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Would you like to inspect the original subtitles? These are the user uploaded subtitles that are being translated: 0 00:00:01,985 --> 00:00:05,042 For our opening address, I have the great pleasure of 1 00:00:05,054 --> 00:00:08,010 introducing our keynote speaker, Dr.Randy Schekman. 2 00:00:08,050 --> 00:00:10,100 Randy, welcome to the future. 3 00:00:10,140 --> 00:00:11,782 Yes. Good morning from Berkeley. 4 00:00:11,822 --> 00:00:12,832 Good morning. 5 00:00:12,872 --> 00:00:15,578 Let me say a few words about our keynote speaker today. 6 00:00:15,618 --> 00:00:19,194 Randy Schekman is a professor in the Department of Molecular 7 00:00:19,218 --> 00:00:22,793 and Cell Biology at the University of California, Berkeley, 8 00:00:22,833 --> 00:00:26,461 and an investigator of the Howard Hughes Medical Institute. 9 00:00:26,501 --> 00:00:31,145 He studied DNA replication as a graduate student at Stanford University, 10 00:00:31,169 --> 00:00:34,501 and his current interest is in cellular membranes. 11 00:00:35,478 --> 00:00:39,046 In 2013, Randy Schekman was awarded the Nobel Prize in Physiology 12 00:00:39,070 --> 00:00:43,478 or Medicine for their discoveries of the machinery regulating vesicle traffic, 13 00:00:44,874 --> 00:00:47,754 a major transport system in our cells. 14 00:00:47,794 --> 00:00:50,030 In addition to the Nobel, his other awards 15 00:00:50,042 --> 00:00:52,238 include the Gairdner International Award, 16 00:00:52,262 --> 00:00:55,794 as well as the the Albert Lasker Award in Basic Medical Research. 17 00:00:57,836 --> 00:01:02,087 Dr. Segment and his team are still conducting research into the mechanisms 18 00:01:02,111 --> 00:01:05,836 of the of traffic in the secondary pathway of eukaryotic cells. 19 00:01:07,308 --> 00:01:10,434 He served as editor or editor in chief for the 20 00:01:10,446 --> 00:01:13,785 annual reviews of Cell and developmental biology. 21 00:01:13,825 --> 00:01:17,709 I beg your pardon and the Proceedings of the National Academies of Science, 22 00:01:17,749 --> 00:01:23,740 and was founding editor and editor in chief of the open access journal eLife. 23 00:01:23,780 --> 00:01:28,030 Since 2018, Dr Schekman has served as the scientific director 24 00:01:28,054 --> 00:01:31,451 of Aligning Science across Parkinson's Disease, 25 00:01:31,491 --> 00:01:34,008 a major philanthropic effort organized by 26 00:01:34,020 --> 00:01:36,729 the along with the Michael J. Fox Foundation 27 00:01:36,769 --> 00:01:40,486 to identify molecular and cellular mechanisms in the 28 00:01:40,498 --> 00:01:44,086 initiation and progression of Parkinson's disease. 29 00:01:44,126 --> 00:01:46,632 If you have any questions for Dr. Shechtman, I would ask 30 00:01:46,644 --> 00:01:49,294 you, please, to post them here in the Q&A box on this page. 31 00:01:49,334 --> 00:01:53,201 All questions will be forwarded to him after the conference and responses 32 00:01:53,213 --> 00:01:56,830 will be published later this year in the official conference report. 33 00:01:56,870 --> 00:01:59,899 So without further ado, I have the great pleasure of 34 00:01:59,911 --> 00:02:03,583 introducing a keynote speaker for today to see the future 2021. 35 00:02:03,623 --> 00:02:06,118 Dr. Randy Schekman. 36 00:02:06,158 --> 00:02:11,293 Thank you very much, Tony, and welcome to my friends in the audience. 37 00:02:11,333 --> 00:02:16,097 I'm going to divide my talk into three subject areas. 38 00:02:16,137 --> 00:02:20,000 The first will be a broad overview of the of the area 39 00:02:20,012 --> 00:02:23,886 of my research as it relates to the current pandemic. 40 00:02:23,926 --> 00:02:30,236 The coronavirus pandemic there is a connection related to cellular membranes. 41 00:02:30,276 --> 00:02:36,171 I'll again devote some time to the issue of scientific publication. 42 00:02:36,211 --> 00:02:38,467 Some of my concerns about how 43 00:02:38,479 --> 00:02:42,154 scholars choose which journals to publish it, 44 00:02:42,194 --> 00:02:46,092 and the control that's exerted by some of the largely commercial 45 00:02:46,104 --> 00:02:50,194 enterprises in which many investigators wish to publish their work. 46 00:02:50,955 --> 00:02:55,585 And finally, I'm going to turn to another topic, one that Tony just introduced, 47 00:02:55,625 --> 00:02:59,707 and that is my personal and professional interest in Parkinson's 48 00:02:59,719 --> 00:03:03,625 disease and a very large international collaborative program, 49 00:03:05,814 --> 00:03:09,426 that I initiated at behest of the Sergei Brin Family 50 00:03:09,438 --> 00:03:13,814 Foundation in collaboration with the Michael J. Fox Foundation, 51 00:03:14,091 --> 00:03:18,193 to bring teams of investigators together to try to get to the molecular 52 00:03:18,205 --> 00:03:22,091 and cellular basis of this scourge of mankind. Parkinson's disease. 53 00:03:24,341 --> 00:03:28,366 Well, let's begin with a topic of current interest to all of us. 54 00:03:28,406 --> 00:03:31,883 This is a picture, a cartoon view of the 55 00:03:31,895 --> 00:03:36,406 outside in a slice of the inside of the coronavirus. 56 00:03:38,761 --> 00:03:42,650 Coronavirus looks very much like a carrier that's found it 57 00:03:42,662 --> 00:03:46,761 in all cells that have a nucleus, a carrier called a vesicle. 58 00:03:46,864 --> 00:03:50,790 But it's been designed by evolution to convey this molecule, an 59 00:03:50,802 --> 00:03:54,864 RNA molecule which is in the interior of the virus for infection. 60 00:03:58,633 --> 00:04:02,794 The outer surface of the virus particle is a membrane. 61 00:04:02,834 --> 00:04:07,227 You'll see a bit more about what a biological membrane consists of. 62 00:04:07,267 --> 00:04:13,119 It's a membrane that has lipids on its surface, so it's kind of a greasy shell. 63 00:04:13,159 --> 00:04:17,990 And most importantly, proteins, one of which is called the spike protein, 64 00:04:18,030 --> 00:04:21,673 that allows the virus to engage a cell and 65 00:04:21,685 --> 00:04:25,594 then enter the cell by engulfing and process, 66 00:04:25,634 --> 00:04:29,587 that allows the RNA to be released into the interior of 67 00:04:29,599 --> 00:04:33,634 a cell for its replication to make more virus particles. 68 00:04:33,988 --> 00:04:38,015 Now let's do just a very brief primer on biological 69 00:04:38,027 --> 00:04:41,988 membranes and how they relate to the corona virus. 70 00:04:42,651 --> 00:04:48,767 This is an image taken in an electron microscope of a thin slice through a cell, 71 00:04:48,807 --> 00:04:52,826 that reveals the perimeter or cell surface membrane consisting of 72 00:04:52,838 --> 00:04:56,807 two layers or a bilayer of lipid molecules called phospholipids, 73 00:04:59,455 --> 00:05:03,115 into which various protein molecules. 74 00:05:03,155 --> 00:05:06,548 I indicated by Green are inserted so that 75 00:05:06,560 --> 00:05:10,695 part of the protein faces the outside of the cell. 76 00:05:10,735 --> 00:05:13,852 And another part of the protein faces the inside of the cell. 77 00:05:13,892 --> 00:05:18,786 This is a depiction that we now generally appreciate about biological membranes. 78 00:05:18,826 --> 00:05:23,027 They all consist of this kind of fluid phospholipid bilayer 79 00:05:23,039 --> 00:05:26,761 that's a kind of a has the viscosity of a light oil, 80 00:05:26,801 --> 00:05:30,696 and then membrane proteins that impart unique personalities to 81 00:05:30,708 --> 00:05:34,801 membranes and generate particular functional qualities to a cell. 82 00:05:36,309 --> 00:05:40,353 This, for instance, might be a receptor, such as the receptor that I'll 83 00:05:40,365 --> 00:05:44,309 tell you about that's responsible for the uptake of the corona virus. 84 00:05:48,658 --> 00:05:55,096 Now, this is a cartoon of a typical cell, a eukaryotic cell. 85 00:05:55,136 --> 00:05:59,234 This is a nucleus that contains all of the chromosomes, 86 00:05:59,246 --> 00:06:03,136 the 23 chromosomes that constitute the human genome. 87 00:06:03,438 --> 00:06:07,350 It's enclosed within a membrane and envelope. 88 00:06:07,390 --> 00:06:12,333 And in the outside the cytoplasmic area, there are a number of organelles, 89 00:06:12,373 --> 00:06:17,578 some of which may be part of the energy producing machine called the mitochondria, 90 00:06:17,618 --> 00:06:22,679 and others of which may be an organ cell, such as the lysosome, 91 00:06:22,719 --> 00:06:24,768 which is responsible for degrading 92 00:06:24,780 --> 00:06:27,959 macromolecules that are no longer wanted by the cell, 93 00:06:27,999 --> 00:06:33,109 and surrounding it all is another membrane that is again a lipid bilayer. 94 00:06:33,149 --> 00:06:36,724 This is in contrast to what a bacterial cell looks like. 95 00:06:36,764 --> 00:06:38,217 It's much smaller. 96 00:06:38,257 --> 00:06:41,775 It doesn't have a nucleus proper, but it has DNA. 97 00:06:41,815 --> 00:06:45,726 It must allow the cell to grow and divide, but it is 98 00:06:45,738 --> 00:06:49,587 much less compartmentalized than a eukaryotic cell. 99 00:06:49,627 --> 00:06:51,517 We are eukaryotes. 100 00:06:51,557 --> 00:06:57,177 Most of the organisms that we see with our naked eye are eukaryotes. 101 00:06:57,217 --> 00:07:00,919 Now this is a sketch of the process that 102 00:07:00,931 --> 00:07:05,097 cells use to manufacture proteins for export. 103 00:07:05,137 --> 00:07:09,116 This has been the subject of my research research over many years. 104 00:07:09,156 --> 00:07:12,504 Eukaryotic cells are organized into compartments. 105 00:07:12,544 --> 00:07:16,626 I mentioned the nucleus surrounding the new nucleus is a network 106 00:07:16,638 --> 00:07:20,544 of membranes referred to as the endoplasmic reticulum or e-r. 107 00:07:21,608 --> 00:07:29,098 And in many cells, these membranes are studied with these green particles. 108 00:07:29,138 --> 00:07:32,605 The color preferred for this description the 109 00:07:32,617 --> 00:07:36,328 green of particles, which are called ribosomes. 110 00:07:36,368 --> 00:07:40,446 Ribosomes are like the little sewing machines in a cell that stitch 111 00:07:40,458 --> 00:07:44,368 amino acids one next to two another to make a polypeptide chain. 112 00:07:45,811 --> 00:07:48,359 This may be, for instance, a cell that such as 113 00:07:48,371 --> 00:07:51,312 the cell in your in your pancreas that makes insulin. 