The Sunday Read: ‘The Woman Who Could Smell Parkinson’s’

[0] Smell is a powerful sensory capability.

[1] It's the most evocative sense we have, the one most bound up with memory.

[2] And we and other animals use it to do some really remarkable stuff.

[3] All sorts of species, fish, birds, probably elephants, rely on smell to guide them on their great migrations, for example.

[4] Rats can sniff out landmines.

[5] And yet, of our various senses, smell is also the one that we tend to neglect.

[6] We treat it as if it were a little bit primitive, sort of childish, or generally unserious.

[7] You might say we look down our noses at smell.

[8] And so when a woman in Scotland realized that she could actually smell Parkinson's disease, that the illness itself gave off what was to her this intense, musty, oily, odor and gave it off years before a diagnosis, It took a little while before doctors and scientists really began to listen.

[9] My name is Scott Sayer, and I'm a contributor to the New York Times magazine.

[10] For a recent piece, I spent a bunch of time with Joy Milne, a Scottish retiree with a really extraordinary nose, and you'll hear about her in this week's Sunday read.

[11] Joy's always been a hyperosmic, or what's maybe better known as a super -smeller.

[12] She actually makes serious adaptations to her life in order to avoid certain sense.

[13] She'll only drink water that comes from a spring, for instance.

[14] She changes sidewalks to avoid the stink of men's spray deodorant, which she particularly detests.

[15] So one day, many years ago, Joy caught a whiff of something new on her husband, a peculiar, unpleasant scent, something stale and thick.

[16] It was only much later, years after he'd been.

[17] diagnosed with Parkinson's, that she realized that everyone else she met with Parkinson's smelled exactly the same as he did.

[18] When Joy first told scientists about this bizarre realization, not too many of them took her seriously, but then they ran some initial tests, and those tests showed that Joy was absolutely, unequivocally, capable of telling Parkinson's patients from people without the disease.

[19] they've also now studied her nose quite extensively, and they're using the particulars of what she smells to develop an early diagnostic test for Parkinson's.

[20] That's a kind of test that doesn't exist yet for the disease, and one researcher told me it's a kind of holy grail for the field.

[21] Joy's ability has profoundly shaped her life, as you might imagine, and it might one day shape the lives of many, many other people.

[22] But to me, what Joy's really doing is seeing.

[23] where until now medicine has only been able to look and she's seeing with her nose so here's my article the woman who could smell Parkinson's read by Robert Petcoff our audio producer today is Adrian Hurst the original music you'll hear was written and performed by Aaron Esposito as a boy Les Milne carried an air of triumph about him and an air of sorrow Les was a particularly promising and energetic young man, an all -Scottish swim champion, head boy at his academy in Dundee, a top student bound for medical school.

[24] But when he was young, his father died.

[25] His mother was institutionalized with a diagnosis of manic depression, and he and his younger brother were effectively left to fend for themselves.

[26] His high school girlfriend Joy was drawn to him as much by his sadness as his talents, by his yearning for her care.

[27] We were very, very much in love, Joy, now a flaxen -haired 72 -year -old grandmother told me recently.

[28] In a somewhat less conventional way, she also adored the way Les smelled, and this aroma of salt and musk accented with a suggestion of leather from the carbolic soap he used at the pool formed for her a lasting sense of who he was.

[29] It was just him, Joy said, A steadfast marker of his identity, no less distinctive than his face, his voice, his particular quality of mind.

[30] Joy's had always been an unusually sensitive nose, the inheritance she believes of her maternal line.

[31] Her grandmother was a hyper osmic, and she encouraged Joy as a child to make the most of her abilities, quizzing her on different varieties of rose, teaching her to distinguish the scent of the petals, from the scent of the leaves, from the scent of the pistols and stamens.

[32] Still, her grandmother did not think odor of any kind to be a polite topic of conversation, and however rich and enjoyable and dense with information the olfactory world might be, she urged her granddaughter to keep her experience of it to herself.

[33] Les only learned of Joy's peculiar nose well after their relationship began on a trip to the Scandinavian Far North.

[34] Joy would not stop going on about the creamy odor of the tundra, or what she insisted was the aroma of the cold itself.

[35] Joy planned to go off to university in Paris or Rome.

[36] Faced with the prospect of tending to his mother alone, however, Les begged her to stay in Scotland.

[37] He trained as a doctor, she as a nurse.

