噬菌体疗法可以战胜耐药性疾病
Phage Therapy Could Beat Drug-Resistant Illnesses
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2019-11-07 22:56
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火星译客

Bobby Burgholzer has cystic fibrosis, a genetic disease that throughout his life has made him vulnerable to bacterial infections in his lungs. Until a few years ago antibiotics held his symptoms mostly at bay, but then the drugs stopped working as well, leaving the 40-year-old medical device salesman easily winded and discouraged. He had always tried to keep fit and played hockey, but he was finding it harder by the day to climb hills or stairs. As his condition worsened, Burgholzer worried about having a disease with no cure. He had a wife and young daughter he wanted to live for. So he started looking into alternative treatments, and one captured his attention: a virus called a bacteriophage.

鲍比·伯格尔泽患有囊性纤维症,这是一种遗传性疾病,这种疾病使他一生都很容易受到肺部细菌感染。直到几年前,因为注射抗生素才使他的症状基本得到控制,但后来这些药物也失效了,这让这位40岁的医疗设备销售员会经常性地喘不过气,心情也持续低落。他一直努力保持身体健康,打曲棍球,但他发现自己在爬小山或楼梯时愈加吃力。随着病情的恶化,伯格尔泽担心自己的病无法治愈。他想为他的妻子和小女儿而活。于是他开始寻找替代疗法,其中一种叫做噬菌体的病毒引起了他的注意。

Phages, as they are known, are everywhere in nature. They replicate by invading bacteria and hijacking their reproductive machinery. Once inside a doomed cell, they multiply into the hundreds and then burst out, typically killing the cell in the process. Phages replicate only in bacteria. Microbiologists discovered phages in the 1910s, and physicians first used them therapeutically after World War I to treat patients with typhoid, dysentery, cholera and other bacterial illnesses. Later, during the 1939–1940 Winter War between the Soviet Union and Finland, use of the viruses reportedly reduced mortality from gangrene to a third among injured soldiers.

众所周知,噬菌体在自然界中无处不在。它们通过入侵细菌并劫持生殖细胞进行DNA复制。一旦侵入某个细胞,这通常注定该细胞无法存活,之后噬菌体就会繁殖到数百个最终全面爆发,通常在这个过程中会杀死细胞。噬菌体只在细菌中进行复制。微生物学家在20世纪10年代发现了噬菌体,第一次世界大战后,医生首次将其用于治疗伤寒、痢疾、霍乱和其他细菌性疾病。后来,在1939-1940年苏芬战争(冬季战争)期间,据报道,使用这种病毒使伤兵的坏疽死亡率降低了三分之一。

Treatments are still commercially available in former Eastern Bloc countries, but the approach fell out of favor in the West decades ago. In 1934 two Yale University physicians—Monroe Eaton and Stanhope Bayne-Jones—published an influential and dismissive review article claiming the clinical evidence that phages could cure bacterial infections was contradictory and inconclusive. They also accused companies that manufactured medicinal phages of deceiving the public. But the real end of phage therapy came in the 1940s as doctors widely adopted antibiotics, which were highly effective and inexpensive.

在前东欧国家,这种治疗性的毒剂仍可在市场上买到,但几十年前这种方法在西方国家就不受欢迎了。1934年,耶鲁大学的两位物理学家门罗·伊顿和斯坦霍普·拜恩-琼斯共同发表了一篇颇具影响力且带轻蔑态度的评论性文章,声称证明噬菌体可以治愈细菌感染的临床成果不成立,因为该依据与现实存在很大的矛盾性,而且至今未成定论。他们还指控制造公司利用药用噬菌体欺骗公众。但噬菌体疗法直到20世纪40年代才真正终结,当时抗生素因其高效便宜而受到医生们的广泛认可。

Phage therapy is not approved for use in humans in any Western market today. Research funding is meager. And although human studies in Eastern Europe have generated some encouraging results—particularly those from the Eliava Institute in Tbilisi, Georgia, the field's research epicenter—many Western scholars say the work does not meet their rigorous standards. Furthermore, a smattering of clinical trials in Western Europe and the U.S. have produced some high-profile failures.

因研究经费不足,目前噬菌体疗法用于人体试验的建议在所有西方市场都未得到批准。尽管东欧国家在人类研究方面已经取得了一些令人鼓舞的成果,其中格鲁吉亚第比利斯的埃利亚瓦研究所的研究成果尤其突出。尽管该研究所是该领域的研究中心,但许多西方学者认为这项工作没有达到其严格的规定标准。此外,西欧和美国也进行了几次临床试验,但都以轰动一时的失败告终。

Yet despite the historical skepticism, phage therapy is making a comeback. Attendance at scientific conferences on the treatment is skyrocketing. Regulators at the U.S. Food and Drug Administration and other health agencies are signaling renewed interest. More than a dozen Western companies are investing in the field. And a new wave of U.S. clinical trials launched this year. Why the excitement? Phage treatments have been curing patients with multidrug-resistant (MDR) infections that no longer respond to antibiotics. The FDA has allowed petitioning doctors to administer these experimental treatments on a “compassionate use” basis when they could show that their patients had no other options—exactly what Burgholzer was hoping to prove.

然而,尽管过去的学者对噬菌体疗法的怀疑不减,但它正试图卷土重来。参加有关这种治疗方法的科学会议的人数直线上升。美国食品和药物管理局(fda)和其他卫生机构的监管机构也再度表示对此很感兴趣。十几家西方公司正在该领域寻找投资机会。今年美国开始了新一轮临床试验。为什么兴奋?噬菌体治疗已经治愈了耐多药(MDR)感染的患者,抗生素对这些患者已不再产生效用。食品和药物管理局已经允许提交申请的医生在“体恤使用”的基础上进行这些实验性的治疗,条件是他们能够证明其病人没有其他治疗选择,而这正是伯格尔泽一直以来力求证明的一点。

MDR infections are a rapidly growing public health nightmare. At least 700,000 people worldwide now die from these incurable maladies every year, and the United Nations predicts that number could rise to 10 million by 2050. In the meantime, the drug industry's antibiotic pipeline is running dry.

