74 – COMBINEDBrain Biobank & Our Partnership with SRF for SYNGAP1

Terry Jo Bichell, PhD, MPH

Terry Jo Bichell worked as a documentary filmmaker in the early days of videotape, then became a public health nurse-midwife after filming a difficult birth in West Africa. When her youngest child, Lou, was diagnosed with Angelman syndrome, she switched from midwifery to clinical research on Angelman syndrome. Eventually, she went back to school to earn a PhD in neuroscience from Vanderbilt University in an effort to find treatments for her son. Along the way, she studied gene-environment interactions in Huntington disease as well as circadian aspects of Angelman syndrome and was a columnist for HDBuzz. After graduating, she was the Founding Director of the Angelman Biomarkers and Outcome Measures Alliance until 2018. Dr. Bichell founded a new non-profit in 2019, COMBINEDBrain (Consortium for Outcome Measures and Biomarkers for Neurodevelopmental Disorders), to assist other rare and ultra-rare neurogenetic disorders with clinical trial preparations.


0:08and then welcome to today’s webinar my name is Olga body and I’m a part of the syngap team

0:14I’m a singap parent here at uh the team with syngap research fund our presentation today is combined brain

0:21biobank and our partnership with srf for syngak one and I have the pleasure today to

0:28introduce today’s speaker is Dr Terry Jo Bishop Dr Bishop worked as a documentary

0:34filmmaker in the early days of videotape and then became a public health nurse

0:40Midwife after filming a difficult birth in West Africa her youngest child Liu was diagnosed

0:47with Angelman syndrome and then she switched from Midwifery to clinical research on Angelman syndrome

0:53eventually she went back to school and earned a PhD in Neuroscience from

0:59Vanderbilt University in an effort to find treatments for her son along the way she studied Gene

1:05environment interactions in Huntington disease as well as circadian aspects of Angelman syndrome and was a columnist

1:12for the HD Buzz after graduating Terry Jo was the founding director of the Angelman

1:18biomarkers and outcome measures Alliance until 2018.

1:23Dr Bissell founded a new non-profit in 2019 combined brain which stands for a

1:30Consortium for outcome measures and biomarkers for neurodevelopmental disorders and this is to assist other

1:36rare and ultra rare neurogenetic disorder with clinical trial preparations

1:42I recorded what version of this webinar will be available on the srf website under webinars on the family menu

1:50and by the end of this presentation you will have the opportunity to get the answer to your questions we’d love to

1:56hear from you please write questions in the Q a below for those of you joining us welcome and

2:02again our speaker today is Dr Terry Joe bishel her presentation today is combined brain biobank and our

2:09partnership with simgap research fund for syngak one it’s now my pleasure to turn things over to Dr Mitchell thank

2:16you Terry too thank you so much thank you for havingWhy Combined Brain

2:21me here I really love working with the sync app research fund and I think this

2:28is really an honor to talk to you about what we do so uh I wanted to start out with just a

2:36little bit about me and my motivations I don’t usually

2:43talk about it that much but uh I want to let you know some of the Back stories so

2:49um let me share my screen and

2:55um I will put it into slideshow mode there you go and so basically what I want to tell you

3:03about is why I started combined brain which is a Consortium of we are up to

3:12now 65 patient advocacy organizations

3:17and each of these patient advocacy organizations represents a whole

3:23disorder all of the disorders that we uh that are

3:29included as member organizations in Combined brain they’re all rare genetic

3:35neurodevelopmental disorders and the reason for that has to do with my own personal story so that’s what I

3:42want to tell you about so this picture is a picture of my son Lou Michelle

3:50um and me at our uh daughter’s wedding um I have five children and Lou is the

3:58youngest he’s 24 now and when he was

4:03um and he has Angelman syndrome um when he was uh born uh 24 years ago

4:14we didn’t have a clue and I’m gonna tell you a little bit of that story which I

