WEBVTT 00:00.410 --> 00:03.327 (Soft piano music) 2021. A man in his fifties is admitted to hospital in San Francisco, California, after experiencing a seizure. He is disoriented, appears distracted and has difficulties with his speech. An MRI scan reveals a lesion in the left temporal lobe of his brain. The source of the lesion is unclear. 00:15.151 --> 00:17.280 (Sirens blaring) - It was a mystery 00:17.280 --> 00:20.230 that consumed multiple teams for multiple weeks, 00:21.180 --> 00:24.690 until our neurologist and pathologist realized 00:24.690 --> 00:27.090 that on the section of his brain 00:27.090 --> 00:29.610 there were forms that looked like cysts, 00:29.610 --> 00:31.160 which is suspicious for amoeba. 00:32.130 --> 00:34.440 And that's how the diagnosis was eventually made 00:34.440 --> 00:36.630 of Balamuthia mandrillaris, 00:36.630 --> 00:38.673 also known as the brain-eating amoeba. 00:39.660 --> 00:42.333 That's actually when I entered the story. 00:42.333 --> 00:44.670 (Light music) 00:44.670 --> 00:47.190 - Granulomatous amoebic encephalitis, 00:47.190 --> 00:51.120 or GAE, is caused when the brain becomes infected 00:51.120 --> 00:54.810 by a free living amoeba called Balamuthia. 00:54.810 --> 00:57.090 It's one of the three pathogenic amoebae 00:57.090 --> 00:58.710 known to infect humans 00:58.710 --> 01:01.890 and cause a devastating brain infection. 01:01.890 --> 01:05.340 Fortunately, GAE is relatively rare. 01:05.340 --> 01:09.420 However, they have an unusually high mortality rate. 01:09.420 --> 01:10.830 Balamuthia, for example, 01:10.830 --> 01:14.460 can infect someone when soil is pushed up the nose 01:14.460 --> 01:15.960 or through the eye 01:15.960 --> 01:19.290 and from there the amoeba can travel to the nervous system, 01:19.290 --> 01:21.270 primarily the brain. 01:21.270 --> 01:24.093 It literally begins to eat its way through the tissue. 01:25.920 --> 01:26.753 - By the time I saw him, 01:26.753 --> 01:28.770 he'd actually been seen, given a diagnosis 01:28.770 --> 01:30.840 and he'd been started onto six medications 01:30.840 --> 01:33.570 which, until this year, were standard of care, 01:33.570 --> 01:35.550 which includes two antifungals, 01:35.550 --> 01:38.253 two antiparasitics and two antibacterials. 01:39.300 --> 01:42.180 It's what has been used successfully on a few survivors 01:42.180 --> 01:44.250 and it's also really toxic. 01:44.250 --> 01:46.770 So, multiple of these drugs had had to be stopped 01:46.770 --> 01:49.860 following bone-marrow suppression, kidney injury. 01:49.860 --> 01:51.780 We were losing drugs to treat him, 01:51.780 --> 01:54.780 and the lesions in his brain were starting to enlarge, 01:54.780 --> 01:57.420 so I felt we were really running quite short on options 01:57.420 --> 01:59.070 and that I had to think really hard 01:59.070 --> 02:01.853 if we were going to try to save his life. 02:01.853 --> 02:04.353 (Light music) A previous case emerged as a crucial piece of the puzzle. 2015. A 74-year old woman was admitted to hospital in San Francisco with a cough and the loss of vision in her left eye. Five days later, an MRI scan showed that her brain had become disrupted by numerous lesions. The patient failed to respond to treatment, and died before a definitive diagnosis could be made. 02:22.776 --> 02:24.930 - We were trying to figure out what killed her 02:24.930 --> 02:26.103 because no one knew. 02:27.630 --> 02:30.900 We used metagenomic next-generation sequencing. 02:30.900 --> 02:32.640 This is a technique where we sequence 02:32.640 --> 02:35.370 all the RNA or DNA from a patient sample 02:35.370 --> 02:37.740 - in this case, cerebral spinal fluid. 02:37.740 --> 02:41.460 This eliminates the idea that you have to know 02:41.460 --> 02:44.400 what you're looking for before you look for it. 02:44.400 --> 02:47.763 In other words, you look for everything simultaneously. 02:48.690 --> 02:52.465 We discovered that she had Balamuthia. 02:52.465 --> 02:54.965 (Light music) 2018. A screen by Joe DeRisi’s team of all medicines with US or EU regulatory approval revealed one drug that showed promise for treating Balamuthia infections. 02:58.020 --> 02:59.400 It's a drug called nitroxoline. 