114 00:07:51,352 --> 00:07:55,436 Insulin, then would start being made by a ribosome such as this 115 00:07:55,448 --> 00:07:59,352 threaded into this salmon colored interior of this membrane, 116 00:08:01,281 --> 00:08:05,304 and then in a series of steps, is conveyed from one step 117 00:08:05,316 --> 00:08:09,281 to the next to finally be exported outside of the cell. 118 00:08:10,499 --> 00:08:15,022 So of the twenty three thousand genes in the human genome, 119 00:08:15,062 --> 00:08:20,100 almost 30 percent of them encode proteins that engage this process 120 00:08:20,140 --> 00:08:24,100 and are delivered either to the cell surface to intracellular membrane 121 00:08:24,112 --> 00:08:28,140 organelles like the lysosome or remain within this within this network. 122 00:08:29,860 --> 00:08:33,842 It's a very elaborate process that has been, as I said, the subject 123 00:08:33,854 --> 00:08:37,496 of my work at MIT, many other cell biologist over many years. 124 00:08:37,536 --> 00:08:40,412 Now, how does this relate to coronavirus? 125 00:08:40,452 --> 00:08:45,468 So here's a another image of the virus, such as you saw in my first slide. 126 00:08:45,508 --> 00:08:49,627 It's again, it's a little membrane that carries a nucleic acid 127 00:08:49,639 --> 00:08:53,508 inside, and then it has the spike protein on its exterior. 128 00:08:54,788 --> 00:08:58,807 This spike protein has a specific affinity binding to one of our 129 00:08:58,819 --> 00:09:02,788 own proteins on cells that has a completely different function. 130 00:09:06,521 --> 00:09:09,235 A protein that's called ACE2. 131 00:09:09,275 --> 00:09:12,088 This protein serves a normal purpose in our 132 00:09:12,100 --> 00:09:14,989 body and the respiratory canals of our body. 133 00:09:15,029 --> 00:09:18,849 But the virus has evolved to hijack this receptor and to 134 00:09:18,861 --> 00:09:23,029 allow the virus to bind and to be internalized into the cell. 135 00:09:24,699 --> 00:09:28,571 Now what happens once it's in the cell is really quite remarkable, 136 00:09:28,583 --> 00:09:32,699 and it engages the very network of membranes that I've just described. 137 00:09:32,848 --> 00:09:38,196 Here, for instance, is another slice through a coronavirus infected cell. 138 00:09:38,236 --> 00:09:39,700 Here are the virus particles. 139 00:09:39,740 --> 00:09:43,152 These are actual virus particles binding on 140 00:09:43,164 --> 00:09:46,978 the cell surface to that ACE2 receptor molecule. 141 00:09:47,018 --> 00:09:50,809 And they may then be swallowed up internalized into these 142 00:09:50,821 --> 00:09:55,018 structures when they are compartmentalized in these structures. 143 00:09:56,992 --> 00:10:02,409 The spike protein adheres to the inner surface of this membrane, 144 00:10:02,449 --> 00:10:06,297 in which the virus has been engulfed and the membranes 145 00:10:06,309 --> 00:10:10,449 surrounding the virus merges with this organelle membrane, 146 00:10:10,761 --> 00:10:14,236 to in a process that's called membrane fusion. 147 00:10:14,276 --> 00:10:18,040 And when that happens, the interior of the virus, the 148 00:10:18,052 --> 00:10:22,107 nucleic acid of the virus, is spilled into the cytoplasm. 149 00:10:22,147 --> 00:10:26,077 The rest of the cell and in the cytoplasm, the RNA that constitutes 150 00:10:26,089 --> 00:10:30,147 the genome of this virus is replicated and more viruses are produced. 151 00:10:32,126 --> 00:10:37,522 Now, the great triumph in this first phase of the pandemic, 152 00:10:37,562 --> 00:10:41,583 has been to realize the possibility of taking an RNA molecule 153 00:10:41,595 --> 00:10:45,562 called a messenger RNA molecule that copies the information. 154 00:10:48,130 --> 00:10:51,859 In part of the spike protein and this RNA molecule, Imani can be 155 00:10:51,871 --> 00:10:56,130 packaged into an artificial membrane called a lipo, a lipid nanoparticle. 156 00:11:01,235 --> 00:11:05,298 And these then are the vaccines that many of you have 157 00:11:05,310 --> 00:11:09,235 received from either BioNTech or Pfizer or Moderna. 158 00:11:09,970 --> 00:11:13,958 These RNA containing lipo lipid like particles can be taken up by 159 00:11:13,970 --> 00:11:17,970 the same process that I've just described injected into the cell. 160 00:11:19,668 --> 00:11:23,034 The RNAs can escape into the cytoplasm, and 161 00:11:23,046 --> 00:11:27,192 that RNA then will make a piece of the spike protein. 162 00:11:27,232 --> 00:11:30,212 It will not create a new infectious virus. 163 00:11:30,252 --> 00:11:34,245 It will only make a part of that spike protein that part 164 00:11:34,257 --> 00:11:38,051 of the spike protein is exported outside of the cell. 165 00:11:38,091 --> 00:11:41,236 And that's what your immune system recognizes 166 00:11:41,248 --> 00:11:44,336 as foreign and generates an immune response. 167 00:11:44,376 --> 00:11:48,364 So this is a subversion of the virus process that has been used by 168 00:11:48,376 --> 00:11:52,376 biotechnology to engineer it quite remarkably, successful vaccine. 169 00:11:57,421 --> 00:12:00,793 Now, that's it for just a very broad view of the 170 00:12:00,805 --> 00:12:04,259 kind of cell biology that we do in my laboratory. 171 00:12:04,299 --> 00:12:08,406 I want to turn my attention for a little while into 172 00:12:08,418 --> 00:12:12,299 what scientists must do to publicize their work, 173 00:12:12,515 --> 00:12:18,134 and that is to publish in journals that other scholars, colleagues can see. 174 00:12:18,174 --> 00:12:21,141 You may be aware that during the 175 00:12:21,153 --> 00:12:25,807 pandemic, a lot of the literature on SARS-CoV-2, 176 00:12:25,847 --> 00:12:30,081 the coronavirus and COVID 19 has been published openly in commercial 177 00:12:30,093 --> 00:12:33,847 or noncommercial journals and made available for all to see, 178 00:12:38,221 --> 00:12:42,241 irrespective of your location in an academic institution or not. 179 00:12:42,281 --> 00:12:46,269 This has been a bright light on a process that is often held 180 00:12:46,281 --> 00:12:50,281 behind a closed door that most of you are not accessible to, 181 00:12:52,666 --> 00:12:55,626 and this is a, I think, a big challenge. 182 00:12:55,666 --> 00:12:59,154 Most of the research that's conducted on 183 00:12:59,166 --> 00:13:03,350 diseases such as COVID is with government funds, 184 00:13:03,390 --> 00:13:07,405 and the work that gets published as a result of this taxpayers fund is in 185 00:13:07,417 --> 00:13:11,390 then published in journals that are not available to the general public. 186 00:13:14,307 --> 00:13:16,954 They are only available in the form of 187 00:13:16,966 --> 00:13:20,443 subscriptions, often very expensive subscriptions. 188 00:13:20,483 --> 00:13:24,497 So I want to tell you how some of us have been trying to change the culture 189 00:13:24,509 --> 00:13:28,483 of scientific publication, and this relates to the challenge that we face. 190 00:13:31,427 --> 00:13:38,294 Now, here's one of the biggest problems that we faced over the past 20 years. 191 00:13:38,334 --> 00:13:40,625 Some of you may be aware that 192 00:13:40,637 --> 00:13:44,211 beginning about a dozen about 10 years ago, 193 00:13:44,251 --> 00:13:48,502 reports started to emerge that very important papers that were published 194 00:13:48,514 --> 00:13:52,251 in the most high profile journals journals like Nature Science, 195 00:13:55,405 --> 00:13:59,136 could actually not be replicated in the very 196 00:13:59,148 --> 00:14:03,390 controlled conditions of a pharmaceutical company. 197 00:14:03,430 --> 00:14:07,811 This company, a major biotech company in the United States called Amgen, 198 00:14:07,851 --> 00:14:13,657 conducted its own study by an Australian investigator who found that. 199 00:14:15,201 --> 00:14:18,995 Over 80 percent of the key experiments in papers on cancer 200 00:14:19,007 --> 00:14:23,201 biology that Amgen wished to use in order to discover new drugs, 201 00:14:25,915 --> 00:14:29,937 that may be chemotherapeutic agents over 80 percent, almost 202 00:14:29,949 --> 00:14:33,915 90 percent of the key experiments could not be reproduced. 203 00:14:34,583 --> 00:14:38,956 Now, a biotech company lives and dies on the accuracy and reproducibility 204 00:14:38,968 --> 00:14:42,583 of what they produce, and if they can't reproduce something, 205 00:14:44,029 --> 00:14:45,795 it is of no commercial value. 206 00:14:45,835 --> 00:14:47,922 So this was quite shocking. 207 00:14:47,962 --> 00:14:51,869 This gentleman, Ed Begley, was the key author on this, and he reported a 208 00:14:51,881 --> 00:14:55,962 number of really quite frightening examples of this failure of replication. 209 00:15:00,683 --> 00:15:02,322 So what to do about this? 210 00:15:02,362 --> 00:15:06,154 After all, the United States at that time already was investing $30 211 00:15:06,166 --> 00:15:10,362 billion a year in biomedical research and institutions across the country. 212 00:15:12,901 --> 00:15:15,344 Congress was, of course, alarmed that much 213 00:15:15,356 --> 00:15:17,811 of this investment might have been wasted. 214 00:15:17,851 --> 00:15:19,561 What to do about this? 215 00:15:19,601 --> 00:15:25,102 Well, at the time, I was just beginning a new open access journal. 216 00:15:25,142 --> 00:15:27,653 Now, open access is different than the 217 00:15:27,665 --> 00:15:30,836 model of commercial licensing and subscriptions, 218 00:15:30,876 --> 00:15:34,445 and open access model journal is where the 219 00:15:34,457 --> 00:15:38,705 author of the work pays for the publication costs. 220 00:15:38,745 --> 00:15:42,879 These in a journal that is adequately supported by philanthropic funds 221 00:15:42,891 --> 00:15:46,745 such as We Were at Eli are modest in comparison to the real cost, 222 00:15:48,271 --> 00:15:52,982 considering the profit margin in some of the very popular commercial journals. 223 00:15:53,022 --> 00:15:56,968 So we decided as an editorial policy to engage 224 00:15:56,980 --> 00:16:01,022 with a group called the Center for Open Science 225 00:16:01,511 --> 00:16:04,031 to conduct our own study on the 226 00:16:04,043 --> 00:16:08,128 reproducibility of key papers in cancer biology. 227 00:16:08,168 --> 00:16:12,396 This was an editorial that we published at the outset of our investigation. 228 00:16:12,436 --> 00:16:14,192 What we did and so this is the 229 00:16:14,204 --> 00:16:16,915 journal that I initiated. It's called eLife. 230 00:16:16,955 --> 00:16:21,072 It was very generously supported by three very important funders 231 00:16:21,084 --> 00:16:24,769 of science the Howard Hughes Medical Institute in the US, 232 00:16:24,809 --> 00:16:28,835 the Max Planck Society in Germany, Germany and the Wellcome Trust in the UK. 233 00:16:28,875 --> 00:16:31,265 These three organizations felt their 234 00:16:31,277 --> 00:16:34,653 presence felt that it was time for active scholars, 235 00:16:34,693 --> 00:16:38,681 to take control of the literature and to change the nature 236 00:16:38,693 --> 00:16:42,693 of how scientific publications are assessed and published. 