrès and his colleagues put sedentary adults on an exercise bike. Each rode at either 40 or 80 percent of their maximum effort. With a needle, they took small plugs of thigh muscle before the ride, right after it, and three hours later. On several genes that help build a cell’s energy supply, the methylation marks dropped, and the genes became more active. Both changes were larger after the harder ride, and the drop in the marks appeared to come first.

One of those genes, PGC-1α, is a master switch for building mitochondria, the parts of a cell that burn fuel. Over months of training, more mitochondria mean more capacity for the next ride.

The ride changes the marks on the genes. The marks change which genes get copied into RNA, a layer called the transcriptome. The copies change which proteins get made, the proteome. The proteins change what the body can do on the next ride. No one layer holds the whole of what exercise does.

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Figure 2. What more mitochondria do for a cyclist, from Pedaling to the Top (2025), YouTube embed. Thumbnail: two mitochondria in lung tissue, electron micrograph by Louisa Howard, public domain.

Milk runs through a much slower loop in people. Babies make their own enzyme for lactose, called lactase, but in most mammals the body stops making it after weaning. In about a third of adults alive today, the body keeps making it. A short stretch of DNA near the gene turns it down after childhood. That is the locked door from the DNA kit. The European key is a single changed letter in that stretch, and it keeps the gene on for life.

The East African keys are other one-letter changes nearby, and each arose on its own. In 2007, the geneticist Sarah Tishkoff and her colleagues traced the most common of them, carried by many herding peoples in Kenya and Tanzania. That key had spread fast, over roughly the last seven thousand years.

Milk and the key ran in a loop of their own. Herds put fresh milk within reach. Adults who carried the key could digest it, got more food from it, and more of their children lived to carry the key too. The more people could drink milk, the more a herd was worth, and herding spread further. This is the other kind of loop, a reinforcing one: a change that feeds itself. Even this loop has a ceiling. A herd can grow only as large as the grass and water around it allow. Neither loop is written in anyone’s DNA.

A DNA sample can show whether someone carries a key. It cannot show the herds that made the key worth carrying, or the grass and water that capped the herds. So a kit report that rules out milk earns one email to the company within the week: which versions did the test look for? A parent who skips the email may cut milk from the children’s plates too, on a test that never looked for the version the family carries. A parent who already cut the milk can still ask.

What the Data Leaves Out

The psychiatrist Felix Tretter calls molecular systems medicine “holistic but still reductive.” It measures as many molecules as it can, then rebuilds the organism one part at a time.

Time is the first thing a single sample loses. Many omics studies draw one tube of blood from each person, once. Peter Senge defines systems thinking as seeing “patterns of change rather than static ‘snapshots.’” A single blood draw is a snapshot. The exercise study needed three samples in one afternoon to see which change came first.

The connections are the second thing lost. The most common analysis tests each part on its own. A study of methylation can run hundreds of thousands of separate tests, one for each marked site on the genome. Each asks whether that one site differs between two groups, such as people with a disease and people without. But many sites share a cause. In the bees, the marks differ between queen and worker larvae on more than two thousand genes. The food that sent the two larvae down different paths never appears. The analysis hands back a list of sites with no lines drawn between them, like a guest list that never says who came with whom.

That one-at-a-time test, run on DNA, has mapped human height. In 2022, a study led by the geneticist Loïc Yengo pooled the genomes of 5.4 million people. It found 12,111 variants tied to height, each with a tiny effect. Together, in people of European ancestry, they account for about 40 percent of how much heights differ. In people of other ancestries, the share falls to about 10 to 20 percent. Part of the 60 percent of height the variants miss is genetic and not yet mapped.

Height also changes faster than a genome can. In the 1800s, Dutch soldiers averaged about 165 centimeters, shorter than men in most of Europe. Dutch men are now the tallest in the world, about 20 centimeters taller. A rise that fast points to food, health, and living conditions, not to new genes.

Say a youth basketball coach ranks twelve-year-olds by a height score built from those 12,111 variants. A parent shown the ranking can ask which people the score was built on. The score says less for players outside the ancestry it was built on, and nothing about what their childhood meals will add.

How Far the Map Reaches

Reading genes runs into the meals outside the body. Writing new genes into a cell runs into something further out.

Malaria kills close to 600,000 people a year, most of them young children in Africa. One of the main malaria drugs is artemisinin, which comes from a plant called sweet wormwood. The supply of wormwood swings. A short harvest sends the price up, so more farmers plant wormwood. Once their crops flood the market, the price falls, and the next shortage begins.