4:20think is exactly the same as your story for all of you who are parents of uh

4:25people who have um Singaporean mutation so my this these

4:33slide deck came from a presentation I made last year at in Park City Utah

4:40where they had a beautiful gondola ride and uh so I will mention that

4:47um but it’s really about luck and it’s about grit and this is my

4:53favorite subject um I always have to say that I do get anAngelman Syndrome

4:59honoraria from Hoffman Larose for being on an Angelman patient Advisory Board

5:05but that’s it uh I do not have any other pharmaceutical money coming in to me

5:13so uh what happened to me was that um I ended up going uh after my son was

5:22born um and realizing that he had a disorder that had at that time no

5:31treatment at all I launched into the work and into the

5:37research trying to see what I could do to help find a treatment for him

5:43and I actually got a little bit frustrated at a certain point because

5:48the treatment wasn’t moving along fast enough so I went back to school as a

5:54middle-aged lady and I got a PhD in Neuroscience

6:02um and this is a picture of me on my graduation day with Lou

6:09who by then was already in his late teens so uh it took me seven years to

6:18get that PhD it was seven years well spent I learned a ton

6:24and uh actually what I studied was not Angelman what I studied was Huntington

6:30disease and in fact that is actually

6:35um kind of important to me because I learned that by studying Huntington’s

6:42disease I could actually learn a whole lot of information that would help me to treat

6:48Angelman syndrome so in fact that’s also what helped me decide to start combined brain because I

6:56realized that we could learn so much from each other rather than just staying in one Silo

7:03about one disorder we can actually learn from what everyone else is doing in a

7:10similar field so anyway let me tell you a little bit more about Angelman syndrome

7:17with Angelman syndrome it’s a mutation on the mother’s 15th

7:24chromosome so if you look at this little diagram here what you can see is that

7:31the green is your is the chromosome you get from your father your 15th

7:36chromosome and the green shows that from your father’s chromosome it’s perfectly

7:41good in Angelman syndrome and what you get from your mother’s chromosome is has a

7:49mutation in my son’s case he has a deletion so he’s missing a chunk of his

7:5715th chromosome so there are these other ways of getting Angelman syndrome you can have a

8:03mutation you can actually end up with zero of your mother’s and have two of

8:08your fathers or you can end up with just a mistake that makes the chromosome look

8:15like it’s from the father when it’s really from the mother so why does it matter

8:22it matters because it turns out that in everybody your paternal chromosome on

8:29this one section of the 15th chromosome is silent the father’s genes right there

8:35are silent in neurons so it’s only the mother’s genes that are expressed

8:42and so if you have a mutation on the mother’s side you get Angelman weirdly enough if you have a mutation on

8:49the Father’s Side you get a totally different disorder it’s called Prada Willy syndrome and so it’s a disorder of

8:56imprinting this is kind of important because it’s the way we figured out how

9:02we could actually treat this disorder so uh

9:07there’s just like syngap for most of the cases of zinc amputation

9:13it’s just bad luck it’s de novo everybody has the same chance of getting

9:20it there are no known risk factors for most of these mutations that cause Angelman

9:27syndrome it’s just a spin of the roulette wheel and Angelman is about one in ten

9:34thousand supposedly incidents of live births

9:40and every woman is born with ten thousand eggs so really Every Woman born

9:47has the same chance of spinning that roulette wheel and getting that egg with

9:52the deletion or a mutation so this is a picture of my son Louie when he was a

9:57baby he was really cute he was really Smiley he was really cuddly and

10:05affectionate and believe it or not it turns out that’s a symptom of Angelman syndromeAngelman Syndrome Symptoms

10:13which I have to say it could be a lot worse I mean the fact that one of the

10:18symptoms is being happy and smiling and cuddly and affectionate that’s actually

10:23quite a godsend so what happened with Lou was that we

10:30started to notice that things were not going well with him uh when he was in

10:36his baby Hood I mean because I had four other kids I really knew and I was a