[38] They married during his residency.

[39] He was soon the sort of capable young physician one might hope to meet, a practitioner of uncommon enthusiasm.

[40] And shortly after his 30th birthday, he was appointed consultant anesthesiologist at Macclesfield District General Hospital outside Manchester in England, the first in his graduating class to make consultant.

[41] The Milnes installed themselves in an ancient stone farmhouse high on a country hill in Cheshire.

[42] By then, they had three young sons, and the edifice, which was old enough to be listed in the Doomsday Book of 1086, was a happy, never -ending project.

[43] They threw elaborate, boozy dinner parties.

[44] They kept geese and hens and took in stray cats, dogs, a duck.

[45] We just seemed to get on and do things, Joy told me. Friends still likened her to Mary Poppins, part twinkly magic, part no frills practicality.

[46] She considers herself to be a never -stop person, she said.

[47] Her husband was the same.

[48] Les spent long hours in the surgical theater, which in Macclesfield had little in the way of ventilation, and Joy typically found that he came home smelling of anesthetics, antiseptics, and blood.

[49] But he returned one August evening in 1982, shortly after his 32nd birthday, smelling of something new and distinctly unsavory, of some thick must.

[50] From then on, the odor never ceased, though neither Les.

[51] nor almost anyone but his wife could detect it.

[52] For joy, even a small shift in her husband's aroma might have been cause for distress, but his scent now seemed to have changed fundamentally as if replaced by that of someone else.

[53] She thought he smelled vaguely of his mother.

[54] Les had lately begun to change in other ways, however, and soon the smell came to seem almost trivial.

[55] It was as if his personality had shifted, Les had rather suddenly become detached, ill -tempered, apathetic.

[56] He ceased helping out with many household chores.

[57] He snapped at his boys.

[58] At parties out, he took to behaving in an excessive, theatrically buoyant way before returning home to collapse in exhaustion.

[59] Joy felt these performances were meant in part to spite her, to prove that her complaints about his new demeanor were unfounded.

[60] There was no empathy, she says.

[61] An odd physical deterioration also seemed to have begun.

[62] At the house, he was awkward with the mower.

[63] On a vacation to the Scottish coast, he and his sons took sailing lessons.

[64] The boys took to it quickly, but Les could not work out the timing.

[65] A golf club slipped from his hands mid -swing.

[66] Playing darts at a friend's house, he somehow managed to throw one into his foot.

[67] Les' sleep, too, was increasingly disturbed and bizarrely, he began acting out his dreams.

[68] He once dreamed of catching a burglar.

[69] Joy lied to friends and colleagues about the source of the bruises she was left with, thinking no one would believe that her husband had attacked her as he slept, nor, at Les' unequivocal demand, did she speak a word of his newfound impotence.

[70] In private, he laid the blame on her.

[71] She had grown too fat, he said, to be of any possible interest.

[72] The man Joy married had no such cruelty in him.

[73] She considered leaving.

[74] After more than a decade of alienation and resentment, however, it began to occur to her that the changes in her husband might have some organic cause, that they might be symptoms of some disease.

[75] When he began referring to the other person, a shadow off to his side, she suspected a brain tumor.

[76] Eventually she prevailed upon him to see his doctor, who referred him to a neurologist in Manchester.

[77] Parkinson's disease is typically classed as a movement disorder, and its most familiar symptoms, tremor, rigidity, a slowing known as Brady -Kinesia, are indeed motoric.

[78] But the disease's autonomic, psychological, and cognitive symptoms are no less terrible and commonly begin during the so -called prodrome, years before any changes in movement.

[79] and yet they do not suggest a diagnosis.

[80] Irritability, fatigue, troubled sleep, these are extremely common among the well, and among the infirm they can be associated with any number of conditions.

[81] In Parkinson's, it is only in retrospect that they are revealed to have been the first trace of the illness.

[82] For Les, Joy realized, the symptoms had begun nearly a decade and a half before he saw a doctor.

[83] Had it only been possible then to see them for what they were, she thought, to reach a diagnosis when they first emerged, so much confusion, so much resentment, and so much pain might have been averted.

[84] Of the truly devastating diseases of neurodegeneration, Parkinson's is, after Alzheimer's, the most prevalent.

[85] It is also said to be among the most treatable.

[86] The existing therapies address its symptoms alone, however.

[87] There is no cure, no intervention to halt the progression of the disease or reverse its damage to the brain.

