Figure 1. Half an inch thick and still traveling. A paper Stanley from the Flat Stanley Project in Miami Beach, 2011. Photo by Llamabr, CC BY 3.0, via Wikimedia Commons.

A real person pressed flat would keep the crease. Still, the book gets one thing right about proteins, the working parts of a body. The same boy, in a new form, does new jobs: a letter, a kite, a painting. A protein is a chain of small building blocks, and the way the chain folds decides what it does. A body builds its proteins from about 20,000 genes. Some proteins, pulled out straight, fold back on their own, the way Stanley went back to round. Others, once folded wrong, never do, and they can teach the wrong fold to their neighbors.

A day is full of folding. A paper airplane glides across a room because of its creases, and the same sheet folded wrong drops nose first to the floor. A fitted sheet, still warm from the dryer, goes into the closet neatly only with a second pair of hands. A road map folded back in a hurry at a gas station, along the wrong creases, never lies flat in the glovebox again.

In a previous essay, genes were recipes, and copies of them decided which dishes got made. The full spread of dishes, every protein a body can make, has a name: the proteome. A liver cell and a nerve cell keep the same cookbook and serve very different dishes (Figure 2), and the dishes change from hour to hour. The first part of this series followed the letters themselves, a field of sprites in a long row, and the imp that inspects them for slips. The second followed one verse of those letters, a single gene, copied onto a thread and carried out to the counter. The dishes are proteins, and each one is built, then folded, before it can do its job.

Figure 2. Different cells, different dishes. Left: human liver, its cells packed in rows; liver cells make albumin, a protein that carries cargo through the blood. Right: a rat nerve cell, its long arms built on a form of tubulin found in nerve cells, stained green, with a second protein, MAP2, in red along the branches. Liver: Department of Histology, Jagiellonian University Medical College, CC BY-SA 3.0, via Wikimedia Commons. Nerve cell: ZEISS Microscopy, CC BY 2.0, via Wikimedia Commons.

For twenty years, the clipboard form at a US blood drive, at work or at church, asked one question with nothing to do with germs. You take the folding chair with the pen cold in your hand and the air smelling of alcohol swabs, a paper cup of orange juice waiting on the table. “From 1980 through 1996, did you spend time that adds up to three (3) months or more in the United Kingdom?” A yes pressed you flat, like the bulletin board on Stanley: turned away for life. A patient who needed a transfusion lost a donor. The reason was one wrongly folded protein, carried in British beef. In 2022, the FDA dropped the question. If you once checked yes, the chair at the next drive may be yours again, like Stanley pumped back to round. So how does a fold, with no germ in it, keep a donor out of the chair for two decades?

How the Builders Read

In the second part, a quick imp named Quill copied one verse of the field onto a thread. Quill touches down at a cluster of stockier imps, the builders, round-shouldered and built for handling. It hands the thread over and lifts off again.

The builders read the thread three beads at a stretch, always three. Each triplet acts like one word rather than three letters. A builder reads the first triplet and reaches into a supply shelf stocked with tiny colored droplets. The builder pulls out the one droplet that triplet calls for, clips it onto a growing chain, and moves on to the next three beads (Figure 3).

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.

If the inspector had missed a slip back on the field, the builders would never know. The wrong letter is copied into the thread like any other. Its triplet may call for a different droplet, and the builders clip it on without a pause. Some of the changed letters on a person’s gene test report began as slips like this one. A letter gained or lost does more harm: every triplet after it is read out of step.

At last a triplet arrives that calls for no droplet at all. The nearest builder reaches for the shelf, comes back empty-handed, and shrugs. The builders let go of the chain: a long, straight row of droplets with no shine to it yet.

Narrator: The builders are ribosomes, and the droplets are amino acids. Each three-bead word is a codon. Four letters can make 64 different codons. Of those, 61 call in one of twenty amino acids. The other three are stop codons, which tell the ribosome to let the chain go. The whole reading, thread to chain, is translation.

Narrator: The working core of a ribosome, the part that joins each amino acid to the next, is not protein at all. That core is made of RNA, the same kind of molecule as Quill’s thread. An RNA machine strings the chain, and the chain still has to fold before it can do anything.

How a Fold Sets the Job

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.

