演化生物學與危險疾病

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演化生物學對鳥類和人類流感的重要意義

教授的有趣論文（對我來說！） 保羅·埃瓦爾德 –

防範最危險的新興病原體：演化生物學的見解

– 涵蓋顯示它們可能導致危險疾病的病原體特徵。

有一個清單，用於評估病原體是否可能是危險的——如果以下任何一項的答案是肯定的，則可能是危險的：

是否有水傳播的傾向？

它是否具有利用人類作為生命週期一部分的能力？

如果是直接傳播的話，在外在環境下是否能耐受？是服務生攜帶的嗎？是針傳播的嗎？

如果它是透過性行為傳播的，它是否容易突變並具有對關鍵細胞類型的趨向性，或者它是否具有侵入性或致癌傾向？

與人、禽（禽）流感有關：

引用：

關於來自既定病原體的強毒變種的出現，第一次世界大戰期間在西線傳播的流感病毒將被認為是危險的，因為文化習俗消除了固定宿主傳播的障礙，而且流感病毒易於突變。因此，毫不奇怪，西線被確定為 1918 年流感大流行高致命性變種的來源，而且如此嚴重的大流行從未再次發生。更重要的是，進化方面的考慮表明，除非流感病毒再次暴露於允許從固定宿主傳播的機會，否則這種致命的大流行不會再次發生，因為它們在家禽養殖場中定期出現高致命性流感爆發。

（我是透過溫蒂·奧倫特（Wendy Orent）在《新共和》上發表的一篇文章了解到這一點的，她說我們並沒有面臨一場高致命性流感的大流行，因為我們不具備必要的條件 [包括因流感而患病的人仍然很容易傳播到其他]；我相信需要訂閱才能查看文章。

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相關文章——提及流感的演變以及與 1918 年的比較——認為 恐懼比禽流感更容易感染你

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Carl Zimmer 的文章 – 馴服病原體：一個優雅的想法，但它會起作用嗎？ – 提到了對演化生物學和病原體的一些批評，但它們似乎並不是無懈可擊的。包括：

引用：

埃瓦爾德抱怨……批評者……遺漏了他工作中一個重要的部分，例如，疾病感染新宿主的模式。如果宿主病得很重而無法移動，寄生蟲只能感染其他靠近的人，除非蚊子等媒介可以傳播它。這個因素對於埃瓦爾德對西班牙流感的解釋至關重要。 ……“我的論點是，在西線，完全無法動彈的人可以聯繫數百或數千人。”生病的士兵被擔架轉移到分診區，然後轉移到臨時醫院，最後轉移到擁擠的火車上。在這種情況下，流感病毒可能會摧毀其宿主，但仍會感染大量人群。 「我的觀點是，除非我們複製西線發生的這種情況，否則我們不會看到 1918 年的大流行，」埃瓦爾德說。

– 也與鳥類有關。家禽養殖場可能成為「疾病工廠」（正如溫蒂·奧倫特所說）；但在野外，禽流感的症狀較輕，因為死鴨子不會飛。

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《科學美國人》部落客（該雜誌的編輯）在以下文章中發表了對演化生物學和流感的一些批評：

不要害怕（鳥）收割者

導致詳細回复：Bird Reaper，Pt II：Wendy Orent 回复

鳥收割者，第三部分：Paul Ewald 回复

上面的回應提供了有關進化生物學的有用資訊。我剛剛發出了一些更簡單的東西：

來吧，這篇關於 H5N1 和演化生物學的混亂內容的文章是在轉移注意力。真正的問題肯定是非凡的 Lindsay Beyerstein - 非凡並不是因為她的博客文章，而是因為（從照片中），天啊，她很性感！

否則，如果大量引用一位匿名的、頭腦糊塗的博客作者，他在沒有明確結論的句子中大肆宣揚大話（或者，為了證明他對非智能設計的信仰？），會表明你正在為《十一月時尚先生》所說的白痴美國做出貢獻。 Toodlepip（來自英國公民，但目前不是英國居民，有缺點，但至少不需要歐普拉解釋全球暖化）

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一位綽號為「瘋狂生物學家麥克」的部落客對埃瓦爾德的想法進行了簡短的批評（溫迪·奧倫特在幾篇文章中對此進行了介紹）；似乎很大程度上取決於流感在出現症狀之前是否可以傳播。

演化、權衡、忽視生物學和流感

看來爭論並不真正有實質；在我看來，一位同事引用的一句相當奇怪的話並沒有幫助，他提到「那些愚蠢的該死的自然歷史事實」。其中一個主要事實再次與流感在出現症狀之前就可以傳播有關（儘管奧倫特指出，h5n1 在人類中不會傳播，或幾乎不會傳播）。我剛剛添加了評論：流感在無症狀階段是否同樣具有傳染性。當症狀明顯時（且病情嚴重的人變得無法動彈）？ 1918 年流感又如何呢？埃瓦爾德認為，它在西線條件下演變只是巧合？ （否則人類流感並不是主要問題；如果它很容易進化為高毒力，那麼它不應該更頻繁地進化，甚至保持這種狀態嗎？） 為什麼普通的禽流感是“溫和的”，卻使家禽陷入「疾病」工廠」並引發一系列高致病性流感？對我來說——一個觀鳥者而不是生物學家——後者似乎可以用奧倫特所寫的想法來巧妙地解釋。 （還有其他理論能夠解釋後面這些事實嗎？家禽養殖場看起來“很好”，偶然的實驗有助於證實埃瓦爾德的理論。）

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剛剛看到威斯康辛大學麥迪遜分校人類學助理教授約翰霍克斯 (John Hawks) 發表的部落格文章；關於埃瓦爾德和里維爾之間的爭論。