[88] The great difficulty of early diagnosis is perhaps the principal hurdle.

[89] Parkinson's disease is still diagnosed essentially as it was 200 years ago on the basis of its characteristic motor symptoms.

[90] Yet by the time these emerge, most of the neurons it will kill have already died.

[91] Trying to rescue the brain from that level of damage is very difficult, says David T. Dexter, a neuropharmacologist who oversees research at the Medical Foundation, Parkinson's UK.

[92] You're trying to close the stable door after the horse has bolted, really.

[93] For a disease -modifying therapy to have a meaningful shot at efficacy, it would most likely need to be applied far earlier, years or even decades before most patients are currently diagnosed.

[94] Tilo Kunat, a professor at the University of Edinburgh, told me that an early diagnostic was a sort of holy grail for the field, the prerequisite for almost everything else.

[95] The Michael J. Fox Foundation for Parkinson's Research, the world's largest non -profit funder of Parkinson's science, has spent more than $900 million looking for such a biomarker.

[96] With the exception of one that involves a spinal tap, which considerably limits its utility, almost nothing has shown promise.

[97] Les was 44.

[98] He began treatment with el -dopa, the amino acid that has now been the standard of care in Parkinson's disease for 60 years.

[99] El -dopa is extremely well -tolerated, but over time, its efficacy fluctuates and wanes.

[100] At a certain point, the dopamine agonist repineral was added to Les's regimen.

[101] It was reasonably effective, but also, as Joy put it to me, vile.

[102] Later, she came to believe it was the cause of much of the inappropriate behavior her husband soon began to display.

[103] At the time, she had no explanation.

[104] Dopamine agonists are now recognized to cause severe problems of impulse control, and Parkinson's patients often develop addictions to shopping or gambling.

[105] In Les, the problems were in the realm of sexuality.

[106] He stockpiled pornography and boasted of his sexual prowess to appalled younger women.

[107] At a party at the house in Cheshire shortly after his retirement at 50, his fatigue in particular had become unmanageable, Les came down the stairs in tartan patterned underwear, sat in the lap of a female guest, and turned to the onlookers in glee.

[108] The symptoms of the disease itself worsened too.

[109] Les's voice quieted and he developed a slow shuffling gait, often freezing mid -stride.

[110] soon he could no longer dress himself he began wearing diapers his sleep was ever more irregular the effects of his medication were also less and less predictable and he seemed to flip randomly from relatively functional on periods to off periods of uncontrollable dyskinesia and despair Alzheimer's is often called the long goodbye but the term is a no less accurate description of parkinson's in which patients bear the added pain of self -awareness, of recognizing that a gulf has opened between themselves and the kingdom of the well, and of watching it grow wider each day.

[111] A friend of joys, Catherine Havranick, had a husband, Yvonne, who likewise had Parkinson's.

[112] Ivan was a devoted amateur cellist.

[113] He chose to turn in his cherished instrument while he was still capable of carrying it up the stairs to the dealer on his own.

[114] He said that it was too good a chance.

[115] He said that it was too good chello to waste on him, Catherine told me. Joy's life was given over almost entirely to Les's care, as well as to the care of his chaotic mother, Helen.

[116] When Les was diagnosed, she really went off the deep end, Joy told me. Helen was once again placed in a psychiatric ward, and she then moved in with Joy and Les.

[117] Soon thereafter, Helen herself was diagnosed with Parkinson's.

[118] In retrospect, it seemed almost certain that her long -standing psychiatric problems were in fact manifestations of the disease, misread for decades by doctors who conceived of Parkinson's as a movement disorder alone, and one erroneously thought to be quite rare in women.

[119] After Helen's death, Joy and Les returned to Scotland, settling in Perth, a town in the Midlands.

[120] They were ever more estranged from each other, locked in their tense routine.

[121] They knew no one.

[122] Feeling desperate, joy of eventually persuaded Les to go with her to a meeting of local Parkinson's patients and their caregivers.

[123] The room was half full by the time they arrived.

[124] Near the coatstand, Joy squeezed behind a man just as he was taking off his jacket and suddenly felt a twitch in her neck as if some fight or flight instinctive had been activated and she raised her nostrils instinctively to the air.

[125] She often had this reaction to strong, unexpected sense.

[126] In this case, bizarrely.

[127] It was the disagreeable odor that had hung about her husband for the past 25 years.