Narrator: In 1961, Christian Anfinsen unfolded a protein in a strong chemical bath, then washed the chemical away. The chain folded itself back, and it worked again, nearly as well as before. The order of the amino acids alone sets the fold, and the fold sets the job. Two folds turn up again and again. The alpha helix is coiled like a phone cord. The pleated sheet is creased back and forth like a paper fan. Some chains still need help, the second pair of hands on the fitted sheet. Proteins called chaperones hold a new chain so it does not stick to its neighbors before it folds.

Where a wrong letter lands in the fold decides whether it matters. Hemoglobin, the protein that carries oxygen in red blood cells, shows how. One letter in its gene, changed from A to T, swaps one amino acid at position six of its chain. That spot lies on the outside of the fold. Once the oxygen is gone, the spot turns sticky, and the folded proteins stick end to end into long, stiff fibers. The fibers bend a red cell into a curved sickle that jams in small blood vessels. One letter, one droplet, one sticky patch: sickle cell disease. A person with one changed copy of the gene and one normal copy carries sickle cell trait, usually with no symptoms. Two carriers have a one-in-four chance, with each child, of a baby with the disease.

A fold can be built to move, too. Squid make proteins called reflectins that pack into thin stacked plates in their skin (Figure 4). When a nerve signal arrives, the reflectins clump tighter, water squeezes out, and the color slides from red toward blue while a diver watches.

Figure 4. A fold built to move. A Caribbean reef squid at Bari Reef, Bonaire. The shimmer in its skin comes from light bouncing off stacked plates of folded protein, not from pigment. Photo by Betty Wills (2005), CC BY-SA 4.0, via Wikimedia Commons.

A fold can also be lost forever. An egg cracked into a hot pan turns from clear to white in seconds. Heat shakes the egg’s proteins out of their folds, and the open chains grab one another into a solid mesh. Cooled on the plate, the white never turns clear again. Anfinsen’s chains had a dilute bath and room to fold back. In the pan, each open chain meets its neighbors first. Not one letter in the egg changed. Some folds go wrong with every letter in place.

When a Fold Copies Itself

At a wedding banquet, the staff fold hundreds of napkins to match one sample on the first table. If the sample is folded wrong, every napkin copied from it comes out wrong, and the bride’s aunt spots each one. The cloth is the same. Only the fold spreads.

Narrator: A prion, a protein that passes on its wrong fold, works like that sample, with no staff needed. Every person makes a protein called PrP on the surface of nerve cells, folded mostly into coils. Its rogue form has the same chain of amino acids, letter for letter, folded instead into flat sheets. When a rogue copy touches a normal one, it refolds the normal one to match, and each new rogue copy refolds more. The rogue copies pile into clumps that kill nerve cells and leave tiny holes all through the brain (Figure 5). Like the road map’s wrong creases, a prion’s fold survives the ordinary cleaning that sterilizes surgical tools. A few patients caught a prion disease from instruments used on an earlier patient’s brain.

Figure 5. The holes a wrong fold leaves. Brain tissue from a case of vCJD, magnified 100 times. The white holes are the sponge-like change prions cause, and many nerve cells are gone. Photo by Sherif Zaki and Wun-Ju Shieh, CDC, public domain, via Wikimedia Commons.

In the 1950s, doctors in the highlands of Papua New Guinea met a disease the Fore people called kuru, from their word for shaking. Doctors began counting the dead in 1957. By the end of 1961, about a thousand people had died of it, most of them women and children. The Fore honored their dead by eating them at funeral feasts, and the women and children ate the brain. When the feasts stopped in the 1950s, kuru slowly died out. In 1966, Carleton Gajdusek’s team passed it to chimpanzees with brain tissue from patients. In 1982, Stanley Prusiner named the agent a prion, short for an infectious particle made of protein, with no genes of its own.

In 1986, British vets found a new brain disease in cattle, mad cow disease, spread through feed made from the remains of other cattle. In 1996, doctors reported ten young people in the UK with a new form of a human prion disease. It was named variant Creutzfeldt-Jakob disease (vCJD), and it most likely came from beef. In 1999, to keep vCJD out of the US blood supply, the FDA asked blood banks to turn away anyone with six months in the UK. In 2002 the line tightened to three months. Three people in the UK later caught vCJD from a blood transfusion, among the 178 who have died of it there. In 2022 the FDA lifted the deferral.

