1 00:00:00,000 --> 00:00:09,328 *rc3 preroll music* 2 00:00:09,328 --> 00:00:15,120 Herald: Welcome back in Halle with Chaos Zone TV, the next talk, will have 3 00:00:15,120 --> 00:00:20,080 interactive elements, so here are the hashtags again. We're on Mastodon with 4 00:00:20,800 --> 00:00:29,840 @Twitter with the hashtag RC3 Chaos Zone and on the IRC channel in Heckint and 5 00:00:29,840 --> 00:00:40,358 which is RC3 Dash Chaos Zone. All right. Lisette will now speak to us with a talk called 6 00:00:40,358 --> 00:00:46,733 "What the Health Beyond Genome Sequencing". Since the 80s, the Human 7 00:00:46,733 --> 00:00:52,988 Genome Project set goals to technical and ethical goals to understand the human 8 00:00:52,988 --> 00:00:58,880 genome. In recent years, these goals have been achieved, and humanity could profit 9 00:00:58,880 --> 00:01:06,160 immensely from what the sciences and the technology the methods could be developed 10 00:01:06,160 --> 00:01:13,318 through the project. Lisette works at the bleeding edge of what it is now a hard 11 00:01:13,318 --> 00:01:18,587 data science. We are very excited to hear about the considerations and the 12 00:01:18,587 --> 00:01:22,024 practicalities of advancing the biology even further. 13 00:01:22,024 --> 00:01:32,640 Lisette: OK. Yeah, thank you very much for the introduction. It's my pleasure to give 14 00:01:32,640 --> 00:01:37,600 some insights into what I've learned throughout my studies and what I'm now 15 00:01:37,600 --> 00:01:44,080 actually also working on. So thank you for providing me this slot. I was a little bit 16 00:01:45,040 --> 00:01:50,640 surprised when I thought, Oh, OK, now I actually have to give the talk. So please 17 00:01:51,280 --> 00:02:00,240 forgive me if I'm sort of nervous, but stay with me and thank you everyone for 18 00:02:00,240 --> 00:02:04,960 watching and for filling in the survey beforehand, and you will have another 19 00:02:04,960 --> 00:02:12,480 option to participate in the poll later on. So I have some things to announce 20 00:02:12,480 --> 00:02:21,600 first, which would be about the content. So it will all be very abstract. So we are 21 00:02:21,600 --> 00:02:28,720 talking more about concepts than about actual disease and suffering. So 22 00:02:28,720 --> 00:02:34,400 there will be no photos. But yeah, the general theme is about medical 23 00:02:34,400 --> 00:02:41,600 examination, everything clinical, about the patient assessing somebody's disease 24 00:02:41,600 --> 00:02:49,120 and disease risk, and also going into the more severe conditions of which you might 25 00:02:49,120 --> 00:02:56,320 die. And we also touch upon family relationships. So just so you know, yeah, 26 00:02:56,320 --> 00:03:02,240 it will come back every now and then. So just for everyone to be aware. And then 27 00:03:02,240 --> 00:03:11,200 also, yeah, I need to disclose that I'm an employee of a company that does work on 28 00:03:11,200 --> 00:03:20,240 marketing genetic tests. So that set aside, this is not this is not any kind of 29 00:03:20,240 --> 00:03:29,680 advertising talk. It's really about what is actually happening technology wise. So 30 00:03:29,680 --> 00:03:36,720 I want to give you the insights into a little bit of the technology, how it came 31 00:03:36,720 --> 00:03:43,040 about and where we are now, and also try and give you an overview of what are the 32 00:03:43,040 --> 00:03:53,200 options in terms of genetic testing for various utilitys and raise awareness just 33 00:03:53,200 --> 00:04:01,600 for also the ethnical issues that might arise from what we can learn from our DNA. 34 00:04:03,280 --> 00:04:15,840 So this is enough of the prolog. Let's go right into looking at a patient which is 35 00:04:16,560 --> 00:04:23,040 classically done from the outside. So we want to know what is different about this 36 00:04:23,040 --> 00:04:30,240 person or a patient. And yeah, there are really layers of information, and you 37 00:04:30,240 --> 00:04:37,280 always assume that there's a relationship with a condition. So be it a rash that you 38 00:04:37,280 --> 00:04:43,760 see on the outside or as swelling that the doctor can't feel or something that they 39 00:04:43,760 --> 00:04:50,960 learn from interrogating the patient. And then there's a bit of a borderline outside 40 00:04:50,960 --> 00:05:00,720 inside test, which would be bodily fluids. So if you test urine, saliva, blood, yeah, 41 00:05:00,720 --> 00:05:06,640 you already look on the inside. So what's happening inside of the patient and the 42 00:05:07,360 --> 00:05:15,840 metabolome? Yeah, what's what's going on in terms of small molecules that you might 43 00:05:15,840 --> 00:05:20,880 detect with the one or the other test? And also what you can see on the inside is 44 00:05:21,680 --> 00:05:30,800 broken bones or cysts that shouldn't be there. So for that, we use imaging which 45 00:05:30,800 --> 00:05:37,120 where x-ray is the oldest, and then there's magnetic resonance and pet 46 00:05:37,120 --> 00:05:44,000 scanning. So these are like the cool, advanced additional layers where you can 47 00:05:44,000 --> 00:05:51,600 look inside of the of the patient. And then of course, there's DNA. So if we look 48 00:05:51,600 --> 00:05:59,600 even deeper and inside each cell, you will have the genetic code of this person, so 49 00:05:59,600 --> 00:06:09,840 to tell how they are different on a very small