In 1905, when geneticist Nettie Stevens peered through her microscope, she made a startling revelation: two delicate X-shaped structures nestled within the cells of female mealworm beetles, but only one X structure and a smaller Y-like counterpart in male beetles.
於1905年，當遺傳學家Nettie Stevens透過顯微鏡凝視時，她獲得了一個驚人的新發現：雌性黃粉蟲(一種甲蟲)的細胞內，有兩個精緻的X形結構物。不過，於雄性甲蟲中，只有一個X結構物及一個較小的Y形結構物。
This groundbreaking discovery helped unlock the daunting mystery of sex determination. Stevens hypothesized this pair of chromosomes, now known as the sex chromosomes, dictates whether an embryo develops into a male or a female. But little did she know she had also just uncovered an important clue toward understanding why diseases manifest differently in males and females.
此突破性的發現有助於解開，該決定性別之令人驚嘆的謎團。Stevens假設，該目前被通稱為性染色體的染色體對，支配胚胎是否發育成男性或是女性。不過，她近乎不知，她確實也已經發現一條，邁向瞭解為何疾病，在男性與女性間，出現差異的重要線索。
Fast forward a hundred years and scientists still don’t fully understand why females are at greater risk of developing certain conditions such as autoimmune and certain neurodegenerative diseases.
飛逝了一百年，科學家們仍然不完全瞭解，為何女性冒較大罹患某些疾病的風險。諸如自體免疫性及某些神經退行性的疾病。
Now, Whitehead Institute researchers are shedding light on this age-old question by investigating the role of X and Y chromosomes beyond sex determination, paying close attention to conditions that mostly — or distinctly — affect females, and mentoring the next generation of researchers to challenge the status quo for a better world.
目前，美國懷特海德生物醫學研究所的研究人員們，正藉由調查研究X及Y染色體，除了決定性別之外的角色，來闡明該老問題、密切注意主要(也就是明顯)影響女性的疾病，及輔導下一代研究人員們，為了更美好的世界，來挑戰此現狀。
The X and Y sex chromosomes in mammals originated from an ancestral pair of chromosomes with identical structures. Over time, the Y chromosome underwent degeneration, resulting in the loss of hundreds of active genes. The X chromosome preserved its original genes while also acquiring new ones.
於哺乳動物中，X及Y性染色體源自一對，具有相同結構的原祖染色體。隨著時間推移，Y染色體經歷了退化，導致喪失數百個活躍的基因。X染色體保存了其原來的基因，同時也獲得了新基因。
But then, possessing two copies of the X chromosome in females meant much higher levels of gene expression from the X chromosome than in males (XY), so a mechanism called X chromosome inactivation evolved. In this process, one of the X chromosomes in females is randomly silenced in each cell, ensuring both sexes have an equal dosage of genes located on the X chromosome.
不過之後，於女性中擁有兩個X染色體，意味著來自X染色體的基因表現程度，比男性中(XY)高得多。因此，演化出一種被稱為X染色體失活的機制。在此過程中，於女性中一個X染色體，在每一細胞中，是隨機被靜默的。這確保了兩性於X染色體上，擁有等份量基因。
Whitehead Institute Member David Page has been studying genetic differences stemming from sex chromosomes between males and females to understand their impact on the prevalence, severity, and progression of certain diseases.
懷特海德生物醫學研究所成員，David Page一直在研究，於男性與女性間，源自性染色體的遺傳差異，來瞭解它們對某些疾病之盛行率、嚴重程度及進展的影響。
Work from the Page Lab has revolutionized the scientific understanding of the X and Y chromosomes by revealing their role as influential regulators of genes. Scientists have found that these sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body and beyond just the reproductive system.
來自Page實驗室的研究，藉由揭露X及Y染色體，作為有影響力之基因調節物的角色，在有關它們的科學理解上，已經起了突破性大變革。科學家們已經發現，此些性染色體能調整細胞中，於其他22對染色體上，數千個基因的表現。這影響遍及整個身體的細胞功能，而不僅是生殖系統。
Now, Page, who is also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Investigator, is taking his lab in a new direction: unveiling the subtle, yet powerful, distinctions within females' pair of X chromosomes.
