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Суператлет через две Олимпиады?

news.bbc.co.uk 4 декабря 2001 17:40

 

Махинации современных спортсменов с препаратами, позволяющими заметно повысить скорость и выносливость, вплотную приблизились к опытам из области генетической инженерии, предупреждают ученые.

По их словам, Олимпийские игры 2012 года станут первыми, на которых выступят "искусственно произведенные" суператлеты.

В пятницу участники конференции по вопросам генетики в спорте выступили с предупреждением о том, что генетической терапией, изначально направленной на лечение сложных заболеваний, злоупотребляют с целью достижения выдающихся спортивных результатов.

Как полагают некоторые работающие в этой сфере специалисты, уже сегодня необходимо начать работу над системой тестирования, которая помогла бы эффективно бороться с подобными явлениями в спорте.

Опасность

Обеспокоенность этой проблемой выказывал не раз и Международный олимпийский комитет, который уже создал специальную группу советников по проблеме генетического допинга.

Три года назад с велогонки "Тур де Франс" была дисквалифицирована целая команда: ее участники были уличены в приеме препарата эритропоэтин.

Этот гормон увеличивает количество красных кровяных телец, благодаря чему заметно повышается снабжение организма кислородом, и спортсмен способен творить чудеса. Но тот же эритропоэтин сгущает кровь. Считается, что в результате этого побочного эффекта на сегодняшний день в мире скончались по меньшей мере 20 велосипедистов.

Но тот, кто всерьез борется за медали, нередко готов рисковать практически всем - и здоровьем, и репутацией.

Скандалы

Доктор Хью Монтгомери из Лондонского университета изучает гены, которые способны воздействовать на скорость и выносливость. Он говорит, что ученым следует соблюдать максимум осторожности, когда речь идет о том, чтобы внедрить генетические материалы в человеческие клетки с целью улучшения спортивных результатов.

Самый громкий олимпийский скандал, связанный с допингом, разразился в 1988 году вокруг канадского спринтера Бена Джонсона. У него отобрали золотую олимпийскую медаль в 100-метровке, когда обнаружили позитивную реакцию на запрещенный препарат. Однако о Джонсоне известно, что его генетические особенности развивались естественным путем.

Между прочим, похожий случай произошел и с одним олимпийским лыжником. Его лишили медали, а потом выяснилось, что его кровь сама по себе, без воздействия препаратов, на 50% более богата красными кровяными тельцами, чем кровь обычного человека.

 

 

Олимпиада XXI века: состязания фармакологов и генетиков

Олимпийцев уже называют киборгами, а их рекорды — нечеловеческими. Осталось назвать спортсменов мутантами, что вскоре не будет преувеличением. На ближайшей Олимпиаде "золото" будут выдавать генетически модифицированным спортсменам.

Чтобы стало бы со спортом, с потрясающими спортивными рекордами и апофеозом человеческого тела, если бы не генная инженерия! Биоинженеры говорят, что Олимпиада в Солт Лейк Сити была последней "позорной" Олимпиадой, на которой легендарных чемпионов "ловили" на банальном гормоне: "Убогая эпоха, когда анализы мочи и крови выдают олимпийцев, закончилась".

Недавно в Лондоне прошла конференция "Гены в спорте " (Genes in Sport). На ней обсуждались довольно любопытные проблемы влияния генов на спортивные достижения. Конференция оказалась любопытна тем, что на ней говорили о генетически встроенных спортивных ориентирах — как семейных, так и национальных.

Оказывается, если двух близнецов с детства тренировать в разных видах спорта, то всё равно оба будут заниматься (или высказывать предпочтение и достигать хороших результатов) в том виде, к которому у них генетическая предрасположенность — даже если они с этим спортом познакомятся в зрелом возрасте. Этим, кстати, можно объяснить существование известных спортивных династий.

Существуют также целые этнические группы, генетически "склонные" к какому-то виду спорта. Так, примерно 80% всех побед в беге на 800 метров принадлежат кенийцам, 40% лучших 50 марафонцев планеты — опять кенийцы. Причём выяснилось, что практически все кенийские спортсмены — выходцы из двух племенных групп, то есть, грубо говоря, принадлежат единому генеалогическому древу.

Профессор Салтин (Bengt Saltin) провёл исследование с целью выяснить, что именно делает их превосходными бегунами. В экспериментах сопоставлялись анализы датских бегунов и кенийских деревенских мальчишек. Оказалось, что секрет кроется в насыщении крови кислородом во время бега. То есть кенийцы органически иначе, что называется, "сжигают энергию".

Энергия кенийского бегуна более рационально расходуется в процессе бега — её расход достигает максимума, причём это происходит без нарушений метаболизма.

Кенийцы уникальны тем, что природа их наделила геном, который сам "включается", когда нужно, и также органически "выключается". Похожий феномен наблюдался и у финского лыжника Мантиранты (Mantyranta), который в Зимней олимпиаде 1964 года в Инсбруке (Innsbruck) взял две золотые медали.

По уровню подготовки он практически ничем не отличался от других спортсменов, но ему повезло больше — у него была врожденная генная мутация — в его крови было на 25-50% красных телец больше, чем у здоровых людей, соответственно, в его лёгкие кислорода поступало гораздо больше, и он легче переносил длинные дистанции.

Пресловутый гормон erythropoietin (EPO), из-за которого вот уже которую олимпиаду разгораются скандалы, естественно вырабатывался в организме финна более интенсивно.

Патология заключалась в том, что у кенийцев гормон, регулирующий количество красных телец, сам "отключается" — перестаёт быть активным, когда кровь достаточно насыщенна ими, а у финского чемпиона кровь продолжала "насыщаться", делая его, если разобраться, генным инвалидом.

Похожая ситуация с повышенным уровнем гемоглобина — у российского конькобежца Шепеля, который сейчас пытается убедить антидопинговую комиссию в том, что не имеет никакого отношения к EPO.

Очевидно, что набрать необходимое количество генных инвалидов для успешного участия в соревнованиях практически невозможно — если, конечно, не организовывать специальный отбор для детей, желающих заниматься спортом.

Но вот сделать нормального человека инвалидом, оказывается, можно, причём первые генетически модифицированные спортсмены ожидаются уже на Олимпиаде 2008 года. Именно к этому году будет завершены эксперименты по введению двух новых генов, которые практически невозможно будет определить никакими спектральными анализами.

Но прежде — несколько слов о том, какие виды допингов используются спортсменами сейчас: о EPO и других запрещённых препаратах. В "чёрных списках" МОК находится 142 препарата, не считая их аналогов и заменителей: 30 видов анаболиков, 32 вида диуретиков, 4 вида пептидов, 42 вида стимуляторов (сюда входит кокаин), 34 вида наркотиков, а также две методики — "кровяной допинг" и "смена мочи".

На ряд препаратов нет прямого запрета, но ограничен уровень содержания присутствующих в них веществ в организме спортсмена — это, например, кофеин. Кстати, шахматисты, которых с недавних пор также обязали проходить допинг-контроль, жалуются именно на кофеиновое ограничение, ведь, оказывается, многие из них — настоящие кофеманы.

Вообще, в качестве допингов могут использоваться симпато-миметические амины (амфетамин, метиламфетамин, эфедрин), стимуляторы центральной нервной системы и аналептики (стрихнин, трансамин, индопан, лептамин), наркотики и болеутоляющие средства (морфин, его производные, опиум), общестимулирующие средства (препараты женьшеня, лимонника китайского, левзеи, ингибиторы МАО), успокаивающие средства (седуксен, элениум, андаксин, ноксирон), этиловый алкоголь в любых смесях и так далее.

Скандалы из-за допингов возникали на олимпийских играх достаточно часто, и нередко поводом к разбирательствам становилась смерть спортсмена во время состязаний.