[128] The man smelled just like him, Joy realized.

[129] So, too, did all the other patients.

[130] The implications struck her immediately.

[131] For nearly all the recorded history of medicine, and until only quite recently, smell was a central preoccupation.

[132] The miasma theory of disease, predominant until the end of the 19th century, held that illnesses of all kinds were spread by noxious odors.

[133] By a similar token, particular scents were understood to be curative or prophylactic.

[134] More than anything, however, odor was a tool of diagnosis.

[135] The ancients of Greece and China confirmed tuberculosis by tossing a patient's sputum onto hot coals and smelling the fumes.

[136] Typhoid fever has long been known to smell of baking bread.

[137] Yellow fever smells of raw meat.

[138] The metabolic disorder phenoketonuria was discovered by way of the musty smell it leaves in urine, while fish odor syndrome or trimethylaminuria is named for its scent.

[139] Dogs are able to smell an extraordinary range of illnesses, including COVID -19, though they have been tested most extensively for cancers.

[140] In one famous case from 1989 reported in The Lancet, a woman in England noticed that her Doberman -Border collie cross had begun sniffing intently at a small mole on her leg.

[141] After several months, the dog tried to bite it off.

[142] This caused the woman to see a doctor.

[143] It was a malignant melanoma.

[144] Most diseases can be identified by methods more precise and ostensibly scientific than aroma, however, and we tend to treat odor in general as a sort of taboo.

[145] A venerable intellectual tradition has associated olfaction with the primitive and the childish, writes Mark Jenner, a professor of history at the University of York.

[146] Modern doctors are trained to diagnose by inspection, palpation, percussion, and auscultation.

[147] Inhalation is not on the list, and social norms would discourage it if it were.

[148] During her time as a nurse, Joy had done it anyway, reflexively, and learned to detect the acetone breath that signaled an impending diabetic episode, the wet brown cardinal.

[149] aroma of tuberculosis, not wet white cardboard because wet white cardboard smells completely different, she explained, or the rancidness of leukemia.

[150] The notion that Parkinson's might have a distinctive scent of its own had not occurred to her then, but when it did occur to her years later, it was hardly exotic.

[151] She and Les worried that the normosmics of the world, unfamiliar with medical smells and disinclined to talk about odor in general might not take her discovery very seriously.

[152] They searched for an open -minded scientist and after several weeks settled on Kuhnaut, the Parkinson's researcher at the University of Edinburgh.

[153] In 2012, Joy attended a public talk he gave.

[154] During the question and answer session, she stood to ask, do people with Parkinson's smell different, Kuhnaut recalls?

[155] I said, do you mean, do people with Parkinson's lose their sense of smell?

[156] Smell loss is, in fact, a common early symptom of the disease.

[157] And she said, no, no, no. I mean, do they smell different?

[158] And I was just like, uh, no. Joy went home.

[159] Kuhnott returned to his usual work.

[160] Six months later, however, at the urging of a colleague who had once been impressed by cancer -sniffing dogs, Kuhnaut found Joy's name and called her.

[161] She told him the story of Les's new smell.

[162] I think if she'd told me that as he got Parkinson's, he had a change in smell, or if it came afterwards, I probably wouldn't have followed up anymore, Kuhnaud told me, but it's this idea that it was years before.

[163] He called Pertita Barron, an analytical chemist, to ask what she made of Joy's claims.

[164] Faron suspected Joy was simply smelling the usual odor of the elderly and infirm and misattributing it to Parkinson's.

[165] I knew because we all know that old people are more smelly than young people, says Baron, who is now a professor of mass spectrometry at the University of Manchester.

[166] Still, Baron was personally acquainted with the oddities of olfaction.

[167] Following a bike accident, she had for several years experienced various bizarre distortions to her own sense of smell.

[168] The idea that Joy might be capable of experience odors that no one else could, did not strike her as entirely outlandish.

[169] She and Coonaut ran a small pilot study in Edinburgh.

[170] Through Parkinson's UK, they recruited 12 participants, six local Parkinson's patients, and six healthy controls.

[171] Each participant was asked to wear a freshly laundered t -shirt for 24 hours.

[172] The worn shirts were then cut in half down the center, and each half was placed in its own sealed plastic bag.

[173] Koonot oversaw the testing.

[174] Joy smelled the T -shirt halves at random and rated the intensity of their Parkinsonian odor.