目前，也是麻省理工學院生物學教授，及霍華休斯醫學研究所調查研究員的Page，正帶領他的實驗室走向一個新方向：也就是，揭露女性X染色體對中，細微卻強有力的諸多差異。
In a recent paper, former Page lab postdoc Adrianna San Roman and colleagues described that the inactive X chromosome is not, in fact, a passive copy playing backup for its more active partner; instead it can modulate expression of genes on the active X chromosome.
在最近的一篇論文中，前Page實驗室的博士後研究員， Adrianna San Roman 及其同僚們描述了，不活躍的X染色體，實際上並非一份，為其較活躍之搭檔，扮演支援者的被動複製物。反而它能調節，於活躍之X染色體上的基因表現。
This overlooked dynamic between the pair of X chromosomes has widespread implications for how scientists understand and treat conditions that disproportionately affect females.
該於X染色體對之間被忽視的動態，對科學家們如何瞭解，及治療不成比例影響女性之疾病而言，具有廣泛的意涵。
Like most biological processes, silencing of genes on the less active X chromosome in females isn’t foolproof. In recent years, researchers have found one more clue on sex differences in disease: when certain genes manage to evade the silencing mechanism on the active X chromosome , it disrupts the normal functioning of the immune system. This may be one of many factors heightening women’s risk of developing autoimmune diseases like multiple sclerosis (MS).
與大多數生物的變化過程一樣，於女性中，在較不活躍之X染色體上的基因靜默，並非萬無一失。於最近幾年，研究人員們已經發現，另一個有關疾病之性別差異的線索：當某些基因設法逃避，於活躍之X染色體上的靜默機制時，這會擾亂免疫系統的正常起作用。這或許是增加女性罹患，諸如多發性硬化症(MS)等，自體免疫疾病風險的諸多因素之一。
This immune-mediated neurodegenerative condition, which is nearly three times as common in females than males, starts off as a misfired immune attack; disease-fighting cells are dispatched to attack the myelin sheath, a protective layer of fat and protein wrapped around the slender bundle of nerve fibers that extend from the body of a neuron.
在女性中，這種免疫介導之神經退化性疾病的普遍性，幾乎是男性的三倍。開始是一次發動不起來的免疫攻擊;抗病細胞被派去攻擊髓鞘。這是包裹從神經元體延伸出，細長神經纖維束周圍之脂肪及蛋白質的保護層。
As this protective wrapping deteriorates — a process known as demyelination — the nerve fibers begin to fray. This disrupts communication between neurons and hallmark symptoms of MS — challenges with cognitive, sensory, and motor function — begin to emerge.
當此保護性的包裹物惡化時(一種被通稱為脫髓鞘的過程)，神經纖維開始磨損。這會擾亂神經元之間的交流，結果是多發性硬化症的特徵症狀(具有認知、知覺及運動功能的問題)開始出現。
Researchers have thus far identified over 200 genetic variations that can heighten one’s risk of developing MS. Most, if not all, of these risk variants are associated with immune system dysfunction.
迄今為止，研究人員們已經確認超過200個，會增加一個人罹患多發性硬化症風險的遺傳變異。即使不是全部，此些風險變異，大多數與免疫系統功能障礙有所關聯。
But now Whitehead Institute Member Olivia Corradin, who is also an assistant professor of biology at Massachusetts Institute of Technology, is taking a unique approach to unravel the mysteries of MS: investigating if — and how — certain genetic risk factors might be rendering the brain less resilient to withstand the injuries inflicted by the immune system.
不過，目前也是麻省理工學院生物學助理教授的懷特海德生物醫學研究所成員，Olivia Corradin正採取一種獨特的方法，來解開多發性硬化症的謎團：也就是，調查研究某些遺傳風險因素，是否及如何可能使大腦變得較少復原力，來經得起遭免疫系統的傷害。
“In order for neurons to get re-myelinated, all the myelin debris from the demyelination process has to be cleared away first and that's the role of a type of cell called microglia,” Corradin explains. “We’re really excited to look at a couple of new gene targets that are directly involved in myelin debris clearance and might be dictating how the brain responds to the immune attack.”
Corradin解釋：「為了使神經元重新獲得髓鞘，首先必須清除來自脫髓鞘過程中的所有髓鞘碎片。亦即，那是一種被稱為小膠質細胞的任務。注意到幾個直接涉及髓鞘碎片清除，及可能指令大腦如何回應免疫攻擊的新基因標的，我們真的很振奮。」
Currently, there is no cure for MS, and available treatments focus on symptom management. However, Corradin's research has the potential to unveil new therapeutic targets that enhance the brain's capacity for recovery following an autoimmune assault, thereby altering the course of the disease.