Один из первых допинговых скандалов разразился в 1967 году, когда английский гонщик Томми Симпсон (Tommy Simpson), употреблявший мощные допинги, умер прямо во время велосипедного марафона Tour de France. По самой распространенной версии, его убила жара, амфетамины и стресс.

На следующий год на Олимпийских играх в Мехико ввели допинг-контроль. Амфетамины также унесли жизни велосипедистов Кнуда Йенсена (I960), Дика Ховарда (I960). От применения анаболических стероидов скончались многоборец Беджит Дрессел (1987) и культурист Дэвид Синг (1987). В 1978 году от передозировки стрихнина умер прямо на велосипедной трассе советский велосипедист Григорий Радченко.

Среди погибших на дорожке было много нидерландских велогонщиков, которым ставили диагноз "сердечная недостаточность", так как к тому моменту ещё не совсем представляли, что такое EPO.

Один из самых громкий скандалов произошёл в Сеуле: тогда с Олимпиады была снята вся болгарская сборная. Болгарские атлеты планировали с помощью катетера ввести себе свежую мочу, чтобы замаскировать приём допинга, но российский спортсмен специально занял туалет — единственное место, где можно было это сделать — и через пять часов сборная отказалась от участия в Олимпиаде.

Среди лыжников и биатлонистов до сих пор широко применяется "кровяной допинг", который практически неопределим. Накануне гонки у спортсмена берётся кровь, а перед самым стартом переливается ему же, мобилизуя возможности организма.

Немецкая атлетка Хайди Кригер, чемпионка Европы 1986 года по толканию ядра была вынуждена из-за физиологических и психологических отклонений в результате применения стероидов изменить пол: теперь она Андреас Кригер.

В 60-е годы ходили слухи, что российские хоккеисты вшивали кусочек плаценты под кожу живота, чтобы интенсифицировать выработку гормонов и увеличить выносливость.

Тогда же поговаривали о том, что в немецкой сборной по плаванию практиковалось "надувание" спортсменов: воздух вводился в прямую кишку, чтобы "увеличить плавучесть". Но методика настолько невероятна, что, кажется, это были всего лишь шутки.

В Сиднее руководство Олимпийской деревни было вынуждено установить в гостиничных номерах специальные мусорные контейнеры для сбора использованных шприцов и игл, которые стали представлять угрозу для здоровья персонала, убирающего комнаты.

Однако более известного и скандального допинга, чем так называемый EPO не было с начала 60-х годов. EPO представляет собой генно-инженерный препарат, применяемый при лечении тяжёлой формы почечной недостаточности. Физиологическое действие: увеличение уровня гемоглобина в крови, способствующее лучшему насыщению мышц кислородом, что приводит к значительному повышению выносливости.

Epogen был синтезирован и стал выпускаться для инъекций биотехнологической компанией Amgen в 1989 году. Его создавали для больных анемией (страдающих от повышенного содержания белых телец в крови), для больных СПИДом и страдающих от почечной недостаточности (именно почки отвечают за выработку этого гормона). На момент создания синтетической версии EPO он не входил в число запрещённых препаратов и был практически не выделим из крови и мочи.

Более того, эффект держался долго, а гормон выходил относительно быстро. Самый скандальный спортивный эпизод, который положил начало войны МОК с EPO, произошел опять же на Tour de France в 1998 году.

Тогда в употреблении этого препарата обвинили лидирующую команду "Фестина". В том же году швейцарский велосипедист Алекс Зулле (Alex Zulle) рассказал, что без этого гормона не обходится ни одно соревнование, и описал свои ощущения после инъекции: "Через три часа после укола твои лёгкие наполняются воздухом, как паруса. Ты находишься в колоссальном потоке энергии, и тебе доступно всё, чего ты только не пожелаешь".

С момента выхода EPO на арену появились способы его выявления, а экстремальные меры по организации допинг-тестов сделали его употребление слишком рискованным предприятием. Кстати, совсем недавно было зафиксировано применение EPO нового поколения — это американский препарат "Аранесп", предназначенный для почечных и онкологических больных, отличается от обычного EPO долгим действием и большей эффективностью.

На сегодняшний день известны три гена, которые, по всей видимости, будут использоваться спортсменами и которые невозможно будет определить существующими методами, причём все они могут вводиться непосредственно в мышечную ткань, как обычная вакцина.

Первый из наиболее мощных — аналогичен EPO и повышает количество красных телец в крови. В процессе его разработки определились две проблемы: сам ген ввести нельзя — необходим "транспортный вирус", но иммунная система здорового человека разрушает "такси" до того, как он доставит ген. Недавно компания Avigen запатентовала модифицированный вирус, который менее уязвим к бунту иммунной системы (adeno-associated viruses — AAVs).

В 1997 году группа исследователей во главе с Джеффри Лейденом (Geoffrey Leiden) из Университета Чикаго использовала adenovirus, чтобы внедрить ген EPO мышам и обезьянам. Годом позже аналогичные опыты на бабуинах проводила в Калифорнии биотехнологическая компания Chiron.

Через десять недель после инъекции гематокриз бабуинов повысился почти на 75% и оставался таким высоким в течение 28 недель — на протяжении всего экспериментального периода. Препарат начали применять на больных, страдающих от анемии, но практика было временно прекращена из-за смерти 18-летнего пациента. В этот период стала актуальной вторая проблема EPO-гена.

Оказалось, что если обычный гормон EPO, который сейчас нелегально используют спортсмены, со временем "выходит" из организма, то ген отключить нельзя. По этой причине чтобы обезьяны, которым уже ввели ген, не умирали от сердечных приступов, им приходилось регулярно пускать кровь или "разжижать" её. Кстати, аналогичная проблема случается и у постоянных доноров, организм которых перестраивается на повышенное производство красных телец.

Второй ген, который ждёт большое будущее в спорте, — ген роста клеток внутренней поверхности сосудов (vascular endothelial growth factor — VEGF). Спортсмены смогут использовать его для улучшения кровоснабжения своих мышц. Разработка этого гена ведётся специалистами Мичиганского университета, группу возглавляет Санджай Раджагопалан (Sanjay Rajagopalan). Ген разрабатывается для пациентов, страдающих от атеросклероза.

Третий перспективный ген способствует наращиванию мышц, и он заменит запрещённые сейчас стероиды. Ген называется insulin-like growth factor 1 — IGF-1, что можно приблизительно перевести как "инсулиноподобный фактор роста". Его особенность заключается в том, что он может использоваться как "ремонтный ген", который ускоряет процесс регенерации мышечных тканей, которые часто повреждаются из-за перегрузок, растяжений и так далее. Существует около пяти вариаций этого гена неуязвимости.

Ген быстрой регенерации и быстрого наращивания мышечной ткани изучают группа под руководством Джеффри Голдспинка (Geoffrey Goldspink), в медицинской школе королевского университета в Лондоне (Royal Free and University College Medical School in London) и группа SweLee Sweeney, физиолога из университета Пенсильвании (University of Pennsylvania).

Первоначально ген был создан для помощи пациентам с мышечной атрофией. Результаты экспериментов на мышах оказались просто потрясающими: за две недели у мышей — естественно, безо всяких тренировок — объём мышечных тканей увеличился на 20%. На людей аналогичные генные инъекции должны действовать менее интенсивно — прирост будет составлять 10% за месяц.

Самое главное достоинство этого гена заключается в том, что он не распространяется дальше мускула, в который его вкололи — то есть если уколоть в ногу, мышечные ткани сердца спортсмена не увеличиваются.

Для того, чтобы определить, была ли сделана инъекция этого гена, нужно будет брать образец мышечной ткани прямо в точке инъекции (которую найти будет почти невозможно) и проводить генетический анализ, который настолько трудоёмкий, что по объёму информации будет сопоставим с процессом расшифровки самого генома.