他指出：

引用：

1. 幾乎沒有關於禽流感威脅的主流媒體報道討論流感的演變。這可能是當今進化論對大眾最重要的影響，但我們幾乎沒有聽到有關病毒如何變化的演化模型。

2. 埃瓦爾德因研究疾病的演化動力學而聞名。就選擇的動態而言，他提出了一個合理的論點。因此，我們有充分的理由認為最壞的情況不會發生，但這一觀點卻被低估了。

3. 到目前為止，該理論僅在相對較少的實例中得到了檢驗——只是還沒有發生如此多的流行病，以至於我們可以從過去的事件中準確地推斷出未來會是什麼樣子。某些新的流感株肯定會以某種意想不到的方式違反該模型，因此政府應該謹慎行事，而不是假設不會出現高毒力大流行。

4. 只要禽流感仍然存在於公眾的認知中，許多公共衛生科學家就會得到很好的工作。這並不意味著他們發出的警報是錯誤的，但這確實意味著他們不會透過淡化威脅而受益。這有點像美國太空總署和小行星撞擊威脅——部分原因是他們更擔心，因為他們對威脅及其可怕影響了解更多，部分原因是他們的工作就是擔心。

5. 有很多生物學家不使用或不理解選擇。

埃瓦爾德禽流感口角

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來自通訊員回覆上述貼文中的第 4 點：

引用：

也許我對背景的理解比較正確。小行星
撞擊威脅並不是研究的最終目標，但更重要的是
重要的是相同的研究工具（寬視野自動望遠鏡
和管道分析）可以應用於不同的目標
學術興趣。它們不會很有吸引力（至少對於
開始）向公眾。 NASA 人員需要一個不同的、
追求其原始科學興趣的更受歡迎的目標。
這些望遠鏡現在被用來快速追蹤觀測
伽馬射線暴、死亡彗星的回收以及當前的其他目標
流行的天文學問題。哈伯空間的“藍皮書”
望遠鏡類似，但產生的結果比原來好得多
預期的。

我不知道流感專家是否也採取類似的措施
當然，或者他們認為流行病是一種真正的、可預見的威脅。但
據我所知，頂級病毒學家似乎更
是故意的，並警告大眾不要危言聳聽。我認為
這些人認為這是一個真正的威脅，並敦促各國政府
為「上限」災難做好準備。他們大概是這麼想的
不足以為「預期平均值」做好準備（可能會得出
來自演化生物學）。

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與自然選擇和 H5N1 有過冗長的通信，並帶有「通訊員」；也引發了溫蒂·奧倫特的評論。
> 表示引用文字區塊中的引用文字 - 恐怕會變得有點複雜。

免得有興趣，這裡是：

同樣，埃瓦爾德的論文預測了包括流感在內的病原體的重新進化：

引用：

是的，這是眾所周知的。這是學習中的名篇
從自然選擇的角度來看生態學。這也是專家認為的一個原因
比人類更害怕長途運輸（人類或鳥類）
逐漸的地理入侵。

但我們無法準確預測，特別是當不同物種
都參與其中。我們甚至不知道為什麼 LPAI 如此“進化”
野鴨身上有“靜電”，但它們對人類有如此大的致病性
當他們恰巧進入人類世界的時候。唯一的事實是
“自然選擇起作用”，但我們可能不知道或處理所有
自然選擇的因素。

但再次強調：埃瓦爾德做出預測，流感不會成為致病性進入人類世界。

需要特殊的條件——病得很重的人很容易傳播——才能發展出危險的流感。
最極端的時期是 1918 年：第一次世界大戰。

毛澤東可能是導致 1957 年和 1968 年流感的罪魁禍首。

今天沒有這樣的特殊情況；因此埃瓦爾德認為我們今天不會感染高致病性人類流感。

他的理論預測，禽流感對野生鳥類的影響較輕。需要有鳥類飛行來攜帶流感，因此進化為溫和的病毒株。所以，對我來說，我們確實知道為什麼 LPAI 在野生鳥類中是「進化靜態」的。
高處的路徑會衝進野鳥，然後很快就會進入低處的路徑。或滅絕。

直接引用埃瓦爾德的話：

「關於未來，我預測這種高度致命的大流行（即每50 例感染中有1 人死亡）不會發生，不是由H5N1 引起的，也不是由任何其他流感病毒引起的，除非地區條件允許從不動的宿主傳播，就像他們 1918 年在西線所做的那樣。這是基於對理論和證據的仔細考慮的預測。未來將證明它是否準確。
http://blog.sciam.com/index.php?title=bird_reaper_pt_iii_paul_ewald_replies&more=1&c=1&tb=1&pb=1

我感覺合理。

可以對鳥類進行類似的預測（埃瓦爾德對家禽進行了類似的預測）：
– 無限期地聚集在一起，因此病禽很容易傳播：並發展出危險的流感
– 野生情況，需要鳥類飛翔才能傳播，流感較輕時達到平衡

也就是說，預測符合我們的觀察結果。對我來說這就是科學；而不是猜測。

對我來說唯一的謎團是為什麼這一點被如此廣泛地忽視。

引用：

> 今天沒有這樣的特殊條件；所以埃瓦爾德認為我們不會得到
現今的高致病性人類流感。

正如我（間接）從流感專家那裡聽到的那樣，有些人認為病毒
不會以HP形態進入人類世界，但別人的說法
不同的是──我們（甚至病毒學家）不知道高致病性禽流感會如何表現。

“1918 年最極端：第一次世界大戰”

> 今天沒有這樣的特殊條件

飛機、運動、人口密度不是很特別嗎？
我們從未在如此高度全球化的情況下遇到大流行病
世界——我們並沒有真正的經驗。

> 他的理論預測禽流感對野生鳥類的影響較輕。需要有
飛行的鳥類攜帶流感病毒，因此進化成溫和的病毒株。所以，為了
對我來說，我們確實知道為什麼 LPAI 在野生鳥類中是「進化靜態」的。