scale. So that is the dogma of 50 00:06:09,840 --> 00:06:18,560 molecular biology that you go from DNA, which is your genetic blueprint, and then 51 00:06:18,560 --> 00:06:24,800 certain parts are transcribed so the cell makes copies of the DNA, which what I'm 52 00:06:24,800 --> 00:06:30,960 called RNA, because it's a different chemistry and these are then translated 53 00:06:30,960 --> 00:06:37,680 into chains of amino acids, so there's a code which amino acid should be attached 54 00:06:37,680 --> 00:06:42,080 to which one. And then you fold it properly and then you have a functional 55 00:06:42,080 --> 00:06:48,320 protein. And then now why you sequence the DNA is because you assume that there's a 56 00:06:48,320 --> 00:06:56,560 mistake made, which then leads to a faulty protein. And then in the end, something in 57 00:06:56,560 --> 00:07:06,240 your body doesn't work. So, yeah, it's a very simple concept, if you will. And 58 00:07:06,240 --> 00:07:14,720 then, yeah, when we check in the DNA and in the RNA is about 20000 protein coding 59 00:07:14,720 --> 00:07:23,200 genes. And then there's also a different types of RNA that do not code for proteins 60 00:07:23,200 --> 00:07:30,560 that regulate other stuff so that the correct genes are actually transcribed and 61 00:07:30,560 --> 00:07:37,680 translated. So that's an additional 20 to 30 thousand, potentially more. And so if 62 00:07:37,680 --> 00:07:45,600 you combine any of these two, see like a certain signature of a person, you already 63 00:07:45,600 --> 00:07:52,160 have billions of combinations. So as you can imagine, there are many, many, many 64 00:07:52,160 --> 00:07:59,520 signatures possible. But yeah, which of these will actually tell you something 65 00:07:59,520 --> 00:08:13,440 about the patient? So. Let's go back to how we sequence the DNA. So it is actually 66 00:08:13,440 --> 00:08:25,120 very simple. All of our usually 46 chromosomes so that 23 pairs are made of 67 00:08:25,680 --> 00:08:33,040 at double stranded code, which is the DNA. And then you see here in the unfolded 68 00:08:33,040 --> 00:08:41,760 region that where a gene is starting, it usually starts with A T G and these are 69 00:08:42,400 --> 00:08:52,400 ciramated bases. So you have here in the chemical metal insert and the A and the T, 70 00:08:52,400 --> 00:08:59,440 which form a pair. So the red thing is in between are hydrogen bonds that keep them 71 00:08:59,440 --> 00:09:06,800 together. And A and T always want to be together. And C and G always want to be 72 00:09:06,800 --> 00:09:12,000 together. C and G actually form three of those bonds. So in a little bit more 73 00:09:12,000 --> 00:09:21,360 stable. And so as you can see, this double stranded DNA is hands always inverted on 74 00:09:21,360 --> 00:09:27,120 the other strand, so we call it the complementary strands. So if you have ATG 75 00:09:27,120 --> 00:09:35,600 on one strand, you always have TAC on the other. So you only sequence one and we 76 00:09:35,600 --> 00:09:42,880 defines the direction of the gene because we know in which direction it makes sense 77 00:09:42,880 --> 00:09:46,960 because, you know, only in one direction you can then make a protein out of this 78 00:09:47,920 --> 00:09:56,320 code. So enough for the chemistry and the principle. So we really want to know and 79 00:09:56,320 --> 00:10:02,880 to map where on each chromosome, which letter occurs. So you can imagine that 80 00:10:02,880 --> 00:10:11,680 this is quite an adventure and takes a lot of effort. And actually, it has also 81 00:10:12,240 --> 00:10:20,720 started very early on in the 70s. So maybe you have heard of Sanger sequencing. So 82 00:10:20,720 --> 00:10:28,000 that was the first generation of sequencing from 1977, where you 83 00:10:28,000 --> 00:10:36,240 essentially cut the strand in little pieces and you know which one ends with an 84 00:10:36,240 --> 00:10:42,240 A, ends with a T.. So you have all kinds of fragments with different lengths which run 85 00:10:42,240 --> 00:10:48,960 over a gel, which is not that important. But it's it is also called capillary 86 00:10:48,960 --> 00:10:56,640 sequencing, which then helped finding the first human disease gene, which is called 87 00:10:56,640 --> 00:11:02,160 the Huntington team. You might heard of the disease where it belongs to Korea, 88 00:11:02,160 --> 00:11:09,280 Huntington's. And so this was the first association that was really confirmed 89 00:11:09,280 --> 00:11:17,280 that, OK, you have a defect in a certain gene, which directly translates into a 90 00:11:17,280 --> 00:11:24,640 disease phenotype, but this is very rare. So usually it is a lot more complex and we 91 00:11:24,640 --> 00:11:35,520 will also get to that. So the capillary sequencing still lasted for a while, so 10 92 00:11:35,520 --> 00:11:39,520 years later, you had really cool instruments for the first time from 93 00:11:40,400 --> 00:11:47,200 Applied Biosystems so that you can sequence a little bit quicker, but still 94 00:11:48,560 --> 00:11:56,320 far from looking at the whole genome. So that was then planned starting in 1988. 