為什麼噬菌體病毒可能成為治療致命感染的關鍵——如果它們能夠被安全地利用的話
人們對如何利用鮮為人知的病毒來克服耐藥細菌越來越感興趣。
資料來源：海蒂•萊德福德 / 2023 年 6 月 26 日 / 書評 / 自然
噬菌體病毒（綠色）將其基因注入細菌中進行自我複制。圖片來源：Biophoto Associates/SPL
好的病毒：噬菌體不為人知的故事：地球上最豐富的生命形式以及它們能為我們做些什麼 / Tom Ireland Hodder Press (2023)
世界上充滿了病毒：它們在水、土壤和我們的腸道中繁殖。 在 COVID-19 大流行之後，可以肯定地說，病毒不太可能贏得任何人氣競賽。 然而，在《好病毒》中，科普作家湯姆•愛爾蘭試圖提高他們的聲譽。
這本引人入勝的書透過關注一組稱為噬菌體的病毒來強調病毒世界光明的一面，這些病毒會感染細菌和古細菌等微生物。 社會往往忽視噬菌體； 引起我們注意的病毒通常屬於一組引起疾病的恐怖病毒，例如 SARS-CoV-2、愛滋病毒和伊波拉病毒。 但愛爾蘭認為，如果研究人員成功開發出可以治療致命的耐藥細菌感染的噬菌體，那麼這種恥辱就可以消除。
研究人員在公民科學家的幫助下，已經在梳理世界各地收集的噬菌體，尋找最佳的醫學候選者。 材料並不短缺：一升水可以含有數十億個病毒，它們每年促使受感染的細菌向海洋釋放約三十噸碳。
為什麼聯邦調查局要追踪諾貝爾獎獲得者微生物學家薩爾瓦多•盧里亞？
噬菌體也是實驗室的寵兒，對我們對遺傳學和分子生物學的理解產生了巨大的影響。 Martha Chase 和 Alfred Hershey 在 20 世紀 50 年代使用噬菌體進行了傳奇而優雅的實驗，確定 DNA（而非蛋白質）為遺傳物質（A. D. Hershey & M. Chase J. Gen. Physiol. 36, 39–56；1952）。 第一個被定序的完整基因組便來自噬菌體。
但即使是那些研究噬菌體的人也往往只關注少數病毒。 圍繞著被忽視的大多數人的謎團使本書的某些部分變得令人愉悅。 了解更多關於噬菌體的信息，就是發現一個隱藏世界的迷人細節，噬菌體在其中塑造微生物生態系統，並透過與宿主交換基因來加速進化。 有一天，工程噬菌體可以將藥物輸送到大腦，甚至可能被納入醫院使用的抗菌建築材料中。
一種歷史而又未來的療法
愛爾蘭在書中用大量篇幅討論了噬菌體作為感染和殺死耐藥細菌菌株的藥物的潛在優點。 隨著耐藥性問題的加劇，這個想法變得越來越有吸引力。 據估計，到 2050 年，每年將有 1,000 萬人死於抗生素耐藥性感染。這是一個既不公正又嚴峻的未來：正如愛爾蘭指出的那樣，「預計其中 90% 的死亡將發生在非洲和亞洲」。
有人說，噬菌體療法可以讓我們避免這種結果。 如果可以利用這些病毒來治療感染，那麼使用噬菌體混合物（每種噬菌體都有自己的感染細菌細胞的方式）可以減緩耐藥性的出現。 病毒本身能夠改變，並且在發展過程中可能進化出抵禦細菌耐藥機制的方法。
一種歷史而又未來的療法
愛爾蘭在書中用大量篇幅討論了噬菌體作為感染和殺死耐藥細菌菌株的藥物的潛在優點。 隨著耐藥性問題的加劇，這個想法變得越來越有吸引力。 據估計，到 2050 年，每年將有 1,000 萬人死於抗生素耐藥性感染。這是一個既不公正又嚴峻的未來：正如愛爾蘭指出的那樣，「預計其中 90% 的死亡將發生在非洲和亞洲」。
有人說，噬菌體療法可以讓我們避免這種結果。 如果可以利用這些病毒來治療感染，那麼使用噬菌體混合物（每種噬菌體都有自己的感染細菌細胞的方式）可以減緩耐藥性的出現。 病毒本身能夠改變，並且在發展過程中可能進化出抵禦細菌耐藥機制的方法。
在數千種病毒中發現的 CRISPR 工具可以促進基因編輯
這是一個既未來又具有歷史意義的想法：一些國家——尤其是前蘇聯成員國——近一個世紀以來一直使用噬菌體療法來治療感染。 其中一些實驗室在蘇聯解體後立即倒閉，當時喬治亞等國家面臨一段經濟不穩定時期。 愛爾蘭對提比里斯的一個噬菌體實驗室進行了引人入勝的描述，該實驗室擁有數百名員工，在高峰時期每年供應數噸噬菌體藥物。 20世紀90年代，蘇聯解體後留下來的研究人員在停電、設備生鏽和基本物資短缺的情況下，努力提供一些噬菌體療法。 從那時起，其中一些實驗室已經恢復元氣。
一次冒險的嘗試？
然而大多數西方醫生和科學家拒絕了這種方法。 偏見無疑加劇了這種懷疑，但部署噬菌體療法確實存在後勤障礙。 儘管曾有透過最後一刻的介入措施挽救生命的戲劇性軼事，但目前還沒有數據支持此類治療的廣泛使用。