Дон Кэтлин (Don Catlin), биохимик, работающий на МОК в Калифорнийском университете (University of California in Los Angeles) считает, что определить наличие этих генов в организме спортсменов будет практически невозможно.

Конечно, можно идти на следующие меры: например, неожиданно для спортсменов менять время начала состязаний и тренировок — а потом брать анализы. Если, несмотря на изменение нагрузки на организм, уровень красных телец остается прежним, то это верный признак сделанной инъекции. Но КПД этих мер стремится к нулю и местами его достигает.

В марте в США пройдёт первая международная встреча экспертов, посвящённая вопросам генетического допинга. По всей видимости, на ней попытаются выработать какие-то меры этической борьбы, но сомнительно, что частные генные инженеры, которые осознают финансовую прибыль от разработок, устыдятся и прекратят исследования.

Ученые унив. Пенсильвании при помощи генной инженерии открыли секрет омоложения Помещено Вторник, Февраль 26 @ 13:34:48 EET от AntGod

 

                                                                                                                                                                                                                                    news.bbc.co.uk
                                                                                                                                                                                                        Thursday, 21 March, 2002, 00:39 GMT

Sport's genetic engineering concerns

 

The World Anti-Doping Agency (Wada) is set to clamp down on the unapproved use of genetic engineering. Wada has expressed concern that genetic engineering could become the next step in illegally enhancing athletic performance. The agency has just held a three-day conference on Long Island. "Akin to doping in the present generation, genetic-transfer technology that is non-therapeutic and merely performance enhancing should be prohibited." The recent mapping of the human genome was heralded as one of man's greatest scientific achievements and already rudimentary technology to manipulate genes exists. Wada chairman Dick Pound expressed fears that genetics could become the future battleground in the war against doping. "Wada is committed to confronting the possible misuse of gene transfer technology in sport," he said.

Technology abuse

 

 

Someday Soon, Athletic Edge May be From Altered Genes (NEW YORK TIMES) article

May 11, 2001 PUSHING THE LIMITS (NEW YORK TIMES) Getting the Athletic Edge May Mean Altering Genes By JERE LONGMAN

For three decades, the International Olympic Committee has been engaged in a game of chemical cat-and-mouse. Athletes use drugs to enhance their performances, scientists devise tests to identify those drugs, then the athletes move on to more sophisticated doping techniques.

Now, the rules of the game may be changing, leaving the Olympic committee even further behind.

Concerned that athletes would soon employ genetic engineering in attempting to run faster, to jump higher and to throw farther, the I.O.C. and the affiliated World Anti-Doping Agency are about to convene inaugural meetings on the subject. "For once we want to be ahead, not behind," Dr. Patrick Schamasch of France, the I.O.C.'s medical director, said.

Genes serve as a script that directs the body to make proteins. It seems fantastic today to think that injecting a gene could result in more fast-twitch muscle fibers, enabling a sprinter to run 100 meters in six seconds instead of just under 10. Or injecting a gene that could increase oxygen-carrying capacity so that a marathoner could run 26.2 miles in one and a half hours instead of just over two. Some scientists and Olympic committee officials believe genetic engineering in sports is a decade away. Some believe it may appear in two years. Still others believe crude forms might already be in use, at great health risk to athletes.

"I think certain methods could have already started," said Johann Olav Koss, the 1994 Olympic speed skating champion from Norway who is a member of the I.O.C. and a doctor.

Medical applications of gene therapy — efforts to cure or prevent disease — are at a very rudimentary stage, with only one form of gene therapy having been shown conclusively to work. Little is understood about the implications of introducing genes into a human body, so any use aimed at improving athletic performance would now be considered dangerous and unethical.

But the human genome has been mapped out and the technology, however immature, is evolving rapidly. Athletes, who are often eager for an edge in competition, are not very likely to wait for science to perfect gene therapy. Inherently, athletes are risk takers. And there is enormous financial pressure and reward to win, to produce records and to keep up with other athletes who are succeeding through illicit means.

Genetic engineering in sport will foster not only a greater potential health risk for athletes than does conventional doping, but also a greater potential for performance enhancement, said Dr. Jacques Rogge, a Belgian surgeon who is an I.O.C. delegate and vice chairman of its medical commission. Instead of repeatedly ingesting pills or taking injections, an athlete may be able, with a single insertion of genetic material, to sustain bulked-up muscle mass or heightened oxygen-carrying capacity for months or even years. Such genetic manipulation would be extremely difficult, if not virtually impossible, to detect using current methods, scientists said.

At the coming meetings of the Olympic committee and the anti-doping agency, officials will discuss the potential benefits and risks of genetic engineering and the potential detection methods, and they will face a number of ethical questions. Should genetic manipulation be banned entirely in sport? Should it be allowed for athletes healing from injury or recovering from disease? If the technology can be made safe, do healthy athletes have the right to engineer themselves like race cars to push the boundaries of achievement? Will two classes of competition be needed?

"What if you're born with something having been done to you?" Maurice Greene of Los Angeles, the Olympic champion at 100 meters, said. He wondered, would manipulation of an egg or an embryo be considered cheating? "You didn't have anything to do with it," he said.

The Olympic committee scheduled a meeting for June 6 on genetic engineering only after the anti-doping agency announced plans for its own gathering in September, an apparent political gesture to appear out front on the issue, said Dr. Arne Ljunqvist of Sweden, who is an I.O.C. delegate and chairman of the anti-doping agency's medical, health and research committee.

The second meeting is considered the more significant of the two; the agency hopes to gather three dozen athletes, sports scientists, genetics experts, ethicists and policy officials from the Food and Drug Administration and the National Institutes of Health in Cold Spring Harbor, N.Y.

"For the first time, a substantial group of people involved in sports administration, sports science and genetic science will sit around the same table and discuss a common potential problem," Dr. Ljunqvist said.

The concerns range from the pragmatic to the philosophical. Do the Olympic committee and other sports organizations have the willpower or financial resources to combat the use of genetic engineering? The total cost of conventional drug tests are already about $1,000 each.

Ultimately, at the heart of the issue will be a profound question: what is a human athlete?

"What are the endpoints of manipulation?" said Dr. Theodore Friedmann, director of the gene therapy program at the University of California at San Diego and a member of the anti-doping agency's health and research committee. "Is the hope to incrementally sneak up on the one-and-a-half-minute mile? Or six seconds for 100 meters? Is the question, How fully can we engineer the human body to do physically impossible things? If it is, what do you have at the end of that? Something that looks like a human, but is so engineered, so tuned, that it's no longer going to do what the body is designed to do."

Anything for an Edge?

Athletes, scientists and sports administrators agree that someone will attempt genetic engineering, if they have not already. Concern over health and safety issues has not been a strong deterrent to the epidemic use of conventional performance-enhancing drugs.

In a 1995 survey, nearly 200 aspiring American Olympians were asked if they would take a banned substance that would guarantee victory in every competition for five years and would then cause death; more than half answered yes.

A recent seminar on teenage steroid use, held in New York City, revealed these desperate efforts to boost athletic performance: A female basketball player asked a doctor to break her arms and reset them in a way that might make them longer; pediatricians were being pressured by parents to give their children human growth hormone to make them taller and perhaps more athletic; doctors were being asked by the parents of football players to provide steroids so their sons might gain college scholarships.

A molecular scientist, speaking on condition of anonymity, said in an interview that a foreign exchange student staying with the scientist's family was approached at a swimming pool by a stranger and was told, "You are absolutely beautiful; I'll give you $35,000 for one of your eggs." The student accepted the offer. It is not inconceivable that some parent looking to create an elite athlete would offer far more money for such an arrangement with, say, Marion Jones, the world's fastest woman.

"In theory, you could do in vitro fertilization, stick in a gene for x, y or z and you've built a kid," the scientist said. "It's been done in mice. But I'd consider that brave new world stuff. It's not happening with humans."