是的，這解釋了“為什麼”。我們並不完全知道「如何」。這
意味著我們不知道選擇壓力到底是如何運作的。 (也
我們不知道 Zq 菌株如何保留通往自然宿主的高路徑）。
由於我們還沒有看到由 Zq 菌株引起的 LPAI，因此我們不知道
此過程所需的時間範圍（可能不是“非常快”）。

> 高路徑衝向野鳥，然後迅速轉向低路徑。或者
滅絕。

大多數看起來都快要滅絕了（即R0），但飛機、擁擠的環境等對他來說還不夠；沒那麼特別。
需要病重的人——因疾病而無法行動——隨時
傳播病毒。
如果重病的人留下來，擁擠在這裡並不重要
回家/住院。

但流感在潛伏期就已經具有傳染性。
交通量比第一次世界大戰少嗎？人少了？ （想像東京
火車）雖然我無法弄清楚效果，但所有現有因素
似乎增加了更致命的流行病的風險。

> 我認為對於野生鳥類來說，總是存在潛在的劇毒
流感的演化。
在我看來毒力譜（這來自化學背景，
不是病毒）：取得一些較高的路徑，其他較低的路徑。得到一個
平衡，取決於當時的條件。
由於需要飛鳥在野外傳播流感，平衡為
很大程度上傾向於無毒形式。高路徑形式仍然很少見。 （這
再次來自化學；我重新系統時的一些記憶
達到平衡。

謝謝！這更容易理解。如果「隨機」分佈
突變形式接近高斯，自然選擇起作用
以這種方式（對於特定物種）。如果離高斯分佈很遠，
我們不能確定（因為沒有有效的平均值——這可能
解釋一些社會現象，如齊普夫定律）。如果有一些怎麼辦
種群（由於遺傳多樣性）更具抵抗力（並非所有種群）
感染者死亡，但可以排出大量的
病毒）—我們可能需要一個更複雜的視圖。自然選擇對
也可能出現潛伏期。

> 很可能是什麼鳥類並不重要：如果塞進
圈養，感染流感，鳥類有很大機會感染
高路徑形式可以傳播流感，然後將進化為
更高的致病形式。

如果這取決於人口密度，我們如何確定我們的
人口密度低於高路徑應變可以的閾值
持續進行有意義的（有效的傳輸到下一個
集群）時間？與家禽雞的主要區別是什麼？
（嗯，最近各家公司的一些流行病計劃似乎
假設症狀較輕的員工「被迫工作」—他們
在移動或乘坐出租車時將健康人群混合在一起——我們可能會
最終成為家禽雞

再談一談“平衡理論”，為什麼我們從未見過人類
大流行毒株最終形成非致病性形式（如 LPAI
野鴨？
（為什麼「進化停滯」永遠不會達到）

順便說一句，在考慮選擇壓力時，廣泛的
在大流行中使用達菲會導致毒性更強的菌株嗎？不是
必然有抗藥性，但我們不會選擇更具神經營養性的嗎？
應變（因為達菲不能有效地穿過血腦屏障），
我向公共衛生專家提出了這個問題，但尚未收到
回答。這可能是與以往大流行不同的另一個因素。

好吧，現在你問我希望我能得到所有答案的問題！ – 真的應該直接去找保羅·埃瓦爾德，因為我有一些了解，但相對膚淺（我將轉發給科學作家溫迪·奧倫特，她根據他的想法寫了幾篇文章，我和她有過一些通信；她現在在愛錶）。

擁擠的人群、東京的火車或香港的購物中心，並不是那麼重要——如果人們生病了，很快就去睡覺/去醫院。

發現流感在出現症狀前就已經具有傳染性；溫迪對此詢問。
我想知道，如果不是咳嗽/打噴嚏的話，傳染性有多大？不做這些事情怎麼傳播病毒呢？

高斯曲線：不確定，但這是我理解事物的方式，正如基於（物理）化學所指出的那樣。

對埃瓦爾德來說，家禽養殖場的主要問題是，即使是病得很重的雞也可能發生（現成的）傳播——因此危險的形式可以傳播，甚至加劇。

溫迪指出，1918 年流感確實變得無毒，並且仍在傳播。

我也不知道達菲；不知道這個大腦。
對我來說，廣泛使用它似乎並不明智；參見抗生素和抗藥性。
相反，我也對疫苗接種持懷疑態度，也許這有助於維持 h5n1（當疫苗接種和監測不夠完美時）。

引用：

> 發現流感在出現症狀前就具有傳染性；溫迪對此詢問。
我想知道，如果不是咳嗽/打噴嚏的話，傳染性有多大？你如何傳輸
病毒不做這些事？

如果高路徑機制（無需胰蛋白酶進行複製）確實有效，
我們不一定需要呼吸器官。病毒複製
身體各處。

> 溫迪指出，1918 年流感確實變得無毒，並且仍在傳播。

1918年流感曾經一度消失（1950年左右），後來又再次出現
（可能來自實驗室）現在正在流傳。

引用：

如果有一些怎麼辦
種群（由於遺傳多樣性）更具抵抗力（並非所有種群）
感染者死亡，但可以排出大量的
病毒）—我們可能需要一個更複雜的視圖。

我注意到這種可能性確實令人擔憂。如果這樣的話
個體（或不同物種的個體）是零星的，我們
不用擔心。但如果這些人的鏈條
已確立的？ ——這對應於「滲透理論」。
（你可能讀過西蒙·萊文的《脆弱的統治》或考夫曼的
「在宇宙中的家」與滲透相關
相變及其在生態系中的作用）。

引用：

> 嗯，不確定水傳播疾病是否應該更專門化
人與人之間的這種傳播途徑。就像霍亂一樣。
就像霍亂一樣，無法想像它會廣泛傳播，但在少數國家會傳播得更多
衛生條件差的地方。
（據我們所知）醫院外最嚴重的非典疫情顯然是
來自污水（顯然來自廁所，不知何故到達人們的淋浴間，
以及公寓大樓內有幾人被感染）。看起來很嚇人，但是
證明是孤立的。