超越冠狀病毒：病毒的發現改變了生物學
在這裡，愛爾蘭走在刀鋒上：儘管一次性的積極故事暗示了一種可能的方法來拯救更多的生命，但它們也有可能給處於絕望境地的人們帶來虛假的希望。 是的，偏見阻礙了這一領域的發展；是的，藥物監管可能會減緩療法的發展，當某人的生命處於危險之中時，這可能會令人痛苦。 但監管機構確實有理由感到擔憂。
噬菌體療法存在風險
如果製劑中含有過多來自原始細菌宿主的物質，它可能會引發致命的免疫反應。 人們對噬菌體在定居並與鄰居交換基因時如何影響我們體內的微生物生態系統知之甚少。 例如，已知細菌只有在感染特定噬菌體後才成為人類病原體（P. L. Wagner & M. K. Waldor Infect. Immun. 70, 3985–3993; 2002）。
好病毒來得正是時候。 人們對噬菌體療法的興趣與日俱增：生物技術公司正在爭奪一席之地； 關鍵的臨床試驗終於開始了； 提比里斯和其他地方的噬菌體生產再次蓬勃發展。 對於一個長期以來被不公平地忽視的領域來說，這是一個激動人心的時刻。 但我們還有很長的路要走，才能知道噬菌體是否能讓我們擺脫即將到來的耐藥性噩夢，並讓病毒世界煥然一新。
自然 618, 905-906 (2023)
doi：https://doi.org/10.1038/d41586-023-01982-2
Why phage viruses could be the key to treating deadly infections — if they can be harnessed safely
Interest is growing in how little-known viruses could be used to overcome drug-resistant bacteria.
Heidi Ledford / 26 June 2023 / BOOK REVIEW / Nature
Phage viruses (green) inject their genes into bacteria to replicate themselves.Credit: Biophoto Associates/SPL
The Good Virus: The Untold Story of Phages: The Most Abundant Life Forms on Earth and What They Can Do For Us Tom Ireland Hodder Press (2023)
The world is teeming with viruses: they flourish in water, soil and our guts. In the wake of the COVID-19 pandemic, it is safe to say that viruses are unlikely to win any popularity contests. Yet, in The Good Virus, science writer Tom Ireland attempts to improve their reputation.
This engaging book highlights the brighter side of the viral world by focusing on one group of viruses, called bacteriophages (phages), that infect microorganisms such as bacteria and archaea. Society tends to overlook phages; the viruses that grab our attention typically belong to a cohort of disease-causing terrors, such as SARS-CoV-2, HIV and Ebola. But the stigma can be lifted, argues Ireland, if researchers succeed in developing phages that can treat infections by deadly, drug-resistant bacteria.