Other techniques now being tested on lab animals seem much less futuristic. For instance, the gene that codes for the hormone erythropoietin, or EPO, has been identified. Produced by the kidneys, EPO regulates the production of red blood cells. A synthetic version can serve as a wonder drug for patients suffering from anemia, AIDS or cancer. Because it enhances oxygen-carrying capacity, EPO is believed to be in widespread use in such endurance sports as cycling and distance running.

Conventional illicit doping measures require athletes to be injected at regular intervals with EPO to maintain the endurance benefit. The insertion of a gene, however, could theoretically turn the body into an EPO factory. Last year a study by Dr. Steven M. Rudich, a transplant surgeon then at the University of California at Davis, indicated that a single injection of the EPO gene into the leg muscles of monkeys produced significantly elevated red blood cell levels for 20 to 30 weeks.

"An athlete would be out of his mind to want to use this," Dr. Rudich, who is now at the University of Michigan, said. Ruefully, he said about genetic engineering in sports, "I bet it exists."

Muscular Mice

Genetic material can be delivered to the body by several methods. Dr. Rudich took a weakened virus, inserted a snippet of EPO gene, then injected it into the monkeys' thigh muscles. Each gene consists of DNA, the ladder-like structure that serves as a genetic carpenter, instructing the body what to construct. In this case, the DNA signaled the muscles to produce EPO, which stimulated the production of red blood cells.

Other hormones and proteins that can be used in gene therapy for performance enhancement are human growth hormone and a protein called insulin-like growth factor-1, or IGF-1. Growth hormone can be used to treat dwarfism in children and to prevent muscle loss in the aging process. IGF-1 is critical to the repairing of muscle tissue. Both substances are believed to be used illicitly now by athletes using conventional methods to increase muscle size and strength.

Ten years ago, Dr. Helen Blau of Stanford demonstrated that a gene could be introduced into a mouse to stimulate production of normal levels of human growth hormone in the bloodstream for as long as three months, compared with 10 minutes if the drug were taken directly. Recently, she and others showed that oral antibiotics could be used as a switch to turn the gene on and off.

"In theory, it is possible that an athlete could be genetically engineered to have a gene so you could increase muscle strength, train with it and shut it off when you want to, which would make drug testing more difficult," said Dr. Blau, chairwoman of the department of molecular pharmacology at Stanford Medical School. "Whether it's happened, I have no idea. In theory, it's possible. It's something to keep an eye on. It could be a future concern for the Olympics."

A 1998 study by scientists at the University of Pennsylvania and Harvard involving IGF-1 used gene therapy in mice to halt the depletion of muscle and strength that comes with old age. Older mice increased their muscle strength by as much as 27 percent in the experiment, which suggested possibilities for athletes as well as for preserving muscle strength in elderly people and increasing muscle power in those who suffer from muscular dystrophy.

"We called them Schwarzenegger mice," said Dr. Nadia Rosenthal, an associate professor at Harvard Medical School and a co-author of the study. It has since been demonstrated that mice enhanced with the IGF- 1 gene continue to gain size and strength when exercising on a wheel without any apparent adverse health effects, she said.

"I'd be totally surprised if it was not going on in sports," Dr. Rosenthal said, speaking generally of crude attempts at genetic engineering. "Those with terminal cancer and AIDS want to know, `What will keep me alive?' Athletes want to know, `What will make me win?' "

Hidden Dangers

The danger in attempting genetic engineering now for athletics, Dr. Rosenthal and other researchers cautioned, is that experiments with mice and monkeys might not work the same way in humans and might lead to negative side effects.

If a gene for producing EPO cannot be shut off properly, the blood will begin to thicken with excessive red blood cells and that could cause strokes and heart attacks.

If the gene for human growth hormone is not regulated, muscles might grow until they outstripped the blood supply or overwhelmed tendons and ligaments. Misuse could also lead to heart and thyroid disease and cause the size of someone's head, jaw, hands and feet to increase dramatically.

The entire process of genetic engineering remains imprecise. Dr. Thomas Murray, president of the Hastings Center, a biomedical ethics research institute in Garrison, N.Y., likened it to firing at the bull's-eye of a target with a spray of shotgun pellets. It is not known exactly where the virus and DNA go when injected, how they get where they are going or what the body's immune response will be.

An attempt to strengthen the shoulder muscles of a javelin thrower, for instance, might lead inadvertently to an enlargement of the heart muscle. Or worse. A teenager died in 1999 during a therapeutic study at the University of Pennsylvania, apparently in reaction to the virus carrying genes intended to treat a metabolic disorder.

"We don't know the technology well enough even to be sure what's happening in a therapeutic setting," Dr. Friedmann of California-San Diego said. "We certainly don't know the technology well enough to know how safe a gene is going to be to an athlete."

Before athletes are fitted with designer genes, the next advance may be to create more synthetic versions of drugs like EPO and growth hormone that mimic the effects of genetic engineering, scientists said. But genetic manipulation of the human body for sport is sure to come. The question is, to what extent?

Michael Johnson, the Olympic sprinting champion, said he thought the health risks would scare off many athletes. Werner Franke, a German molecular biologist who helped bring to light the systematic doping of athletes by East Germany, said he was not particularly worried about genetic engineering because chemical footprints left by the inserted virus and DNA would facilitate detection.

"I think it will be mostly science fiction," Mr. Franke said. He accused the I.O.C. of "purposely barking up the wrong tree" in an attempt to camouflage its lack of commitment to catching athletes who cheat by conventional methods.

Many scientists, however, disagree with Mr. Franke's assessment of the potential ease of detecting altered genes. With available technology, they say, scientists would have to know exactly where the gene was inserted in order to identify it, which would most likely require muscle biopsies.

"No athlete in his right mind is going to allow himself to be probed here and there for evidence of a virus," Dr. Friedmann said.

Eventually, some noninvasive detection methods might be developed, like chemical markers or a chip that could be encoded with the sequence of a specifically altered gene. But some researchers believe that only a change in cultural attitudes will curb genetic engineering, just as a cultural shift has led to an intolerance for smoking.

"We have to change the fundamental mind-set about doping," Dr. Don Catlin, who operates the Olympic drug-testing lab at U.C.L.A., said.

There appears to be little fear that human cloning will have a significant effect in sport. If say, Michael Johnson were cloned, the result would almost certainly not be the same world record-setter as the original, researchers say, because environmental, nutritional and motivational factors also play significant roles in developing athletes.

"If I'm the clone of Michael Johnson, I've got to bend myself into all sorts of shapes to run, because genetically that's what I'm destined to be," Dr. Friedmann said. "I run and run and run, and I can't ever get anywhere. Then what am I? I'm a Michael Johnson who can't run. That's a nobody. That must be a crushing experience to learn you're not what you're genetically destined to be."

Moral and Athletic Limits

Cloning aside, many athletes and sports officials say they would abhor genetic engineering in sport. "It is supposed to be a test of human capability, not a chemical war or a genetic war," Brandi Chastain of the American women's soccer team said.

If genetic engineering is used, "then sport is dead," said Dr. Bengt Saltin, director of the Center for Muscular Research at Copenhagen University in Denmark.

Yet, American society tolerates other types of enhancement, from the caffeine stimulation of coffee to breast enlargement to erectile function. And although there has been an outcry about genetically engineered corn, there was mass celebration when Mark McGwire broke the major league home run record in 1998 using androstenedione, a steroid precursor that is banned by the Olympics and many professional sports.

"Nobody cared about what McGwire was using," said Jon Drummond, a member of the victorious American 4x100-meter relay team at the Sydney Olympics. "They just wanted to see him break the record."

If genetic engineering can be made safe, with fewer side effects even than conventional methods of doping, it may grow increasingly difficult to find supportable arguments against using gene alteration to achieve excellence in sport, Dr. Friedmann said.