10:42nurse Midwife at that time so I helped all kinds of people breastfeed I helped

10:48them you know figure out how to handle their newborn babies and so I really

10:53thought there was something not right about the baby and I’m just gonna go back to that slide where it shows you

11:00again how Smiley he was and sweet and yet I knew there wasn’t something right

11:06and I kept carrying him to the doctors my husband’s a doctor

11:12all our friends were doctors and so I would take him to a party or a picnic or

11:17whatever and I would say look at the baby there’s something to matter with the

11:22baby what’s the matter with the baby and I’m sure everybody thought I was crazy

11:28but I I knew there was something that mattered I knew so well that I actually

11:34enrolled him in a study of communication at the age of four months I told

11:41everybody my friends and relations the baby’s not communicating with me and

11:47they all thought I was nuts because how can a four-month-old baby communicate but once you’ve had a couple kids you

11:54know that they do communicate with you they give you eye contact they try to

11:59get your attention they respond to things you do and he wasn’t doing that and yet at the same time he was smiling

12:06and cuddly anyway it was hard to figure out but I enrolled him in this communication study

12:13at UCSD because we lived in San Diego then and they did a whole battery of tests on

12:19him for a whole entire day and in fact he was rolling over then which was the right appropriate month for him to learn

12:26to roll over and at the end of the day they gave me

12:31the results and they said he can’t be a control

12:38okay that was bad they meant that there was something there was something the matter

12:46so uh we knew there was something but nobody could figure it out

12:51and I still kept asking every doctor friend I knew look at the baby look at

12:58the baby and my husband and I had a book called congenital malformations in uh

13:05humans and it was the old way that people figured out what genetic disorders uh

13:14there were because we really weren’t using the internet well at that point and so everybody had this textbook if

13:21you were in the field of Pediatrics or Midwifery or obstetrics you had this

13:27textbook on your shelf and we would shovel through all of those pages and

13:32every time we came to the Angelman page I’d say this isn’t that funny he looks a

13:38lot like the people on this page and my husband would look at it too and we would think yeah but he can’t possibly

13:45have that because he’s so bright and I don’t know if that’s because we were in denial or if that’s because

13:52intelligence is really complicated but what I knew then was that he had such a

13:58good sense of humor we thought he had to be really smart well like I said it turns out sense of

14:03humor is a symptom of Angelman syndrome and cognitive disability is also a symptom of Angelman syndrome so finally

14:11a year later after bugging everybody we knew we got a blood test and the one

14:18blood test they drew was for Angelman syndrome and so we had the diagnosis of Angelman

14:25which was devastating um because they told us

14:30he would probably never walk he would probably never feed himself he would be dependent his entire life he would

14:38likely never move Beyond a one-year-old developmental stage he would likely have

14:44terrible seizures he would never sleep and he would live a normal lifespan

14:49meaning that we needed to find a way to take care of him for at least 35 years after we were gone

14:56it was a very scary diagnosis

15:02so weirdly enough I was in Mexico at the time working at a Mexican Midwifery

15:08School there really wasn’t internet anywhere near me I had to walk down this path and

15:15beautiful San Miguel to the nearest internet and pay for some of the

15:20internet to be able to look up Angelman syndrome and what I saw there

15:26was that there was a conference in Finland six weeks later

15:31so I packed up my mom my Intrepid mother and the baby

15:38and we flew to Finland in July when it’s the night it’s the Midnight

15:45Sun and we were up all night because uh people with Angelman don’t sleep and

15:51there was Sunshine all night in Finland in July and I was pacing the lobby

15:59with the baby so my mom could get some sleep up in the room and at three in the morning there was

16:06also Dr beaudette art bodet also hanging out in the lobby because he couldn’t

16:12sleep either it turns out he was the man who had

16:18identified the gene for Angelman syndrome just a couple years before that this was 19 this was 2000 the year 2000