Researchers — aided by citizen scientists — are already combing through phages collected around the world for the best medical candidates. There is no shortage of material: one litre of water can contain billions of the viruses, and they promote the release of an estimated three gigatonnes of carbon from infected bacteria into the seas each year.
Why did the FBI track Nobel-winning microbiologist Salvador Luria?
Phages are also laboratory darlings that have had an outsize impact on our understanding of genetics and molecular biology. The legendary and elegant 1950s experiments by Martha Chase and Alfred Hershey that established DNA — not protein — as hereditary material were performed using phages (A. D. Hershey & M. Chase J. Gen. Physiol. 36, 39–56; 1952). The first full genome to be sequenced was from a phage.
But even those who study phages tend to focus on only a handful of viruses. The mystery surrounding the overlooked majority makes some sections of the book a delight. To learn more about phages is to discover fascinating details about a hidden world in which they mould microbial ecosystems and accelerate evolution by swapping genes with their hosts. Engineered phages could one day deliver drugs to the brain and might even be incorporated into antibacterial building materials used in hospitals.
A historical, yet futuristic, therapy
Ireland devotes much of the book to discussing the potential merits of phages as medicines for infecting and killing drug-resistant strains of bacteria. The idea has become more appealing as the problem of drug resistance has grown. By some estimates, 10 million people will die each year from antibiotic-resistant infections by 2050. It is a future as unjust as it is grim: as Ireland notes, “up to 90% of those deaths are predicted to occur in Africa and Asia”.
Phage therapy, some say, could allow us to avoid that outcome. If these viruses can be harnessed as a treatment for infection, administering a mixture of phages — each with its own way of infecting bacterial cells — could slow the emergence of resistance. The viruses themselves are capable of change and could evolve ways to fend off a bacterium’s resistance mechanisms as they develop.
CRISPR tools found in thousands of viruses could boost gene editing
It is an idea both futuristic and historical: some countries — particularly former members of the Soviet Union — have used phage therapy to treat infections for nearly a century. Some of these labs foundered in the immediate aftermath of the fall of the Soviet Union, when countries such as Georgia faced a period of economic instability. Ireland offers riveting accounts of a phage lab in Tbilisi that had a staff of hundreds and supplied tonnes of phage medicines each year at its peak. The researchers who remained after the Soviet Union’s collapse struggled, in the 1990s, to provide some phage therapies, amid electricity outages, rusting equipment and a shortage of basic supplies. Since then, a few of these labs have bounced back.
A risky endeavour?
Yet most Western doctors and scientists have rejected the approach. Prejudice has no doubt contributed to that scepticism, but there are real logistical hurdles to deploying phage therapy. Despite dramatic anecdotes of lives saved by last-minute interventions, the data simply do not yet exist to support the widespread use of such treatments.
Beyond coronavirus: the virus discoveries transforming biology
Here, Ireland walks a knife edge: although positive one-off stories hint at a possible way to save more lives, they also run the risk of giving false hope to people in desperate circumstances. Yes, prejudice has held the field back and yes, drug regulation can slow the development of therapies in ways that can be galling when someone’s life is on the line. But it is also true that regulators have reasons to be concerned.
Phage therapy carries risks.
If a preparation contains too much material from the original bacterial host, it can trigger a deadly immune response. And little is known about how phages could affect the microbial ecosystems in our bodies as they take up residence and swap genes with their neighbours. There are, for example, known cases of bacteria that become human pathogens only after they are infected with specific phages (P. L. Wagner & M. K. Waldor Infect. Immun. 70, 3985–3993; 2002).
The Good Virus is timely. Excitement about phage therapy is growing: biotechnology firms are jockeying for position; key clinical trials are finally getting under way; and phage production in Tbilisi and elsewhere is flourishing once again. It’s an exciting time for a field that has, for too long, been unfairly overlooked. But there is still a long way to go before we know whether phages will spare us from the drug-resistant nightmare on the horizon and cast the viral world in a better light.
Nature 618, 905-906 (2023)
doi: https://doi.org/10.1038/d41586-023-01982-2