[175] She would find a positive one and would say, there, it's right there.

[176] Can you not smell it?

[177] Kuhnott recalled.

[178] Neither he nor the graduate student assisting him could smell a thing.

[179] Kuhnott unblinded the results at the end of the day.

[180] We were on a little bit of a high, he recalled.

[181] Not only had Joy correctly identified each sample belonging to a Parkinson's patient, but she was also able by smell to match each sample half to its partner.

[182] Barron's skepticism evaporated.

[183] Still, Joy's record was not perfect.

[184] She had incorrectly identified one of the controls as a Parkinson's patient.

[185] The researchers wondered if the sample had been contaminated, or if Joy's nose had simply gotten tired.

[186] By Baron's recollection, Kuhnaut's response was, It's fine, it's one false positive.

[187] Baron herself was slightly more cautious.

[188] Joy had mislabeled both halves of the man's t -shirt.

[189] Of more immediate interest, though, was the question of what was causing the smell in the first place.

[190] The odor seemed to be concentrated not in the armpits, as the researchers had anticipated, but at the neckline.

[191] It took them several weeks to realize that it perhaps came from sebum, the lipid -rich substance secreted by the skin.

[192] Sebum is among the least -studied biological substances.

[193] It is actually another waste disposal for our system, Barron says, but no one had ever thought that this was a bodily fluid we could use to find out about disease.

[194] Barron set out to analyze the sebum of Parkinson's patients, hoping to identify the particular molecules responsible for the smiths.

[195] joy detected.

[196] A chemical signature of the disease, one that could be detected by machine and could thus form the basis of a universal diagnostic test, a test that ultimately would not depend on joys or anyone else's nose.

[197] No one seemed to be interested in funding the work, though.

[198] There were no established protocols for working with Sebum and grant reviewers were unimpressed by the tiny pilot study.

[199] They also appeared to find the notion of studying a grandmother's unusual olfactory abilities to be faintly ridiculous.

[200] The response was effectively, Oh, this isn't science.

[201] Science is about measuring things in the blood, Barron says.

[202] Barron turned to other projects.

[203] After nearly a year, however, at a Parkinson's event in Edinburgh, a familiar -looking man approached Koonot.

[204] He had served as one of the healthy controls in the pilot study.

[205] You're going to have to put me in the other category, he said, according to Koonot.

[206] The man had recently been diagnosed with Parkinson's.

[207] Koonot was stunned.

[208] Joy's misidentification had not been an error, but rather an act of clairvoyance.

[209] She had diagnosed the man before medicine could do so.

[210] Funding for a full study of joy, the smell and its chemical components now came through.

[211] We saw something in the news and we thought, wow, we've got to act on that, says Samantha Hutton, the director of translational research at the Michael J. Fox Foundation.

[212] The NIH is not going to fund that.

[213] Who's going to fund it, if not us?

[214] At 25 NHS clinics in England and Scotland, Barron arranged for nurses to swab the upper backs of Parkinson's patients with small squares of medical gauze and to mail her the samples by standard post.

[215] Unlike blood, sebum does not require a cold chain.

[216] In Manchester, she and her colleagues fed the samples into a gas chromatograph mass spectrometer.

[217] A GCMS machine separates a substance into its component molecular parts for identification.

[218] It cannot tell you how they smell, however, or even if they smell at all.

[219] Like all sense perceptions, smell is the brain's internal representation of the outside world.

[220] Without a nose and brain to translate it into scent, a molecule is simply a molecule.

[221] What it is about any particular molecule that causes it to smell the way it does is one of the great outstanding mysteries of the senses.

[222] Barron added an odor port to the usual GCMS setup, a rather goofy two -foot length of tube that resembled an elephant's trunk emerging from the side of the machine.

[223] Joy was positioned there, breathed, in each type of molecule as it came off the separation column.

[224] Of the more than 200 molecular fragments the machine distinguished, Joy reported a strong Parkinson's -like scent in the presence of just three, icosane and octadecanal, which are known to have weak, waxy, or oily smells, and hypuric acid, which is not typically reported to have any smell at all.

[225] Each of the chemicals was found in notably higher concentrations in the sebum, of Parkinson's patients then in controls, the researchers wrote in their 2019 report.

[226] This was the source of the Parkinson's scent.

[227] But why those particular chemicals were arriving on the skin and what exactly they represented remained uncertain.