95 00:11:56,960 --> 00:12:01,760 They defined the goals for the Human Genome Project, which would then take from 96 00:12:01,760 --> 00:12:13,520 1990 until 2003 to complete one full human genome. So full in the sense that it still 97 00:12:13,520 --> 00:12:21,120 had gaps. So there are some regions which are tricky to sequence, so these gaps were 98 00:12:21,120 --> 00:12:31,040 filled later on. But still, yeah, this was a huge undertaking which cost about two to 99 00:12:31,040 --> 00:12:39,920 three billion US dollars. And eventually, in 2000, they announced that they had a 100 00:12:39,920 --> 00:12:48,960 first draft of the human genome, and then it got published in 2001 in the two big 101 00:12:50,960 --> 00:12:58,640 scientific journals, Nature and Science, both on the cover the human genome. So 102 00:12:58,640 --> 00:13:05,440 that was and is a big step. So it's yeah, that's just crucial to know, what we are 103 00:13:05,440 --> 00:13:13,360 looking at to have a map of our complete genome, where then you can map other 104 00:13:13,360 --> 00:13:23,280 people's sequences to as well. So that's what started also in 2005. But then for 105 00:13:23,280 --> 00:13:31,040 different types of cancer, it's called TCGA from the genome, the Cancer Genome 106 00:13:31,040 --> 00:13:39,440 Atlas, and it also lasted for a couple of years. But then they were much quicker in 107 00:13:39,440 --> 00:13:49,600 sequencing, because 2005 was also the year of next generation sequencing machines. So 108 00:13:49,600 --> 00:13:56,000 nowadays we don't do Sanger sequencing anymore or rarely. We usually rely on 109 00:13:57,440 --> 00:14:06,800 heavy, high throughput parallel sequencing so that you can sequence a lot more 110 00:14:06,800 --> 00:14:15,840 different pieces, so to say, at the same time and with very high accuracy. So 111 00:14:16,560 --> 00:14:26,160 essentially, this means, that we now have access to 3.1 billion base pairs, which 112 00:14:26,160 --> 00:14:33,360 were first collected during this human genome project. And this nice 113 00:14:33,360 --> 00:14:38,640 advertisement when they were looking for volunteers is really cute, actually, 114 00:14:38,640 --> 00:14:46,240 because they also say here that this photo of the project will have tremendous impact 115 00:14:46,240 --> 00:14:52,160 on future progress of medical science and lead to improved diagnosis and treatment 116 00:14:52,160 --> 00:14:58,560 of hereditary diseases. Volunteers will receive information about the project and 117 00:14:58,560 --> 00:15:04,080 sign a consent form. No personal information will be maintained or 118 00:15:04,080 --> 00:15:12,800 transferred, and a small monetary embarrassment will be provided. So, yeah, 119 00:15:12,800 --> 00:15:21,120 they were promised that their data would be kept anonymously and also they 120 00:15:21,920 --> 00:15:29,440 collected blood from female volunteers or sperm from male volunteers. And then they 121 00:15:29,440 --> 00:15:34,480 collected a lot more samples than what they would need so that in the end, you 122 00:15:34,480 --> 00:15:41,360 couldn't tell anymore from whom the genome was actually derived. And there was one 123 00:15:41,360 --> 00:15:49,920 volunteer at Roswell Park and hence called RP11, who had happened to have 124 00:15:50,640 --> 00:15:58,320 exceptional quality sequencing reads. And then so the first human genome was mainly 125 00:15:58,320 --> 00:16:06,560 based on this one person, and we have multiple new versions published of the 126 00:16:06,560 --> 00:16:13,120 human reference genome today. Its version 38 and still about 70 percent are 127 00:16:13,120 --> 00:16:23,760 untouched from this first genome assembly. And a small thing about the cost. So I 128 00:16:23,760 --> 00:16:32,320 mentioned that this was a really costly project. Two to three billion dollars. And 129 00:16:32,320 --> 00:16:42,320 now we have actually cracked the $1000 threshold. So it is possible to sequence a 130 00:16:42,320 --> 00:16:48,320 full human genome for about a thousand bucks, which is remarkable. So this is 131 00:16:48,320 --> 00:16:57,680 really an enormous drop in the cost just because the technology made such a big 132 00:16:57,680 --> 00:17:07,200 leap when we came to the next generation sequencing. And also one genome. If you 133 00:17:07,200 --> 00:17:13,280 have it sufficiently covered so that you are sure about which base pairs and which 134 00:17:13,280 --> 00:17:21,760 position, then you have about 180 gigabytes of raw rids. And if you align 135 00:17:21,760 --> 00:17:29,040 them to the reference genome, which is, of course, now your atlas, if you will, so 136 00:17:29,040 --> 00:17:34,640 you can put all our rids to the correct place. And then this is called an 137 00:17:34,640 --> 00:17:39,840 alignment file, which is about 80 gigabytes. And if you then only keep the 138 00:17:39,840 --> 00:17:45,760 positions where something is different from the reference genome and you compress 139 00:17:45,760 --> 00:17:52,960 it, you are left with about 5 percent of that. So 4 gigabytes per person. 