"Our society has already decided partly that maybe there isn't a lot wrong with it, and that we can build ourselves, change ourselves, as much as we'd like, consistent with safety and medical ethics," he said. "If a weight lifter makes massive muscles and with a flinch of the finger can lift a few hundred pounds, what's wrong with that ethically? I'm not sure you'll get good answers to that."

Not all athletes will have equal access to genetic engineering, but not all of them have equal access today to the same nutrition and training facilities. Not every distance runner, for instance, can train at altitude. Should sea-level athletes be allowed to take EPO to match the oxygen-carrying benefits for those who live at altitude?

The most effective argument against genetic enhancement may be that it will coerce others to alter their fundamental makeup, perhaps at great risk, if they want to compete.

"The argument in favor of allowing people to do this is based on our American tradition of giving individuals a huge amount of autonomy over their own bodies," said Dr. Eric Juengst, an ethicist at Case Western Reserve University in Cleveland. "The limits on that kind of freedom are interpersonal. Once your actions cross the line of affecting just yourself and begin to affect other people, we have license to step in."

That right to set moral limits, however, will inevitably clash with a desire to break athletic limits. Anyone who could run 100 meters in six seconds "has no place in sports," said Mr. Greene, the world record- holder at 9.79 seconds. But, he added, "If anyone can run the 100 in six seconds, I'd like to see it."

Copyright 2001 The New York Times Company

This article can also be viewed at: http://www.nytimes.com/2001/05/11/sports/11GENE.html?pagewanted=all

 

 

 

GENE THERAPY OR DOPING OF THE FUTURE

 

STURBOIS Xavier, MAIER Eddie, SCHAMASCH Patrick, CUMMISKEY Joseph

 and Prince Alexandre de MERODE

 

 

Summary

In theory everything seems to be in place regarding scientific research for a probable confrontation in the sporting world between cell therapy and gene therapy to enhance the performance of athletes. What are the stakes and what are the means at the disposal of scientists to manipulate the genome? A review of the situation is necessary.

 

Key words

Doping, genome, DNA, gene manipulations, gene therapy, adenovirus, retrovirus and liposomes.

 

Introduction

Today, sport is very important in society with, as a corollary: many different controversies. Athletes are easily suspected of doping and we must admit that the virtues of competition are not always respected.

Since the beginning of time, many doubtful practices have existed and the public authorities as well as the International Olympic Committee and sports governing bodies have condemned doping since the 60s: « Use of substances or methods that are likely to enhance performance and that can be dangerous for health ». Until today, the concerned substances were essentially clinical products from the pharmaceutical industry. Nevertheless, the situation may evolve and concern many biological laboratories that work on cell and gene therapy.

 

 

The human genome

The human genome represents the whole gene message that gives to each individual his/her own characteristics, thanks to a combination of communicable traits of the cell and of its descendants. These properties lie in the DNA chromosome or Desoxyribonucleic Acid and form a double helix of base composed nucleotides (A=adenine, G=Guanine, T=Thymine and C=Cystosine) linked with hydrogen bonds (A-G and T-C). The genetic information code is determined by the sequence of the bases in the chains of nucleotides. This code owes its precision and complexity to more than three billion base pairs. The human chromosomes (23 pairs) contain the genetic message in the cell nucleus, as each chromosome owns a fragment of the DNA double helix. The message imposes the assembly order of the amino acids to create a determined protein such as the enzymes, which are necessary for the metabolism. The quantity of necessary information to obtain a specific protein is called “gene”. The chromosomes assemble thousands of genes that are now almost completely decoded (2002). The genetic information is not always completely expressed from the origin of the cell line (primary or differentiated cell) but progressively to acquire differentiation and maturity (differentiated cell).

 

The manipulations of the human genome

Many pathologies are caused by errors in the genetic code. They concern a single or many genes at the same time. The idea of a possible correction of the pathological gene comes from the observation of the development of certain tumours by viral infection. It consists of the injection of viral DNA in somatic cells. In the same era (1960), we understood the interest of the viruses as the vectors of a new genetic material. Therefore, the problem was to find how to allow viruses or other carriers to enter efficiently the desired somatic cells. Friedmann’s work, who uses the in-vitro manipulations of reimplanted cells in the organism, marked the beginning of tangible progress towards an in-vivo approach, where the DNA could be directly introduced in the cells of the organism. These modifications of the somatic cells do not lead to any genetic transmission. This would not be the case for germ cells.

If a gene is absent from the dysfunctional, it will lead to the appearance of “genetic” diseases or cancers. Some functional disturbances will also appear if there is the slightest transcription error of the gene.

The principle of the gene transfer is based on the injection in the cell, of a “therapeutic” gene into the place of the absent or abnormal gene. The vectors of the therapeutic gene can be the adenovirus, the retrovirus and the liposome. The adenovirus (cold) is made innocuous by the withdrawal of its own genetic material and becomes vector by the injection of the therapeutic gene in its nucleus. The pathogenicity of the retrovirus, which is smaller than the previous one, must be depressed before introducing the therapeutic gene in its DNA. The liposome is a lipid microcapsule in which the repairing gene is positioned.

The in vivo introduction of the gene material in the human pathological cells is effectuated with aerosols or injection. It is also possible to collect somatic cells and to reimplant them after introducing in vitro the adequate genetic material. These methods over all concern the viruses and retroviruses. The liposomes and the outer membrane are of the same nature. They fix themselves on it and thanks to it; they will leave in the cell the genetic material of which they are the vectors. Because of their cutaneous application, the liposomes are part of the cosmetic substances.

In the cell, the adenovirus acts no matter what biocellular phase. The new genetic material stands apart from the deficient gene and replaces it as long as the cell lives. The retrovirus integrates the genetic material of that (genome) of the deficient cell, mainly during the cell division. This is a real genetic graft. The action of the liposomes is little known and the issue of the artificial chromosomes is still in its infancy.

In theory, we can have the greatest hopes for cancer treatment, for instance, and of certain pathologies of the osteoarticular system by a cell therapy. However, we must note that current practice does not enable the successful clinical exploitation of the efforts of research. Nevertheless, it turns out that the sport community will probably be very soon confronted with this problem in the years to come.

 

Applications of the gene therapy

The inventory of research was effectuated in September 2001. It currently includes 311 studies against cancer, 52 against genetic diseases, 41 as part of the cardiac diseases, 36 against AIDS and 3 respectively in the autoimmune, osseous and neurological matters. Some people think that within 5 years, the sport community could be concerned with gene therapies, which would aim at increasing the auto production of EPO, of the growth factors, the muscles (angiogenic factors of the cardiac and skeletal muscle), the vascular development (endothelia-vascular growth factor), the analgesic peptides (endorphins, enkephalins, etc.) and a great number of hormones (hypophysis), etc. Therefore, the genetically modified man is looming on the horizon of the third millennium. This phantasmagorical image becomes true when you learn that genetically modified baboons endogenously produce fifteen times more EPO than the normal.

 

Screening methods

This last observation raises the question of the screening methods that could counter this kind of doping. Of course, some abnormally high concentrations of hormones that are likely to enhance performance could be an important incriminating piece of evidence. Moreover, certain vector viruses could leave, in blood, the trace of an antigen and antibody reaction towards their specific proteins. The use of chips that are able to analyse quantitatively a lot of genes will enable to underscore the under or over expression of specific proteins and to establish, therefore, a suspicion of doping. What emerges is that in this field also, the part seems to be difficult but not insoluble thanks to the evolution of certain complementary techniques such as, for instance, the composed oligonucleotide probes.