237 00:16:45,291 --> 00:16:49,307 So what we did in our investigation of key papers that were published in 238 00:16:49,319 --> 00:16:53,291 Cancer Biology was to conduct a study in two stages in the first stage. 239 00:16:53,945 --> 00:17:01,945 But certain research groups were commissioned to design experiments, 240 00:17:04,109 --> 00:17:06,694 that would test the reproducibility of key experiments 241 00:17:06,706 --> 00:17:08,925 in the papers that had already been published. 242 00:17:08,965 --> 00:17:12,555 We asked these groups of contract organizations 243 00:17:12,567 --> 00:17:16,094 to write what it's called a registered report. 244 00:17:16,134 --> 00:17:19,708 This is a report where they simply describe in detail 245 00:17:19,720 --> 00:17:23,572 exactly how they intend to attempt to repeat the studies. 246 00:17:23,612 --> 00:17:25,528 There are no studies yet conducted it, 247 00:17:25,540 --> 00:17:27,864 just a report of how they plan to go about it. 248 00:17:27,904 --> 00:17:31,577 These registered reports were reviewed by the normal 249 00:17:31,589 --> 00:17:35,204 procedures we had and the Editorial Board of eLife. 250 00:17:35,244 --> 00:17:39,499 And if finally approve, these registered reports were published in our journal, 251 00:17:39,539 --> 00:17:42,384 and then the contract groups were then commissioned to 252 00:17:42,396 --> 00:17:45,356 conduct the actual investigation, the replication study. 253 00:17:45,396 --> 00:17:48,666 So here are the parameters of this. 254 00:17:48,706 --> 00:17:51,710 Ultimately, this took quite quite a long time. 255 00:17:51,750 --> 00:17:55,827 Ultimately, about half of the studies that we initially investigated 256 00:17:55,839 --> 00:17:59,750 were published of replication studies, and the outcome was mixed. 257 00:18:01,591 --> 00:18:05,195 A report in Science magazine found that of the first five 258 00:18:05,207 --> 00:18:08,822 papers that went through this rigorous two stage process, 259 00:18:08,862 --> 00:18:14,049 only two of the five really could adequately be replicated. 260 00:18:14,089 --> 00:18:17,918 The other three, we didn't necessarily feel were fraudulent 261 00:18:17,930 --> 00:18:21,963 or where the data was manipulated in the original publication. 262 00:18:22,003 --> 00:18:26,442 It's just that we required that the protocols, 263 00:18:26,482 --> 00:18:30,296 the detailed experimental protocols that were used in the initial 264 00:18:30,308 --> 00:18:34,482 publications be replicated precisely as written by our contract groups. 265 00:18:36,120 --> 00:18:39,343 We were not allowed to consult with the original authors to see if 266 00:18:39,355 --> 00:18:42,783 there were some variations that they hadn't described in their papers, 267 00:18:42,823 --> 00:18:45,818 and that may explain some of the problem with these 268 00:18:45,830 --> 00:18:48,894 three that did not did not succeed by our standards. 269 00:18:48,934 --> 00:18:55,271 But just to summarize that part of the part of the investigation that he likes, 270 00:18:55,311 --> 00:18:59,411 it left us with a feeling that replication studies are 271 00:18:59,423 --> 00:19:03,311 very difficult to do it properly is very expensive, 272 00:19:03,629 --> 00:19:09,134 very time consuming and would be a burden on most investigators. 273 00:19:09,174 --> 00:19:12,991 It's just a cautionary note that one must be very careful in being 274 00:19:13,003 --> 00:19:17,174 completely open and transparent in the original publication of the work, 275 00:19:18,558 --> 00:19:21,975 and all of the protocols that are a part of 276 00:19:21,987 --> 00:19:25,572 that study must be described in great detail. 277 00:19:25,612 --> 00:19:30,096 Now I'm going to turn to another theme related to scientific publication, 278 00:19:30,136 --> 00:19:33,733 and that is the challenge that an investigator 279 00:19:33,745 --> 00:19:37,277 such as myself faces when we want to publish. 280 00:19:37,317 --> 00:19:41,766 And what are these very so-called high profile journals, nature or science? 281 00:19:41,806 --> 00:19:46,038 And the problem that many of us feel that has been a key. 282 00:19:46,078 --> 00:19:51,006 So part of the failure of the system is the peer review process. 283 00:19:51,046 --> 00:19:54,858 So let me describe for those of you who may not know what's what 284 00:19:54,870 --> 00:19:59,046 happens in a peer review process, a paper is submitted to any journal, 285 00:20:00,124 --> 00:20:02,923 a member of the editorial board of that journal, then decides 286 00:20:02,935 --> 00:20:05,792 whether that paper is appropriate for that particular journal, 287 00:20:05,832 --> 00:20:09,606 and he or she then assigns that paper to two or more 288 00:20:09,618 --> 00:20:13,832 outside experts who are knowledgeable in the subject area. 289 00:20:14,101 --> 00:20:18,887 They then assess the work in detail. They write individual reports. 290 00:20:18,927 --> 00:20:22,836 The individual reports are then considered by the member of the editorial 291 00:20:22,848 --> 00:20:26,927 board, and if a final decision is made about the about the fate of the work. 292 00:20:28,549 --> 00:20:32,285 Now let me give you an example of a paper, a rather 293 00:20:32,297 --> 00:20:36,549 notorious paper that had a very severe impact on our life. 294 00:20:37,637 --> 00:20:41,362 Now, nearly 20 years later, roughly 20 years ago, a 295 00:20:41,374 --> 00:20:45,254 paper was published in the journal called The Lancet, 296 00:20:45,294 --> 00:20:48,370 a very important clinical journal that's published by the major 297 00:20:48,382 --> 00:20:51,518 publisher of scientific literature in the world called Elsevier. 298 00:20:51,558 --> 00:20:56,351 This journal Lancet is a British journal of long note. 299 00:20:56,391 --> 00:20:59,567 About 20 years ago, they received a report 300 00:20:59,579 --> 00:21:02,693 from one Andrew Wakefield in in the U.K., 301 00:21:02,733 --> 00:21:08,816 and part of the message of this of his study was that there may be a connection, 302 00:21:08,856 --> 00:21:11,796 between immunization and the development 303 00:21:11,808 --> 00:21:15,192 of autism in young children who are immunized. 304 00:21:15,232 --> 00:21:19,880 Of course, this was a frightening, frightening prospect. 305 00:21:19,920 --> 00:21:23,452 Now I know from behind the scenes what happened in the review of 306 00:21:23,464 --> 00:21:26,898 that paper it was subjected to the normal peer review process. 307 00:21:26,938 --> 00:21:29,505 The outside reviewers felt that the paper was 308 00:21:29,517 --> 00:21:32,600 inadequate, that the data wasn't up to the conclusion. 309 00:21:32,640 --> 00:21:37,406 The internal members of the board who were employees of Lancet felt. 310 00:21:37,446 --> 00:21:40,056 Likewise, the paper was about to be rejected. 311 00:21:40,096 --> 00:21:46,196 But because the message was so important was somehow really couldn't be held back. 312 00:21:46,236 --> 00:21:49,253 The publisher decided to publish this this paper, 313 00:21:49,265 --> 00:21:52,294 now many of you heard of the consequence of this. 314 00:21:52,334 --> 00:21:54,378 The paper was eventually found to be fraudulent. 315 00:21:54,418 --> 00:21:56,259 Some of the data was manipulated. 316 00:21:56,299 --> 00:21:57,696 Wakefield was. 317 00:21:57,736 --> 00:22:02,495 The paper was after 12 years finally retracted by the journal. 318 00:22:02,535 --> 00:22:06,292 Wakefield was kicked out of his home institution, but he 319 00:22:06,304 --> 00:22:10,535 continues to agitate with anti-vaccine groups around the world, 320 00:22:13,624 --> 00:22:17,570 all because of this one publication fraudulent 321 00:22:17,582 --> 00:22:21,624 publication that failed the peer review system. 322 00:22:22,053 --> 00:22:24,692 This is a concern that we all have now. 323 00:22:26,389 --> 00:22:29,155 Another problem is that these journals, such as I 324 00:22:29,167 --> 00:22:31,833 mentioned, science and nature, are so powerful, 325 00:22:31,873 --> 00:22:35,861 and they operate to make themselves exclusive by accepting 326 00:22:35,873 --> 00:22:39,873 only a very small number of the papers that are submitted. 327 00:22:40,438 --> 00:22:43,495 And the problem is that this leads to bad 328 00:22:43,507 --> 00:22:47,452 behavior on the part of scientists, sometimes papers. 329 00:22:47,492 --> 00:22:51,450 Our data is manipulated to make it look better or conclusions are 330 00:22:51,462 --> 00:22:55,492 overdrawn that cannot be just justified by the by the experiments. 331 00:22:58,438 --> 00:23:01,157 And here are a couple of comments that are published in this 332 00:23:01,169 --> 00:23:03,856 very nature is the nature and science magazines themselves. 333 00:23:03,896 --> 00:23:07,826 An immunologist at MIT to pluck peer review of scientific papers in 334 00:23:07,838 --> 00:23:11,896 top journals is bogged down by unnecessary demands or extra lab work, 335 00:23:12,974 --> 00:23:17,215 or by a team, including Peter Walter at UCSF. 336 00:23:17,255 --> 00:23:20,962 The stress associated with the public and publishing experimental 337 00:23:20,974 --> 00:23:24,298 results can drain much of the joy from practicing science. 338 00:23:24,338 --> 00:23:28,166 Another feature that journals such as Nature used to use to 339 00:23:28,178 --> 00:23:32,338 promote themselves is a number called the journal Impact Factor. 340 00:23:34,111 --> 00:23:38,289 This number was created over four decades ago by something called 341 00:23:38,301 --> 00:23:42,111 the Institute for Science Scientific Information in the US. 342 00:23:42,226 --> 00:23:46,241 It was a number that's used to compute basically how popular a journal is 343 00:23:46,253 --> 00:23:50,226 the number of citations to papers in that journal over a two year period 344 00:23:54,146 --> 00:23:56,707 divided by the number of papers published. 345 00:23:56,747 --> 00:24:00,517 And so here you see this number being advertised by 346 00:24:00,529 --> 00:24:04,747 nature to promote itself to people who wish to subscribe. 347 00:24:05,263 --> 00:24:09,124 The number seemingly highly accurate, in fact, is completely 348 00:24:09,136 --> 00:24:13,263 inaccurate and a misrepresentation of the importance of science. 349 00:24:14,667 --> 00:24:18,561 It is an attempt to quantify popularity or timeliness, and it 350 00:24:18,573 --> 00:24:22,667 is not a measure of scholarship. It never was intended for that. 351 00:24:23,395 --> 00:24:28,487 And yet it has been used by most journals over many years to hype themselves. 352 00:24:28,527 --> 00:24:33,002 Now, even nature recognize the damage done by the use of this number. 