140 00:17:52,960 --> 00:18:05,600 Storable, nice little genome. OK. So this takes me to the first poll, which is on 141 00:18:05,600 --> 00:18:11,920 simple vote. A couple of people already have participated in the monkey 142 00:18:11,920 --> 00:18:21,920 survey. Then, yeah, you don't have to do it again now, but the vote link will also 143 00:18:21,920 --> 00:18:30,240 be in. And you also just fill in any name combination of letters, click OK, and then 144 00:18:30,240 --> 00:18:38,240 you can answer the first question, which I present here. So this is just three 145 00:18:38,240 --> 00:18:43,600 statements about sequencing a full human genome. Whether you believe that it has 146 00:18:43,600 --> 00:18:50,080 replaced fingerprinting in forensic investigations, where do you think that it 147 00:18:50,080 --> 00:18:56,400 gives you all the clinically relevant information for any patient and whether 148 00:18:56,400 --> 00:19:05,280 you think that it is cheaper than a full body MRI scan? So yeah, we will get to the 149 00:19:05,280 --> 00:19:13,040 results in a bit. I will just continue with a couple more slides and then we can 150 00:19:13,040 --> 00:19:19,840 see. What do you guys think, and I'm really curious to actually hear that. And 151 00:19:19,840 --> 00:19:31,360 see it for myself. Let's see. So if you think in terms of complexity, we have 152 00:19:31,360 --> 00:19:38,320 already touched upon Korea, Huntington, which is a single gene, essentially that 153 00:19:38,320 --> 00:19:47,360 gives you a full blown disease if it's not encoded properly. And then you could think 154 00:19:47,360 --> 00:19:58,000 of other diseases that are encoded by a couple of genes, where you can think of 155 00:19:58,720 --> 00:20:04,240 breast cancer over a couple of mutated genes can give you a much higher risk than 156 00:20:04,240 --> 00:20:09,200 average population. And also in Alzheimer's disease, we see that 157 00:20:11,760 --> 00:20:21,600 hereditary component. Brought about by a couple of genes again and then more 158 00:20:21,600 --> 00:20:31,520 general in terms of unknown diseases, you can ask gene panels or full genome 159 00:20:31,520 --> 00:20:38,000 sequencing to help out. And it gets more and more fuzzy, but more and more also, 160 00:20:38,000 --> 00:20:44,960 tests are available if you want to go to a prognosis for this or that condition or to 161 00:20:44,960 --> 00:20:51,680 the correct treatment choice. So I'll try and give you a couple of more examples, 162 00:20:52,800 --> 00:21:02,240 but only after we have talked about the Cancer Genome Atlas, the PCGA . So here 163 00:21:02,880 --> 00:21:10,960 that's also a lot of data. So they claim 2.5 petabytes were collected in the place 164 00:21:10,960 --> 00:21:22,320 it was running from 2006 to 2014. And yeah, in total, 33 different tumor types. 165 00:21:22,320 --> 00:21:28,960 And they did not only look at the DNA and all the mutations, but also RNA and also 166 00:21:28,960 --> 00:21:39,840 proteins, and also different info on the patient's survival and treatment data. So 167 00:21:40,560 --> 00:21:48,000 that is a huge pool and resource of data where people are looking at and finding 168 00:21:48,640 --> 00:21:55,600 signatures of patients with less or more advanced cancers with patients that 169 00:21:55,600 --> 00:22:01,360 progress through treatment or not. But it's all. Yeah, you still really need to 170 00:22:01,360 --> 00:22:08,640 take it with a pinch of salt because, for example, since 2006, treatment of cancer 171 00:22:08,640 --> 00:22:14,640 has changed tremendously, and you cannot just use any signature that you took from 172 00:22:15,520 --> 00:22:22,640 the data from PCGA and extrapolate for today's cancer patients. So that's a bit 173 00:22:22,640 --> 00:22:30,720 tricky. PCGA still vastly used. But then, yeah, I would propose that you should 174 00:22:30,720 --> 00:22:39,120 rather use it for validation so you find something in current data from today's 175 00:22:39,120 --> 00:22:45,120 patients and then you can check whether this was also seen in the PCGA data and not 176 00:22:45,120 --> 00:22:57,114 the other way around. But let's get to the results of the poll. See? Can we go there? 177 00:22:57,114 --> 00:23:21,277 What happens? Oh, nice. What's the score? 7.3 So you mostly agree that full body MRI 178 00:23:21,277 --> 00:23:30,210 is more expensive than the full genome sequencing, which is true. So like I said, 179 00:23:30,210 --> 00:23:38,880 the whole genome is now about 1000 dollars, also 1000 euros, and the full body scan in 180 00:23:38,880 --> 00:23:49,600 the MRI will cost about two to six thousand euros, roughly. And then this one 181 00:23:49,600 --> 00:23:58,320 with the fingerprints I have made up. So sorry to fool you. This is not done yet. 182 00:24:00,000 --> 00:24:07,760 And it also cannot potentially give you all clinically relevant information about 183 00:24:07,760 --> 00:24:17,840 the patient. So nice. Thank you for participating. And also, I check the 184 00:24:18,640 --> 00:24:23,680 survey monkey and also there. I have managed to fool some people into believing 185 00:24:23,680 --> 00:24:32,640 that. It's possible to replace fingerprinting with full genome 186 00:24:32,640 --> 00:24:41,440 sequencing, where that's not true. Sorry. So let's go to another level. So not only 187 00:24:41,440 --> 00:24:46,960 the DNA sequencing is interesting. So then you have the map and on the property, 188 00:24:47,520 --> 00:24:56,080 sorry, on the DNA strand, you know, for example, where there's a different letter, 189 00:24:56,080 --> 00:25:04,640 if you will. And then in the reference genome, and then this mutation might be in 190 00:25:04,640 --> 00:25:11,840 one of the regions where the DNA has stored the code for a certain protein like 191 00:25:11,840 --> 00:25:17,600 protein one or protein two. So the code might be different, but also it might be 192 00:25:17,600 --> 00:25:26,640 different how many copies are made. So this is an example here