目前，沒有多發性硬化症的療法，而可資使用的治療方法，著重於症狀處置。然而，Corradin的研究具有揭露，增強大腦在自體免疫攻擊後的復原能力，從而改變疾病進程之新治療目標的潛力。
Corradin isn’t alone in investigating the brain to decipher complex health conditions. Whitehead Fellow Allison Hamilos is deeply immersed in neuroscience, and her research aims to understand how disruptions in neural circuits contribute to the symptoms of psychiatric and neurological diseases.
在調查研究大腦，來破解複雜之健康狀況上，Corradin並不孤獨。懷特海德生物醫學研究所特別研究員，Allison Hamilos深深地沉浸於神經科學領域。因此，她的研究旨在瞭解，於神經迴路中的混亂，如何導致精神病學及神經病學的疾病症狀。
Hamilos' fascination with the brain was sparked by a personal experience — a concussion sustained during college lacrosse. "I'd heard about the potential vulnerability of female athletes to traumatic brain injury, but was it truly so straightforward?" she reflected. This curiosity led her to delve into what resilience and vulnerability to psychiatric and neurological diseases truly entail.
Hamilos對大腦的著迷，是被一次個人經歷所激發。也就是，在大學曲棍球比賽中，遭受的一次腦震盪。她表明：「我曾聽說，有關女性運動員可能容易遭受創傷性的腦損傷。不過，這真的那麼單純嗎？」此好奇心導致了她深入研究，有關精神病學及神經病學之疾病的復原力與脆弱性，真正需要什麼。
It wasn’t until Hamilos began her clinical observations of Parkinson's patients as an MD-PhD that she recognized subtle nuances in movement and behavior as potential indicators of resilience and vulnerability.
身為醫學博士，直到Hamilos開始有關帕金森氏症患者的臨床觀察，她才認識到運動及行為中，難以捉摸的細微差異，是復原力與脆弱性的潛在指標。
When brain circuits that are responsible for regulating reward and movement are disrupted, conditions like Parkinson’s, schizophrenia, and bipolar disorder emerge. Now, Hamilos is using these insights to meticulously "fingerprint" voluntary behavior in mice, so her lab can discern differences in these neural circuits between healthy and disease-affected brains.
當負責調節獎賞及運動的大腦迴路遭到干擾時，出現像帕金森氏症、精神分裂症及雙極性情感障礙等疾病。目前，Hamilos正利用此些洞察力，來嚴謹地"鑒別"小鼠中的自願行為，以便其實驗室能分辨在此些，於健康與受疾病影響大腦間之此些神經迴路的差異。
“My interests may be different than even another female coming into the Whitehead Institute, but what I can say is that given that females have historically been under-studied, and that there are disparities across the spectrum in healthcare, part of seeing that reality is experiencing it yourself,” she says. “I think that it's an exciting moment with Whitehead’s mission to be invested in tackling issues that have not gotten sufficient attention historically because if they were to get that attention, it would make a big difference in people’s lives.”
她宣稱：「我的興趣或許不同於，進入懷特海德生物醫學研究所的另一名他女性。不過，我所能說的是，鑒於在史上女性未曾被充分研究，而且在醫療保健領域，有諸多差異。瞭解那現實性的部分，是親自體驗。我認為，這是一個令人振奮的時刻。由於，懷特海德生物醫學研究所的使命是投資於，解決史上未曾獲得充分關注的問題。因為，倘若她們獲得那種關注，這會在人們的生活中，產生大影響。」
In each instance, Whitehead Institute researchers have discovered that the journey toward comprehending — and ultimately addressing — neglected conditions that predominantly or uniquely impact women is long and winding. But it is also one filled with opportunities that can fundamentally revolutionize our understanding of health and disease.
在每一實例中，懷特海德生物醫學研究所的研究人員們已經發現，邁向瞭解(並最終面對)主要或獨特影響女性，被忽視之情況的旅程是漫長而曲折的。不過這也充滿，能根本使咱們對健康及疾病之瞭解，起徹底變革的機會。
網址：https://wi.mit.edu/news/whitehead-institute-researchers-are-uncovering-answers-longstanding-questions-about-sex
翻譯：許東榮
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