自然選擇的作用就好像病原體正在尋找更高的基礎
繁殖數量（不一定是致命性較低）。如果有病原體
有能力以更有效的方式傳播，這將成為
主要傳播途徑。如果病毒在腸道內複製
或腎臟，污水將是病毒適應的有效場所
（很像禽類感染？？）。

引用：

> 如所討論的，我不相信奧斯特霍爾姆的預測是正確的。

> 但可能發生的情況是，如果發生大流行——無論是否
相對溫和－恐慌會導致問題。
已經有太多問題了（例如擔心、達菲庫存等），甚至
在美國——那裡沒有H5N1，只是害怕這種疾病。

眾所周知，我們的存在依賴現有的生物多樣性
——生態系演化的產物，我們最能適應。
我們不知道我們當前的存在何時會受到多大程度的威脅
生物多樣性退化的速度有多快，但應該會有一些數字
（不容易預測）。我們的社會也是如此；我們的生活
取決於現有的社會制度—社會的產物
進化，我們最能適應。我們不知道什麼時候我們的禮物
世界正受到社會制度退化程度和速度的威脅。
這兩個問題很相似，都是由複雜的自適應過程引起的
系統。複雜的社會系統可能會放大未成年人的影響
死亡。

時間尺度也發揮作用。如果任何變化夠慢，我們
可以，或者生態系統將適應新的形式。如果變化很快
夠了，他們可能會失敗。有一個簡單的物理類比；這
氣體的適應受到聲速的限制。如果改變發生
比聲速快，氣體無法適應－最終結果
是眾所周知的超音速激波。對我們來說也是如此
社會。如果大流行的傳播夠快，我們的系統
就會無法適應。當然，隨著網路的出現，
在浪潮到來之前我們有更好的適應機會。但是
適應的預期結果與實際情況相差甚遠
現行社會制度下，流感大流行的到來將引發
這種反應看起來就像一夜之間改變了世界。
我對社會制度的如此巨大的變化可能會產生懷疑
一夜之間就完成了（連官員都宣稱「立即」），因為沒有人
習慣了變化，並期待情況會發生一些變化
在適應（有巨大變化）和不太適應（很少）之間
在波浪到達之前做出反應，立即恐慌
觸發）。

貼文編輯：馬丁，發表於：2006/02/02 00:49

[馬丁]

是的，是時候打破僵局了；仍然是上面的信件，但這裡是溫蒂奧倫特的一些評論：

引用：

親愛的馬丁，

這些都是好問題。我希望我們能夠明確表示
每個人都知道它本身並不擁擠，這才是關鍵
狀態.這是反覆傳播細菌的能力
將宿主固定到井中。人們可以像沙丁魚一樣擠在一起
火車、地鐵或飛機，甚至幾個小時，什麼事都不做
提高流感等呼吸道病原體的毒性。如果
你病得很重，你不能上飛機，除非
你繼續下去。即使發生了這種事，也有很多人
得了那樣的病，無論感染什麼，都會很快消失
毒力－除非你讓人聚集在一起數週，或者
幾個月，或無論需要什麼時間——沒有人知道。即，你需要一個
疾病工廠以開發毒力和傳播能力，並
保持下去。我想不出任何疾病工廠的條件
地球不是這樣的——第一次世界大戰並不常發生。
整個飛機事件是一個轉移注意力的事情。我們不是在談論
在世界各地傳播疾病；我們正在談論的是
毒力的進化。這不會發生在飛機上
正常情況下——我的意思是，沒有一架飛機被劫持
船上有人病重，讓人被困在船上
和那個人在一起幾個星期。即便如此，這仍然是不確定的…我們不知道如何
毒力或傳播能力的演化需要很長時間。

至於出現症狀之前的傳染性：人們喜歡炫耀這一點。
但它是如何運作的呢？如果有的話，你真的無法散發太多病毒
並不是上呼吸道中的大量累積。你可能是一個
傳染性不大，但也只有一點點。這些症狀讓你
contagious – the sneezing, the coughing – the virus’s little way of
making its host shed it into the world, where it hopes, so to speak,
someone else will pick it up. Anyway, the severest disease appears to
be that where the virus or bacterium replicates most quickly and
exploits the host’s tissues most thoroughly. It doesn’t give itself
the long window of being shed. Plague – the right sort of plague
(from marmots), not all plague – was pretty good at this – it’s
what’s been called a “stealth infection” – it suppresses the immune
response, inflammation, fever, everything – so the body doesn’t know
it’s under siege. That’s what people appear to keel over and die so
suddenly from pneumonic plague. They’re half dead while they’re still
walking around. But they aren’t shedding that much virulent bacteria
for all that time – their lungs have to get pretty destroyed before
they start coughing the blood-tinged sputum that’s infectious. That’s
plague – that’s not flu…you’d cough earlier in flu, but it’s just
not that deadly a disease – even 1918 killed 2-5% of its victims
(pneumonic plague kills 99.9% – it’s too lethal to people to exist
for long as a human-adapted disease.) So rule of thumb is –
contagiousness before symptoms is almost an oxymoron – you’d have to
be sneezing or coughing, at the least, to shed a lot of bugs. I
imagine that the deadlier the disease, the shorter the window of
contagiousness while you’re still up and walking around. Point being:
people with deadly flu aren’t going to be shedding it for very long
before they’re wiped off their feet.

You’re completely right about the wild birds, though I think the
Gaussian thing might be a red herring (though it’s also possible I
don’t clearly understand what you meant. It isn’t a question of the
mean in natural selection.) The thing is, wild birds can catch
high-path flu, die of it, even spread it a little, LOCALLY – but they
CAN’T maintain it. High-path flu can’t survive the sieve of natural
selection.

