Reader's Digest - - Front Page - BY ERIKA HAYASAKI FROM WIRED

ON A SCALE OF ONE TO TEN, how would you rate your pain? Would you say it aches or stabs? Does it burn, or does it pinch? Steven Pete has no idea how you feel. Sit­ting in a café in Longview, Wash­ing­ton, he tells me he can­not fathom aches or pinches, much less the sear­ing scourge of pe­riph­eral neu­ropa­thy that keeps mil­lions of peo­ple awake at night or hooked on pills. He was born with a rare neu­ro­log­i­cal con­di­tion called con­gen­i­tal in­sen­si­tiv­ity to pain, and for 37 years, no mat­ter the wound, he has hov­ered at or near a one on the pain scale. Be­cause he never learned to avoid in­jury, which is the one thing pain is re­ally good for, he gets hurt a lot. When I

ask how many bones he has bro­ken, he lets out a quick laugh.

“I haven’t ac­tu­ally done the count yet,” he says. “But prob­a­bly some­where around 70 or 80.”

A few years ago, Steven no­ticed that the move­ment in his left arm and shoul­der felt off. His back felt funny too. He got an MRI. The doc­tor looked at the re­sults and stared at his pa­tient in dis­be­lief. “You’ve got three frac­tured ver­te­brae.” It turned out that Steven had bro­ken his back eight months ear­lier while in­ner-tub­ing down a snowy hill.

Through­out his body today, Steven feels “a weird ra­di­at­ing sen­sa­tion,” as he de­scribes it, an over­all dis­com­fort but not quite pain as you and I know it. He and oth­ers born with his con­di­tion have been com­pared to su­per­heroes; he even owns a framed sketch of a char­ac­ter in full body ar­mor, with the words “Pain­less Pete.” But Steven knows bet­ter. If he could feel pain, he says, he would prob­a­bly be con­strained to a bed.

“I worry about him all the time,” his wife, Jes­sica Pete, says with a sigh— about him work­ing with his power tools and cook­ing over a grill. “If he has a heart at­tack, he won’t be able to feel it. He’ll rub his arm some­times, and I freak out: ‘Are you OK?’” She looks over at him, and he chuck­les. “He thinks it’s funny,” she says. “I don’t think it’s funny.”

PAM COSTA, who lives about 100 miles away, in Ta­coma, Wash­ing­ton, is on the other end of the pain scale. The 52-year-old was born with a rare neu­ro­log­i­cal con­di­tion called ery­throme­lal­gia, oth­er­wise known as “man on fire” syn­drome, in which in­flamed blood ves­sels through­out her body are con­stant sources of pain. Pam wears loos­e­fit­ting clothes be­cause fab­ric feels like a blow­torch against her skin. She sleeps with chilled pil­lows be­cause the slight­est heat makes her limbs feel as if they’re crack­ling.

Pam takes 50 mil­ligrams of mor­phine twice a day. A col­lege psy­chol­ogy in­struc­tor and the mother of a teenage daugh­ter, she ag­o­nizes over her mor­phine de­pen­dency. But if she goes with­out her med­i­ca­tion, her pain be­comes un­bear­able.

A year ago, she went to Las Ve­gas for a work con­fer­ence and the plane home got stuck on the tar­mac with a me­chan­i­cal is­sue. There was no air­con­di­tion­ing, and the tem­per­a­ture started to rise. With her skin throb­bing, Pam per­suaded a flight at­ten­dant to let her off. “I was so afraid I was go­ing to pass out or throw up or get to where I was im­mo­bi­lized.”

Pam was de­ter­mined not to pass on her con­di­tion. “I had my tubes tied,” she says sadly.

Pam and Steven have never met, and their daily ne­go­ti­a­tions with the world could not be more dif­fer­ent. Yet, thanks in part to stud­ies the two have par­tic­i­pated in, sci­en­tists have un­cov­ered an un­prece­dented ge­netic link that binds their mir­ror-im­age con­di­tions to­gether. Scores of phar­ma­ceu­ti­cal re­searchers are now deep into clin­i­cal tri­als on a new type of drug that would mimic Steven’s con­di­tion as a way to treat Pam and mil­lions of other chronic-pain pa­tients—with­out the some­times se­vere side ef­fects of ex­ist­ing painkillers such as non­s­teroidal anti-in­flam­ma­tory drugs (NSAIDS) and opi­oids.

IF YOU BURN your­self on a stove, it hurts. More specif­i­cally, the nerve cells in your hand sense the heat and send sig­nals to the brain that tell you to stop do­ing what you are do­ing and get help. For­tu­nately, most kinds of acute, or tem­po­rary, pain can be treated: Opi­oids can dull the st­ing from an in­ci­sion; an­ti­in­flam­ma­to­ries can mask the dis­com­fort of a sprain.

Chronic pain, on the other hand, never turns off. It can be in­flam­ma­tory (brought on by dis­eases such as arthri­tis) or neu­ro­pathic (af­fect­ing the nerves, as in some cases of shin­gles, di­a­betes, and chemo­ther­apy treat­ments). Some chronic pain can never be traced to a co­her­ent cause.

