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Wendy Chung 談自閉症-我們所知及未知的部分

Wendy Chung: Autism — what we know (and what we don’t know yet)

 

Photo of three lions hunting on the Serengeti.

講者:Wendy Chung

2014年3月攝於TED2014

 

翻譯:洪曉慧

編輯:朱學恒

簡繁轉換:洪曉慧

後制:洪曉慧

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關於這場演講

在這場以事實為基礎的演講中,遺傳學家Wendy Chung闡述我們對自閉症系列障礙所知的部分-例如,自閉症成因為多重性、甚至連鎖性。超越對自閉症診斷的憂慮和擔心,Chung和她的團隊藉由研究、治療及仔細聆聽,探索我們對自閉症有何瞭解。

 

關於Wendy Chung

在Simons基金會,Wendy Chung致力於研究可能與自閉症有關的遺傳變異患者之行為特徵、大腦結構及功能。

 

為什麼要聽她演講

Wendy Chung是Simons基金會自閉症研究計劃臨床研究主任,從事基礎與應用科學研究,以幫助自閉症系列障礙患者。她是Simons個體變異項目的主要研究者,研究染色體16p11.2發生基因複製變異之參與者的行為特徵、大腦結構與功能,這個變異被認為與自閉症系列障礙有關。

 

Chung也指導哥倫比亞大學臨床遺傳學研究項目。對於評估及治療擁有自閉症系列障礙與智力障礙的兒童,她使用先進的基因診斷技術,探索基於遺傳的神經系統疾病。她十分關切遺傳醫學及基因檢測的相關倫理及情感問題。

 

Wendy Chung的英語網上資料

Home: Sfari.org

 

[TED科技‧娛樂‧設計]

已有中譯字幕的TED影片目錄(繁體)(簡體)。請注意繁簡目錄是不一樣的。

 

Wendy Chung 談自閉症-我們所知及未知的部分

 

「為什麼?」父母們總是問我這個問題。「為什麼我的孩子會有自閉症?」身為兒科醫生、遺傳學家、研究員,我們試著尋找這個問題的解答。

 

但自閉症並非單一症狀,事實上它屬於系列障礙,障礙的形式包括-例如以一位13歲男孩Justin來說,他無法口語表達、無法說話,他藉由iPad、以圖片表達他的想法和意見。當這位男孩情緒不佳,他會開始搖晃身體,最後,當他無法承受時,會開始用頭撞東西,可嚴重到皮開肉綻、需要縫合。Gabriel的情況也被診斷為自閉症。同樣是13歲男孩,他的症狀卻截然不同。事實上他對數學相當有天賦,他可毫不費力地心算三位數相乘結果。然而,與人交談對他來說卻相當困難。他無法與人目光接觸,他很難展開對話,這令他不自在。當他緊張時,隨即封閉自己。但這兩位男孩都被診斷為自閉症系列障礙。

 

令我們擔心的一點是:自閉症是否已成為一種流行病?目前,88個兒童當中就有一個被診斷為自閉症。問題是:為何這張圖表呈現這種趨勢?是因為近年來自閉症患者人數急遽增加?還是因為現在我們開始將某些人診斷為自閉症患者,根據之前早已存在但並未歸類為自閉症的症狀?事實上,80年代末、90年代初,立法通過為自閉症患者提供所需資源及能幫助他們的教材。隨著對自閉症重視的增加,更多父母、兒科醫師、教育工作者瞭解如何識別自閉症特徵,因此更多人被診斷為自閉症患者,並獲得他們所需的資源。此外,我們對自閉症的定義隨時間改變,因此事實上我們放寬了對自閉症的定義,這多少解釋了我們所見的增長情形。

 

下一個大家關心的問題是:自閉症成因為何?一個常見的誤解是:疫苗會造成自閉症。但我相當明確地聲明:疫苗不會造成自閉症(掌聲)。事實上,最初主張疫苗造成自閉症的研究報告完全是造假。這份報告被刊登的《Lancet》期刊撤回,它的作者,一位醫生,被吊銷醫生執照(掌聲)。美國國家醫學研究所、疾病控制中心已進行重複調查,未發現任何可靠證據顯示疫苗會造成自閉症。此外,疫苗成份之一:名為硫柳汞的化合物,曾被認為是造成自閉症的元兇,事實上已在1992年從疫苗中移除。你可看出,它與自閉症增長現象毫無關聯。因此同樣地,沒有證據顯示這是問題的答案。因此問題仍未解決:自閉症成因為何?