引用：

> Rather as I’m also sceptical re vaccinations, perhaps helping
sustain h5n1 (when vaccinations and surveillance less than near
perfect).
A GOOD vaccine would be the way to go, if we had one – but for what
disease? Human-adapted H5N1 doesn’t exist yet, and no one knows what
it would look like if it did.

(I’d meant I was sceptical re vaccinations for poultry)

引用：

Equilibrium theory is for sure a red herring. Selection works on the
level of the individual organism or the individual strain or genetic
line – not on the population or species. A non-pathogenic strain in
people would mean that the virus wouldn’t get shed – it’s got to make
you sick to make you shed X;{ , or we’d all be infected with scads of
things we just pass around all the time, without ever getting sick
(some things, like staph epidermidis, do probably pass around this
way.) But wild birds just pass the bug in their feces – harmless
intestinal bugs, like most enteroviruses in people.

[馬丁]

back to “a correspondent”:

引用：

We need a genetic explanation. Like Niman and ProMED, some people
regard the genetic similarity as evidence for migration theory.
My genetic interpretation is completely the reverse. The lack of
genetic variation is a result of “no natural selection” (evolutionary
stasis), i.e. the observed similarity is a genetic proof against wild
birds as vectors. Such a degree of “no natural selection” (as well as
the lack of reassortment) certainly requires artificial environment,
i.e. poultry. Wouldn’t that be a breakthrough? What we need is an
expert’s verification.

引用：

I have been just informed of a domestic TV program tonight,
highlighting “novel transmission ways” of flu. According to the
program, two new ways will be presented: mildly symptomatic people
(less immune reaction) and Tamiflu-treated people (I have read
numerous reports Tamiflu-treated mildly symptomatic people enter
crowds, spreading the virus). The can easily become “transmission
hubs”, making the spread easier and more preserving the virulence.

Wendy again:

引用：

Nah, this doesn’t work at all. Mildly symptomatic people will produce mild strains…the disease will move towards mildness. That’s the whole point of Ewald’s argument. I don’t know how much Tamiful treatment changes this picture – very little, I would think. The “less immune reaction” is a complete red herring. Less immune reaction is caused by a less virulent strain. In all cases, having people well enough to walk about will only decrease virulence, not maintain it or add to it. I suspect Tamiful-treated people will just recover more quickly and be less effective transmitters – remember, the virus has got to make you sick – coughing and sneezing- to get itself out and into someone else.

and correspondent:

引用：

Not all individuals react to the same (or similar) strain in the
same way. While the virus is less virulent to some people, there
still remains a possibility of a higher virulence to the rest.
(We already know the present H5N1 has shown different reactions to
different ages, but the reason is unknown. An asymptomatic crow
infection, with systemic viral replication, is already experimentally
known, which excreted sufficient viral load to infect other birds.
This shows less symptomatic populations in the same species can emerge).

By the way, I am not trying to argue “how dangerous the virus is”,
but Ewald’s argument expects the “expected mean”, not clearly directed
to the “potential upper limit”. Predictions assuming some kind of
an equilibrium or “mean field approximation” would fail in certain
conditions, especially there is a background variation (different
responses in populations). This is the very point recently targeted
by the complex network theory or modern numerical ecology.

[馬丁]

From further email from Wendy Orent:

Natural selection works on a genetic and individual level, not a population level. When you are talking about viruses, think of a swarm of strains, some of which are going to be more effective under the particular conditions they find themselves in (a host, or group of hosts, under particular ecological conditions.)

These influenza strains (say) are all madly jockeying, so to speak, to outreproduce each other (of course, this intentionality is strictly metaphorical.) Now, let’s say we are talking about a population of wild ducks who are infested with low-path H5N1. If there is a wide range of strains within duck A, those strains best at exploiting that duck’s body will reproduce better and faster and more effectively than milder strains. So, in the competition to use up the duck, so to speak, MORE virulent strains will win out.

Now, here’s the thing. That duck is dead – wiped out, gone. But duck B, which happened to get a smaller or a milder set of strains, doesn’t die; he lives to pass whatever virus he is dealing with to ducks C and D. So those milder strains are going to win out – and spread through the duck population. It has nothing to do with equilibrium – only with the balance between within host and outside-host competition. You sometimes do find dead ducks in the wild, because natural selection is blind as a cavefish and can’t see what’s going to happen a duck or so down the road. If you get a mutant that increases virulence, that will put virulent strains at a temporary advantage. But that virulent strain won’t spread – that’s why Ewald speaks of the “sieve of natural selection” when he talks about flu in wild migrating birds.
…
Change the conditions, and you change the equation – that’s the point of “disease factory” conditions – you remove the penalties on viruses for being virulent.

Post edited by: martin, at: 2006/02/06 00:13

[馬丁]

Perhaps useful article, originally in Fortune:
How disease evolves

包括：

引用：

natural selection doesn’t favor very vicious bugs when transmission from sick hosts is difficult, for the hosts literally become dead ends before the bugs can leap to others. In such cases, milder strains tend to become the dominant ones in circulation.

Which in case of bird flu, is roughly summarised by Dead Ducks Don’t Fly

(Even though dead ducks n other birds said to be spreading H5N1)

[馬丁]

whew! – correspondence on this topic getting pretty long, but may be some useful guff within.

Another email from me, to Wendy Orent:

“Change the conditions, and you change the equation” looks to me like what I know of re equilibrium (from physical chemistry).

As you say, each strain (even indiv virus) responds to conditions: important here, what’s likelihood it can be passed to another host. Then, as many different strains/individual viruses, see an overall picture, a population.
To me, seems similar to ensemble (I think that called – some time ago now!) in phys chem. Whole lot of possible states – perhaps of atoms or molecules; as change one or more important variables, change likelihood of occurrence of each of them, and get shift in overall population.