where gene one and 193 00:25:26,640 --> 00:25:33,760 two are equally often transcribed. And then there's these transcripts, which we 194 00:25:33,760 --> 00:25:41,840 call messenger RNA about equal amounts. And this is, let's say, the state how it 195 00:25:41,840 --> 00:25:50,080 should be in the healthy adult. And if you think about any condition like a cancer 196 00:25:50,080 --> 00:25:57,600 tumor, then it might get deregulated and the cancer, for example, then there's this 197 00:25:58,240 --> 00:26:03,440 and only makes very few copies of gene one. And a lot of copies of gene two, 198 00:26:04,160 --> 00:26:12,480 which might lead to effects like bigger growth, faster faster growth, bigger 199 00:26:12,480 --> 00:26:21,280 spread into the tissue, which would normally confine the tumor. So that is 200 00:26:21,280 --> 00:26:27,360 also one level of regulation and that you cannot usually capture with DNA sequencing 201 00:26:27,360 --> 00:26:32,880 or whole genome sequencing. For that, you need to check for the expression which you 202 00:26:32,880 --> 00:26:40,080 do on this level, on the RNA level. And then you have they call in differential 203 00:26:40,080 --> 00:26:47,600 expression, which gives you this kind of picture analysis. So you have some 204 00:26:47,600 --> 00:26:54,560 samples, vertical and then horizontal are the genes, and you see that if you compare 205 00:26:54,560 --> 00:27:01,040 the samples, some genes are more expressed, which is red and some genes are 206 00:27:01,040 --> 00:27:08,240 down compared to the others, which is green. And then you can find clusters of 207 00:27:08,240 --> 00:27:15,840 genes, a group of genes here in the red bar, where Group one, in that case, a 208 00:27:15,840 --> 00:27:23,040 certain kind of breast cancer is highly upregulated and most of the people I 209 00:27:23,040 --> 00:27:27,680 belong to, group two different kind of breast cancer have lower expression of 210 00:27:27,680 --> 00:27:35,600 that team and and the blue cluster is the other way around. So that gives you an 211 00:27:35,600 --> 00:27:42,080 idea of OK, you can maybe use one of these genes to differentiate between the two 212 00:27:42,080 --> 00:27:47,680 groups. And if that helps you to determine what treatment they should get, that's of 213 00:27:47,680 --> 00:27:55,200 course, super useful. And then you have something like a genetic biomarker. If you 214 00:27:55,200 --> 00:28:02,640 have multiple genes, then you usually call it a signature. And so these genetic 215 00:28:02,640 --> 00:28:13,120 signature tests can tell you, are you at risk of a certain disease? They can help 216 00:28:13,120 --> 00:28:22,560 diagnose or get to the exact subtype of of your disease. They can help you with the 217 00:28:22,560 --> 00:28:28,880 correct treatment or monitor whether the disease actually responds to the 218 00:28:28,880 --> 00:28:36,000 treatment, whether anything changes back to normal. And also, it can sometimes be 219 00:28:36,000 --> 00:28:44,000 useful to give a prognosis for a disease progression. So in the end, you always 220 00:28:44,000 --> 00:28:50,080 need to wonder what is the added value of such kind of testing on top of the 221 00:28:50,080 --> 00:28:55,040 clinical variables that are already existing and does give you something 222 00:28:55,040 --> 00:29:02,320 actionable? What can you do something with the knowledge that you gained from this 223 00:29:02,320 --> 00:29:08,400 testing? So there we are already at the problems with genetic testing. So that 224 00:29:08,400 --> 00:29:14,880 would be the second question that you can answer again on Simple Vote. Please feel 225 00:29:14,880 --> 00:29:24,320 invited to help me understand what you think. And here it's just. For you 226 00:29:24,320 --> 00:29:30,240 personally, the question whether you would want to know whether you are at risk of a 227 00:29:30,240 --> 00:29:35,760 genetic disease and would you want to know if you had to pay for it and then slide it 228 00:29:35,760 --> 00:29:39,680 to the right, if you're willing to pay or slide it to the left, if you're totally 229 00:29:39,680 --> 00:29:45,200 not willing to. And then the second slide is the same question when you want to know 230 00:29:45,200 --> 00:29:52,400 if you got the results for free? And then to the right is yes, and more to the left 231 00:29:52,400 --> 00:30:00,160 is no, absolutely not. So again, I will just move on and you can take your time 232 00:30:00,160 --> 00:30:08,880 answering that one. So to give you a bit of a feeling for what is at stake is the 233 00:30:08,880 --> 00:30:18,720 get WHO into testing for genetic risks. It's, of course, good to know your family 234 00:30:18,720 --> 00:30:24,720 history of disease. And also, if you're planning to have children, for example, 235 00:30:24,720 --> 00:30:30,160 would you want them to know that they potentially carry a certain risk or not? 236 00:30:32,400 --> 00:30:39,760 Then health or life insurance might have an interest in knowing what people's risks 237 00:30:39,760 --> 00:30:46,320 are, what they have to expect. So there are certain instances where they are 238 00:30:46,320 --> 00:30:52,400 eligible to know and certain instances where at this moment in time, they 239 00:30:52,400 --> 00:30:58,800 absolutely are not. So this is something that's probably going to change in the 240 00:30:58,800 --> 00:31:05,120 future. The