353 00:24:33,042 --> 00:24:37,030 And the former editor in chief Philip Campbell wrote an editorial 354 00:24:37,042 --> 00:24:41,042 five years ago calling for a reform of the journal Impact Factor. 355 00:24:42,697 --> 00:24:45,621 His comments were very, very measured. 356 00:24:45,661 --> 00:24:48,524 But I think highly effective metrics are 357 00:24:48,536 --> 00:24:52,323 intrinsically reductive and as such can be dangerous. 358 00:24:52,363 --> 00:24:55,780 Relying on them as a yardstick of performance, 359 00:24:55,820 --> 00:24:59,291 rather than as a pointer to underlying achievements 360 00:24:59,303 --> 00:25:02,987 and challenges usually leads to pathological behavior. 361 00:25:03,027 --> 00:25:09,081 The journal impact factor is just such a metric, and I can assure you that is true. 362 00:25:09,121 --> 00:25:13,227 And unfortunately, although nature has issued the use of this number, 363 00:25:13,267 --> 00:25:17,134 it continues to be used by scientific societies and journals to 364 00:25:17,146 --> 00:25:21,267 advertise their journals and to promote them for popular attention. 365 00:25:23,267 --> 00:25:30,593 Now, one of the pathological consequences of this is in countries, 366 00:25:30,633 --> 00:25:34,143 that where the intellectual infrastructure is 367 00:25:34,155 --> 00:25:38,136 not up to the challenge of reviewing the literature 368 00:25:38,176 --> 00:25:44,754 by use of experts to evaluate the quality and importance of work in China. 369 00:25:44,794 --> 00:25:48,065 As of a few years ago, many of the institutions, 370 00:25:48,077 --> 00:25:51,627 including one called the Chinese Academy of Science, 371 00:25:51,667 --> 00:25:55,332 issued a bulletin such as You See Here, which I've had translated. 372 00:25:55,372 --> 00:25:59,278 It's a bulletin that basically offers a bounty a cash reward to Chinese 373 00:25:59,290 --> 00:26:03,372 scholars who happen to win the lottery and publish in cell nature science. 374 00:26:07,364 --> 00:26:10,918 This is the equivalent in China of thirty three 375 00:26:10,930 --> 00:26:14,422 thousand U.S. dollars personal spending money, 376 00:26:14,462 --> 00:26:18,535 just for the privilege of having published in these journals, irrespective 377 00:26:18,547 --> 00:26:22,141 of the content of the paper and journals of perceived lower rank, 378 00:26:22,181 --> 00:26:25,157 including the Proceedings of the National Academy of 379 00:26:25,169 --> 00:26:28,664 Sciences, are worth much less bounty for these investigators. 380 00:26:28,704 --> 00:26:32,167 This is a this is a distortion in the nature 381 00:26:32,179 --> 00:26:35,267 of scholarship, and it must be stopped. 382 00:26:35,307 --> 00:26:39,684 It really is. It leads to pathological behavior. 383 00:26:39,724 --> 00:26:43,983 Now, many of us are feeling strongly about this issue gathered 384 00:26:43,995 --> 00:26:47,724 together in San Francisco now about a dozen years ago. 385 00:26:48,532 --> 00:26:52,274 So to write a declaration called the Declaration of Research 386 00:26:52,286 --> 00:26:56,532 Assessment, you can find us online if you Google Dora San Francisco. 387 00:26:58,615 --> 00:27:02,687 And although there are many recommendations in this declaration, in this 388 00:27:02,699 --> 00:27:06,615 declaration, the big message is that scholars, academic institutions, 389 00:27:10,572 --> 00:27:14,472 department chairs, university administrators granting agencies and 390 00:27:14,484 --> 00:27:18,572 publishers should move away from the use of these misleading numbers, 391 00:27:19,354 --> 00:27:21,034 particularly impact factor. 392 00:27:21,074 --> 00:27:23,964 They should assess outputs on their own merits. 393 00:27:24,004 --> 00:27:28,640 For instance, maybe reading the paper to evaluate its importance. 394 00:27:28,680 --> 00:27:32,745 And there are always new tools that may be available to do this. 395 00:27:32,785 --> 00:27:36,224 There are now many more people who have this, people 396 00:27:36,236 --> 00:27:39,882 and individual institutions who have signed on to this. 397 00:27:39,922 --> 00:27:43,028 So it is a growing movement that continues. 398 00:27:43,068 --> 00:27:47,111 But nonetheless, in the face of this opposition, there are still journals 399 00:27:47,123 --> 00:27:51,068 that insist on measuring themselves by this mis measure of scholarship. 400 00:27:51,695 --> 00:27:54,175 The impact factor? 401 00:27:54,215 --> 00:27:58,147 Now, my own institution, the University of California, has conducted a 402 00:27:58,159 --> 00:28:02,215 long term battle with the major publishers Springer Nature and Elsevier, 403 00:28:05,513 --> 00:28:09,430 to force these commercial organizations to offer their 404 00:28:09,442 --> 00:28:13,513 recent the research that we scholars in the U.S. system, 405 00:28:14,511 --> 00:28:19,375 publish in their journals that ought to offer it free and open access format. 406 00:28:20,955 --> 00:28:25,349 I'm very proud of the librarians of our system for several years. 407 00:28:25,389 --> 00:28:29,900 We simply canceled our contract with Elsevier. Throughout the UC system. 408 00:28:29,940 --> 00:28:34,009 Scholars no longer had access to the many publications of elsewhere because 409 00:28:34,021 --> 00:28:37,940 Ellesmere was simply unwilling to cut into their enormous profit margin, 410 00:28:39,711 --> 00:28:42,514 and allow our scholars, constituting roughly 10 411 00:28:42,526 --> 00:28:45,692 percent of the scholarly output in the United States, 412 00:28:45,732 --> 00:28:49,864 to have their papers viewed in an open access format. 413 00:28:49,904 --> 00:28:56,747 Fortunately, this past year, a satisfactory contract has been rereleased, 414 00:28:56,787 --> 00:28:59,154 which will allow the university and 415 00:28:59,166 --> 00:29:02,272 individual investigators to share the expense, 416 00:29:02,312 --> 00:29:08,051 and to give the opportunity for this work to be published open access. 417 00:29:08,091 --> 00:29:09,662 So it is a battle. 418 00:29:09,702 --> 00:29:15,289 The Wellcome Trust in Britain has taken a very strong position on open access. 419 00:29:15,329 --> 00:29:18,791 Welcome Trust investigators throughout funded investigative 420 00:29:18,803 --> 00:29:21,525 throughout Britain are now obliged to publish, 421 00:29:21,565 --> 00:29:25,880 in the highest so-called gold standard open access publications. 422 00:29:25,920 --> 00:29:29,634 And this is a move that has taken root largely in Europe through an 423 00:29:29,646 --> 00:29:33,920 organization called Coalition S with a publication policy plan called Plan S, 424 00:29:36,946 --> 00:29:41,024 which calls for all funding agencies around the world to change and 425 00:29:41,036 --> 00:29:44,946 to require that their investigators, as the Wellcome Trust does, 426 00:29:45,776 --> 00:29:47,084 to publish an open access journal. 427 00:29:47,124 --> 00:29:50,417 So I think the tide is turning in favor of this 428 00:29:50,429 --> 00:29:53,802 more greater openness in scientific scholarship. 429 00:29:55,620 --> 00:29:59,178 There are many suggestions that I would like to 430 00:29:59,190 --> 00:30:03,354 consider to journals, the journal Lancet, for instance, 431 00:30:03,394 --> 00:30:09,510 took 12 years to publish a retraction of this dangerous Wakefield paper. 432 00:30:09,550 --> 00:30:12,520 I think journals like Lancet, like Nature, like 433 00:30:12,532 --> 00:30:15,266 Science, really need to own their mistakes. 434 00:30:15,306 --> 00:30:19,326 They need to be more open and provide space to authors wish to 435 00:30:19,338 --> 00:30:23,306 challenge the work that's been published in their page pages. 436 00:30:23,931 --> 00:30:26,826 These very selective journals are rather reluctant to 437 00:30:26,838 --> 00:30:29,799 do so because they don't like to admit their mistakes. 438 00:30:29,839 --> 00:30:33,261 The review process needs to be more open. 439 00:30:33,301 --> 00:30:37,529 There needs to be more collegial collaboration in a decision 440 00:30:37,541 --> 00:30:41,295 about whether a paper is worth worthy of publication. 441 00:30:41,335 --> 00:30:43,812 The comments of the reviewers should be 442 00:30:43,824 --> 00:30:46,873 made publicly available in an open access forum, 443 00:30:46,913 --> 00:30:49,660 so that readers can see what went on behind the 444 00:30:49,672 --> 00:30:52,834 behind the scenes in the decision to publish the work. 445 00:30:54,980 --> 00:30:57,978 There are also problems with how misconduct 446 00:30:57,990 --> 00:31:01,685 is investigated that I don't have time to talk about. 447 00:31:01,725 --> 00:31:05,396 Many now have post require that articles that have been 448 00:31:05,408 --> 00:31:08,959 submitted for publication be posted in open archives, 449 00:31:08,999 --> 00:31:10,914 and this has been true during the pandemic. 450 00:31:10,954 --> 00:31:14,048 A huge number of papers have been posted even before 451 00:31:14,060 --> 00:31:17,634 they've been peer reviewed and are available for all to see. 452 00:31:17,674 --> 00:31:21,693 And of course, most importantly, stop advertising this misleading 453 00:31:21,705 --> 00:31:25,674 number and use other evaluations for the measure of scholarship. 454 00:31:27,552 --> 00:31:31,571 Now I'd like to turn in the final portion of my talk to something 455 00:31:31,583 --> 00:31:35,552 of great interest around the world and a personal concern to me, 456 00:31:39,490 --> 00:31:44,577 neurodegenerative disease is on the rise. 457 00:31:44,617 --> 00:31:49,317 We will eventually control the pandemic, but as of this year, 458 00:31:49,357 --> 00:31:55,609 there still is little or no progress in arresting the inexorable development 459 00:31:55,649 --> 00:32:00,308 of such debilitating diseases as Alzheimer's and Parkinson's. 460 00:32:00,348 --> 00:32:04,339 They are rising in the incidence as the population 461 00:32:04,351 --> 00:32:07,961 ages and both diseases relate to these cells, 462 00:32:08,001 --> 00:32:11,675 the nerve cells in our brain, how they sustain 463 00:32:11,687 --> 00:32:16,001 themselves and how with damage of some unknown origin, 464 00:32:17,208 --> 00:32:21,760 they progressively die and lead to loss of cognitive function, 465 00:32:21,800 --> 00:32:24,576 or loss of control of movement characteristics 466 00:32:24,588 --> 00:32:27,317 of either Alzheimer's or Parkinson's disease. 467 00:32:28,889 --> 00:32:34,626 So the problem is enormously complex, it can be viewed as a huge puzzle. 468 00:32:34,666 --> 00:32:37,163 Much more complex than this image of the 469 00:32:37,175 --> 00:32:40,296 human brain deconstructed into pieces of a puzzle. 470 00:32:40,336 --> 00:32:48,240 The human brain has roughly 10 to 12 billion nerve cells. 