That kind of un­di­ag­nos­able pain cre­ates its own is­sues. When Pam was a child, she was some­times ac­cused of hav­ing be­hav­ioral prob­lems. In school, she’d sneak off to wa­ter foun­tains to wipe down her limbs with cold wa­ter. She would daw­dle in the deep gut­ters near her home, the cool, mucky wa­ter pro­vid­ing mo­men­tary pain re­lief. One physi­cian said her symp­toms were psy­cho­so­matic. Then, in 1977, when Pam was 11, a let­ter from the Mayo Clinic ar­rived. A cousin had been re­ferred to the med­i­cal cen­ter af­ter com­plain­ing of con­stant pain. The doctors there dis­cov­ered that 29 mem­bers of Pam’s ex­tended fam­ily ap­peared to have ery­throme­lal­gia. Af­ter learn­ing more about Pam’s symp­toms, a Mayo re­searcher told her par­ents that their daugh­ter had ap­par­ently in­her­ited the same prob­lem.

Pam was de­ter­mined not to pass on her man on fire syn­drome. “I had my tubes tied right af­ter my 18th birth­day,” she says, a hint of grief fill­ing her voice. “Al­ways, since I was a lit­tle girl, I wanted to be a mother more than any­thing in the world.” When she got mar­ried, she and her hus­band adopted a daugh­ter.

STEPHEN WAX­MAN was a med­i­cal stu­dent in the early 1970s when he be­came fas­ci­nated by pain—how peo­ple feel it, how the body trans­mits it, and how, as a fu­ture neu­rol­o­gist, he could learn to con­trol it. Later in his ca­reer, when his fa­ther was in the fi­nal stages of ag­o­niz­ing di­a­betic neu­ropa­thy, he be­came

ob­sessed with help­ing pa­tients who could find no re­lief from their pain. “We sim­ply had to do bet­ter,” he says.

Today, Dr. Wax­man, 72, is the di­rec­tor of the Cen­ter for Neu­ro­science and Re­gen­er­a­tion Re­search at the Yale Univer­sity School of Medicine. For much of his ca­reer, he has been in­ter­ested in sodium chan­nels—por­tals that al­low charged par­ti­cles to flow in and out of nerve cells. In par­tic­u­lar, he be­lieved that one of those chan­nels, Nav1.7, played a pow­er­ful role in how we ex­pe­ri­ence pain.

In his the­ory, a stim­u­lus trig­gers the Nav1.7 chan­nel to al­low sodium ions to pass through, which then en­ables mes­sages of sting­ing, sore­ness, or scald­ing to regis­ter in the brain. When the trig­ger sub­sides, Nav1.7 closes. In those with cer­tain mu­ta­tions in their Nav1.7 chan­nels, sen­sa­tions that typ­i­cally wouldn’t regis­ter with the brain are in­stead trans­lated into ex­treme pain.

In 2004, Dr. Wax­man’s team was search­ing for sub­jects with some form of in­her­ited pain so they could de­ter­mine ex­actly how the Nav1.7 chan­nel worked to ei­ther cause or dampen painful sen­sa­tions. That same year, sci­en­tists in a Bei­jing lab pub­lished the re­sults of their study of a Chinese fam­ily af­flicted with man on fire, in which they linked the dis­or­der to mu­ta­tions in a sin­gle sodium chan­nel gene, SCN9A. When Dr. Wax­man spot­ted the ar­ti­cle, he di­rected his team to find fam­i­lies with ery­throme­lal­gia. Pam Costa’s was the first.

Dr. Wax­man’s team gath­ered DNA from 17 of Pam’s cousins, aunts, and un­cles who suf­fered from ery­throme­lal­gia and se­quenced their genes to find the mu­ta­tions. Then the team in­tro­duced the mu­ta­tions into DNA that en­coded nor­mal sodium chan­nels and tracked how these chan­nels re­sponded to stim­uli.

The re­sults proved Dr. Wax­man’s the­ory cor­rect, not only demon­strat­ing that SCN9A mu­ta­tions made Nav1.7 chan­nels more likely to open (mean­ing harm­less stim­uli of­ten trig­gered feel­ings of pain) but also show­ing that when those chan­nels opened, they did so for longer, am­pli­fy­ing the feel­ing of dis­com­fort. “We now had a fully con­vinc­ing link from Nav1.7 to pain.”

If his team could some­how reg­u­late or even turn off the Nav1.7 chan­nel, they could reg­u­late or turn off how we ex­pe­ri­ence cer­tain kinds of pain.

“I worry all the time,” Steven’s wife says. “If he has a heart at­tack, he won’t feel it.”

AT AROUND six months old, Steven Pete chewed off part of his tongue. As he got older, he would bang his head against walls. His par­ents made him wear a hel­met and wrapped his arms and legs in long socks.

His younger brother, Chris, had many of the same symp­toms. A day rarely passed when one of them didn’t bleed or bruise. The boys were even­tu­ally di­ag­nosed with con­gen­i­tal in­sen­si­tiv­ity to pain. Some years later, a doc­tor told Chris that a life­time of in­juries had caused so much dam­age he would likely end up in a wheel­chair be­fore he was 30. It was too much for Chris to bear. He hanged him­self, nine years ago. He was only 26. “It felt like los­ing ... my life,” Steven says.