A prion passes on a fold, not a sequence: a shape copies itself. Other proteins fold wrong and stack too. In Alzheimer’s disease, a short protein called amyloid beta stacks its sheets into the sticky clumps that build up between nerve cells. In 2024, doctors in London described five people who developed Alzheimer’s decades after childhood treatment with growth hormone taken from the brains of the dead. Nothing suggests Alzheimer’s spreads between people in daily life. Can a drug stop a wrong fold, the way it stops a germ?

When the Builders Jam

A dose of azithromycin, a common antibiotic, reaches a germ and jams its builders. Bacteria have builders too, and many antibiotics work this way. The drug clips onto a bacterial ribosome and stops it from reading, and a bacterium that cannot build its proteins cannot grow. Human ribosomes are built differently enough that the drug leaves the body’s own mostly alone.

A cold comes from a virus, and a virus has no builders of its own. It hands its thread to the body’s builders. When a parent brings in a child with a sore throat, one question decides whether an antibiotic can help: is this infection bacterial? Viruses cause most sore throats, and most get better on their own within a week. Strep throat is the common exception, and a quick swab can tell. An antibiotic taken for a cold finds nothing to jam.

A prion gives a drug nothing to jam either: a prion has no builders, just a crease that spreads. Against a fold that copies itself, the guard a blood drive had was a question on a form.

Not every chain the builders make stays where it was built. One of them folds into an imp named Hush, who lays caps on the letters and decides which verses get read at all. A chain the builders let go comes back to choose which threads the builders will be handed next.

A Closing Invitation. Stanley stood for a protein: the same chain, in a new fold, does a new job, and a wrong fold can copy itself. One chain comes back as three checks: its builders, its copied fold, its letter.

1. Look at your last antibiotic. Open the pharmacy app on your phone, or turn the bottle in the cabinet, and watch its date come up. Was it for a cold, a scratchy throat, a cough that cleared in a week? Ask the builders’ question: was that infection bacterial? What will you ask at the next cold?
2. Take the chair back. If a blood drive at work or at church once turned you away from the chair for time in the UK, call the blood bank this month. Ask to be checked again. The question is gone. Who in your family heard that no, and would take the next chair beside you?
3. Ask about the sticky letter. Before a pregnancy, yours or a sibling’s, ask at your next checkup whether either partner carries one copy of the sickle cell letter. A simple blood test, one pinch in the arm, finds it. Two carriers have a one-in-four chance with each child. Who in your family already knows their result?

Stanley went back to round with a pump, and a donor turned away can ask for the chair back with one call. Many proteins fold back on their own, unless a wrong fold has taught them another.

Worth remembering Save as image

Most working parts of your body are proteins: chains folded into shape, the way creases make a paper airplane fly. The crease decides the job, and a wrong crease can spread to other chains of the same kind.

Where This Came From

In 1958, Francis Crick set down what he called the central dogma: “once ‘information’ has passed into protein it cannot get out again.” He meant one thing by information: “the precise determination of sequence.” Prusiner’s prions looked at first like a break in that rule, an infection with no genes. A prion copies no sequence, though. It hands its fold to a chain the cell built from its own gene, so Crick’s rule holds.

Intellectual Honesty Note. The sprites, imps, droplets and the field are invented staging; each mechanism they act out is standard biology, checked in the Narrator’s asides. The ribosome reads codons with the help of transfer RNAs, which the builders’ shelf stands in for. Anfinsen’s experiment used ribonuclease, and his 1961 work was summed up in his 1973 paper. Reflectins change color as many molecules shift together, not as one fold. How a rogue fold kills nerve cells is still debated. The prion form’s coil and sheet contents are from one 1993 measurement. The Flat Stanley plot follows summaries of the 1964 book.

References

AABB Donor History Task Force. (2005). Full-length donor history questionnaire (Version 1.1). AABB.

Alpers, M. P. (2008). The epidemiology of kuru: Monitoring the epidemic from its peak to its end. Philosophical Transactions of the Royal Society B, 363(1510), 3707–3713.

Anfinsen, C. B. (1973). Principles that govern the folding of protein chains. Science, 181(4096), 223–230.

Banerjee, G., Farmer, S. F., Hyare, H., Jaunmuktane, Z., Mead, S., Ryan, N. S., et al. (2024). Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Nature Medicine, 30(2), 394–402.

Brown, J. (1964). Flat Stanley (T. Ungerer, Illus.). Harper & Row.

Brown, P., Brandel, J.-P., Sato, T., Nakamura, Y., MacKenzie, J., Will, R. G., et al. (2012). Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerging Infectious Diseases, 18(6), 901–907.