more we know, the more we want to use that knowledge. And then there's 241 00:31:05,680 --> 00:31:11,520 the problem that some genes are very often found to be up and downregulated, and 242 00:31:11,520 --> 00:31:17,840 there seems to be a difference. But it's just yeah, in the nature of those genes, 243 00:31:18,960 --> 00:31:25,200 and we have sometimes multiple signatures for the same problem. And then, yeah, 244 00:31:25,200 --> 00:31:32,160 doctors and patients just don't know what to choose from. So I'll go through some of 245 00:31:32,160 --> 00:31:44,640 those issues in more detail. I have mentioned the TCGA before, and this cancer 246 00:31:44,640 --> 00:31:52,080 genome atlas is really a limited source that is now exhausted, but it's still 247 00:31:52,080 --> 00:32:06,600 oftentimes used as the silver bullet. So. Let's see if we already have votes. Well. 248 00:32:10,640 --> 00:32:24,000 So that would be. Yes. OK, so if you if you could know your genetic risk and you 249 00:32:24,000 --> 00:32:30,160 would get it for free, then most people are inclined to say, yes, I would like 250 00:32:30,160 --> 00:32:36,960 that very much. And if they had to pay for it, then it seems to go more towards no, 251 00:32:36,960 --> 00:32:45,120 but it's actually kind of neutral, which was surprising. Yeah, I would have thought 252 00:32:45,120 --> 00:32:50,080 that you would all say, no, I don't want to know. But that was just my assumption, 253 00:32:50,080 --> 00:32:59,840 and I was apparently wrong. Cool, thank you. Poll number three third question is 254 00:32:59,840 --> 00:33:07,760 about a commercially available DNA test, which is not actually sequencing, but they 255 00:33:07,760 --> 00:33:14,720 use a panel of mutations that are now known because we have already sequenced 256 00:33:15,520 --> 00:33:22,640 thousands and nearing a million complete full genomes. And yeah, I was wondering 257 00:33:23,440 --> 00:33:31,440 whether you would know. So that's quite a number three. What institutions they 258 00:33:31,440 --> 00:33:37,280 partner up with. So this DNA test is goal 23 and me. And if you don't know what it 259 00:33:37,280 --> 00:33:45,520 is, then there's also an answer option for this one. No clue what it is. It does. And 260 00:33:45,520 --> 00:33:52,480 for the rest, yeah, I propose that they work together with Broad Institute, that 261 00:33:52,480 --> 00:33:59,280 they work together with GlaxoSmithKline, GSK and they got 300 million US dollars 262 00:33:59,280 --> 00:34:05,360 from them, that they work together with general practitioners in the US, that they 263 00:34:05,360 --> 00:34:13,680 got subsidy from Google 4 million US dollars or and Amazon 9 million US 264 00:34:13,680 --> 00:34:20,880 dollars. So, OK, let's see what you think or how many of you don't know the text. 265 00:34:23,520 --> 00:34:32,080 And in the meantime, I'll present two cases to you, where genetic testing would 266 00:34:32,960 --> 00:34:38,800 play a role like, for instance, in the case of inhealthy adult, where the dad was 267 00:34:38,800 --> 00:34:44,080 diagnosed with this heart condition, hypertrophic cardiomyopathy, where the 268 00:34:44,080 --> 00:34:50,880 heart tissue gets scars and at some point it cannot pump properly anymore. And so if 269 00:34:50,880 --> 00:34:56,640 you have one parent with that disease, you have a 50 percent risk that you have 270 00:34:56,640 --> 00:35:03,600 inherited those genes from your parents. So this healthy adult and their siblings 271 00:35:03,600 --> 00:35:14,880 got the offer to get tested. So the costs are covered by the health insurance, but 272 00:35:15,440 --> 00:35:23,520 there is no cure for this condition. So you can. Yeah, have a stricter 273 00:35:23,520 --> 00:35:29,120 surveillance, and you can get access to early treatment if you develop symptoms, 274 00:35:29,120 --> 00:35:36,640 but yeah. Other than that, yeah, it's still just a risk gene. So to say so if 275 00:35:36,640 --> 00:35:41,120 you know you have the gene, it doesn't mean you will get the disease. It just 276 00:35:41,120 --> 00:35:47,440 means you have an elevated risk. So it's really hard to grasp. And this is one case 277 00:35:47,440 --> 00:35:54,480 where at least in the Netherlands, the life insurance would be eligible to know 278 00:35:54,480 --> 00:36:01,920 if you got tested and you do have that gene. So in the end, this person said, No, 279 00:36:01,920 --> 00:36:08,720 no test, please. I will just go see a cardiologist every now and then, have it 280 00:36:08,720 --> 00:36:14,480 checked nonetheless. But I don't want to know if I have those things OK. A second 281 00:36:14,480 --> 00:36:27,040 case? Yeah. So that's an infant delayed in development. It was still a bit fuzzy. 282 00:36:27,040 --> 00:36:34,560 Like what should an infant be able to do or not do at the age of one? But then the 283 00:36:34,560 --> 00:36:44,480 parents started observing seizures in the in that case, it was absences, so it was 284 00:36:44,480 --> 00:36:53,040 not cramping, but just very absent. So eventually, they got access to tests, 285 00:36:53,040 --> 00:36:59,840 genetic tests where distinct genes were analyzed. Nothing was found. Then panels 286 00:36:59,840 --> 00:37:05,360 of genes with increasing size and nothing was found. And then the whole genome 287 00:37:05,360 --> 00:37:13,520 sequencing was done. And then you always have to compare to the parents. And 288 00:37:13,520 --> 00:37:22,400 essentially, parents and child who trust that and the child had a mutation in a 289 00:37:22,400 --> 00:37:29,680 gene where the parents had nothing and it was just the very rare X-linked mutation. 