In the mean­time, out­side Van­cou­ver, Bri­tish Columbia, a small com­pany was inch­ing to­ward a break­through in un­der­stand­ing the brothers’ con­di­tion. The com­pany, which is now called Xenon Phar­ma­ceu­ti­cals, stud­ied rare sin­gle-gene dis­or­ders in an ef­fort to cre­ate drugs to treat more com­mon ail­ments with sim­i­lar symp­toms. In 2001, it heard about a fam­ily in New­found­land in which four mem­bers could not feel pain. Sus­pect­ing their ill­ness was ge­netic, Xenon started hunt­ing for more sub­jects.

Fol­low­ing news re­ports and word of mouth, the re­searchers tracked down and stud­ied 12 fam­i­lies with in­sen­si­tiv­ity to pain. (The Petes were not among them.) Xenon found one com­mon trait: mu­ta­tions in a sin­gle gene, SCN9A, and the sodium chan­nel it en­codes, Nav1.7.

“This sin­gle chan­nel, when it is non­func­tion­ing in a hu­man be­ing, ren­ders them un­able to un­der­stand or feel any form of pain,” Robin Sher­ring­ton, PHD, then se­nior di­rec­tor of bi­o­log­i­cal sciences at Xenon, says. If Xenon could de­velop a drug that mim­icked this con­di­tion—“to in­hibit the Nav1.7 chan­nel to par­tially repli­cate that ab­sence of pain,” he ex­plains—it could use it to relieve chronic pain with­out any of the side ef­fects of opi­oids and other painkillers.

It is rare for a sin­gle gene to have such a black-or-white ef­fect on a sin­gle sen­sa­tion. Sher­ring­ton’s and Dr. Wax­man’s teams learned of each other’s dis­cov­er­ies only through pub­lished re­ports and jour­nal ar­ti­cles. They were as sur­prised as any­one

See­ing the med­i­cal proof “was the most val­i­dat­ing ex­pe­ri­ence in my en­tire life.”

that peo­ple like Pam Costa and Steven Pete had any­thing in com­mon. “I was over­whelmed when we saw both sides of the ge­netic coin,” Dr. Wax­man re­mem­bers. “SCN9A re­ally is a mas­ter gene for pain.”

TECH­NI­CIANS at Xenon even­tu­ally found a com­pound that plugs up Nav1.7 with­out ma­jor side ef­fects. Un­for­tu­nately, when it was tested on 330 pa­tients who suf­fered from nerve pain, the re­sults were dis­ap­point­ing. Af­ter four weeks, their pain lev­els did not im­prove sig­nif­i­cantly.

At Yale, Dr. Wax­man and his re­searchers helped Pfizer test five ery­throme­lal­gia pa­tients with a dif­fer­ent Nav1.7 blocker. Sci­en­tists trig­gered the sub­jects’ pain with heat­ing blan­kets. Three of the pa­tients de­scribed a de­crease in pain af­ter tak­ing the drug.

There are other, less con­ven­tional ap­proaches un­der way too. At Am­gen, a phar­ma­ceu­ti­cal com­pany in Thou­sand Oaks, Cal­i­for­nia, sci­en­tists dis­cov­ered that the toxin of a Chilean taran­tula can tar­get Nav1.7. They’ve since en­gi­neered a syn­thetic ver­sion that’s more po­tent than the orig­i­nal.

There are still ob­sta­cles to find­ing a treat­ment, such as cre­at­ing com­pounds that will al­low some pain to regis­ter with­out cut­ting it off al­to­gether. But many now see a way for­ward. “I hope,” says Steven, “that one day, par­ents will be able to make a choice for their chil­dren who don’t feel pain, to ac­ti­vate that sodium chan­nel so that their chil­dren can live a nor­mal life.”

NO PROGRESS would have been made with­out peo­ple like Pam and Steven, who have taken part in stud­ies for years.

Pam still re­mem­bers meet­ing Dr. Wax­man at Yale in 2011, six years af­ter his team first reached out to her fam­ily to study their genes. On a com­puter, he pulled up an im­age of the neatly folded amino acids that form a nor­mal per­son’s sodium chan­nel. Then he pulled up an­other im­age: The amino acids zigzagged al­most off the screen. “This is you,” he said.

Her en­tire life, Pam could only tell oth­ers how she felt—she could never show them. See­ing the med­i­cal proof of her pain, she says, “was the most val­i­dat­ing ex­pe­ri­ence in my en­tire life.”

On the other hand, the work to tar­get the Nav1.7 chan­nel won’t help Steven or oth­ers with con­gen­i­tal in­sen­si­tiv­ity to pain—there’s no point block­ing a por­tal that’s per­ma­nently closed. The con­di­tion re­mains one with a known cause but no cure, passed down from one gen­er­a­tion to the next.

When his daugh­ter was born in 2008, Steven asked the doc­tor in the de­liv­ery room, “Does she feel pain?”

“They pricked her,” his wife re­mem­bers. “And she cried.” It felt some­thing like re­lief.

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