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all. But the chance never seemed to presentitself—until one time, when he was about8. Douglas got all the way to third base andtagged it. Then he announced, “Okay, I’msafe. I’m safe, right?!” When the ump andother players agreed, he took several stepsback toward second and slid into third.“He was the happiest child in the world.He wouldn’t let me wash his uniform,” saysFickel.She kept hoping that Douglas would bethe exception, that he wouldn’t end up in awheelchair. He played kickball at the partyfor his 9th birthday. By 10 he couldn’t; hedepended on his wheelchair. Douglas, now11, thinks it would be a good idea for him tomeet the Steelers’ Bill Cowher and give himsome ideas for plays. He loves skateboarderTony Hawk. His best friends are his older sisters,Sam and Emma. The world stops whencountry music star Toby Keith is singing.Douglas still plays baseball, but now herides an electric retrofit bike to get aroundthe bases.He hasn’t been able to read since thirdgrade, but he has a sharp memory. For aspelling test, he and his classmates were toldto each pick 10 or so words from a list of244. They would each be tested on the wordsthey’d chosen.Fickel got a call from the teacher.“Douglas wants to do all 244,” she said.“Let him.”Guess who scored highest for accuracy.Maybe you’ve heard this annoyingadage from a wise grandmotherlytype: Difficulty teaches us thingswe might not otherwise have known aboutourselves. In the world of biomedical science,it’s not unusual for researchers to study ananomaly to learn about what healthy bodiesdo. A-T offers a particularly revealing moleculardance. This harrowing and rare diseasehas pointed scientists toward vital clues tounderstanding the mechanisms involved incancer and DNA repair.Christopher Bakkenist has never metDouglas Fickel. But he, too, spends his dayswith A-T, though he doesn’t have the illness.Bakkenist, who was raised in the middle ofEngland, studied and trained at the Universityof London, Oxford University, and St. JudeChildren’s Research Hospital in Memphis.Last year he joined the faculty at Pitt. He is38, reserved, a still talker, and gravely seriousabout his research. His work is inspired bythe idea that scientists can “actually make animpact and change the way people look at theworld.” If you ask how, he’ll say the path issimple: “You put the diseased children first. Assoon as we put ourselves first, we’ve lost it.”Before coming to Pitt last year, he workedas a postdoc with prominent ATM researcherMichael Kastan at St. Jude. By then, scientistshad identified a number of importantproteins that the ATM pathway activated,including a tumor suppressor called p53. Thisprotein itself is profoundly powerful.“It’s mutated in 50 percent of all 100 kindsof cancer,” notes Robert Abraham (PhD’81), vice president of oncology for WyethResearch in Pearl River, N.Y., who studiedpharmacology at Pitt.“There’s a very solid argument out therethat if [cancer] patients don’t have a p53mutation, they have a mutation somewhereelse in the p53 pathway. It’s like a necessarymilestone a cancer cell has to pass to becomea fully malignant cell.”Several labs identified other importantproteins that are set off downstream of ATM(which is a kinase, so it sets off chemical reactions).But no one could figure out exactlyhow ATM sounded the alarm that DNAdamage was taking place, notes Abraham.“One of the burning questions in thefield was, How does ATM actually respond todouble strand breaks?”During his fellowship, Bakkenist createda sensitive reagent that allowed him to seein detail what was happening during theATM response. Bakkenist and Kastan werethen able to show that ATM is made up ofat least two inactive molecules. When bothDNA strands break after a blast of ionizingradiation, ATM releases two single, and nolonger dormant, ATM molecules. The scientistsalso described the unexpected transfer ofphosphates that takes place within the proteinitself before the single ATM molecules sendphosphates downstream to activate importantproteins like p53. Those downstream actorsstop the cell cycle to allow repair to occur orto set in motion the extinguishing of unrepairablecells.A news article in Nature notes that Kastanand Bakkenist revealed that “the sensitivity,extent and speed of the ATM response aretruly astonishing. Doses of irradiation thatcause only a few [double strand breaks] ina human cell activate the majority of ATMwithin minutes.”It was a seminal finding, says Abraham:“The failure of this pathway explains thewhole syndrome.”But how is ATM tipped off to a doublestrand break?Chromosomes are made up of buildingblocks called chromatin that include DNAand proteins. Kastan and Bakkenist showedthat changes to chromatin structure let ATMknow there’s a problem.Bakkenist can see how such findings couldopen the door to better cancer therapies:“If you can inhibit the [ATM] protein,you may be able to increase the efficacy ofDNA damage therapy, including radiotherapy,in human cancer. The other approach is,if you can activate ATM artificially, you maybe able to temporarily activate p53 as well. Ifyou transiently activate p53, before the canceris actually developed, you may be able to usethe p53 to kill off precancerous cells.“So you may be able to use it as a prophylacticcancer therapy, to prevent humancancer.”ATM has a sister protein that sits next toit at the top of the DNA damage pathway. It’scalled ATR (ATM related) and orchestratesthe response to another brand of DNA damage—thatcaused by UV light. This responseblocks the progression of DNA replication.(Mutations that pass through this pathwaycan show up as skin cancer.) Bakkenist is nowinterested in studying ATR, and Abraham isoptimistic about what he’ll find:“This is really important work. I think thatChris is better positioned than just about anybodyelse to pursue this work. These are verylarge proteins that pose many challenges.”Because her son is at risk of developingcancer, Pam Fickel carefully monitorshis lymph nodes to make sure theydon’t grow larger.She had uterine cancer a few years ago.Fickel is a carrier of the mutated ATM gene(as is her husband; both parents must be carriersfor a child to get the disease). There’s aschool of thought that says if she had beengiven radiation therapy or a drug that mimickedstrong doses of ionizing radiation, theresults could have been fatal.Fickel knew about this risk only becauseof Douglas’ strange disease. So Douglas, justby being himself, may have saved his mom’slife.■for more information, we recommendthe A-T children’s project: www.atcp.orgFALL 2006 31