 

Ethical considerations

Once more, the fight against doping, in view of the current inadequacy of the screening techniques, will mainly rest on the education in this field and on the moral promotion of an ethical attitude. Indeed, we must recognise that the transfer of genetic material, even if the objective is justified, can lead to important risks for health. Indeed, those risks are caused by possible abnormalities of the transferred genetic material that can lead to abnormal gene expressions, which cause diseases. In the medical practice, there is no question of harming his/her patient, especially when it is not a matter of treating a sick person. Until now, sport has not been considered as a disease and the physician has to treat the cause before the effects. Moreover, the human being must be considered as a combination of coordinated systems and the deterioration of a single piece of the jigsaw can ruin the harmony of the combination. Similarly, human testing will have to be rigorously controlled by the monitoring organisations, in view of the risks that patients are confronted with, even if they volunteer. Nevertheless, the current testing only aims at studying a therapy adapted to a pathological situation and strictly distinguishes itself from any attempt to create an advantage for a non-medical purpose. Competition must keep on providing a winner on the field and not by gene manipulation in a laboratory, the dangers of which are evident and not yet evaluated at their full magnitude. Nevertheless, we will have to accept that an athlete, who decides to have gene therapy to treat a pathology he would suffer from and thanks to which he would be cured, participates in the competition.

 

Conclusion

The International Olympic Committee, after taking the opinion of six international independent experts, wants here and now and in the current situation to announce its recommendations about gene therapy:

            -           Gene therapy is admittedly very promising for everyone, and even athletes

who participate in the Olympic Games ;

            -           The IOC recognises the validity of the development and application of

gene therapy to prevent and treat the diseases ;

-           The IOC firmly warns against the potential abuse of gene therapy and will establish as soon as possible any procedure and analytical method necessary to identify the athletes who would be suitable for the appropriate use of these therapies;

-           The IOC is confident of acquiring the capacity to master the abuses and to set the ethically acceptable use procedures;

-           The IOC makes a solemn call to each medical and scientific sports governing bodies to support its stance about gene therapy in sports.

 

Xavier STURBOIS is a Professor in the Medical Faculty of the Catholic University in Louvain and a member of the Medical Commission of the International Olympic Committee.

Eddie MAIER, Research DG, European Commission.

Patrick SCHAMASCH, medical Director of the International Olympic Committee.

Joseph CUMMISKEY, MD coordinator of the CAFDIS project.

Prince Alexandre de MERODE, President of the Medical Commission of the International Olympic Committee.

 

 

 

 

 

Gene genie casts ominous shadow
By Peter Hamlyn  (Filed: 03/12/2001) (Peter Hamlyn is a consultant neurosurgeon at St Bartholomew's and the Royal London Hospital)

 

A WEEK ago the world learned that a human cell had been cloned for the first time in an American laboratory.

The news threw up all sorts of fantastic possibilities, but a few days later in London, a conference entitled Genes in Sport, was told of a dark side to this science. Before we produce the next generation's atom bomb we must digest the ethical and political questions this science poses . . .

The conference focused on the genes beneficial to sporting achievement and the evidence for a genetic component to sporting achievement is immediately apparent when you consider that families of winners have been seen in several sports. Football produced Jack and Bobby Charlton and tennis has the Williams sisters. Twins abound: cricket with the Waughs, football has the de Boers, tennis produced the Gulliksons.

In addition, particular ethnic groups seem to have an edge in some events. The presence of Mike Boit, the former 800 metres world record holder, served to emphasise the remarkable achievements of a small nation with so little resource that is today's Kenya. In all distances over 800m Kenyans now make up 40-80 per cent of the current record holders. Forty per cent of the current top 50 marathon runners are Kenyan. They all stem from two tribes who have an ancestry of running. Their achievements have highlighted the complex interaction between genes and the environment; the question of how much of sporting achievement is nature and how much nurture. Clearly both factors are essential. In 1990, of those marathon runners capable of putting up times of less than 2hr 20min, 65 were from the US, 54 from the UK and 12 from Kenya. By the year 2000, the figures were 16, seven and 222 respectively. Here is proof beyond doubt that effort produces results and the lack of it the reverse.

The Danes have put a lot of effort into finding out how it is the Kenyans do so well. Professor Bengt Saltin told of their work comparing Danish runners with Kenyan village boys. They discovered there were only slight differences in their ability to take oxygen - in other words to burn energy.

There were modest differences in the time they could maintain energy consumption close to its maximum before their metabolic efficiency dropped off. Both differences were in favour of the Kenyans. However, the biggest difference was in the efficiency with which this energy was converted into forward motion.

Why? Well, the answer appears simple. The Kenyans have beautiful legs - a fact Mike Boit seemed only too pleased with when I pointed it out to him. The Danes proved what to you or I might seem obvious. Compared with the Danish runners they had longer, thinner legs. The fact that the Danish champion had relatively heavy calf muscles meant he had to shift the extra weight back and forwards with each stride. Hence, he came third in the race with the village boys.

Sir Roger Bannister was also at the conference. Watching Boit and he in conversation I was struck by how alike were their physiques - both are tall and thin with long legs. The similarity does not end there. Bannister is an eminent neurologist, contributing much to sport's medicine, and it was he who first emphasised the importance of lower-limb anatomy to running ability.

A group from St Thomas' Hospital, London, headed by Dr Alex MacGregor, have established a registry of more than 1,500 pairs of twins, to study the 'nurture versus nature' question. Looking at tennis, swimming and running, they have found that twins of either kind tend to play the same sports - which is evidence of nurture. But it is only in the identical pairs that they have commonly seen both twins achieve high success - suggesting the influence of nature.

Horse racing remains an area of interest for geneticists as all of the 500,000 thoroughbreds in the world today originated from just four horses selected in Britain during the mid-18th century.

An almost complete record of their breeding exists and from those four stallions stems a third of the genetic make-up of the existing horses. Selection for breeding was strict from the very start, so that 80 per cent of the genes now derive from the first 21 ancestors.

Like the human genome project, the mapping of horse genes is now some 90 per cent complete. The conference was informed that the comparative price of stallion brothers would soon be determined by the closeness of their genes to those of a successful ancestor lineage. The Victorian habit of making ashtrays from the hooves of successful rides will achieve a lucrative, contemporary pertinence. The DNA of that ancestral winner can now be unravelled from these toe clippings.

These studies showed that 35 per cent of a horse's performance was genetically determined - that leaves 65 per cent to nurture, so no threat to the trainers as yet.

So, what of the dark side to genetic research? The announcement from Massachusetts of the human cloning was made not by a scientist but by the chief executive of the company who own the cells. Chilling, especially when you think Phillip Morris own much of the rights to the genes likely to be of use in treating lung cancer. The Icelandic people have worked out their entire family tree and genome only to see part of the information sold on to a drug company whose turnover dwarfs that of many nations.

As a medic, I am entirely used to drug companies protecting their investment with patents. It means drugs can be developed faster than by other means. However, I can't help feeling we might all be better to wait a little longer when it comes to genetic

I am not necessarily recommending this but simply saying to those who suggest that the progress of knowledge is unstoppable, that it is in this instance materially retardable development.

If international law were to outlaw the patenting of genetic knowledge, the rate of investment and therefore advance would slow dramatically..

The upside of genetic research in sport is that we may be able to identify those among us who are likely to develop complications. The Appo E gene is important in determining those whose brains are particularly susceptible to developing the punch-drunk syndrome of dementia when exposed to the repeated head injuries intrinsic to boxing, jump jockeying and rugby. Other genes will help identify those whose joints will suffer disabling arthritis in middle age.

The downside is that with genetic therapy for disease will come genetic doping in sport. Dr Peter Scherling, a senior researcher from Copenhagen, warned the conference of the awesome potential for "gene cheats".

When it comes to muscle there are two ways of getting an advantageous gene in: it can be directly injected into the targeted muscle or delivered to all muscles by a tame virus - nature's gene therapist.

The injections are a technical possibility. You could take a tall, skinny marathon runner and inject the leg muscles so as to put him or her on an invincible pair of sprinting legs. The only way to tell if it had been done would be to cut out pieces of the muscle and compare it with the uninjected muscles.