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Figure 3. A short history of malaria drugs, from NPR’s Skunk Bear (2012), YouTube embed.

In 2003, a team led by the chemical engineer Jay Keasling, at Berkeley, looked for a steadier source. They gave E. coli a chain of genes from baker’s yeast and one gene from wormwood, and the bacteria made an early form of the drug. When the team pushed for more, the cells stalled. Each gene they added did its job. The trouble was their pace.

Donella Meadows calls an amount that builds up or drains over time a stock, like water in a bathtub. Partway down the chain, a compound called HMG-CoA was a stock. One step filled it, the next step drained it, and the filling ran faster than the draining, so the pile rose. HMG-CoA is toxic to E. coli, and the cells grew worse. The fix was more of the draining enzyme. The pile fell, and the cells grew again.

No single gene showed the jam. Finding jams like this one (which parts affect which, in what order, and how fast) is the work of systems biology.

Keasling’s team then moved the work to yeast. In April 2013, the drug company Sanofi started making artemisinin with yeast in Garessio, in northern Italy. That year, the factory made about 8 percent of the world’s supply.

By 2015, farmers had a great year. So much wormwood grew that artemisinin from the plants sold for less than $250 a kilogram. Sanofi needed $350 to $400 to break even. That is at least $100 a kilogram above the plants. Its rivals would not buy from it, and the world wanted no more of the drug than before.

“If that price is already very low and there’s a bumper crop,” Keasling said, “there’s no reason to fire up a fermenter.” The fermenter stood idle. The yeast still knew how to make the drug.

That is where even a full map of the cell stops. No layer inside the yeast held the price of wormwood. Tretter names this as one of three gaps a molecular theory cannot bridge: the gap between an organism and the world around it. The exercise bike left its marks on the muscle within hours. A sample of those marks cannot say which ride left them. Every -ome ends at the edge of what was sampled.

A test report that asks someone to give up a food they eat every day has sampled one layer of their cells. A friend holding such a report can ask three things before giving up the food. What did the test look for? Which people was it built on? What else is the result connected to? The larva’s genes could not say which bee it would become. The jelly in its cell could.

A Closing Reflection. The bike and the price of wormwood were jelly too. Each reached in from outside, touched no gene, and changed what the genes ended up doing.

1. Spot the idle fermenter. Right now, look around for something you paid for that still works and stands unused: a bread maker in the cupboard, an app on the phone in your hand. Nothing inside it broke. What around it changed?
2. Find the jam. Trace back one morning this week when you sped up a step, a quicker commute or an earlier school run, and something further along jammed instead. Where did the pile-up show, a knot in your stomach or a queue at the school gate, and who at home noticed it first?
3. Ask about the key. When the next report tells you to give up a food, from a DNA kit or your next checkup, ask what the test looked for before the shopping changes. One question may keep the cheese on the table. Who would give the food up with you, the one who cooks or the one who shops?

Open a packet of baker’s yeast and smell it. Split the dough: one bowl by a warm window, one in a cool corner. Look again in an hour. Nothing in the packet changed. One bowl was raised like a queen.

Worth remembering Save as image

Your genes are the cookbook, not the dinner. Food and exercise can change which recipes get cooked, so a DNA test can read every page and still miss the meal.

Where This Came From

This piece follows systems thinking into a single cell. Konopka’s post on systems thinking (2026) suggested reading the HMG-CoA jam as a stock. The hive details are standard beekeeping descriptions.

Intellectual Honesty Note. The stakes paragraph’s report is hypothetical, and which keys a kit tests depends on the kit. This piece reads the lactose switch as a balancing loop, the HMG-CoA jam as a stock, and lactase persistence as a reinforcing loop with a grazing ceiling. It adds the exercise loop’s last step, “more capacity for the next ride.” Its points about the ride’s marks and the bees’ sites are its own reading, not a finding. Two terms are simplified: the molecule that pulls the lac repressor off is allolactose, and the stretch of DNA near the lactase gene is an enhancer, which raises a gene’s activity. The exercise study measured one ride. The 60 percent and the $100 gap are subtractions made here from the cited numbers. The protein step and the link from PGC-1α to mitochondria are standard physiology. The bee experiment switched the methylation enzyme off by hand; how much methylation steers caste in an ordinary hive is still debated (Oldroyd and Yagound, 2021).

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