Centers for Disease Control and Prevention. (n.d.). Healthy habits: Antibiotic do’s and don’ts. Retrieved October 5, 2026, from https://www.cdc.gov/antibiotic-use/about/index.html

Centers for Disease Control and Prevention. (2024, April 17). Sore throat basics. Retrieved October 17, 2026, from https://www.cdc.gov/sore-throat/about/index.html

Centers for Disease Control and Prevention. (2024, May 15). What is sickle cell trait? Retrieved October 17, 2026, from https://www.cdc.gov/sickle-cell/sickle-cell-trait/index.html

Crick, F. H. C. (1958). On protein synthesis. Symposia of the Society for Experimental Biology, 12, 138–163.

DeMartini, D. G., Izumi, M., Weaver, A. T., Pandolfi, E., & Morse, D. E. (2015). Structures, organization, and function of reflectin proteins in dynamically tunable reflective cells. Journal of Biological Chemistry, 290(24), 15238–15249.

Eaton, W. A., & Hofrichter, J. (1990). Sickle cell hemoglobin polymerization. Advances in Protein Chemistry, 40, 63–279.

Food and Drug Administration. (2022). Recommendations to reduce the possible risk of transmission of Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease by blood and blood components: Guidance for industry. Notice of availability, Federal Register, 87(100), May 24, 2022.

Gajdusek, D. C., Gibbs, C. J., & Alpers, M. (1966). Experimental transmission of a kuru-like syndrome to chimpanzees. Nature, 209(5025), 794–796.

Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature, 475(7356), 324–332.

Ingram, V. M. (1957). Gene mutations in human haemoglobin: The chemical difference between normal and sickle cell haemoglobin. Nature, 180(4581), 326–328.

McGee, H. (2004). On food and cooking: The science and lore of the kitchen (Rev. ed.). Scribner.

National CJD Research & Surveillance Unit. (2025). Variant CJD cases worldwide and CJD monthly statistics. University of Edinburgh. Retrieved October 17, 2026, from https://www.cjd.ed.ac.uk/surveillance/data-and-reports

National Human Genome Research Institute. (n.d.). Codon. In Talking glossary of genomic and genetic terms. Retrieved October 17, 2026, from https://www.genome.gov/genetics-glossary/Codon

National Human Genome Research Institute. (n.d.). Translation. In Talking glossary of genomic and genetic terms. Retrieved October 4, 2026, from https://www.genome.gov/genetics-glossary/Translation

National Library of Medicine. (2000). Proteome. In Medical Subject Headings (MeSH, D020543). Retrieved October 17, 2026, from https://meshb.nlm.nih.gov/record/ui?ui=D020543

Nissen, P., Hansen, J., Ban, N., Moore, P. B., & Steitz, T. A. (2000). The structural basis of ribosome activity in peptide bond synthesis. Science, 289(5481), 920–930.

Pan, K.-M., Baldwin, M., Nguyen, J., Gasset, M., Serban, A., Groth, D., et al. (1993). Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proceedings of the National Academy of Sciences, 90(23), 10962–10966.

Pauling, L., & Corey, R. B. (1951). The pleated sheet, a new layer configuration of polypeptide chains. Proceedings of the National Academy of Sciences, 37(5), 251–256.

Pauling, L., Corey, R. B., & Branson, H. R. (1951). The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain. Proceedings of the National Academy of Sciences, 37(4), 205–211.

Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science, 216(4542), 136–144.

Wells, G. A. H., Scott, A. C., Johnson, C. T., Gunning, R. F., Hancock, R. D., Jeffrey, M., et al. (1987). A novel progressive spongiform encephalopathy in cattle. Veterinary Record, 121(18), 419–420.

Will, R. G., Ironside, J. W., Zeidler, M., Cousens, S. N., Estibeiro, K., Alperovitch, A., et al. (1996). A new variant of Creutzfeldt-Jakob disease in the UK. The Lancet, 347(9006), 921–925.

Wills, B. (2005). Caribbean Reef Squid colors [Photograph]. Wikimedia Commons. CC BY-SA 4.0.

Wilson, D. N. (2014). Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology, 12(1), 35–48.

Near the edge of the frame, a few cells hang straight down, long and bumpy, like peanut shells made of wax (Figure 1). In each one, a larva floats on a pool of thick white jelly, far more than it can eat.