What athlete would rightly consent to that kind of dope test? Peeing in a pot is one thing, but having your legs cut open is another.

Injections will always be a painful transient and potentially hazardous method of getting ahead genetically. It will always require expensive laboratory and medical support. The viral method is of more concern.

Genes to increase the number of red blood cells and thus the carriage of oxygen to the muscles have successfully been implanted with viruses into monkeys. Two different genes have been infected into mice, each of which produces major muscle growth. Yet another gets rid of surplus body fat.

As yet, the technology is extremely risky. The genes cannot be turned off and usually prove lethal. But this remains the single obstacle to gene therapy becoming widespread - Scherling predicted that the solution was probably only 10 years away.

The risks will put off all but the most determined for some time, though the morals which lead coaches to give gymnasts in their early teens anabolic steroids might rise to the task. When it comes to horse racing, the hazards are not likely to prove such an impediment.

The prospect of turning an old farmyard nag's offspring into a Derby winner worth millions will be in the minds of many. The technology means that a yard could achieve in a few years what has taken the thoroughbred business two and a half centuries.

Gene doping by the viral mechanism will by any practical means be untraceable. The genetic sequences are all entirely natural and could be hidden anywhere in the DNA sequence. The virus will infect every cell and a piece of dandruff could be used for the analysis. However, for each contestant the task would be as big as the Human Genome Project itself. It would be akin to looking for a needle disguised as hay in a haystack the size of the universe.

Finally, Prof Steven Jones, one of the world's most accomplished geneticists, quoted to the conference the US Attorney General, who recently admitted: "I wish genetics had never been invented".

 

Drug scandals in sport would be nothing compared to the potential for genetic engineering to create "super-athletes". Christie Aschwanden investigates

A TENSE HUSH falls on the Olympic stadium as the sprinters crouch on the starting blocks for the men's 100-metres final. With the 2008 Olympic games in full swing, athletes have shattered records as never before, usually by an ample margin. Television ratings are soaring, and as the finalists prepare to compete for the title of world's fastest man, the crowd expects the winner to obliterate this record, too.

Though the Olympic flame still burns in the stadium, these athletes are nothing like their heroic predecessors. Athletes of old honed their bodies with toil and sweat, but at the 2008 games most of the champions have altered their genes to help them excel at their sport. Weightlifters' arms and sprinters' thighs bulge as never before, and long-distance runners have unparalleled stamina—all the result of a few crucial genetic upgrades. Officials are well aware that such "gene doping" is going on, but as the practice is virtually undetectable, they are powerless to stop it.

This may sound like the ultimate sporting nightmare, but the technology to make it come true could well arrive even before 2008. Scientists around the world are working to perfect gene therapies to treat genetic diseases. Soon, unscrupulous athletes may be able to use them to re-engineer their bodies for better performance.

Need more endurance? Add a gene to bolster delivery of oxygen to labouring tissues. Want bigger muscles? Inject them with a gene that will make them grow. Both techniques are under development, and if they work in humans as they do in lab animals, they will change the face of nearly every sport. But at what cost? Knowing how to boost performance is one thing; knowing how to do it safely is quite another. If athletes do turn to gene therapy, these genetically enhanced champions risk paying for their success with heart disease, strokes and early death.

Genes matter when it comes to sport. At the 1964 Winter Olympics in Innsbruck, for example, Finnish sportsman Eero Mäntyranta won two gold medals in cross-country skiing. Though his training programme wasn't radically different from those of his teammates and rivals, Mäntyranta had a distinct advantage: he was born with a genetic mutation that loaded his blood with 25 to 50 per cent more red blood cells than the average man's. Since these cells shuttle oxygen from the lungs to the body tissues, Mäntyranta's muscles got more of the oxygen they needed for aerobic exercise, so he could ski faster for longer.

Mäntyranta got his extra red blood cells because of a mutation in the gene that produces the receptor for the hormone erythropoietin (epo). The kidneys normally churn out epo when oxygen levels in the body's tissues drop, as they do at high altitude, where the air is thin. Epo commands the body to manufacture new red cells, which raises the blood's capacity to carry oxygen. Once oxygen regains its normal level in the blood, the epo receptor should shut down epo production. But Mäntyranta's mutation turned off this crucial feedback, so his body kept making more red cells.

Mäntyranta's mutation is exceedingly rare. But anyone can boost their red cells simply by adding more epo to their bloodstream. In 1989, the biotech company Amgen began marketing Epogen, an injectable form of epo produced by recombinant bacteria, as a treatment for severe anaemia—a serious problem in patients with AIDS or kidney failure.

Athletes were quick to exploit the drug, even though such doping is banned in most sports. At the 1998 Tour de France, for example, French officials caught an employee of the Festina cycling team with a carload of performance-enhancing drugs, including epo. The scandal exposed a dirty secret: "Doping is part of the business of cycling," Swiss rider Alex Zulle told reporters after he confessed to taking epo and other banned drugs.

Secret weapon

Cycling isn't the only sport sullied by allegations of epo use. At the Australian Open tennis championships a year ago, the player Jim Courier told reporters that he suspects epo use is rampant in the game. "I can't play 35 weeks a year and God knows how many matches and keep going. I just can't do it and I don't think anybody else can, either. But they are." Courier says epo makes such superhuman performance possible. Athletes in cross-country skiing, football and track and field athletics are also rumoured to use the drug. "The fact is, we only reward winners, and drugs work," says Charles Yesalis, an epidemiologist at Pennsylvania State University who has interviewed more than a thousand athletes who have admitted to taking banned drugs. With epo rumoured to make athletes run up to 20 per cent faster, the drug's allure is hard for many to resist, he says.

The problem may grow even more widespread if athletes can insert a gene that makes their bodies produce extra doses of the hormone. Instead of injecting themselves with epo several times a week, athletes could use this "gene therapy" to acquire the equivalent of Mäntyranta's super-gene with a single shot. The technology may be just around the corner, as several academic groups and a handful of biotech companies hammer out ways to use epo gene therapy to treat anaemia.

The gene-therapy techniques under development use viruses to carry the epo gene into cells. Researchers remove the genes that make a disease-causing virus harmful and insert the epo gene in their place. "The virus acts as a taxicab," says Philip Whitcome, chairman of the biotech company Avigen in Alameda, California. "You need to get these instructions inside the cells to the machinery that can follow the instructions and make the protein."

Adenoviruses, like the ones that cause the common cold, are a favourite delivery system for gene therapy because they are relatively large and can carry big genes in their payload. However, they are easily recognised and destroyed by the immune system. "There's a race going on to see if the immune system will destroy the taxi before it delivers its passenger to the inside of the cell," says Whitcome. So to evade the body's defences, Avigen has patented the use of adeno-associated viruses (AAVs) for delivering epo. Smaller than an adenovirus, an AAV can't carry as much cargo but is less vulnerable to attack from the immune system, says Whitcome.

Both viral types have shown exceptional results in early tests of epo gene therapy. In 1997, a group led by Jeffrey Leiden, then at the University of Chicago, used an adenovirus to deliver the epo gene to mice and monkeys. After the scientists injected the virus into the animals' muscles, it infiltrated their cells, inserting the epo gene and spurring the cells to pump out the protein. This boosted mouse hematocrits (the proportion of the blood volume made up of red blood cells) from 49 per cent to 81 per cent, while the monkeys' hematocrits rose from 40 per cent to 70 per cent or more (Human Gene Therapy, vol 8, p 1797). A single injection elevated hematocrits for over a year in the mice and for 12 weeks in the monkeys.

Researchers at the biotech company Chiron in Emeryville, California, reported similar results in a 1998 trial that used AAVs to deliver the epo gene to two baboons (Gene Therapy, vol 5, p 665). After 10 weeks, their hematocrits had risen from 38 per cent and 40 per cent to 62 and 75 per cent, respectively, and stayed at those levels for the entire 28 weeks of the study.