[228] In a 2021 metabolomic analysis of Parkinsonian sebum published in Nature Communications, Barron and her colleagues found evidence of changes in two important human metabolic pathways, the first implicating mitochondria, the second additionally implicating the organelles known as lysosomes.

[229] The pathways in question exist in cells throughout the body, but they are particularly active in our brains, where disruptions to mitochondrial and lysosomal function are known features of Parkinson's disease.

[230] The byproducts of these disrupted pathways, the molecules Joy detected, were it seemed being somehow transported to the surface of the body.

[231] With her nose, the researchers came to suspect, Joy was smelling the very death of the brain.

[232] Joy has attained a certain prominence in the Parkinson's realm.

[233] The work she inspired is, in the words of the research director at the Cure Parkinson's Foundation, Simon Stott, likely to become that stuff of legend.

[234] Joy is listed as a co -author on all the papers.

[235] She was named to the Clinical Science Subcommittee of the World Parkinson Congress.

[236] She has given the inevitable TEDx talk.

[237] She has the ear of some of the world's most respected scientists.

[238] We need to trace it back from what she detects to its origin to see what caused that, the Nobel laureate Randy Sheckman, who serves as scientific director of the Parkinson's research initiative known as ASAP, told me. She's a rare commodity.

[239] She has twice been flown to Tanzania for testing on tuberculosis.

[240] In East Africa, the non -profit organization Apopo uses giant pouched rats to diagnose the disease.

[241] Joy outsmells the rats.

[242] Amazon has been in touch with her co -authors about the possibility of adding a smell functionality to its Alexa devices.

[243] The fascination with Joy is, of course, attributable to the fact that she can smell the way she can, but it is heightened by the fact that no one knows why.

[244] She is hyperasmic by any reasonable definition, but hypersmia has been the object of so little serious scientific investigation, the smell taboo in action, no doubt, at least in part, that it lacks even a set of agreed -upon definitional criteria.

[245] Its specific cause is unclear.

[246] Professor Thomas Hummel of the Dresden University of Technology, a preeminent clinical investigator of olfactory function, told me his research suggests that self -reported hyperosmics have more connectivity in the higher brain regions responsible for olfaction.

[247] These people pay more attention to odors.

[248] They take more out of the olfactory signal, Hummel said.

[249] But at this stage, this is merely a hypothesis.

[250] Hyperosmics also seem to have more consensual compromise -seeking personalities, he noted.

[251] It's a very weak correlation, Hummel said, but it's there.

[252] They also report more enjoyment of sex.

[253] Joy has enjoyed her fame, but the smell work also radicalized her in its way, and she has a reputation for being a bit intransigent in her advocacy.

[254] The initial scientific skepticism toward her was of a peace she thought with what she already held to be the medical corps' hopeless wrongheadedness about Parkinson's disease.

[255] For Joy, as for many caregivers, the psychological aspects of the illness were by far the most difficult to manage, much less except, and these happened to be precisely the symptoms neurologists seemed least interested in acknowledging, let alone addressing.

[256] You're saying things to doctors and nurses, and they're not believing you, Joy told me. Eventually, Les's dementia and sexual compulsion intensified to such a point that she worried about leaving him alone with his young grandchildren.

[257] Are neurology really willing to accept that they allow people to get that bad and for the families to be going through that, she asked?

[258] It's unethical.

[259] Les was hospitalized at one point and Joy arranged for him to be monitored under a protocol for patients with psychological disturbances.

[260] A nurse had the protocol lifted because he only had Parkinson's, Joy said.

[261] They shut the door, put the cotsides up and left him.

[262] And in the middle of the night, he walked across the bed, hit the wall with his head and was on the floor for goodness knows how long.

[263] To Joy's mind, still more proof of this medical obstinacy came from the discovery that she was not alone in her ability to smell Parkinson's disease.

[264] When the research first began to attract attention in the media, Baron and Cunot received messages from around the world from people reporting that they too had noticed a change in the smell of their loved ones with Parkinson's.

[265] The correspondence described an odor that was musty, oily, or akin to sour milk.

[266] A man from New Mexico claimed to have diagnosed an acquaintance a year before his doctor.

[267] A Parkinson's patient wrote of the social isolation he experienced as a result of his own strong odor.

[268] One woman began, I am a well -educated and sane person, so please, don't disregard my email.