471 00:32:48,280 --> 00:32:56,221 Each nerve cell can make up to 10000 connections to adjoining nerve cells, 472 00:32:56,261 --> 00:32:59,716 which leads to perhaps over a trillion 473 00:32:59,728 --> 00:33:04,261 possible synaptic connections in the entire brain. 474 00:33:04,934 --> 00:33:09,058 So this is a supercomputer at an enormous scale, all a process of evolution 475 00:33:09,070 --> 00:33:12,934 that's allowed us to be constructed as thinking, feeling human beings. 476 00:33:18,707 --> 00:33:23,367 And when a piece of this puzzle is removed, that can cause great damage. 477 00:33:23,407 --> 00:33:27,474 Now, reconstructing this puzzle is the challenge of trying to understand the 478 00:33:27,486 --> 00:33:31,407 molecular and cellular basis of a of these terrible progressive diseases, 479 00:33:35,857 --> 00:33:38,535 such as Alzheimer's and Parkinson's. 480 00:33:43,825 --> 00:33:45,640 My slide is not advancing. 481 00:33:48,836 --> 00:33:50,664 OK. 482 00:33:50,704 --> 00:33:51,814 Oops! 483 00:33:53,624 --> 00:33:57,159 Here is just a little bit of data that suggests 484 00:33:57,171 --> 00:34:00,939 where we stand in relation to Parkinson's disease. 485 00:34:00,979 --> 00:34:04,995 It is rising in incidence quite dramatically, even more rapidly than the 486 00:34:05,007 --> 00:34:08,979 increase in the prevalence of Alzheimer's disease in the next 10 years, 487 00:34:10,204 --> 00:34:13,229 it will be close to 20 million. 488 00:34:13,269 --> 00:34:17,761 Some fraction of the disease is attributable to genetic influences. 489 00:34:17,801 --> 00:34:21,983 There are now some 20 genes and perhaps as many as 100 different 490 00:34:21,995 --> 00:34:25,801 genetic loci that are found in familial forms the disease, 491 00:34:28,345 --> 00:34:31,821 where the disease appears, at least in part to be 492 00:34:31,833 --> 00:34:35,390 inherited, passed along from parents to the child. 493 00:34:35,430 --> 00:34:39,129 There are, of course, other possible origins 494 00:34:39,141 --> 00:34:43,430 having to do with industrial pollutants or smoking, 495 00:34:44,148 --> 00:34:49,212 or just the people living longer, and these things inevitably happening. 496 00:34:49,252 --> 00:34:53,548 Nonetheless, whatever, whatever the origin of the disease, it is progressing 497 00:34:53,560 --> 00:34:57,252 around the world that, like the pandemic, observes no boundaries. 498 00:34:57,393 --> 00:35:00,845 In the next 10 years, it's estimated that over half of 499 00:35:00,857 --> 00:35:04,572 the new cases of Parkinson's disease will emerge in China. 500 00:35:04,612 --> 00:35:08,678 So what we need is a massive increase in investment 501 00:35:08,690 --> 00:35:12,612 in trying to understand the basis of the disease. 502 00:35:15,329 --> 00:35:19,247 The disease was first recognized now 200 years ago, and 503 00:35:19,259 --> 00:35:23,329 yet in that two centuries, very little has been achieved. 504 00:35:25,773 --> 00:35:28,622 That changes the arc, the progression of the disease. 505 00:35:28,662 --> 00:35:31,680 There are palliative treatments, but they are. 506 00:35:31,720 --> 00:35:33,379 There are no cures. 507 00:35:33,419 --> 00:35:35,981 Now let me take a deep dove into the brain and then 508 00:35:35,993 --> 00:35:38,666 into individual nerve cells to tell you a little bit, 509 00:35:38,706 --> 00:35:43,777 about what we know about the most common aspect of Parkinson's disease. 510 00:35:43,817 --> 00:35:46,264 Parkinson's disease. 511 00:35:46,304 --> 00:35:50,261 At least a major portion of it is attributable to the death of 512 00:35:50,273 --> 00:35:54,304 cells in the mid brain that make the neurotransmitter dopamine. 513 00:35:57,052 --> 00:35:59,520 Dopamine is packaged into little vesicles, 514 00:35:59,532 --> 00:36:02,242 like I described in the first part of my talk. 515 00:36:02,282 --> 00:36:06,563 And it is these vesicles discharge dopamine 516 00:36:06,575 --> 00:36:10,282 to the space between two nerve cells, 517 00:36:10,397 --> 00:36:14,269 and the dopamine crosses the gap and activates the receptor on the 518 00:36:14,281 --> 00:36:18,397 other cell to turn that cell on and to continue to convey information. 519 00:36:18,584 --> 00:36:22,640 Now, most but not all, of the dopamine in the brain is made 520 00:36:22,652 --> 00:36:26,584 in a region of the mid brain called the substantia nigra. 521 00:36:27,195 --> 00:36:30,289 Those cells, some tens of thousands of them 522 00:36:30,301 --> 00:36:33,902 also produce a pigment melanin that we know of it. 523 00:36:33,942 --> 00:36:35,693 It's a skin pygmy pigmentation. 524 00:36:35,733 --> 00:36:39,661 But it also happens to be a product of the metabolism of dopamine 525 00:36:39,673 --> 00:36:43,733 and can be detected by a simple stain on sections of a human brain. 526 00:36:44,526 --> 00:36:48,125 In this case, the brain of someone who died for other reasons. 527 00:36:48,165 --> 00:36:51,251 The section was stained so as to reveal this melanin and 528 00:36:51,263 --> 00:36:54,307 and you can see this as a band in the mid brain region. 529 00:36:54,347 --> 00:37:01,229 Now, a patient who died of Parkinson's may have lost most of these cells. 530 00:37:01,269 --> 00:37:06,636 When a patient first presents, sometimes in as young as in their 20s. 531 00:37:06,676 --> 00:37:10,819 More often, patients present in their 70s. 532 00:37:10,859 --> 00:37:14,995 They present often with a tremor or a movement disorder. 533 00:37:15,035 --> 00:37:18,503 By the time the patient presents with the symptoms, it's 534 00:37:18,515 --> 00:37:22,178 estimated that maybe half of these cells have already died. 535 00:37:22,218 --> 00:37:26,120 And as the disease progresses and becomes more severe, more and more 536 00:37:26,132 --> 00:37:30,046 of these cells die by for reasons that we don't entirely understand. 537 00:37:30,086 --> 00:37:33,576 And here is a slice of the patient brain who succumb 538 00:37:33,588 --> 00:37:37,222 to Parkinson's, showing much of the standing gone now. 539 00:37:37,262 --> 00:37:41,383 About 100 years ago, a British clinician named Louis examined 540 00:37:41,395 --> 00:37:45,262 in the microscope the region of the brain from a patient, 541 00:37:47,696 --> 00:37:50,161 who has come from succumb to Parkinson's 542 00:37:50,173 --> 00:37:52,952 disease and noticed that the substantia nigra 543 00:37:52,992 --> 00:37:56,591 included many cells dopamine producing cells that also had 544 00:37:56,603 --> 00:38:00,213 inclusions inside the cell that looked more dark staining. 545 00:38:00,253 --> 00:38:04,374 We now know that these inclusions are a collection of various 546 00:38:04,386 --> 00:38:08,253 proteins and filaments and membranes aggregated proteins. 547 00:38:10,502 --> 00:38:17,438 One key protein in the Lewy body is a protein called alpha synuclein. 548 00:38:17,478 --> 00:38:21,587 This protein is itself one of the genes that, when 549 00:38:21,599 --> 00:38:25,478 mutated, causes a familial form of the disease. 550 00:38:25,876 --> 00:38:29,708 There are some patients who have a mutation in this gene that 551 00:38:29,720 --> 00:38:33,625 renders the alpha synuclein product more prone to aggregation, 552 00:38:33,665 --> 00:38:35,929 to be included in these Lewy bodies. 553 00:38:35,969 --> 00:38:39,987 Or there are patients who have three copies of this gene by a gene 554 00:38:39,999 --> 00:38:43,969 duplication event that results in a higher level of that protein, 555 00:38:44,203 --> 00:38:49,330 which also makes it more prone to aggregation and be able to see now. 556 00:38:49,370 --> 00:38:53,045 In a postmortem, these inconclusive they're called Lewy bodies. 557 00:38:53,085 --> 00:38:56,075 Unfortunately, there is no way to visualize 558 00:38:56,087 --> 00:38:59,226 Lewy bodies in the brain of a living patient. 559 00:38:59,266 --> 00:39:02,991 We desperately need a noninvasive stain that would allow 560 00:39:03,003 --> 00:39:06,740 us to detect these structures to mark their progression, 561 00:39:06,780 --> 00:39:09,564 during the march of this terrible disease. 562 00:39:09,604 --> 00:39:14,780 Now, subsequently, after the initial work of Louis, 563 00:39:14,820 --> 00:39:18,916 a German clinician by the name of Dr. Brock looked at many postmortem brain 564 00:39:18,928 --> 00:39:22,820 sections of patients who died of Parkinson's disease at various stages, 565 00:39:26,313 --> 00:39:30,381 and observed these Lewy bodies appear in the brain 566 00:39:30,393 --> 00:39:34,313 stem and as the disease progresses, he believes. 567 00:39:34,914 --> 00:39:37,793 Of course, this is by reconstruction, not by 568 00:39:37,805 --> 00:39:41,017 actual inspection, as the patient him or herself. 569 00:39:41,057 --> 00:39:44,985 Advances he observes that Lewy bodies in later stages referred to 570 00:39:44,997 --> 00:39:49,057 as Broch Stages three and four appear to be elsewhere in the brain, 571 00:39:52,005 --> 00:39:57,947 possibly by some kind of spread between the cells, the nerve cells of the brain. 572 00:39:57,987 --> 00:40:02,770 Eventually, they may appear throughout the brain in the cortex. 573 00:40:02,810 --> 00:40:05,843 They may cause other, more advanced aspects 574 00:40:05,855 --> 00:40:09,454 of the disease emotional and cognitive disturbance. 575 00:40:09,494 --> 00:40:12,600 It's estimated that about 30 percent of patients 576 00:40:12,612 --> 00:40:15,921 who suffer from Parkinson's progressed to dementia, 577 00:40:15,961 --> 00:40:20,649 a dementia that's different in pathology from that seen in Alzheimer's disease. 578 00:40:20,689 --> 00:40:24,071 But nonetheless, just it can be just as severe. 579 00:40:24,111 --> 00:40:27,152 And so these Lewy bodies then appear to be a marker 580 00:40:27,164 --> 00:40:30,099 of the disease, though that remains to be proven. 581 00:40:32,349 --> 00:40:36,091 Now it's possible to reproduce in the laboratory the build 582 00:40:36,103 --> 00:40:39,921 up of these aggregated proteins, including alpha synuclein. 583 00:40:39,961 --> 00:40:43,561 This is an image of a thin slice seeing a nerve cell that's 584 00:40:43,573 --> 00:40:46,945 been incubated in the laboratory for a couple of weeks, 585 00:40:46,985 --> 00:40:52,728 under conditions where a fibrous form of Elvis synuclein seeds, 586 00:40:52,768 --> 00:40:56,579 the accumulation of the structure which has been given a false color here, 587 00:40:56,619 --> 00:40:59,685 is seen in an image with a special microscopic 588 00:40:59,697 --> 00:41:02,448 technique called fluorescence microscopy, 589 00:41:02,488 --> 00:41:07,132 where you can see a discrete particle not not one that's enclosed within membranes, 590 00:41:07,172 --> 00:41:08,757 but includes, but does include 591 00:41:08,769 --> 00:41:11,165 membranes and filaments and other proteins. 