Promising though these results appear, gene therapy may not be risk-free. Last autumn, an 18-year-old patient died after receiving gene therapy for a rare liver ailment, delivered via an adenovirus. It is still uncertain what went wrong, but scientists are anxiously re-examining the safety of gene therapy in the light of this incident.

Unless safety turns out to be an insuperable problem, we could see clinical trials of epo gene therapy within the next few years. And if the trials prove successful, athletes would inevitably be tempted to hike up their hematocrit - and thus their endurance - with a single injection. But elevating the red blood cell count is a risky business, as the blood thickens when it is packed with so many red cells. "The heart has to pump sludge blood through small vessels, and that puts you at high risk for high blood pressure and stroke," says Leiden. In one family with a mutation similar to Mäntyranta's, for example, the father died of a stroke in his 50s, and a son suffered a heart attack at age 40, notes Josef Prchal, an epo researcher at the University of Alabama in Birmingham.

Even successful gene therapy could still lead to problems, mainly because there's no way to turn the gene off once it has been inserted. "Some of the monkeys in our experiment made too much epo, and we had to bleed them to thin their blood and keep them alive," says Leiden. Healthy athletes who indulged in epo gene therapy might likewise require frequent bleedings to keep their hematocrit low enough to prevent strokes—and they'd still have a heightened risk of high blood pressure and atherosclerosis, says Prchal.

If epo gene therapy can give athletes added endurance and stamina, a different sort of gene therapy can give them the muscles to match, says Geoffrey Goldspink, a biologist at Royal Free and University College Medical School in London. Scientists believe that hard exercise, the kind that leaves you sore the next day, builds muscle by inducing microscopic damage to the muscle fibres. These "micro tears" are repaired by beefing up the fibres with extra proteins so they will be adapted to the exercise the next time. A protein called insulin-like growth factor 1 (IGF-1), which is turned on by mechanical signals such as stretch or exercise overload, seems to play a role in this repair process. IGF-1 exists in at least five different forms, whose parts are spliced together in different ways. All the forms are produced by a single gene.

Pumping genes

Goldspink's group is working on gene therapy that uses a form of IGF-1 called mechano growth factor (MGF) to treat muscle-wasting diseases such as muscular dystrophy. Since MGF is made in muscle tissue and doesn't seem to circulate in the blood, Goldspink expects its effects to be localised to muscle. His group has tested MGF gene therapy in mice, with impressive results. The researchers gave mice a single injection of the MGF gene, and two weeks later the injected muscles had grown by 20 per cent. "We seem to have found the magic potion that makes muscles grow," says Goldspink.

Across the Atlantic, researchers are having similar success with another form of IGF-1 which is made in the liver as well as in muscle. When it circulates in the blood, IGF-1 raises blood sugar levels. But when it is in muscle tissue, "IGF-1 seems to be mainly involved in repairing and building muscles," says Lee Sweeney, a physiologist at the University of Pennsylvania.

Sweeney and his colleagues used an adenovirus to deliver the IGF-1 gene into the leg muscles of mice. Their results, published in December 1998 in Proceedings of the National Academy of Sciences (vol 95, p 15 603), made headlines and caught the attention of bodybuilders everywhere. After three months, the mouse leg muscles injected with the IGF-1 gene had grown by 15 per cent, even though the animals had not taken any special exercise. Sweeney is convinced that similar IGF-1 gene therapy could allow people to custom-build their physiques.

"What happened in our mice is that they are essentially expressing IGF-1 as if they had just been exercising hard. They are enormous, and they have no body fat," says Nadia Rosenthal, a geneticist at Massachusetts General Hospital in Boston who also worked on the study. Though the mouse muscles don't need the extra IGF-1, they do much better with it, she says. Sweeney believes IGF-1 could even account for the difference between weaklings and muscle men. "It may be that some people naturally make more IGF-1. That might explain why some people can build muscle more easily than others," he suggests.

IGF-1 gene therapy promises to be relatively safe because the protein produced by the newly added gene seems to stay in the muscle that receives the injection. "We didn't find any IGF-1 circulating in the animals' bloodstream, and so that suggests that it was in fact being made and used locally in the muscle," says Rosenthal. That's important, because it means that IGF-1 injected in, say, a tennis player's biceps won't lead to an enlarged heart, nor will it alter blood sugar levels.

The ability to target IGF-1 therapy at specific muscles could be especially enticing to athletes. "A 20 per cent increase in muscle mass is probably pretty easy with IGF-1 alone. If we start adding in other growth factors it could be as high as 50 per cent," predicts Sweeney. "This could give you the ability to grow new muscle on demand. Because its effects are local, you could just inject the IGF-1 gene directly into the muscle you want to enlarge. You could potentially re-engineer your body."

Sweeney speculates that IGF-1 therapy might be available as soon as two years from now. Rosenthal, however, warns that several problems stand in the way. "Mice are not humans. We have already determined that a completely different protocol would be necessary for larger animals because it's harder to access the inside of a large muscle," she says.

Even if IGF-1 therapy does work, there's no guarantee that it will last over the long haul. "It might wear off more quickly in athletes because they damage the muscle more often than sedentary people. When you damage the muscle through exercise you run the risk of losing the genes that you've put in there," Sweeney says. "These issues are a big unknown because no one really knows to what extent people turn over their muscle cells. Every cell that's in your heart when you're born is there when you die, but we're not sure if that's true of other muscles."

If an athlete's gene therapy does stop working, there's no guarantee that a second dose will have the same effect as the first one. "There's a problem with repeated dosing: your body will build antibodies against the virus that inserts the gene into your cells, so if you give another injection with the same virus, your body's immune system may very well wipe out the virus before it can deliver its genes," says Sweeney. But athletes and their doctors aren't likely to be put off so easily. They might, for example, be able to get around this problem by turning to alternative viruses for delivering their illicit genes.

Catching cheaters

So does this mean that the authorities will finally lose their long battle against drugs in sport? Don Catlin, a biochemist who studies gene therapy abuse at the Olympic drug testing lab at the University of California in Los Angeles, has little doubt that athletes and their doctors will resort to gene doping. "I don't like what they do - it's dirty - but I have to admit I'm impressed with the sophistication of doctors on the 'other side'," he says.

Detecting abuse won't be easy. The big problem is that proteins made by engineered genes look identical to the ones the body makes naturally. About the only way scientists might detect illicit gene therapy would be to find traces of the virus that delivered the gene. "If you were looking for MGF or IGF-1, you could take a biopsy from the muscle and look for viral DNA. But you would have to know exactly where it was put in. You're essentially looking for a pinprick in the body," says Goldspink. The same method could detect epo therapy, but again you'd have to know where the gene was injected, says Leiden.

No one seriously expects athletes to line up for muscle biopsies before they go out to compete at the Olympics, so clearly a less invasive strategy must be found. One approach would be to look for abnormally high levels of a gene's product. "You could get the athlete to remain inactive for, say, 12 hours, and then test for MGF," says Goldspink. "If the levels were still high you would have a good indication that you've got a gene that's been switched on all the time instead of being induced by natural activity." But he admits: "Athletes are probably the people least likely to stay inactive for 12 hours, and even that may not be long enough."

This approach might be more useful for detecting epo gene doping, however. People with plenty of red blood cells should have little or no epo circulating in their blood, so if testers found epo in those circumstances, says Leiden, "you'd have a pretty good indication that something was going on." But even there, testing could not separate illegal gene dopers from athletes who carry natural - and presumably legal - mutations such as Mäntyranta's.

If history is any guide, scientists will have a tough time staying ahead of the cheats. That, at least, is nothing new. "There's a lot of money at stake, and drug tests are easy to circumvent," say Yesalis, who thinks many of the records set in the past 30 years have been drug aided. "Users have kicked butt on the drug testers for 40 years. What makes anyone think that's going to change?"