 

事實上或許答案不只一個。如同自閉症屬於系列障礙,它的病因、成因也不只一種。根據流行病學資料,我們知道其中一個原因、或應該說其中一個關聯是:高齡父親。也就是說,受精時父親是否較為高齡。此外是另一個脆弱而關鍵的發展階段:母親懷孕期間。這段期間胎兒的大腦正進行發育,我們知道曝露於特定化學物質中確實會增加罹患自閉症的風險,尤其是某種叫丙戊酸的藥物,罹患癲癇的孕婦有時會服用,我們知道它會增加罹患自閉症的風險。此外,某些傳染性因素也會導致自閉症。

 

我會花很多時間說明的其中一項因素是:基因也會造成自閉症。我著重於這一點的原因並非在於這是造成自閉症的唯一因素,而是因為這是較容易界定的自閉症成因,可藉此對生物學及大腦運作方式更加瞭解,因此我們可找到得以應對的策略。然而,我們尚不瞭解的其中一項遺傳因素是性別之間的差異。罹患自閉症的男女比例是4:1,我們尚不瞭解其中原因。

 

我們瞭解遺傳是其中一項因素的方式是藉由觀察所謂的「共患率」。換句話說,如果一位手足罹患自閉症,其他手足罹患自閉症的可能性是多少?我們可觀察三種手足之間的情況:同卵雙胞胎:擁有100%相同遺傳訊息的雙胞胎、身處相同的宮內環境;相較於異卵雙胞胎:擁有50%相同遺傳訊息的雙胞胎;相較於一般手足:同樣擁有50%相同遺傳訊息,但所處宮內環境不同。當我們觀察這些共患率時,你會發現令人驚訝的一點是,以同卵雙胞胎來說,共患率是77%。值得注意的是,並非100%。基因並非造成自閉症的唯一因素,但它們的影響相當大。因為當你觀察異卵雙胞胎,共患率只有31%。另一方面,異卵雙胞胎與一般手足之間也有所差異,暗示著異卵雙胞胎與一般手足所受的環境影響或許有所不同。

 

因此這提供了一些自閉症與遺傳有關的資訊。那麼它與遺傳有多大關聯?當我們將它與其他我們熟悉的病症比較時,例如癌症、心臟病、糖尿病,事實上基因對自閉症的影響遠勝於這些疾病。但這無法讓我們得知造成影響的是哪些基因,甚至無法讓我們得知對某個孩子來說,造成影響的是一個基因或一組基因。因此對某些自閉症患者來說,它確實來自遺傳;也就是說,造成自閉症的是一個強大、決定性的基因。然而,對另一些人來說,它也來自遺傳;也就是說,它是發展過程中一組基因共同決定罹患自閉症的風險。我們無法確認對某個患者來說屬於哪種情況,除非我們進行更深入的研究。

 

因此這個問題變成:我們如何確認這些基因為何?容我提出一個不那麼直觀的說明。對某些人來說,他們可能因遺傳因素而罹患自閉症,但原因並不在於他們有自閉症家族史,而在於某些人的基因發生改變或突變,並非來自父親或母親的遺傳,而是由他們本身開始。卵子或精子在受精時產生突變,而非家族中代代遺傳的結果。我們可藉由這種方式瞭解及識別導致這些人罹患自閉症的基因。因此在Simons基金會,我們採用2600位沒有自閉症家族史的樣本。我們以孩子及其父母為樣本,藉此嘗試瞭解在這些樣本中導致自閉症的基因。為了達成目標,我們必須全面研究所有遺傳訊息,確認父母與孩子之間的差異為何。為了這麼做-先說聲抱歉,我打算使用較過時的比喻,以百科全書比喻,而非維基百科-但我試著藉此表達其中的意義。當我們進行清查時,必須觀察大量遺傳訊息。我們的遺傳訊息分類成46冊。當我們這麼做時,必須清查46冊中的每一冊。因為對某些自閉症來說,原因在於某冊書的缺失,但我們必須獲得更詳細的資訊,因此我們需要打開這些書。在某些情況下,基因的改變更加微妙;或許是某個段落有所缺失,甚至更細微的缺失-某個字母。30億字母中的一個有所改變,對大腦運作及行為造成深遠影響。藉由對家族基因進行這樣的研究,我們得以解釋,這些家族中,約25%的自閉症成因在於單一而強大的遺傳因子;另一方面,75%的成因尚不瞭解。

 