Figure 1. Two queen cells on the comb, one turn of a loop. A larva fed royal jelly in each will come out a queen, and the queen will lay the eggs of the workers who feed the next one. Photograph by Piscisgate (2014), Wikimedia Commons, CC BY-SA 4.0.

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 (Figure 2), 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 2. 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.

Think of a larva’s genes as a cookbook. Each gene is a recipe for one molecule the body uses, and every larva in the hive carries the same book. Cells can stick small chemical marks onto some of the recipes, like notes in the margin that say “skip this one.” Biologists call them methylation marks. They help decide which recipes the cell cooks and which it skips.

In 2008, a team at the Australian National University, in Canberra, tested whether those notes were what the jelly changed. The team switched off one gene in newly hatched larvae: the recipe for the enzyme that writes the notes. Then they fed the larvae a worker’s diet. Most of them came out as queens, with full ovaries. The team called the result “a royal jelly-like effect.” Each larva kept the cookbook it was born with. What changed was which recipes got cooked.

Which bee each larva became depended on what its cookbook was connected to: the notes, the food, and the workers who chose which larvae to feed. Any cookbook raises five questions: what it counts, what it keeps, what it answers, what it misses, and what it cannot decide.

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 puts the recipe for digesting milk away after childhood. Some people carry a one-letter difference in the cookbook that keeps the recipe in use. In Europe, most people who have one share the same spelling. Many families who kept cattle in East Africa carry a different spelling that keeps the same recipe in use. Say the test looks only for the European spelling. A person who carries the East African one gets a report that finds nothing it knows and says the recipe is closed. That person gave up milk for nothing. The test read the right page, looked for the wrong spelling, and 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?

What the Cookbook Counts

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 human DNA would turn out to hold. Biology was about to get its first full cookbook for a person: every gene, every recipe (Figure 3).

Figure 3. The human genome printed as books at the Wellcome Collection, in London: a volume or more for each chromosome, from 1 to 22, then X and Y, in type almost too small to read. Photograph by Russ London (2010), Wikimedia Commons, CC BY-SA 3.0.

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. A person and a worm carry cookbooks of about the same size, so the number of recipes 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. Here the parts are the genes, and the rules decide which recipes get cooked, when, and how much. Two kitchens with the same book can serve very different dinners.

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.

In this piece’s kitchen, the genome is the cookbook, and the epigenome is the notes in its margins. 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 book also closes some recipes on its own schedule, and a single letter can keep one open for life.

What the Cookbook Keeps

Milk is the recipe most bodies put away. Babies make their own enzyme for lactose, the sugar in milk. The enzyme is called lactase, and in most mammals the body stops making it after weaning. A short stretch of DNA near the gene closes the recipe after childhood. In about a third of adults alive today, the recipe stays open. The European spelling is a single changed letter in that stretch, and it keeps lactase coming for life.

The East African spellings are other one-letter differences 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. It had spread fast, over roughly the last seven thousand years.

Why keep that page open? Herds. Herds put fresh milk within reach. Adults who carried the spelling could digest the milk, got more food from it, and more of their children lived to carry the spelling too. The more people could drink milk, the more a herd was worth, and herding spread further. In Meadows’ terms for feedback, that is a reinforcing loop: 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. The cookbook kept the page. The herds outside made it worth keeping.

A DNA sample can show which spelling someone carries. It cannot show the herds that made the spelling 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 spellings 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 spelling the family carries. A parent who already cut the milk can still ask.

What the Cookbook Answers

The herds and their milk changed the book over thousands of years. The body asks the book questions every day, and it answers within hours.

In 2012, Romain Barrès and his colleagues put eight sedentary men on an exercise bike twice, at least a week apart. One ride was easy, at 40 percent of each man’s maximum effort, and one was hard, at 80 percent. Both rides stopped once the rider had burned 400 calories. With a needle, the researchers took small plugs of thigh muscle before each ride, right after it, and three hours later.

One recipe they read was PGC-1α, which tells a cell to build more of its energy supply. Right after the hard ride, the notes on PGC-1α had dropped to about half their resting level. Three hours later, the muscle was cooking that recipe several times as much as at rest. After the easy ride, the notes barely moved, yet the recipe still got cooked more. The notes are one rule among several.

That energy supply is mitochondria (Figure 4), 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 notes. The notes change which recipes get copied out to the counter, a layer called the transcriptome. The copies change which dishes get made, the proteome. The dishes change what the body can do on the next ride. The cookbook answers the ride, and the answer shapes the next question.