So with ducks, being stubborn here (!), we see equilibrium for reasons you note: dead ones don’t fly/move, their virus populations go extinct (tho always latent potential for creating them in numbers), and see population of low-path virus.
Shove ducks together, so v sick ones can more readily pass high-path strains, and the higher path strains can increase. See a shift in the equilibrium point – overall virus population moves to higher path, tho still a mix, with potential to have lower path virus as well as higher path.
Move back to having ducks in wild conditions, needing to fly to transmit, and those higher path viruses will disappear again, the lower path ones will increase. Equilibrium point shifts back.
or am I talking codswallop; hazy thinking this morning for some reason

I hadn’t been aware re population biologists thinking on – err – population levels. Whole lot of giraffes growing longer necks, instead of some individuals born with longer, some shorter, and longer more successful (as it looks to me like you’re saying). Curious; treating at population levels would just seem convenient way of achieving some simplification, which could be useful, whilst surely should remain keenly aware of individuals.

Wenday again:

引用：

natural selection isn’t a population-level phenomenon. Evolution is – in the sense that individuals don’t evolve. But selection has everything to do with competition within populations. Population biologists know this, in a sense, but they often don’t keep the levels of selection straight and they keep slipping.

The term “equilibrium” as you used it in the last e-mail is very slippery – I think the analogy to chemistry may not be helpful. You do get different strains within a population of hosts, which is why, for example, you can’t just go get a marmot and hope to isolate from that marmot a killer strain of plague – or dig up any old anthrax spores from the soil and think you’re going to get a bioweapon. But that doesn’t mean the strains are in any sort of balance, or that it’s in the least helpful to think of them that way. Viruses are continuously generating variation: some changes will lead to greater virulence, some to less.

The reason many are so prone to copying error, which is what mutation is, is that they have to keep changing to meet changing conditions in their host population. (i.e. they might encounter stronger or less-strong immune systems; their hosts might be in a greater or worse position to pass strains on, etc.) Some of these “errors” will benefit the virus in a particular line, and they’ll be selected. That is what adaptation is.

You can see that process at work in one or two Turkish cases – scientists found that some of the swarms of strains in the host’s body showed some better adaptation to people. They were better able to adhere to non-ciliated cells (human flu receptors), and they were able to grow higher up in the nasal passages – therefore at cooler temperatures. But the hosts were dead and the new lineages died with them.

These results show that the H5N1 virus can adapt, at least a bit, to human beings. There was no reason to think it couldn’t. But you’d need a long chain of human beings passing on these changes from one to another for any real adaptation to occur – i.e. before bird-adapted H5N1 flu became human-adapted H5N1. Could it happen? Yes – if governments keep covering up their bird flu cases. Is it likely? Not very – but it is certainly possible.

Surveillance is the single best way to stop it – quarantine would work very well before the virus got very adapted to people. Once it is, you can’t control human-adapted flu with quarantine. But you can BEFORE it gets there. That’s why the phrase “mutate to transmissibility” is so ridiculous. It implies that one or two chance mutations can produce adaptation – in the absence of natural selection.

(translation: to “mutate to transmissibility” means that some chicken, somewhere, is carrying a strain that has somehow mutated to be adapted to people. It then infects a person, who passes it on – and bingo. But selection does not and cannot work this way. A change that pre-adapts the strain for human infection and transmissbility cannot survive in chickens. Someone would have to catch it before the miraculously-mutated human-adapted strain got pushed aside by selection for chicken flu within the chicken’s own body. Thinking probabilistically – this chance is, uh, vanishingly small. Not to say non-existent.)

You can talke about “evolve to transmissibility” – but that’s a host/pathogen activity – it requires long chains of human beings (no one know how long – but more than a few, simply because so many changes are obviously required.) This process can happen, and has happened, with earlier flus. That is not in doubt. But the human-adapted flu strains will lose virulence, or never evolve it, because of the requirements imposed by transmission. Res ipsa locutor.

me again:

My equilibrium notions from now somewhat hazy memories of phase space, from lectures. Think I retain the gist, and not slippery.
Continuous variation – multitude of potential states – crucial here too. But overall picture not random.

Key, perhaps, would be:
With flu – would we expect overall virus to have different levels of virulence, which could be predicted if we have all the equations and numbers (surely impossible)?
Suppose had variations as follows – and only these variations (would be considerably more complex in practice):

Zero or effectively zero probability of spread by immobile carriers.
10% probability of spread by immobile carriers
30% probability of spread by immobile carriers
70% probability of spread by immobile carriers

If, over time, virus [as population] would evolve to a certain level of virulence, and maintain it while conditions persist, would surely have equilibrium. (Even though in each case, still potential for individual viruses to replicate to different states. Equilibrium at macro level doesn’t mean that stopped the perpetual mutations etc to various states – it’s just that probabilities individual states can persist/increase have changed.)

If levels of virulence of virus population would just fluctuate wildly, not settling over time, then indeed no equilibrium.

From all I’d seen before, I’d thought “miraculously-mutated human-adapted strain” was what all disease experts believed in; hadn’t really thought more re this – if WHO etc said it was so that virus could mix in a pig, then go on to devastate humanity, maybe it was so.

Back to Wendy:

引用：

As for equilibrium, I think you make a reasonable argument – and that it is one way to look at what we’re seeing. The problem is that it is a species – or population-level argument – which is not Darwinian. (translation: no traits can evolve or be maintained anywhere, under any circumstances, that are bad for the individual or individual genetic line, and good for the group. Darwin himself that that if one such example could be found, it would destroy his entire theory.

Keeping a population at some sort of equilibrium suggests that there is an advantage to the population as a whole in having variants around. Sounds good, but evolution, if you will forgive my putting it so bluntly, doesn’t work that way. Any traits that exist for the benefit of the group that jeopardizes its carrier’s fitness will be swiftly eliminated.