但研究過程中,我們深感所知的不足。因為我們意識到,導致自閉症的並非單一基因。事實上,目前的估計是有200-400個不同基因可導致自閉症,這部分解釋了為何自閉症的症狀相當廣泛。雖然其中包含許多基因,仍有跡可循。這並非200-400個隨機分布的基因,它們彼此有所關聯。它們連成一條路徑、形成一個網路,使我們得以開始瞭解大腦運作的情形。我們從基礎到整體開始進行,識別這些基因、蛋白質、分子,瞭解它們如何互動、使神經元運作;瞭解這些神經元如何互動,使大腦迴路運作;瞭解大腦迴路的運作如何控制行為表現;瞭解自閉症患者與正常人的認知差異。但早期診斷對我們來說相當重要。若能及時診斷可能罹病的患者,我們就有能力在大腦發展的關鍵階段造成改變及影響。因此例如Ami Klin發展出適用於嬰幼兒的方法。藉由生物標記,例如目光接觸及眼球追蹤,識別嬰兒是否有罹患自閉症的風險。你可看見這個嬰兒與這位女士保持良好的目光接觸,當她唱著:「可愛的小小蜘蛛」時。這個嬰兒不具罹患自閉症的風險,我們知道這個嬰兒沒問題。另一方面,另一個嬰兒有罹患自閉症的風險,你可看見這個孩子無法保持良好的目光接觸。他的目光無法集中、進行交流,而是看著嘴巴、鼻子及其他方向,無法保持目光交流。若能藉由這種方法,對嬰幼兒罹患自閉症的風險進行大規模篩檢,藉由某些相當有效而可靠的方法,將有助於我們在能造成最大影響的早期階段進行干預。

 

我們如何進行干預?這或許得考量不同因素。對某些人來說,我們將嘗試採用藥物治療。因此對我們來說,確認影響自閉症的基因相當重要,以確認用藥目標,確認可能造成影響、且確實是治療自閉症所需的方法,但這並非唯一解決之道。除了藥物,我們將採用教育策略。自閉症患者的情況可能與常人不同,他們的學習方式不同、他們對環境的認知不同,我們必須以對他們來說最佳的方式進行教育。此外,在座許多人或許對可用的新科技有極佳的想法。任何可用來鍛煉大腦的裝置,使它更加有效彌補其運作有所缺失的區域,甚至使用Google Glass之類的裝置。例如想像一下,有社交障礙的Gabriel或許能佩戴Google Glass、戴上耳機,讓一位指導者幫助他。幫助他思考對話內容、展開話題,甚至某天邀一位女孩出來約會。

 

這所有的新科技將提供我們許多引導自閉症患者的機會。但我們還有很長的路要走。儘管我們已有所瞭解,不瞭解的地方更多。因此我想邀請所有人,幫助我們思考如何做的更好。集思廣益、造成改變,尤其是有自閉症家族史的人。我邀請各位加入自閉症互動網,成為尋找解決方案的一員,因為這需要眾人的力量。思考什麼是重要的?什麼可造成意義深遠的改變?當我們思考可能的解決方案,它的效用如何?這是否確實能造成生活上的改變,對自閉症患者或擁有自閉症家族史的人來說?我們需要所有年齡層的人,從年輕人到年長者,以及所有不同症狀的自閉症患者,確保我們能造成某些改變。因此我邀請各位加入這個陣容,為自閉症患者創造更美好、更豐富的生活,謝謝。(掌聲)

 

以下為系統擷取之英文原文

About this Talk

In this factual talk, geneticist Wendy Chung shares what we know about autism spectrum disorder — for example, that autism has multiple, perhaps interlocking, causes. Looking beyond the worry and concern that can surround a diagnosis, Chung and her team look at what we’ve learned through studies, treatments and careful listening.

About the Speaker

At the Simons Foundation, Wendy Chung is working to characterize behavior, brain structure and function in people with genetic variations that may relate to autism.Full bio.

Transcript

"Why?" "Why?" is a question that parents ask me all the time. "Why did my child develop autism?" As a pediatrician, as a geneticist, as a researcher, we try and address that question.

But autism is not a single condition. It's actually a spectrum of disorders, a spectrum that ranges, for instance, from Justin, a 13-year-old boy who's not verbal, who can't speak, who communicates by using an iPad to touch pictures to communicate his thoughts and his concerns, a little boy who, when he gets upset, will start rocking, and eventually, when he's disturbed enough, will bang his head to the point that he can actually cut it open and require stitches. That same diagnosis of autism, though, also applies to Gabriel, another 13-year-old boy who has quite a different set of challenges. He's actually quite remarkably gifted in mathematics. He can multiple three numbers by three numbers in his head with ease, yet when it comes to trying to have a conversation, he has great difficulty. He doesn't make eye contact. He has difficulty starting a conversation, feels awkward, and when he gets nervous, he actually shuts down. Yet both of these boys have the same diagnosis of autism spectrum disorder.

