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.
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.
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.
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.
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.
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.
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.
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.
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。”
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.