592 00:41:11,205 --> 00:41:14,112 So given that we can replicate the 593 00:41:14,124 --> 00:41:17,961 production and build up of these Lewy bodies, 594 00:41:18,001 --> 00:41:21,598 it may be possible to use cells grown in the laboratory 595 00:41:21,610 --> 00:41:24,897 to investigate their influence on cell physiology, 596 00:41:24,937 --> 00:41:29,643 not having to rely on on an animal or on the human patient. 597 00:41:29,683 --> 00:41:32,017 These can be human cells grown in the laboratory. 598 00:41:34,223 --> 00:41:38,255 Now, let me tell you, near the end of what we 599 00:41:38,267 --> 00:41:42,223 know about two other aspects genetic aspects 600 00:41:43,804 --> 00:41:51,097 that come from different genes that have been identified in some families 601 00:41:51,137 --> 00:41:54,695 that have a familial form of Parkinson's disease. 602 00:41:54,735 --> 00:41:57,832 I told you about the first one that's alpha synuclein that 603 00:41:57,844 --> 00:42:01,006 affects the viability of cells that are secreting dopamine. 604 00:42:01,046 --> 00:42:02,835 But there are many other genes, and 605 00:42:02,847 --> 00:42:05,198 each one has a different story associated with 606 00:42:05,238 --> 00:42:11,923 I'm going to tell you about one now that affects the ability of cells, 607 00:42:11,963 --> 00:42:14,965 to control the health of a very important 608 00:42:14,977 --> 00:42:18,421 organelles in the cell called the mitochondria. 609 00:42:18,461 --> 00:42:23,423 So this is a electron microscope image of the mitochondria. 610 00:42:23,463 --> 00:42:25,616 It's the powerhouse of the cell. 611 00:42:25,656 --> 00:42:30,779 It's the organelles that makes the energy currency of the cell called ATP. 612 00:42:30,819 --> 00:42:33,905 And it is highly elaborate in its mechanism. 613 00:42:33,945 --> 00:42:38,073 We don't have time to discuss this, but the mitochondria and unlike other 614 00:42:38,085 --> 00:42:41,945 organelles in a cell, even has its own DNA molecule, its own genome. 615 00:42:43,509 --> 00:42:47,468 That genome has to be housed protected within the mitochondria 616 00:42:47,480 --> 00:42:51,009 if it escapes from the mitochondria and for any reason, 617 00:42:51,049 --> 00:42:54,199 the Cell C's DNA in the cytoplasm. 618 00:42:54,239 --> 00:42:59,906 And that sets in train a series of steps that leads the cells to kill itself. 619 00:42:59,946 --> 00:43:04,016 Because DNA in the cytoplasm is an indication that something has gone very 620 00:43:04,028 --> 00:43:07,946 wrong and the cell needed to kill itself before other damage can occur. 621 00:43:11,795 --> 00:43:17,729 So this is a cartoon of the structure of the envelope of the mitochondria. 622 00:43:17,769 --> 00:43:22,077 The details of this are not necessarily important. 623 00:43:22,117 --> 00:43:26,274 This is a fluorescence image of a cell. 624 00:43:26,314 --> 00:43:30,273 This is the nucleus of the cell, and the mitochondria form a kind of 625 00:43:30,285 --> 00:43:34,314 a particular network different from the air that I described earlier. 626 00:43:34,834 --> 00:43:38,633 But each individual mitochondria can be highlighted 627 00:43:38,645 --> 00:43:42,603 and shown to contain its own chromosome DNA molecule, 628 00:43:42,643 --> 00:43:45,911 quite distinct from that found in the nucleus of the cell. 629 00:43:48,986 --> 00:43:52,940 Now, when a cell senses that some damage has occurred and 630 00:43:52,952 --> 00:43:56,986 the mitochondria can no longer contain DNA or oxygen free, 631 00:44:02,655 --> 00:44:08,071 free radicals of oxygen that are generated during the production of ATP, 632 00:44:08,111 --> 00:44:12,432 the cell has evolved a means of capturing and destroying damaged mitochondria 633 00:44:12,444 --> 00:44:16,111 and other damaged organelles, and this is depicted in this slide. 634 00:44:19,022 --> 00:44:23,038 It's a process that involves the formation of a membrane that surrounds 635 00:44:23,050 --> 00:44:27,022 the damaged organelles, a membrane that then merges with the lysosome. 636 00:44:30,431 --> 00:44:34,577 Remember, I told you the lysosome is a is kind of the stomach of the cell. 637 00:44:34,617 --> 00:44:40,174 It has the gist of enzymes that will chew up anything that is delivered to it. 638 00:44:40,214 --> 00:44:43,319 And so after some time, these damaged mitochondria, 639 00:44:43,331 --> 00:44:45,789 including their DNA and their membranes, 640 00:44:45,829 --> 00:44:49,900 are just completely destroyed down to the nucleotides and amino acids and 641 00:44:49,912 --> 00:44:53,829 sugars and these individual components and can be reused in the cells. 642 00:44:55,407 --> 00:45:01,280 This is a very important process called autophagy or selectively for mitochondria. 643 00:45:01,320 --> 00:45:03,758 It's called mitophagy. 644 00:45:03,798 --> 00:45:05,766 Now, why am I telling you this? 645 00:45:05,806 --> 00:45:09,681 It's important because two genes that have been discovered in recent 646 00:45:09,693 --> 00:45:13,806 years in familial forms of Parkinson's affect the machinery in the cell, 647 00:45:16,708 --> 00:45:20,815 that is required to recognize when a mitochondria has become damaged 648 00:45:20,827 --> 00:45:24,708 and to cause it to become engulfed and degraded in the lysosome. 649 00:45:27,886 --> 00:45:31,165 These jeans are called pink one and parkyn, it 650 00:45:31,177 --> 00:45:35,029 doesn't matter what these jeans do for the time being. 651 00:45:35,069 --> 00:45:38,719 Let me just tell you that it's part of what is has a 652 00:45:38,731 --> 00:45:42,117 general term called a quality control mechanism. 653 00:45:42,157 --> 00:45:46,057 The quality control mechanism consists of a sensor that recognizes 654 00:45:46,069 --> 00:45:50,157 if the mitochondrion has lost some important aspect of its integrity, 655 00:45:55,687 --> 00:45:59,702 and once recognized the damaged mitochondria and is given a little protein 656 00:45:59,714 --> 00:46:03,687 or fragment of a protein tag, a tag of a protein that's called ubiquitin. 657 00:46:07,826 --> 00:46:09,359 So it's a little tag. 658 00:46:09,399 --> 00:46:13,197 It's basically a special code that says this is now damaged 659 00:46:13,209 --> 00:46:17,399 material and it should be engulfed and destroyed in the lysosome. 660 00:46:20,333 --> 00:46:25,037 So tags are given then to damaged, but not to healthy mitochondria. 661 00:46:25,077 --> 00:46:26,854 These tags are recognized. 662 00:46:26,894 --> 00:46:29,316 They then become allow the organelles to become 663 00:46:29,328 --> 00:46:31,761 enveloped and destroyed in the in the lysosome. 664 00:46:34,472 --> 00:46:39,694 Now, so that's two genes of some fraction of patients. 665 00:46:39,734 --> 00:46:43,213 So a genetic disease of Parkinson's. 666 00:46:43,253 --> 00:46:50,088 And there are now ongoing efforts to try to control this process. 667 00:46:50,128 --> 00:46:54,670 Oh, let me actually go back to this. 668 00:46:54,710 --> 00:46:58,831 I forgot to give the punch line, of course, patients who lack 669 00:46:58,843 --> 00:47:02,710 pink one or parkin now fail to mark damaged mitochondria. 670 00:47:06,518 --> 00:47:10,976 These damaged mitochondria then persist in the cell, 671 00:47:11,016 --> 00:47:15,043 and the cells eventually accumulate so much damaged 672 00:47:15,055 --> 00:47:19,016 material that they die of other natural processes. 673 00:47:20,862 --> 00:47:23,585 So ordinarily, this would be taken care of would 674 00:47:23,597 --> 00:47:26,276 be part of the housekeeping function of a cell. 675 00:47:26,316 --> 00:47:29,754 The cell could survive because the damaged mitochondria are disposed of. 676 00:47:29,794 --> 00:47:33,214 But when you fail to recognize these damaged mitochondria 677 00:47:33,226 --> 00:47:36,184 that ultimately results in the death of the cell, 678 00:47:36,224 --> 00:47:39,222 and as a result, these patients who have 679 00:47:39,234 --> 00:47:42,684 these mutations lose progressively many cells. 680 00:47:42,724 --> 00:47:45,938 But most importantly, they lose those cells in 681 00:47:45,950 --> 00:47:49,450 the brain that make the neurotransmitter dopamine. 682 00:47:49,490 --> 00:47:52,977 Now, let me to conclude turn to another 683 00:47:52,989 --> 00:47:57,362 gene that is understood it now a molecular level. 684 00:47:57,402 --> 00:48:00,751 It's a different gene that turns up in many patients 685 00:48:00,763 --> 00:48:03,871 who have Parkinson's disease with familial form. 686 00:48:03,911 --> 00:48:07,759 It's a gene called Il R K two or look to for short and 687 00:48:07,771 --> 00:48:11,911 some very interesting recent experiments have illuminated, 688 00:48:14,762 --> 00:48:22,142 how Lark two may control the viability the survival of doping neurons. 689 00:48:22,182 --> 00:48:26,363 Lark two is an enzyme that modifies another protein, and this other protein 690 00:48:26,375 --> 00:48:30,182 is required in various avenues of membrane traffic within the cells. 691 00:48:34,555 --> 00:48:38,451 It's a kind of a molecular tag this other protein that allows a 692 00:48:38,463 --> 00:48:42,555 protein to move within a vesicle from one compartment to the next. 693 00:48:43,745 --> 00:48:47,316 And so it's a normal part of normal cell function. 694 00:48:47,356 --> 00:48:51,313 Now, patients who have the most common mutations in the last two 695 00:48:51,325 --> 00:48:55,356 gene produce this enzyme that has even more activity than normal. 696 00:48:59,778 --> 00:49:01,512 It's a kind of an unusual situation. 697 00:49:01,552 --> 00:49:03,906 Mutations most often cause a protein to 698 00:49:03,918 --> 00:49:06,579 be less active and enzyme to be less active. 699 00:49:06,619 --> 00:49:10,663 But in this case, these mutations actually make the enzyme the last two 700 00:49:10,675 --> 00:49:14,619 enzyme more active, and it more actively modifies its target protein. 701 00:49:17,305 --> 00:49:20,492 And as a result, that target protein loses its 702 00:49:20,504 --> 00:49:23,499 normal function because it's over modified. 703 00:49:23,539 --> 00:49:27,410 One of the functions of this normal protein is to 704 00:49:27,422 --> 00:49:31,539 allow cells in the brain to make a little appendage, 705 00:49:33,012 --> 00:49:37,610 a little membrane appendage on the surface of the cell called a psyllium. 706 00:49:37,650 --> 00:49:41,600 Many cells have a psyllium that serves as a kind of 707 00:49:41,612 --> 00:49:45,650 an antenna as an antenna on the surface of the cell, 708 00:49:47,465 --> 00:49:52,609 that is open for the receipt of signals from other cells. 