One of the things that concerns us is whether or not there really is an epidemic of autism. These days, one in 88 children will be diagnosed with autism, and the question is, why does this graph look this way? Has that number been increasing dramatically over time? Or is it because we have now started labeling individuals with autism, simply giving them a diagnosis when they were still present there before yet simply didn't have that label? And in fact, in the late 1980s, the early 1990s, legislation was passed that actually provided individuals with autism with resources, with access to educational materials that would help them. With that increased awareness, more parents, more pediatricians, more educators learned to recognize the features of autism. As a result of that, more individuals were diagnosed and got access to the resources they needed. In addition, we've changed our definition over time, so in fact we've widened the definition of autism, and that accounts for some of the increased prevalence that we see.

The next question everyone wonders is, what caused autism? And a common misconception is that vaccines cause autism. But let me be very clear: Vaccines do not cause autism. (Applause) In fact, the original research study that suggested that was the case was completely fraudulent. It was actually retracted from the journal Lancet, in which it was published, and that author, a physician, had his medical license taken away from him. (Applause) The Institute of Medicine, The Centers for Disease Control, have repeatedly investigated this and there is no credible evidence that vaccines cause autism. Furthermore, one of the ingredients in vaccines, something called thimerosal, was thought to be what the cause of autism was. That was actually removed from vaccines in the year 1992, and you can see that it really did not have an effect in what happened with the prevalence of autism. So again, there is no evidence that this is the answer. So the question remains, what does cause autism?

In fact, there's probably not one single answer. Just as autism is a spectrum, there's a spectrum of etiologies, a spectrum of causes. Based on epidemiological data, we know that one of the causes, or one of the associations, I should say, is advanced paternal age, that is, increasing age of the father at the time of conception. In addition, another vulnerable and critical period in terms of development is when the mother is pregnant. During that period, while the fetal brain is developing, we know that exposure to certain agents can actually increase the risk of autism. In particular, there's a medication, valproic acid, which mothers with epilepsy sometimes take, we know can increase that risk of autism. In addition, there can be some infectious agents that can also cause autism.

And one of the things I'm going to spend a lot of time focusing on are the genes that can cause autism. I'm focusing on this not because genes are the only cause of autism, but it's a cause of autism that we can readily define and be able to better understand the biology and understand better how the brain works so that we can come up with strategies to be able to intervene. One of the genetic factors that we don't understand, however, is the difference that we see in terms of males and females. Males are affected four to one compared to females with autism, and we really don't understand what that cause is.

One of the ways that we can understand that genetics is a factor is by looking at something called the concordance rate. In other words, if one sibling has autism, what's the probability that another sibling in that family will have autism? And we can look in particular at three types of siblings: identical twins, twins that actually share 100 percent of their genetic information and shared the same intrauterine environment, versus fraternal twins, twins that actually share 50 percent of their genetic information, versus regular siblings, brother-sister, sister-sister, also sharing 50 percent of their genetic information, yet not sharing the same intrauterine environment. And when you look at those concordance ratios, one of the striking things that you will see is that in identical twins, that concordance rate is 77 percent. Remarkably, though, it's not 100 percent. It is not that genes account for all of the risk for autism, but yet they account for a lot of that risk, because when you look at fraternal twins, that concordance rate is only 31 percent. On the other hand, there is a difference between those fraternal twins and the siblings, suggesting that there are common exposures for those fraternal twins that may not be shared as commonly with siblings alone.

So this provides some of the data that autism is genetic. Well, how genetic is it? When we compare it to other conditions that we're familiar with, things like cancer, heart disease, diabetes, in fact, genetics plays a much larger role in autism than it does in any of these other conditions. But with this, that doesn't tell us what the genes are. It doesn't even tell us in any one child, is it one gene or potentially a combination of genes? And so in fact, in some individuals with autism, it is genetic! That is, that it is one single, powerful, deterministic gene that causes the autism. However, in other individuals, it's genetic, that is, that it's actually a combination of genes in part with the developmental process that ultimately determines that risk for autism. We don't know in any one person, necessarily, which of those two answers it is until we start digging deeper.