290 00:37:30,320 --> 00:37:39,520 And eventually they now know what is going on, which was only due to the possibility 291 00:37:39,520 --> 00:37:47,360 of whole genome sequencing. And in the end, the parents also said, Yes, I want to 292 00:37:47,360 --> 00:37:53,040 know what else is found in this whole genome sequencing. So that isn't actually 293 00:37:53,600 --> 00:38:03,840 case free, where one of the parents is the carrier of a mutation in a in a protein, 294 00:38:04,560 --> 00:38:14,240 that when it's faulty or when you get a faulty version from both parents, then you 295 00:38:14,240 --> 00:38:19,520 will develop this condition. Cystic fibrosis. So that is really good to know 296 00:38:20,640 --> 00:38:26,800 when you are a carrier of this and also your future kids can get tested to see 297 00:38:26,800 --> 00:38:35,440 whether they got this faulty version from you. So let's have a look at the poll 298 00:38:35,440 --> 00:38:48,480 number three. This is here. So the DNA test 23 and me. Let's see where's the. I 299 00:38:48,480 --> 00:38:55,440 have no clue what this test is. So this is just a four. OK, so not that many people 300 00:38:57,680 --> 00:39:07,840 voted for this one. Twenty nine votes. Oh, well, actually. Twenty nine votes. And 301 00:39:07,840 --> 00:39:20,080 then what you thought it would do. So you'll have here, you approve of it, 302 00:39:20,080 --> 00:39:25,200 working in conjunction with general practitioners in the U.S., which is not 303 00:39:25,200 --> 00:39:32,400 true. Sorry. Yes, it did get subsidy from Google, 4 million US dollars in the 304 00:39:32,400 --> 00:39:43,840 very beginning. No, no, no. Sanger sequencing Yes. GSK 300 million. They want 305 00:39:43,840 --> 00:39:52,800 to use their data to find new drug targets. And I also made this one up. So 306 00:39:52,800 --> 00:40:00,560 Amazon did not give any money to 23 and me, but you can order through Amazon. So 307 00:40:00,560 --> 00:40:13,600 that's possible. OK, thank you. And I'll think I will wrap up after just presenting 308 00:40:15,120 --> 00:40:21,760 this problem here quickly. So breast cancer is one of the pioneering fields of 309 00:40:21,760 --> 00:40:30,080 genetic testing. So you have five commercially available tests that can tell 310 00:40:30,080 --> 00:40:35,760 you what type you have, what treatment options would be best for you and what 311 00:40:35,760 --> 00:40:42,480 your prognosis is. So you really need a well-informed team of doctors if you want 312 00:40:42,480 --> 00:40:51,040 to make use of this. OK, I'll skip a few slides. Mean, validation is important. 313 00:40:51,040 --> 00:40:57,040 Takes a lot of time. And I think in the future, it's not only going to be a whole 314 00:40:57,040 --> 00:41:03,280 genome sequencing, but there will be a lot more to it, like the immune system and 315 00:41:03,280 --> 00:41:10,114 your gut microbiome and everything, which is in there is also, of course, influenced 316 00:41:10,114 --> 00:41:16,899 by outside factors what you eat, how much sunlight you get, how much you move. So 317 00:41:16,899 --> 00:41:23,645 this is also already available, this data from your smart watch, for example. So I 318 00:41:23,645 --> 00:41:30,040 think in the end, if we get to personalized medicine, this will also play 319 00:41:30,040 --> 00:41:36,880 a role. And to recap, if you sequenced the whole genome, this is not the same as 320 00:41:36,880 --> 00:41:43,557 ordering any tests online, where you also might run into data security issues with 321 00:41:43,557 --> 00:41:52,326 tests like 23 and me. And that's also not the same a deceases signature. And then, yeah, 322 00:41:52,326 --> 00:41:59,358 if you have a new cool diagnostic signature that is published, it might 323 00:41:59,358 --> 00:42:05,537 still take a long time and couple of validation studies before it actually 324 00:42:05,537 --> 00:42:12,876 enters the everyday clinic and you get it reimbursed from your health insurance. And 325 00:42:12,876 --> 00:42:19,440 for this, it also needs very well trained physicians and informed patient and 326 00:42:19,440 --> 00:42:27,240 family. I think there's no way in stopping this. But that's just my take. So we will 327 00:42:27,240 --> 00:42:35,105 see a lot more from the molecular side of things in the future, and these are also 328 00:42:35,105 --> 00:42:42,414 to be retrieved online. So everything all the tests that are registered also you can 329 00:42:42,414 --> 00:42:47,762 filter for countries, for Germany, for example. And then you see even which 330 00:42:47,762 --> 00:42:55,786 university clinic offers which kind of testing. And if you ever hear the term 331 00:42:55,786 --> 00:43:03,400 liquid biopsy, that's usually a black sample where, yeah, all kinds of things 332 00:43:03,400 --> 00:43:09,200 are measured, so you have DNA in there, but you also have metabolites in there, 333 00:43:09,200 --> 00:43:15,640 you can have little fragments of cancer cells and cancer derived DNA. So this is 334 00:43:15,640 --> 00:43:21,884 something that's coming forward more and more that you just need a blood draw. And 335 00:43:21,884 --> 00:43:29,367 then, yeah, you have a lot of insight, not only the whole genome, but even more RNA 336 00:43:29,367 --> 00:43:37,517 sequencing data, for example. So thank you very much for inviting me, for listening, 337 00:43:37,517 --> 00:43:48,655 and I'm happy to take your questions now. Herald: It's again, the social media 338 00:43:48,655 --> 00:43:55,040 hashtags on Mastodone and Twitter RC3ChaosZone without a dash and then on 339 00:43:55,040 --> 00:44:01,030 IRC unchecked, and the channel is RC3 with a dash. Chaos Zone. 340 00:44:01,030 --> 00:44:05,662 Lisette: Do we already have any specific questions? 