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Figure 4. 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.

To see the answer, the team had to sample the muscle three times in one day. 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.’” One tube is a snapshot. It can show the notes in the margins, but not which ride wrote them.

What the Cookbook Misses

Reading 5.4 million genomes still left out the meals. In 2022, a study led by the geneticist Loïc Yengo pooled those genomes. It found 12,111 small spellings 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 other ancestries, the share falls to about 10 to 20 percent. Part of the 60 percent the spellings miss is genetic and not yet mapped.

The rest sits on the plate. 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. They stand about 20 centimeters taller, most of a head above those soldiers. A cookbook cannot change that fast. Food, health, and living conditions can.

Say a youth basketball coach ranks twelve-year-olds by a height score built from those 12,111 spellings and cuts the bottom three. 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.

What the Cookbook Cannot Decide

A cell can hold a recipe and still never cook it.

Malaria kills close to 600,000 people a year, most of them young children in Africa. One of the main malaria drugs is artemisinin (Figure 5), 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 5. 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 copied recipes from baker’s yeast and one from wormwood into E. coli, and the bacteria made an early form of the drug. The team then moved the work into yeast itself. 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. Sanofi’s 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, the steel tank where the yeast grows, stood idle. The yeast still had the recipe. The price of wormwood decided.

That is the edge of every cookbook. No page inside the yeast held the price of wormwood. The jelly, the herds, the ride, the meals and the market all came from outside the book, and each one decided what got cooked.

A test report that says to give up a daily food has read one book. A friend holding such a report can ask three things first. What did the test look for? Which people was it built on? What else is the result connected to? The larva’s cookbook could not say which bee it would become. The jelly in its cell could.

A Closing Reflection. The cookbook counted, kept, answered and missed, and it did not decide. The jelly, the herds, the ride, the plate and the price of wormwood each changed which recipes reached the table, and none rewrote a recipe.

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. It still has its recipe. What around it changed?
2. Read the margin notes. Think back to one habit that changed this year. Something around you changed first: a new gym on your street, an office move that added forty minutes to the commute, a friend who started walking at six. Which of your own recipes got cooked more, which got skipped, and who at home noticed first?
3. Ask which spelling. 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. Same packet, same recipe. One bowl rose like a queen.

Worth remembering Save as image

You can read every page of the cookbook and still not know what is for dinner. Your genes hold the recipes; what gets cooked is decided outside the book.

Where This Came From

This piece follows systems thinking into a single cell. Konopka’s post on systems thinking (2026) started it.

Intellectual Honesty Note. The cookbook is this piece’s image, not a biologist’s term: genes as recipes, methylation marks as notes in the margin, gene variants as spellings, RNA copies as recipes copied out, proteins as dishes. A methylation mark does not always mean “skip”; on the genes in the exercise study, fewer marks went with more activity. The hive scene is built from standard beekeeping descriptions, not one hive.

The stakes paragraph’s report is hypothetical, and which spellings a kit tests depends on the kit. This piece reads 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 point about a snapshot not naming the ride is its own reading, not a finding. The stretch of DNA near the lactase gene is an enhancer, which raises a gene’s activity; “closes the recipe” simplifies how it is turned down. The exercise study measured single rides, not months of training. The 60 percent and the $100 gap are subtractions made here from the cited numbers, and the ride’s “about half” and “several times” are read off the exercise paper’s Figure 2. 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).

References

Altun, Z. F., & Hall, D. H. (2009). Introduction. In WormAtlas. https://doi.org/10.3908/wormatlas.1.1

Barrès, R., Yan, J., Egan, B., Treebak, J. T., Rasmussen, M., Fritz, T., et al. (2012). Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metabolism, 15(3), 405–411. https://doi.org/10.1016/j.cmet.2012.01.001

Buttstedt, A., Ihling, C. H., Pietzsch, M., & Moritz, R. F. A. (2016). Royalactin is not a royal making of a queen. Nature, 537(7621), E10–E12.

Enattah, N. S., Sahi, T., Savilahti, E., Terwilliger, J. D., Peltonen, L., & Järvelä, I. (2002). Identification of a variant associated with adult-type hypolactasia. Nature Genetics, 30(2), 233–237.

Gerbault, P., Liebert, A., Itan, Y., Powell, A., Currat, M., Burger, J., et al. (2011). Evolution of lactase persistence: An example of human niche construction. Philosophical Transactions of the Royal Society B, 366(1566), 863–877.