So the question becomes, how can we start to identify what exactly those genes are. And let me pose something that might not be intuitive. In certain individuals, they can have autism for a reason that is genetic but yet not because of autism running in the family. And the reason is because in certain individuals, they can actually have genetic changes or mutations that are not passed down from the mother or from the father, but actually start brand new in them, mutations that are present in the egg or the sperm at the time of conception but have not been passed down generation through generation within the family. And we can actually use that strategy to now understand and to identify those genes causing autism in those individuals. So in fact, at the Simons Foundation, we took 2,600 individuals that had no family history of autism, and we took that child and their mother and father and used them to try and understand what were those genes causing autism in those cases? To do that, we actually had to comprehensively be able to look at all that genetic information and determine what those differences were between the mother, the father and the child. In doing so, I apologize, I'm going to use an outdated analogy of encyclopedias rather than Wikipedia, but I'm going to do so to try and help make the point that as we did this inventory, we needed to be able to look at massive amounts of information. Our genetic information is organized into a set of 46 volumes, and when we did that, we had to be able to account for each of those 46 volumes, because in some cases with autism, there's actually a single volume that's missing. We had to get more granular than that, though, and so we had to start opening those books, and in some cases, the genetic change was more subtle. It might have been a single paragraph that was missing, or yet, even more subtle than that, a single letter, one out of three billion letters that was changed, that was altered, yet had profound effects in terms of how the brain functions and affects behavior. In doing this within these families, we were able to account for approximately 25 percent of the individuals and determine that there was a single powerful genetic factor that caused autism within those families. On the other hand, there's 75 percent that we still haven't figured out.

As we did this, though, it was really quite humbling, because we realized that there was not simply one gene for autism. In fact, the current estimates are that there are 200 to 400 different genes that can cause autism. And that explains, in part, why we see such a broad spectrum in terms of its effects. Although there are that many genes, there is some method to the madness. It's not simply random 200, 400 different genes, but in fact they fit together. They fit together in a pathway. They fit together in a network that's starting to make sense now in terms of how the brain functions. We're starting to have a bottom-up approach where we're identifying those genes, those proteins, those molecules, understanding how they interact together to make that neuron work, understanding how those neurons interact together to make circuits work, and understand how those circuits work to now control behavior, and understand that both in individuals with autism as well as individuals who have normal cognition. But early diagnosis is a key for us. Being able to make that diagnosis of someone who's susceptible at a time in a window where we have the ability to transform, to be able to impact that growing, developing brain is critical. And so folks like Ami Klin have developed methods to be able to take infants, small babies, and be able to use biomarkers, in this case eye contact and eye tracking, to identify an infant at risk. This particular infant, you can see, making very good eye contact with this woman as she's singing "Itsy, Bitsy Spider," in fact is not going to develop autism. This baby we know is going to be in the clear. On the other hand, this other baby is going to go on to develop autism. In this particular child, you can see, it's not making good eye contact. Instead of the eyes focusing in and having that social connection, looking at the mouth, looking at the nose, looking off in another direction, but not again socially connecting, and being able to do this on a very large scale, screen infants, screen children for autism, through something very robust, very reliable, is going to be very helpful to us in terms of being able to intervene at an early stage when we can have the greatest impact.

How are we going to intervene? It's probably going to be a combination of factors. In part, in some individuals, we're going to try and use medications. And so in fact, identifying the genes for autism is important for us to identify drug targets, to identify things that we might be able to impact and can be certain that that's really what we need to do in autism. But that's not going to be the only answer. Beyond just drugs, we're going to use educational strategies. Individuals with autism, some of them are wired a little bit differently. They learn in a different way. They absorb their surroundings in a different way, and we need to be able to educate them in a way that serves them best. Beyond that, there are a lot of individuals in this room who have great ideas in terms of new technologies we can use, everything from devices we can use to train the brain to be able to make it more efficient and to compensate for areas in which it has a little bit of trouble, to even things like Google Glass. You could imagine, for instance, Gabriel, with his social awkwardness, might be able to wear Google Glass with an earpiece in his ear, and have a coach be able to help him, be able to help think about conversations, conversation-starters, being able to even perhaps one day invite a girl out on a date.

All of these new technologies just offer tremendous opportunities for us to be able to impact the individuals with autism, but yet we have a long way to go. As much as we know, there is so much more that we don't know, and so I invite all of you to be able to help us think about how to do this better, to use as a community our collective wisdom to be able to make a difference, and in particular, for the individuals in families with autism, I invite you to join the interactive autism network, to be part of the solution to this, because it's going to take really a lot of us to think about what's important, what's going to be a meaningful difference. As we think about something that's potentially a solution, how well does it work? Is it something that's really going to make a difference in your lives, as an individual, as a family with autism? We're going to need individuals of all ages, from the young to the old, and with all different shapes and sizes of the autism spectrum disorder to make sure that we can have an impact. So I invite all of you to join the mission and to help to be able to make the lives of individuals with autism so much better and so much richer. Thank you. (Applause)


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