709 00:49:52,649 --> 00:49:56,144 One of the signaling pathways that operates between 710 00:49:56,156 --> 00:50:00,001 cells as a funny name, it's called the hedgehog pathway. 711 00:50:00,041 --> 00:50:03,625 And when the target of LARC two is over 712 00:50:03,637 --> 00:50:08,041 modified, those cells fail to make the psyllium. 713 00:50:11,356 --> 00:50:15,140 They thus fail to have an antenna that would allow this hedgehog 714 00:50:15,152 --> 00:50:19,356 signaling pathway that actually comes from the dopamine neurons itself. 715 00:50:23,155 --> 00:50:28,079 This pathway fails to deliver this signal. 716 00:50:28,119 --> 00:50:30,993 The response is not received. 717 00:50:31,033 --> 00:50:34,968 The dopamine cells then suffer because this signaling pathway is required 718 00:50:34,980 --> 00:50:39,033 for the target cell to make a growth factor that sustains dopamine neurons. 719 00:50:45,649 --> 00:50:49,611 A growth factor called GDNF is manufactured by these target cells and will 720 00:50:49,623 --> 00:50:53,649 only do so when this signaling pathway elicits a response from the ceiling. 721 00:50:57,154 --> 00:51:01,105 But when the psyllium gone, this process is arrested 722 00:51:01,117 --> 00:51:05,154 in the absence of GDNF in these Parkinson's patients. 723 00:51:05,846 --> 00:51:10,632 The dopamine neurons fail to be nourished, and they die. 724 00:51:10,672 --> 00:51:14,842 So this is a model of yet another independent 725 00:51:14,854 --> 00:51:18,672 means by which dopamine neurons may fail. 726 00:51:19,273 --> 00:51:23,645 Now, let me tell you about my involvement in this process. 727 00:51:26,227 --> 00:51:30,077 Several years ago, after a long period of suffering, my 728 00:51:30,089 --> 00:51:34,227 wife, who had Parkinson's disease, died now four years ago, 729 00:51:34,586 --> 00:51:36,827 and at the time I was approached by a 730 00:51:36,839 --> 00:51:39,923 representative of the Sergey Brin Family Foundation 731 00:51:39,963 --> 00:51:43,923 to consider organizing an international collaborative research effort 732 00:51:43,935 --> 00:51:47,963 to understand the molecular and cellular basis of Parkinson's disease. 733 00:51:51,819 --> 00:51:55,484 We were given an enormous philanthropic donation, and we 734 00:51:55,496 --> 00:51:59,044 decided to team up with the Michael J. Fox Foundation, 735 00:51:59,084 --> 00:52:02,820 which is the major philanthropic organization that looks to 736 00:52:02,832 --> 00:52:06,579 patients around the country and certainly around the world. 737 00:52:08,520 --> 00:52:12,161 That the donor in this case felt that in spite of all 738 00:52:12,173 --> 00:52:15,555 of the important clinical work that was going on, 739 00:52:15,595 --> 00:52:19,123 we still, after all this time didn't really have a clear 740 00:52:19,135 --> 00:52:22,861 picture of the molecular and cellular basis of the disease, 741 00:52:22,901 --> 00:52:25,498 unlike the few examples that I've just given you. 742 00:52:25,538 --> 00:52:30,982 Most forms of Parkinson's cannot be explained as I've just done so. 743 00:52:31,022 --> 00:52:37,738 Together with the team, we have decided to create a funding initiative. 744 00:52:37,778 --> 00:52:39,134 And we've done so now. 745 00:52:39,174 --> 00:52:41,951 Over the course of two years, we've identified 746 00:52:41,963 --> 00:52:45,168 teams of investigators, not individual investigators. 747 00:52:45,208 --> 00:52:48,250 We feel that people really on a problem like Parkinson's. 748 00:52:48,290 --> 00:52:52,075 We feel that people really need to get together to work 749 00:52:52,087 --> 00:52:56,290 collaboratively to try to tackle this, this terrible disease. 750 00:52:57,175 --> 00:53:00,389 So here are the pillars of our effort. 751 00:53:00,429 --> 00:53:03,614 We've decided to focus on four themes the 752 00:53:03,626 --> 00:53:07,280 genetics and associated biology of the disease. 753 00:53:07,320 --> 00:53:14,710 We know that there are, as I said, 20 different genes and probably more loci. 754 00:53:14,750 --> 00:53:17,939 We think there's a great deal to be learned of the sort that I've just 755 00:53:17,951 --> 00:53:21,197 described about the individual genes and how they affect the viability, 756 00:53:21,237 --> 00:53:23,466 the survival of dopaminergic neurons. 757 00:53:23,506 --> 00:53:25,774 So this continues to be a major theme. 758 00:53:25,814 --> 00:53:29,433 We also estimate that there is an impact of the immune system, 759 00:53:29,473 --> 00:53:34,492 both the immune cells of the brain and the body's immune responses 760 00:53:34,532 --> 00:53:41,276 that may initiate or perhaps exacerbate the progression of damaged neurons. 761 00:53:41,316 --> 00:53:45,607 There's evidence that lesions in the brain associated with Alzheimer's 762 00:53:45,619 --> 00:53:49,316 and Parkinson's may be inflamed by an innate immune process. 763 00:53:50,706 --> 00:53:53,391 And we really don't understand that and need to work on that. 764 00:53:53,431 --> 00:53:55,123 So that's another area. 765 00:53:55,163 --> 00:53:57,657 A third area is just the circuitry. 766 00:53:57,697 --> 00:53:59,165 The dopaminergic neuron. 767 00:53:59,205 --> 00:54:01,995 The neuron that makes dopamine is the most common 768 00:54:02,007 --> 00:54:04,809 one of the most complex nerve cells in the brain. 769 00:54:04,849 --> 00:54:07,203 It's enormously extended. 770 00:54:07,243 --> 00:54:11,764 It makes many different connections to different regions of the brain, 771 00:54:11,804 --> 00:54:15,563 and we have yet to understand the circuitry of all the cells that 772 00:54:15,575 --> 00:54:19,804 interact with the dopamine secreting neuron just in the normal situation. 773 00:54:20,933 --> 00:54:24,613 And we we feel that knowing that will help us further 774 00:54:24,625 --> 00:54:28,933 understand Parkinson's that leads to the death of these cells. 775 00:54:29,974 --> 00:54:33,705 And finally, the most mysterious kind of series of 776 00:54:33,717 --> 00:54:37,974 syndrome precede the eventual development of the disease. 777 00:54:40,671 --> 00:54:44,401 It's called the prodromal period that can appear 778 00:54:44,413 --> 00:54:48,384 20 years before the onset of the movement disorder. 779 00:54:48,424 --> 00:54:50,300 There are certain. 780 00:54:50,340 --> 00:54:54,608 Simple characteristics of patients who eventually progressed to Parkinson's, 781 00:54:54,648 --> 00:54:58,583 sometimes they very often they report having a poorly developed sense of smell. 782 00:54:58,623 --> 00:55:00,963 Often they have problems with constipation. 783 00:55:01,003 --> 00:55:05,974 Obviously, these are not key indicators of just Parkinson's, they are more common. 784 00:55:06,014 --> 00:55:08,683 But patients who present eventually with 785 00:55:08,695 --> 00:55:12,161 Parkinson's often have these symptoms years earlier, 786 00:55:12,201 --> 00:55:16,153 and one that is a more clear indication of progression 787 00:55:16,165 --> 00:55:20,201 of disease as a syndrome called R.E.M. sleep disorders. 788 00:55:21,482 --> 00:55:25,339 Patients who have REM sleep disorder lose their ability to 789 00:55:25,351 --> 00:55:29,482 discriminate their nightmares or dreams from wakeful thoughts. 790 00:55:30,830 --> 00:55:36,478 They often live out nightmares in their sleep, flailing around in bed, 791 00:55:36,518 --> 00:55:39,525 sometimes throwing themselves off of the bed onto the 792 00:55:39,537 --> 00:55:42,556 floor or harming themselves or harming their partner. 793 00:55:42,596 --> 00:55:46,341 It's a quite frightening syndrome that's poorly understood, 794 00:55:46,381 --> 00:55:48,681 and what is most distressing about it is that 795 00:55:48,693 --> 00:55:51,004 within five or 10 years, 80 percent of people 796 00:55:51,044 --> 00:55:55,091 who present with REM sleep disorder do progressed to Parkinson's. 797 00:55:55,131 --> 00:55:59,038 So we're really keen to have a cohort of patients who have such symptoms 798 00:55:59,050 --> 00:56:03,131 that could then be used to try to investigate where the disease originates. 799 00:56:09,367 --> 00:56:13,310 And finally, finally, let me tell you where 800 00:56:13,322 --> 00:56:17,367 we stand in the course of identifying teams. 801 00:56:17,560 --> 00:56:21,716 We started last year with a selection of 15 teams. 802 00:56:21,756 --> 00:56:25,380 We selected these teams because they contain. 803 00:56:25,420 --> 00:56:29,339 They have assembled four or five principal investigators 804 00:56:29,351 --> 00:56:33,420 in laboratories, either at one in one or two institutions. 805 00:56:33,674 --> 00:56:36,913 These investigators, we we we preferred investigators 806 00:56:36,925 --> 00:56:40,056 who'd already had some experience in collaboration. 807 00:56:40,096 --> 00:56:43,425 It's very important to understand how you can interact with 808 00:56:43,437 --> 00:56:46,890 other scientists, it's not normal, most scientists act alone, 809 00:56:46,930 --> 00:56:50,444 but many collaborate, and we favored people who had already demonstrated 810 00:56:50,456 --> 00:56:53,789 a facility to engage in the give and take of a collaborative effort. 811 00:56:53,829 --> 00:56:56,838 We look for those teams that showed that kind of 812 00:56:56,850 --> 00:57:00,488 interaction that showed a willingness to share new results 813 00:57:00,528 --> 00:57:04,731 even before publication to post their work on an archive, 814 00:57:04,771 --> 00:57:07,616 as it's ready to be published and then to publish 815 00:57:07,628 --> 00:57:10,427 in open access journals, as I described earlier. 816 00:57:10,467 --> 00:57:14,612 We selected 15 teams consisting of about 100 different individual 817 00:57:14,624 --> 00:57:18,467 investigators in 60 different institutions and 11 countries. 818 00:57:18,982 --> 00:57:23,201 We've just concluded another competition for slightly different 819 00:57:23,213 --> 00:57:26,982 topics within the four that we that I've just mentioned, 820 00:57:29,291 --> 00:57:33,802 and we've identified another 16 or so teams, 821 00:57:33,842 --> 00:57:37,897 that find 15 teams that will join so that we now have thirty 822 00:57:37,909 --> 00:57:41,842 six teams of around one and fifty different investigators. 823 00:57:43,213 --> 00:57:47,370 These people have been integrated into an online network and are expected 824 00:57:47,382 --> 00:57:51,213 not merely to share their results with other members of their team, 825 00:57:52,620 --> 00:57:56,020 but also to communicate on a regular basis with 826 00:57:56,032 --> 00:57:59,515 other teams with who have overlapping interests. 827 00:57:59,555 --> 00:58:02,111 So we've created this network. 828 00:58:02,151 --> 00:58:05,667 We were going to do this even before the pandemic, but it's 829 00:58:05,679 --> 00:58:08,972 worked out perfectly well to do so during the pandemic. 