02:59.400 --> 03:01.620 It's been around for many, many years, 03:01.620 --> 03:04.230 mainly sold in Europe and in Asia 03:04.230 --> 03:07.050 as a drug to treat urinary-tract infections, 03:07.050 --> 03:11.160 but it's never been used in amoebic encephalitis before. 03:11.160 --> 03:15.360 This drug appears to bind to divalent metals. 03:15.360 --> 03:17.880 In this way, its antibacterial activity 03:17.880 --> 03:19.050 is thought to happen 03:19.050 --> 03:22.320 because it's robbing those organisms of metals 03:22.320 --> 03:24.930 that they need for their enzymes. 03:24.930 --> 03:26.850 So, we published that paper 03:26.850 --> 03:28.110 and, like many academics, 03:28.110 --> 03:30.510 maybe that was going to be the end of the story. 03:32.700 --> 03:34.440 - When I saw that my patient was getting worse, 03:34.440 --> 03:35.550 one of my colleagues advised me 03:35.550 --> 03:38.073 to look at Joe's paper and to talk to Joe. 03:39.030 --> 03:39.967 He picked up the phone and said, 03:39.967 --> 03:41.772 I know a company that makes it. 03:41.772 --> 03:43.795 (Soft piano music) 03:43.795 --> 03:48.212 (Speaking Mandarin) 04:58.410 --> 05:00.960 - Altogether, it took close to a month 05:00.960 --> 05:03.120 from request to shipping 05:03.120 --> 05:05.160 to getting it into UCSF pharmacy. 05:05.160 --> 05:07.380 It is not a trivial process, 05:07.380 --> 05:10.500 and I have to say that I was really living on edge 05:10.500 --> 05:13.503 and in some state of terror throughout that entire month. 05:15.090 --> 05:17.190 After a week, we got a repeat MRI 05:17.190 --> 05:18.630 that showed not only improvement 05:18.630 --> 05:21.840 but near resolution of these huge areas of his brain 05:21.840 --> 05:24.180 that had been super oedematous and swollen, 05:24.180 --> 05:27.090 and a huge abscess, and it was getting better. 05:27.090 --> 05:28.680 We never stopped the other drugs 05:28.680 --> 05:31.080 but I do think that it was nitroxoline, 05:31.080 --> 05:33.180 especially given the in vitro data 05:33.180 --> 05:36.081 and the fact that he got better when we added it. 05:36.081 --> 05:38.581 (Light music) 2022. The grandmother of a young Texan girl with an amoebic infection discovers a preprint article published on the 2021 case. Physicians treating the child contact Asieris Pharmaceuticals for an emergency supply of nitroxoline. 05:45.679 --> 05:47.880 - It's kind of an amazing tale of science 05:47.880 --> 05:49.860 of how one thing leads to another 05:49.860 --> 05:52.500 and you don't really know where it's going to go. 05:52.500 --> 05:54.450 We didn't know we'd have fantastic partners 05:54.450 --> 05:55.710 in Asieris Pharmaceuticals. 05:55.710 --> 05:57.000 They were generous enough 05:57.000 --> 05:59.823 to gift us the drug to treat this patient. 06:00.976 --> 06:05.393 (Speaking Mandarin) 06:22.749 --> 06:25.200 - Right now, the CDC, on their website, 06:25.200 --> 06:26.730 is offering nitroxoline 06:26.730 --> 06:30.000 for patients with confirmed Balamuthia, Acanthamoeba 06:30.000 --> 06:31.290 and or Naegleria. 06:31.290 --> 06:32.700 So, clinicians who have a patient 06:32.700 --> 06:35.940 who they think may have a brain-eating-amoeba disease 06:35.940 --> 06:38.590 can call the CDC and ask for a supply of nitroxoline. 06:39.780 --> 06:42.240 I think one of the really cool things about this project 06:42.240 --> 06:43.860 is that everything comes together 06:43.860 --> 06:46.470 in a way that it kind of never does. 06:46.470 --> 06:48.390 The idea that I could learn from my patient 06:48.390 --> 06:51.420 and from the original patient who'd passed away 06:51.420 --> 06:55.170 and help a girl I've never met... that feels amazing. 06:55.170 --> 06:58.140 I am so grateful to have gotten to be a part of their story 06:58.140 --> 07:00.946 and that that little child is alive. 07:00.946 --> 07:03.446 (Light music) Some patients in China have also recovered successfully from amoebic infections. In 2024, Asieris Pharmaceuticals was granted permission to use nitroxoline in China as an Investigational New Drug to tackle amoebic infections. Infections by Balamuthia and other amoebae are not just a public health issue in the US and China. Global collaboration will help more people worldwide to recover from such infections.