[269] But for the smell taboo, Joy thought, someone somewhere might have taken these people seriously, and the importance of the odor might have been realized decades sooner.

[270] That Parkinson's has a distinctive odor and chemical signature has now been thoroughly demonstrated, but on its own, this concept is not much more than a curiosity.

[271] The reason for the initial interest in joy was not merely her claim that a smell existed, but the that it occurred very early in the course of the disease.

[272] But Joy's ability to smell Parkinson's had not yet been tested on early stage patients.

[273] It is difficult to recruit such people into studies precisely because there is no good way to find them.

[274] They haven't yet been diagnosed with Parkinson's.

[275] A few years ago, after reading about Joy, the neurologist Werner -Puva called Barron with what he thought might be a solution.

[276] Poova, a prominent Parkinson's researcher and clinician at the Medical University of Innsbruck, had lately been interested in the condition known as isolated REM sleep behavior disorder, or IRBD, in which patients act out their dreams.

[277] Les had developed the condition years before his Parkinson's diagnosis, and IRBD is now known to be strongly predictive of Parkinson's.

[278] nearly eight in every 10 new IRBD patients will be diagnosed with Parkinson's or a related disease within a decade.

[279] Reports of IRBD and related disorders increased during the COVID -19 pandemic, and some researchers fear a coming wave of Parkinson's diagnoses.

[280] In Austria, three dozen people were recruited, some with IRBD, some with Parkinson's, and controls with neither condition.

[281] A nurse swabbed the participant's upper backs, and the samples were sent to Barron and Joy for chemical and olfactory analysis.

[282] This was merely a pilot study, Poova cautioned, but the results were almost too good to believe.

[283] In subjects with IRBD, Joy found a scent that was similar to that of Parkinson's, but less offensive and clearly distinguishable.

[284] She described it as Biscuity Sweet.

[285] The chemical signatures that appeared in GCMS were likewise distinctive, and it was possible to distinguish Parkinsonian sebum from IRBD sebum from control sebum with perfect accuracy.

[286] Yet IRBD shared a great number of the chemical features of Parkinson's at somewhat lower levels.

[287] The condition appeared, the researchers wrote in a draft of their findings posted last year to the pre -print server bio -archive to be an intermediary phenotype, a waypoint along the path toward the disease.

[288] The shared chemical features could be early indicators of pre -manifest PD, they concluded, which is to say an early diagnostic.

[289] Much remains to be done.

[290] The results must be confirmed in larger cohorts and by separate research groups, and the actual predictive power of the test must be established.

[291] for a given level of these early indicators, with how much certainty can it be said that a person will, in fact, develop Parkinson's, in what time frame?

[292] Answers to these questions will come only from longitudinal studies, and it will be years before the answers are known.

[293] But Baron, Cunot, and Joy have begun to imagine the possibility of using sebum tests to screen for Parkinson's on a broad scale.

[294] Kuhnott mentioned to me that he had recently turned The Scottish health system automatically mailed him a stool sampling kit to screen for bowel cancer.

[295] In a similar manner, it would be simple to send out cotton swabs for Parkinson's.

[296] Barron and the University of Manchester have spun off a company, Sebumics, to commercialize such a test.

[297] Barron is also enthusiastic about the prospect of detecting other conditions in sebum, which turns out to be a repository of all sorts of information.

[298] To be honest, I really think that was the biggest discovery, she told me. Poova is more circumspect.

[299] He envisions sebum analysis as perhaps one of a constellation of screening tests from which a risk profile could emerge, he says.

[300] I don't think this will be the test.

[301] But if a sebum swab suggested Parkinson's in a patient with no outward signs, perhaps the patient would undergo more invasive testing.

[302] Perhaps she would then begin early treatment with whatever neuroprotective drugs were by then available, their development having itself been made possible by the ability to identify and study early stage Parkinson's patients.

[303] And perhaps, as a consequence, the patient would never go on to develop the classical symptoms of Parkinson's at all.

[304] I think that's realistic for the future.

[305] I think that will happen, Poova says.

[306] The question is when?

[307] In the meantime, the question is what good it would do to tell an otherwise healthy person that he or she will someday fall victim to a terrible disease, and whether such a person would want or should want to know.

[308] It helps research, Poova says.

[309] I'm not sure it helps people.

[310] In the past half century, medicine has come to favor a high degree of transparency.

[311] The patient's autonomy is paramount, and he or she thus is, enjoys a right to know enshrined most famously in the doctrine of informed consent.