Only the traits that enhance their carrier’s fitness will be represented in the next generation – there are accidents, of course, like a tree falling on all the fittest members of the group, but natural selection will zap the less fit in the next generation. Remember that natural selection is not “survival of the fittest” but rather “differential reproduction.” )

To say that, for instance, flu viruses in wild birds are essentially stable simply means, from the perspective of evolutionary biology, that the strategy of low virulence continues to work well, and that the environmental conditions the bug finds itself in are stable. It doesn’t mean the bug isn’t just as mutagenic as ever; it’s just that low-pathogenic strains will continue to be at a selective advantage, which keeps the phenotypic variability in check.

So from this perspective, “settling over time” just means that the environmental conditions are stable. Certainly viral evolution will occur more quickly as a virus adapts to a new host. The mutation rate doesn’t change, so far as we know, though it might…we just don’t know if there is an actual viral mechanism to increase copying error; it sure sounds unlikely to me, but you never know. But selection pressure is more intense. We could see intensive selection pressure to adapt to human beings – but you’d need a string of human beings, ad seriatum, for the virus to adapt to.

Have I misunderstood anything in your argument? Please let me know.

to which I added:
What you write doesn’t seem at variance with my picture, deluded as I may be!
Equilibrium at macro level doesn’t mean all is nice n stable for individual viruses.

Phase space, as I recall rather more dimly than i might wish, partly about probabilities for individual states.

So here with flu, there’s a host of probabilities for forms a virus might take – here, only worrying re those that are more or less virulent (but surely others that better for being passed on, several that utterly useless).
All occurring – so with a virus, surely can have carriers lacking fitness for being passed on, for replicating. Not many of them, and as they are dead ends with normal conditions (virus that could wipe out the planet, say), they remain tiny populations, so nigh on invisible when look at population as a whole.
Can get “sports” in larger animals – birds with oddly curved mandibles etc, but v few (large animal populations tiny compared to viruses), and not surviving long enough or well enough to continue. So, see variations around some kind of mean.
But, one example known in UK is a moth: usually pale, resting on silver birch during day; a few dark variants. Add pollution, darken trees, get more predation of normal light form, and dark form became dominant near factories etc.

Change the conditions w virus, here to immobile carriers, and those rare mutations leading to increased virulence can increase, as they are passed on, can multiply; so virus as a whole becomes more virulent. Still all the mutations happening.
Reduce immobile carrier transmission, and these virulent forms become scarcer again, the virus back to low virulence.

HIV again: i saw re drug resistant strains appearing in people taking drugs. Again, surely v rare normally – maybe examine the virus population and wouldn’t notice them. But, when regular HIV blocked, the resistant strains become dominant (which to me looks like shift in equilibrium point).
Stop the drugs with this person, and evolves back again, so that later can again use the drugs.

Post edited by: martin, at: 2006/02/09 12:26

[馬丁]

more from a correspondent:

引用：

Perhaps you know this “experimental” incidence (coevolution
of pathogens with hosts):

http://www.rabbit-control-forum.net/Speeches/Kerr.pdf
“Myxoma Virus and Rabbits”

This example was also referred to by our specialist in predicting
the future of H5N1, but he said “there is a tendency like this,
but uncertainties remain”. This myxoma virus (though it’a a vector-
mediated) once got less lethal, but regained half-lethal, perhaps
a result of some sort of host-pathogen equilibrium. A frequently
cited example in an ecology textbook.

引用：

Yet another – evolution of host-pathogen relation, and
possible emergence of virulence from population structure:

http://www.sciencemag.org/cgi/content/full/303/5659/842
“Large Shifts in Pathogen Virulence Relate to Host Population
Structure”

Here we show that rapid evolution of virulence can occur as
a consequence of bistability in the evolutionary dynamics of
pathogens associated with changes in host social structure.

[馬丁]

Article by Paul Ewald on website of the Edge Foundation, in answer to question re what’s his dangerous idea includes:

引用：

Today experts on infectious diseases and institutions entrusted to protect and improve human health sound the alarm in response to each novel threat. The current fears over a devastating pandemic of bird flu is a case in point. Some of the loudest voices offer a simplistic argument: failing to prepare for the worst-case scenarios is irresponsible and dangerous. This criticism has been recently leveled at me and others who question expert proclamations, such as those from the World Health Organization and the Centers for Disease Control.

These proclamations inform us that H5N1 bird flu virus poses an imminent threat of an influenza pandemic similar to or even worse than the 1918 pandemic. I have decreased my popularity in such circles by suggesting that the threat of this scenario is essentially nonexistent. In brief I argue that the 1918 influenza viruses evolved their unique combination of high virulence and high transmissibility in the conditions at the Western Front of World War I.

A New Golden Age of Medicine

[馬丁]

after I posted little info to a discussion group re H5N1 and conservation, this message from a virologist:

引用：

Just a little point about influenza in humans- transmission is largely before any illness, as the peak of viral shedding occurrs before interferon release and the specific immune response e.g. T-cell response. This curtails viral replication and reduces shedding.

Any person admitted to hospital ill from influenza will have already transmitted the virus to another/s. The epidemic peak is very sharp in human influenza and it is probably the percentage of immune individuals in the population that brings the epidemic to an end. Therefore I don’t agree with your evolutionary biology idea.

It may be that the number of immune persons in the population after the circulation of the virus for a year forced changes in the HA molecule to escape from neutralising antibody and this had an effect on the virulence of H1N1 but the reason for the virulence of that virus and why it arose and then changed is I believe not known.

I sent a reply:

– evolutionary biology not my idea!