Howard, L. (n.d.). Mitochondria, mammalian lung – TEM [Electron micrograph]. Wikimedia Commons, public domain. https://commons.wikimedia.org/wiki/File:Mitochondria,_mammalian_lung_-_TEM.jpg

Kamakura, M. (2011). Royalactin induces queen differentiation in honeybees. Nature, 473(7348), 478–483.

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

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

Martin, V. J. J., Pitera, D. J., Withers, S. T., Newman, J. D., & Keasling, J. D. (2003). Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nature Biotechnology, 21(7), 796–802.

Meadows, D. H. (2008). Thinking in Systems: A Primer. Chelsea Green.

National Human Genome Research Institute. (n.d.). Epigenome. In Talking Glossary of Genomic and Genetic Terms. https://www.genome.gov/genetics-glossary/Epigenome

National Human Genome Research Institute. (n.d.). Gene Sweepstakes (GeneSweep). https://www.genome.gov/virtual-exhibits/GeneSweep

National Human Genome Research Institute. (n.d.). Genome. In Talking Glossary of Genomic and Genetic Terms. https://www.genome.gov/genetics-glossary/Genome

NCD Risk Factor Collaboration. (2016). A century of trends in adult human height. eLife, 5, e13410.

NPR. (2012, December 17). Herbs and empires: A brief history of malaria drugs | Skunk Bear [Video]. YouTube. https://www.youtube.com/watch?v=IrNL27eWKOI

Oldroyd, B. P., & Yagound, B. (2021). The role of epigenetics, particularly DNA methylation, in the evolution of caste in insect societies. Philosophical Transactions of the Royal Society B, 376(1826), 20200115.

Paddon, C. J., Westfall, P. J., Pitera, D. J., Benjamin, K., Fisher, K., McPhee, D., et al. (2013). High-level semi-synthetic production of the potent antimalarial artemisinin. Nature, 496(7446), 528–532.

PATH. (2013, April 11). Sanofi and PATH announce the launch of large-scale production of semisynthetic artemisinin against malaria. https://www.path.org/our-impact/media-center/sanofi-and-path-announce-the-launch-of-large-scale-production-of-semisynthetic-artemisinin-against-malaria/

Pedaling to the Top. (2025, January 23). Improve your mitochondria, improve your cycling [Video]. YouTube. https://www.youtube.com/watch?v=sy-4P_aN97k

Peplow, M. (2016). Synthetic biology’s first malaria drug meets market resistance. Nature, 530(7591), 389–390.

Piscisgate. (2014). Honeybee queen cells 14 [Photograph]. Wikimedia Commons, CC BY-SA 4.0. https://commons.wikimedia.org/wiki/File:Honeybee_queen_cells_14.jpg

Ro, D.-K., Paradise, E. M., Ouellet, M., Fisher, K. J., Newman, K. L., Ndungu, J. M., et al. (2006). Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 440(7086), 940–943.

Russ London. (2010). Wellcome genome bookcase [Photograph]. Wikimedia Commons, CC BY-SA 3.0. https://commons.wikimedia.org/wiki/File:Wellcome_genome_bookcase.png

SciShow. (2015, July 6). How bees choose their queen [Video]. YouTube. https://www.youtube.com/watch?v=m_SlH3Uwslc

Senge, P. M. (1990). The Fifth Discipline: The Art and Practice of the Learning Organization. Doubleday.

Spieth, J., & Lawson, D. (2006). Overview of gene structure. In WormBook. https://www.ncbi.nlm.nih.gov/books/NBK19701/

Stulp, G., Barrett, L., Tropf, F. C., & Mills, M. (2015). Does natural selection favour taller stature among the tallest people on earth? Proceedings of the Royal Society B, 282(1806), 20150211.

Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., et al. (2007). Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genetics, 39(1), 31–40.

Visscher, P. M., Medland, S. E., Ferreira, M. A. R., Morley, K. I., Zhu, G., Cornes, B. K., et al. (2006). Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings. PLoS Genetics, 2(3), e41.

World Health Organization. (2024). World malaria report 2024: Addressing inequity in the global malaria response. World Health Organization.

Yengo, L., Vedantam, S., Marouli, E., Sidorenko, J., Bartell, E., Sakaue, S., et al. (2022). A saturated map of common genetic variants associated with human height. Nature, 610(7933), 704–712.