830 00:58:09,012 --> 00:58:13,331 We will have our first in-person meeting of the principal investigators 831 00:58:13,343 --> 00:58:17,012 next year, but thus far this network has become very active. 832 00:58:18,126 --> 00:58:20,796 Groups are expected to present their work 833 00:58:20,808 --> 00:58:24,001 in an online forum in front of other individuals, 834 00:58:24,041 --> 00:58:28,257 and they are expected to talk about new data and not just publish data. 835 00:58:28,297 --> 00:58:31,773 So we're very hopeful that through this 836 00:58:31,785 --> 00:58:36,058 kind of living network organism of interactions, 837 00:58:36,098 --> 00:58:39,145 we will bring to bear one hundred and fifty 838 00:58:39,157 --> 00:58:42,495 six of the finest laboratories around the world 839 00:58:42,535 --> 00:58:46,523 to challenge the devastation of this disease, and the plan is 840 00:58:46,535 --> 00:58:50,535 to carry on for 10 years and to assess our progress thus far. 841 00:58:55,542 --> 00:58:58,152 We've committed of almost a half a billion 842 00:58:58,164 --> 00:59:00,785 dollars to the teams that we've assembled. 843 00:59:00,825 --> 00:59:02,766 And there's more where that came from. 844 00:59:02,806 --> 00:59:04,466 So we're very hopeful. 845 00:59:04,506 --> 00:59:11,566 We feel this is going to be more effective than just funding individual scientists. 846 00:59:11,606 --> 00:59:14,116 So I'd be happy to discuss this with you if 847 00:59:14,128 --> 00:59:16,593 you have questions after the presentation. 848 00:59:16,633 --> 00:59:17,800 Thank you for your attention. 849 00:59:20,648 --> 00:59:24,228 Randy, thank you very much for that. Absolutely fascinating. 850 00:59:24,268 --> 00:59:28,014 And as a non-scientist, clear and informative presentation, 851 00:59:28,054 --> 00:59:31,394 I'm sure all of us here wish you and your team 852 00:59:31,406 --> 00:59:34,830 and your colleagues every success in that park, 853 00:59:34,870 --> 00:59:37,048 to know that I can't think of a family 854 00:59:37,060 --> 00:59:39,811 where it doesn't, it isn't infected in some way. 855 00:59:39,851 --> 00:59:41,237 And this is the global conference. 856 00:59:41,277 --> 00:59:47,208 So it's going to be seen by researchers are all around the world with your... 857 00:59:47,248 --> 00:59:49,820 I'm going to we haven't got time for questions, and they're all 858 00:59:49,832 --> 00:59:52,295 going to be lots of questions which will forward answer you. 859 00:59:52,335 --> 00:59:54,673 But I'm going to have moderator's privilege 860 00:59:54,685 --> 00:59:57,035 just for a second and ask you one question, 861 00:59:57,075 --> 01:00:02,552 and that is with your if it's possible with your with your crystal ball, 862 01:00:02,592 --> 01:00:06,850 how long do you think it's going to be before we have the diagnostic tools, 863 01:00:06,890 --> 01:00:11,449 in place to be able to identify Parkinson's 864 01:00:11,461 --> 01:00:14,890 symptoms and and treat it early? 865 01:00:15,771 --> 01:00:17,311 Yeah. Right. 866 01:00:17,351 --> 01:00:21,100 Well, even if we could find a diagnostic molecule, the 867 01:00:21,112 --> 01:00:25,351 progression of disease, there's still no effective treatment. 868 01:00:26,213 --> 01:00:28,175 So, you know, with cancer and 869 01:00:28,187 --> 01:00:31,249 heart disease, it's best to catch it early. 870 01:00:31,289 --> 01:00:34,475 But with Parkinson's or Alzheimer's, you 871 01:00:34,487 --> 01:00:38,309 know, there's so far no meaningful intervention. 872 01:00:38,349 --> 01:00:41,588 So, but still, it is important to have a marker. 873 01:00:41,628 --> 01:00:45,961 See what the problem with one of the problems with Parkinson's 874 01:00:45,973 --> 01:00:49,628 is that the disease appears with different symptoms, 875 01:00:50,457 --> 01:00:54,923 and then it progresses in different ways, depending on the patient. 876 01:00:54,963 --> 01:00:58,833 And so a clinician, a neurologist, is faced with a dilemma how to 877 01:00:58,845 --> 01:01:02,963 advise patients and their families what to expect in the years ahead. 878 01:01:03,407 --> 01:01:06,264 I found this the most frustrating aspect of the disease myself. 879 01:01:06,304 --> 01:01:11,892 In dealing with my wife, I had access to some of the world's best neurologists. 880 01:01:11,932 --> 01:01:17,061 She had developed dementia, a form of dementia called diffuse Lewy body disease, 881 01:01:17,101 --> 01:01:19,165 because it was based just on her 882 01:01:19,177 --> 01:01:22,292 behavior, not on a biopsy of her brain tissue. 883 01:01:22,332 --> 01:01:24,481 And I asked every time, What what 884 01:01:24,493 --> 01:01:27,290 can I look forward to? Where is this going? 885 01:01:27,330 --> 01:01:31,039 And they would all have answers, but they were always wrong. 886 01:01:31,079 --> 01:01:33,491 They were always wrong. 887 01:01:33,531 --> 01:01:37,321 We had developments that that no one could have predicted. 888 01:01:37,361 --> 01:01:41,273 And eventually she died in the middle of the night, likely of a heart attack. 889 01:01:41,313 --> 01:01:43,910 So no one had told me that this was one of the 890 01:01:43,922 --> 01:01:46,475 consequences, not that I could have prepared. 891 01:01:46,515 --> 01:01:49,033 So this is, of course, tragic and enormously 892 01:01:49,045 --> 01:01:51,574 frustrating for patients and their families. 893 01:01:51,614 --> 01:01:53,972 But I can understand your passion for wanting to contribute. 894 01:01:54,012 --> 01:01:55,578 Also activates will do so. 895 01:01:55,618 --> 01:01:58,090 Let me let me tell you one thing that we are 896 01:01:58,102 --> 01:02:00,696 doing if not to intervene therapeutically yet, 897 01:02:00,736 --> 01:02:05,051 but at least have a basis to help patients prepare. 898 01:02:05,091 --> 01:02:08,392 We fund an organization called PMI. 899 01:02:08,432 --> 01:02:11,704 It's Parkinson's Progression Monitoring Index, 900 01:02:11,716 --> 01:02:15,349 and this is a clinical group that is assembled now. 901 01:02:15,389 --> 01:02:19,189 Thousands of patients with different genetic or non-drug forms, 902 01:02:19,229 --> 01:02:22,825 including these prodromal patients who have REM sleep disorder. 903 01:02:22,865 --> 01:02:27,054 and they are collecting these patients have committed to providing not only DNA, 904 01:02:27,094 --> 01:02:35,094 but tissue blood samples, urine, spinal taps and all this material is collected, 905 01:02:35,262 --> 01:02:38,965 stored and made available to investigators to qualified investigators. 906 01:02:39,005 --> 01:02:43,131 And as a result of this collection, there is 907 01:02:43,143 --> 01:02:47,005 now one promising preclinical diagnostic, 908 01:02:47,753 --> 01:02:49,959 which is not yet commercially available, 909 01:02:49,999 --> 01:02:53,529 and that relates to this protein synuclein that I mentioned. 910 01:02:53,569 --> 01:02:59,344 This protein can be detected in the Spinal Tap fluid. 911 01:02:59,384 --> 01:03:03,290 The protein itself doesn't appear to change in its abundance during the 912 01:03:03,302 --> 01:03:07,384 progression of the disease, but the form of the protein appears to change. 913 01:03:08,295 --> 01:03:12,000 The form that appears to increase is the form that is more 914 01:03:12,012 --> 01:03:16,295 aggregation prone, which is what constitutes the core of Lewy body. 915 01:03:16,716 --> 01:03:22,020 This needs to be turned into a routine clinical assay that can be done in a lab, 916 01:03:22,060 --> 01:03:28,416 a lab that's not equipped with necessarily with an electron microscope. 917 01:03:28,456 --> 01:03:32,284 Anyway, that's that's a hopeful development that will allow 918 01:03:32,296 --> 01:03:36,456 patients at least to have some knowledge and perhaps to prepare. 919 01:03:38,015 --> 01:03:40,879 The most important thing is to proceed with 920 01:03:40,891 --> 01:03:44,224 these molecular clues that we have from the genes. 921 01:03:44,264 --> 01:03:48,466 And there are a number of biotech companies that have very promising 922 01:03:48,478 --> 01:03:52,264 approaches to target synuclein and its aggregation character. 923 01:03:54,295 --> 01:03:58,121 There's a drug that's being tested now in phase one clinical trials on 924 01:03:58,133 --> 01:04:02,295 human patients that reduces the aggregation prone character of of synuclein. 925 01:04:05,416 --> 01:04:09,254 And so maybe that will help mitigate the progression of the disease. 926 01:04:09,294 --> 01:04:13,131 There are there are two different drug development 927 01:04:13,143 --> 01:04:17,294 efforts underway to target this gene, called LARC two. 928 01:04:17,807 --> 01:04:22,560 I told you that mutations in that gene actually make the enzyme more active. 929 01:04:22,600 --> 01:04:26,089 And so you can look for inhibitors that dampen that activity, 930 01:04:26,129 --> 01:04:29,440 or you can look for drugs that affect its 931 01:04:29,452 --> 01:04:33,249 ability to target to change the target protein, 932 01:04:33,289 --> 01:04:36,100 that we think may be involved in the production of cilia. 933 01:04:36,140 --> 01:04:39,020 So, there are leads that come from the 934 01:04:39,032 --> 01:04:42,889 genes, but that that's only the tip of the iceberg. 935 01:04:42,929 --> 01:04:46,917 You know, there are still many other genes that cause the disease, and 936 01:04:46,929 --> 01:04:50,929 there are many patients who have no parents genetic indication at all. 937 01:04:51,467 --> 01:04:53,265 That sounds like it's going to give you and your 938 01:04:53,277 --> 01:04:55,197 first scientists busy for many, many years to come. 939 01:04:55,237 --> 01:04:56,447 Yeah. 940 01:04:56,487 --> 01:04:58,250 So better all signs. 941 01:04:58,290 --> 01:05:00,542 But but it's a great challenge. Great. 942 01:05:00,582 --> 01:05:02,992 Randi, thank you very much again for this inspiring, inspiring thing. 943 01:05:03,032 --> 01:05:07,389 Keynote and thank you again for addressing the key to the future audience. 944 01:05:07,429 --> 01:05:10,446 As I mentioned earlier, we're going to be collecting questions. 945 01:05:10,486 --> 01:05:13,042 There'll be lots of questions which will forward to you, 946 01:05:13,082 --> 01:05:16,162 and those responses will be published in the U.S.A. future 947 01:05:16,174 --> 01:05:19,161 official report would be published after the conference. 948 01:05:19,201 --> 01:05:22,403 Again, thank you for your time and good luck. 949 01:05:22,443 --> 01:05:25,068 And please join us in a few moment, few 950 01:05:25,080 --> 01:05:28,640 minutes for the next presentation and say the future.91685

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