耐多药感染正迅速发展为公共卫生的噩梦。全世界每年至少有70万人死于这些无法治愈的疾病,联合国预测,到2050年,该数字可能会上升到1000万。与此同时,制药行业的抗生素供应渠道日渐枯竭。

Like all viruses, phages are not really alive—they cannot grow, move or make energy. Instead they drift along until by chance they stick to bacteria. Unlike antibiotics, which kill a range of helpful bacteria as they kill the strains making a person sick, a phage attacks a single bacterial species, and perhaps a few of its closest relatives, and spares the rest of the microbiome. Most phages have an icosahedral head—like a die with 20 triangular faces. It contains the phage's genes and connects to a long neck that ends in a tail of fibers, which bind to receptors on a bacterium's cell wall. The phage then plunges a kind of syringe through the wall and injects its own genetic material, which co-opts the bacterium into making more phage copies. Other types of phages, not used medically, enter the same way but live dormantly, reproducing only when the cell divides.

像所有的病毒一样,噬菌体并不是真实存在的活体——它们不能生长、移动或产生能量。相反,它们随波逐流,直到偶然地附着在细菌上。与抗生素不同的是,噬菌体只攻击一种细菌,或许还会攻击与之亲缘关系最近的几种细菌,而不攻击微生物群落的其他部分。大多数噬菌体的头部接近于二十面体,看上去像有20个三角形面。它包含噬菌体的基因,并与长颈相连,长颈末端有纤维,纤维与细菌细胞壁上的受体相结合。然后,噬菌体将通过注射器穿过细胞壁,注入自己的遗传物质,从而协同细菌制造更多的噬菌体副本。其他类型的噬菌体,不用于医学,但侵入细胞的方式是相同的,平常就处于休眠状态,只有在细胞分裂时才开始繁殖。

Phages have co-evolved with bacteria for billions of years and are so widespread that they kill up to 40 percent of all the bacteria in the world's oceans every day, influencing marine oxygen production and perhaps even Earth's climate. The spotlight on phages as medical tools is getting brighter as technological advances make it possible to match the viruses to their targets with better accuracy. The few facilities that are technically able to provide phage therapy, under strict regulatory protocols, are being overwhelmed with requests.

噬菌体与细菌相成相生,这一过程已经持续了数十亿年。噬菌体分布如此广泛,以至于每天会杀死世界海洋中40%的细菌,从而影响海洋氧气的产生,甚至可能影响全球气候。随着技术的进步,病毒能够更准确地与目标匹配,噬菌体作为医疗工具的前景越来越光明。在严格的监管协议下,在超负荷的需求下,技术上能够提供噬菌体治疗的设施却屈指可数。

Clinical trials underway are beginning to generate the high-quality data needed to convince regulators that phage therapy is viable, but considerable questions remain. The biggest is whether phage therapy can tackle infections on a large scale. Clinicians have to match phages to the specific pathogens in a patient's body; it is not clear whether they can do that cost-effectively and with the speed and efficiency needed to bring phages into routine use. Also problematic is a shortage of regulatory guidelines governing the production, testing and use of phage therapy. “But if it has the potential to save lives, then we as a society need to know whether it will work and how best to implement it,” says Jeremy J. Barr, a microbiologist at Monash University in Melbourne, Australia. “The antibiotic-resistance crisis is too dire to not embrace phage therapy now.”

因为目前进行的临床试验所产生的数据的质量越来越高,监管机构也更加相信噬菌体疗法的可行性。但这一领域还存在着相当多的问题。其中最严重的问题是噬菌体疗法能否大规模地解决感染问题。临床医生必须使噬菌体与病人体内的特定病原体相匹配;在确保成本效益的条件下,能够达到使噬菌体投入日常使用的速度和效率,关于他们是否能做到这一点目前还不清楚。同样存在问题的是,缺乏规范噬菌体治疗的生产、检测和使用的管理准则。澳大利亚墨尔本莫纳什大学的微生物学家杰里米·巴尔(Jeremy J. Barr)说:“但如果它有可能拯救生命,那么就社会层面来看,我们需要知道它是否有效,以及如何找到最优实施方法。”“抗生素耐药性危机太可怕了,现在不能不接受噬菌体疗法。”

Trading Vulnerabilities

交换漏洞

Burgholzer learned about phages by talking to other people with cystic fibrosis around the country. While scouring the Internet for more information, he came on a YouTube video made by phage researchers at Yale University. Soon he was corresponding with Benjamin Chan, a biologist in Yale's department of ecology and evolutionary biology. Since arriving there in 2013, Chan has accumulated a “library” of phages, harvested from sewage, soil and other natural sources, that he makes available to doctors at Yale New Haven Hospital and elsewhere.

伯格尔泽通过与全国其他囊性纤维化患者交谈了解了噬菌体。当他在互联网上搜寻更多信息时,他看到了一个由耶鲁大学噬菌体研究人员制作的YouTube视频。很快,他就和耶鲁大学生态与进化生物学系的生物学家本杰明·陈取得了联系。自2013年抵达那里以来,陈安道建立了一个贮藏了众多噬菌体的“图书馆”,在馆内收集了来自污水、土壤和其他自然资源的噬菌体,供耶鲁纽黑文医院(Yale New Haven Hospital)和其他地方的医生使用。

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