341 00:44:05,662 --> 00:44:10,664 Many think people would like to know. Herald: And targeted gene modification 342 00:44:10,664 --> 00:44:16,933 with CRISPR and Cas9 is not even allowed on plants and animals in the EU. Do you 343 00:44:16,933 --> 00:44:21,154 think there will ever be gene therapy for humans? 344 00:44:21,154 --> 00:44:35,360 Lisette: There was gene therapy. So, for example. I'm not sure whether it was a 345 00:44:35,360 --> 00:44:45,440 typo, low key a or an immune defect where they tried to cure children with gene 346 00:44:45,440 --> 00:44:50,282 therapy, so there were clinical trials, but something went horribly wrong, and I 347 00:44:50,282 --> 00:45:01,040 think actually one of the children suffered so much from how they inserted 348 00:45:01,040 --> 00:45:10,560 the gene that it developed a type of cancer. But I'm still hesitant to say that 349 00:45:10,560 --> 00:45:18,480 this is the end of gene therapy. So it has potential in very severe cases where 350 00:45:18,480 --> 00:45:24,960 there's no other option. But yes, it's also true that we don't really know what 351 00:45:24,960 --> 00:45:31,360 we're doing at the moment. So there's a lot more research needed to make sure that 352 00:45:31,360 --> 00:45:38,000 there's no off target effects if you cut out a gene and put in a new sequence. So, 353 00:45:38,000 --> 00:45:45,280 yeah, no, I don't think we can guarantee that as of yet, but it's it's not 354 00:45:45,280 --> 00:45:48,888 unthinkable. Herald: All right. Huh, interesting. 355 00:45:48,888 --> 00:45:56,772 Sounds like the technology isn't there yet for a couple of years or decades. 356 00:45:56,772 --> 00:46:03,104 Lisette: Oh, well, I think the technology is there, it's just not secure enough. 357 00:46:03,104 --> 00:46:08,280 Herald: All right. I see. Lisette: So, yeah, it's done in the lab 358 00:46:08,280 --> 00:46:14,788 big time, but then we don't usually use humans. Only a cell line or yeah. 359 00:46:14,788 --> 00:46:23,201 Something that is easy to control. Herald: All right. Um, and then a dynamic 360 00:46:23,201 --> 00:46:31,423 methods for tests, for example, for diseases such as COVID, our target 361 00:46:31,423 --> 00:46:41,440 tests, for example, the PCR test. Do you think now the testing for infections might 362 00:46:41,440 --> 00:46:46,400 shift to be more exploratory approaches, for example, through sequencing instead of 363 00:46:46,400 --> 00:47:00,541 targeted PCR? Lisette: Yeah, that depends if you have a 364 00:47:00,541 --> 00:47:05,612 suspicion that the infection has reached the bloodstream and you're close to 365 00:47:05,612 --> 00:47:11,851 sepsis, then it might be your last resort to make a hole. Yeah. Just sequence 366 00:47:11,851 --> 00:47:18,052 everything that is in the blood, but then you need to be, of course, aware that the 367 00:47:18,052 --> 00:47:23,059 majority will be human, so you need to filter out a lot. And then what is left, 368 00:47:23,059 --> 00:47:29,451 you might be able to map to a certain microbe genomes, which are also pretty 369 00:47:29,451 --> 00:47:38,286 well annotated. So I'm not sure about nasal swabs or something like that, where 370 00:47:38,286 --> 00:47:46,965 you can find out which flu you have received. So that doesn't really make too 371 00:47:46,965 --> 00:47:54,277 much sense to me unless you have a good treatment options. But for example, 372 00:47:54,277 --> 00:48:02,998 tuberculosis is one disease where if you do sequence the germs now more and more 373 00:48:02,998 --> 00:48:10,553 because a lot of strains of these bacteria have multiple antibiotic resistances. 374 00:48:10,553 --> 00:48:17,640 And then if you start treating with the wrong antibiotics, you are really screwed. 375 00:48:17,640 --> 00:48:24,526 So there, yeah, it's already well- established that the university clinics at 376 00:48:24,526 --> 00:48:29,366 least sequenced the strains before the patient gets treatment. 377 00:48:29,366 --> 00:48:37,520 Herald: Interesting, yes. Sounds very cool. All right. Thank you so much, 378 00:48:37,520 --> 00:48:42,080 Lisette. Very inspiring. Lisette: You are welcome.It was a 379 00:48:42,080 --> 00:48:50,000 pleasure. I hope I could convey the message. Just be aware of, yeah, your 380 00:48:50,000 --> 00:48:56,080 genes and your data. So yeah, that's that's just there's a lot of potential in 381 00:48:56,080 --> 00:49:00,800 there. But of course, we shouldn't be. We should not be careless. 382 00:49:00,800 --> 00:49:04,800 Herald: So, yes, definitely. Lisette: That's all from my side. Thank 383 00:49:04,800 --> 00:49:09,020 you. Herald: Thank you so much. 384 00:49:09,020 --> 00:49:16,000 *rc3 postroll music* 385 00:49:18,624 --> 00:49:22,512 Subtitles created by c3subtitles.de in the year 2022. Join, and help us!