Is peak of shedding always before main symptoms? I know little of this, but some info from WHO suggests virus shedding peaks with symptoms.
http://www.cdc.gov/ncidod/EID/vol12no01/05-1370_app.htm
How do asymptomatic people transmit virus – just by talking (if not coughing, sneezing)? – and if lower probability of transmission this way, might this have an impact on virus evolution? – to evolve/sustain a virulent flu, maybe need fair percentage of those infected to be able to transmit to others?
Sadly, I’ve seen only fairly brief info from Paul Ewald, not his book, Evolution of Infectious Diseases.

also contacted Wendy Orent, who responded:

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I believe she is incorrect about transmission before any illness. There may be (in human influenza after it is fully adapted to the human species) some slight transmission before symptoms set in. But not much. It would have to be shed by breathing and talking – these are not efficient means of transmission. What are symptoms for? Why do we ccough and sneeze?/ Viruses settle in the upper airways and irritate us precisely in order to get us to cough and sneeze. In certain diseases, measles for instance, you transmit fairly early in the course of the disease, before you’re bed-ridden. Measles makes you sneeze. But you are still symptomatic!

Of course, before the disease has adapted to human beings, transmission tends to happen late in the illness, e.g. SARS. Had SARS continued to transmit, it would have adapted to people by becoming a more efficient shedder and spreading earlier in the course of the infection – it would have evolved to mildness like all coronaviruses, which are just common colds in people. It didn’t have that chance – it was wiped out before it became efficiently transmissible.

Just read your answer [after I’d sent in second email], and you are absolutely right – except for the bit about the “fair percentage” – I think you are still thinking in population terms.

She is also, I believe, incorrect about the “not known.” We have a very good idea why the virulence evolved, and why it diminished over time.

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[As noted above hin this thread I believe, but I sent to discussion group, maybe useful as summary:] I learned of evolutionary biology and diseases thro Wendy; don’t know all about it by any means (must read Ewald’s book!) – till then believed a monster human h5n1 pandemic flu was imminent. But to me, seems good, and explains a few things re flu that I’d otherwise find puzzling:
– 1918 flu occurring at same time as major world war (with trench warfare)
– human flus otherwise normally of low virulence
– wild avian flus mild (maybe even 1961 in S Africa common terns was from farms)
– ready transformation of wild flus in poultry farms, to viruses that are highly pathogenic for poultry (and, now, wild birds)
– inability of wild birds to sustain HPAIs (not just H5N1)

To me interesting that when Wendy mentioned to Paul Ewald re some ducks being able to survive H5N1, he predicted they shed only low amounts, as observed.

[馬丁]

Further evidence of evolutionary biology at work in poultry farms comes from UK's H7N3 outbreak. (Not conclusive here, but fits evol biology – as ever with flu.)

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Birds on the free range unit, however, suffered only a mild form of the flu and none died from the infection…. the virus was transported from the egg farm to the Banhams chicken farm, where it killed some 400 chickens and triggered a drop in egg production by other birds.

note also, from intensive farms:

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Blood samples from birds on their farm showed that they had been exposed to the H7N3 virus as long ago as four weeks.

– during which, presumably, the virus evolved towards virulence in the "disease factories" Vets track spread of bird flu strain

[馬丁]

Article by Wendy Orent, in LA Times, includes:

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… the factors that set off a pandemic remain unknown. No one has ever tracked the evolution of a new pandemic. All we have seen — in 1918, 1957 and 1968 — is the aftermath of that evolution. Still, we are told that all it would take for H5N1 to become a pandemic would be for the virus to mutate so it could spread in a sustained way from person to person. This is known as "mutation to transmissibility." … The H5N1 virus faces several barriers in jumping to and transmitting among humans. The most important is its ability to replicate in and adapt to human tissues, specifically the upper respiratory tract (not in deep lung tissue, where it now seems to grow). In the windpipe, the virus would be more likely to spread in a cough or sneeze, infecting other humans. …

[Earl] Brown recognizes what seems to elude most people who worry about pandemic outbreaks: What's necessary to produce a human-adapted virus is humans — a series of person-to-person infections. Without that chain of transmission, any human adaptation of H5N1 is difficult to imagine. … interact with other viral genes in a human host to improve its ability to infect the host. This is an adaptive process — and it is true whether the new virus arises directly through mutation or even through recombination with a common flu strain. H5N1 is beautifully, tragically adapted to chickens and has proved a monstrous predator. It evolved this way by preying on chickens packed into huge commercial chicken farms in Asia. The bird flu virus is still at the starting gate when it comes to humans. But should any strain of H5N1 manage to survive many sequential transmissions, Darwin's charioteer may drive off. The best transmitters will be favored by selection, as evolutionary biologist Paul W. Ewald of the University of Louisville contends. The process will continue, human by human, until a fully human-adapted, explosive strain emerges. …

At the beginning, viral adaptation to a host is slow. A disease just beginning to transmit is controllable. Surveillance, flexibility, willingness to impose or undergo quarantines, along with international cooperation, will be necessary to stop pandemic flu — or any other disease moving from animals to humans — before Darwin's driver gets ahead of us and nothing can be done.

What Darwin has to say about bird flu Can the disease mutate into a widespread threat to humans? Possibly, but it won't happen overnight.

I emailed Wendy to check whether this rather ominous last sentence (and "explosive strain") meant some change in her thinking re not being possible right now to evolve a virulent flu.

Her reply:

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No, I haven't changed my position. A pandemic (without WWI etc. conditions) would NOT be a lethal pandemic – just an ordinary one, like 57 or 68. And quarantine would work in the early stages, as the virus adapts. An explosive strain merely means a highly transmissible strain, not a lethal strain. I am afraid many people may understand this the way you did. It's actually the same argument I've been making for years – just another piece of it. It would be awful if people think I've changed my position, under pressure maybe. Not at all. I haven't changed a bit – I just wanted to show why the phrase "mutate to transmissibility" is essentially meaningless, and that the evolution of any pandemic would have to come through natural selection. That's how it happened in the past; that's how it could happen in the future.

[作者]

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