[312] At the same time, technological progress has vastly expanded the realm of the knowable.

[313] But knowledge can punish or paralyze.

[314] Too often, information has been viewed to be an unmitigated blessing, the Oxford University law scholars Jonathan Herring and Charles Foster have written.

[315] Life and medicine are not that similar.

[316] I met Joy the spring before last at her home in a tidy subdivision on Canule Hill in Perth, Scotland, overlooking the expansive Green Valley of the Tay.

[317] Les died in 2015 at 65.

[318] Joy lives alone with a spoiled fat sheep dog named Queenie, a short walk up from the house she and Les shared.

[319] She gave me a tour of her manicured garden and took out photographs of the family's old farmhouse in Cheshire, but she was most excited to show me her spice collection.

[320] This is my delicious drawer, she told me in the kitchen with an air of mischief.

[321] I had assumed that, given her extreme sensitivity, joy would be attracted to only the mildest sense.

[322] Totally the opposite, she said, and she began pulling out jars of ground ginger, coriander, two distinct cinemas, a cumulus garam masala.

[323] She opened a vial of all spice and banged on the side, to release a bit of powder into the air.

[324] It's all around us now, she crowed.

[325] After a bit of rifling, she drew out some cardamom pods.

[326] She transferred a few to a mortar, pestled them, softly closed her eyes, and bent over the bowl in reverence.

[327] I found Joy's ingenuous thrill to be strongly endearing, but I, like many others, was also a bit terrified of her nose.

[328] The radio journalist Elise Spiegel met Joy several, years ago for a story on NPR.

[329] Alzheimer's, which Joy can detect, runs in Spiegel's family.

[330] If she did smell it, would I be able to tell?

[331] Spiegel wondered in her report.

[332] How good was her poker face?

[333] It is Joy's policy not to disclose disease odors to the people she meets, and she politely evaded Spiegel's questions.

[334] For whatever reason, she was more direct with me. one morning in her living room she commented unbidden upon my strong male scent i was aghast i wasn't going to bring this up i said no no it isn't like that joy assured me it's a normal male smell almost like salt and a few chemicals and it's sharp but deep it's when it gets to that creamy smell and loses that sharpness that I begin to think, oh, what's wrong?

[335] It was relieving to receive a clean bill of health.

[336] Given Joy's usual non -disclosure policy, I did wonder if she might be telling me a white lie, but I concluded eventually that she would not have offered one unprompted.

[337] On the other hand, it was discomforting to know that she had been smelling me at all.

[338] Our notions of privacy are calibrated to the sensory capabilities of the average other person.

[339] learn to live with the reality that if someone is just a foot away, he or she may be able to see the tiny pimple on our chin or smell our breath, or perhaps hear the swash of our saliva.

[340] But we assumed that at a slightly greater distance we are safe, that these intimate embarrassments will pass undetected.

[341] I am pleased to say that I am not a smelly person, or so I am told, but it was hard not to fret about what else, beyond my male smell, might be accessible to Joy's nose.

[342] Nor is it always straightforward for joy.

[343] She smells disease everywhere without seeking it out, in the checkout at Marks and Spencer, on the street, on her friends and neighbors.

[344] When we met, Joy informed me that Les's mother was not the only other member of the family to be diagnosed with Parkinson's.

[345] So too, she eventually discovered, were Les' maternal grandfather, his maternal uncle, his estranged younger brother.

[346] His was evidently a hereditary form of the disease, and given its incidence in Les' family, almost certainly an autosomal dominant form, which is to say a form that would be quite likely to manifest in his children.

[347] In all probability, at least one of his and Joy's three sons would have inherited the gene.

[348] Joy declined to discuss any genetic testing her sons may have undergone, and though she promised several times to put me in contact with them, she never did.

[349] I saw no dignified reason to press the matter any further.

[350] In the abstract, however, I can just as easily imagine them, fathers themselves, choosing to remain ignorant of their inheritance and of their likely fate as choosing to learn it.

[351] Some of us like to feel the wind of providence in our faces and others like everything planned, write the legal scholars Herring and Foster, each person should be allowed to choose how to approach his or her future.

[352] Joy, of course, will have no such choice.

[353] The wind of Providence is always blowing.

[354] Her nose cannot help making out whatever tragedies may float upon it.

[355] Whatever her own wishes, she will be made to know.