16:26he had identified the gene in 1996. and I got to know him in the middle of

16:33the night in the lobby in Finland and one of the most amazing things about

16:38him was that he thought Angelman syndrome could be cured

16:45that was pretty cool nobody else I knew thought that anything

16:52genetic could be cured and by the way people still think that

16:57people still think that just because it’s genetic means it’s incurable

17:04and in fact nothing could be farther from the case because now 23 years later

17:11we happen to know that having the genetic cause knowing the gene behind

17:18the disorder makes it imminently possible that we might be able to find a

17:24treatment or a genetic-based cure so that was a fantastic

17:30a piece of information or news for me to hear at that point in my son’s life and

17:37it set me off into um the research and I I’ve always feltAngelman Syndrome Research

17:42like that was incredible luck that it was incredible luck to get his

17:48diagnosis just in time to make it to the first ever international meeting that

17:54would it was incredible luck to meet art Buddha in the lobby in the middle of the

18:01night three or four nights in a row and chat with him about the possible research and I’ve always

18:08felt like a lucky person and I talk about this a lot I won’t belabor it

18:15um today but there are a lot of things that I think were lucky about our life

18:21and my life and uh about being a person with Angelman

18:26syndrome because right now if you’re a person with sync app

18:32or a person with Angelman syndrome it’s a pretty damn lucky time to have been born

18:37because if you were born 30 years ago you really had nothing but you’re born now there’s a lot of

18:45Hope so at any rate at that point art beaudette had this idea that maybe

18:52we could turn on the paternal Gene remember that paternal Gene is was off

18:58in everybody but it’s just sitting there perfectly good why can’t we just turn it on so he had a

19:06great idea to try to turn it on with methylating agents and those methylating agents were actually

19:11over-the-counter supplements so in fact I helped him start and with a

19:18lot of other people uh the very first trial human clinical trial in Angelman

19:24syndrome which had to do with trying to turn on the paternal chromosome with

19:30these methylating agents and then I’m going to fast forwardAngelman Syndrome Trials

19:35to 10 years later that did not work uh

19:40that particular trial we were not able to turn on uh the paternal chromosome

19:45and um we there were a couple other Trails started

19:50um also looking at the paternal chromosome trying to activate it that didn’t work

19:56and then we also tried a Parkinson drug and that didn’t really work and we so we

20:02we had a few clinical trials and at that point I started thinking

20:07nobody cares about this as much as me all these academics they’re just trying

20:15to get their next Grant they’re trying to publish they’re not trying to cure a

20:21kid it’s going to be up to me well that’s pretty silly because anyway it

20:27turned out other people did fantastic stuff and most of them were academics and there are fantastic academics but

20:33that was what I thought at the moment so I thought all right I’m gonna get a PhD and do it myself so

20:40I was probably the oldest person to get a neuroscience PhD at Vanderbilt I don’t

20:47know if I’m the oldest person in the world to get one but I’m I was pretty dangled because I was 50 when I started

20:54it and I did start out studying Angelman syndrome but uh in fact I had actually

21:01some really fantastic good luck uh working in the lab

21:07um look again there it is um we made stem cells and this was a

21:14while back now like 14 years ago or 12 years I don’t remember exactly when but

21:19stem cells ipscs were kind of new on the scene and it was hard to make them it

21:25was not um a simple protocol and I got lucky I

21:30made um stem cells in my first try and um I was able to

21:37um get some really good work done and then unfortunately my boss quit not the boss in this

21:45picture a different bus and that’s why I had to move into

21:50Huntington but I did learn a ton about Huntington at that moment I really had to make up my mind

21:57did I want to stick with it or quit because

22:02um I wasn’t going to be able to study Angel mini anymore I was going to have to study something else

22:08and at that point I thought you know what I’ve already finished I thought I’d already finished the hard

22:13part which is also laughable but I I don’t think you could do a PhD as a middle-aged person unless you’re pretty

22:20naive about how hard it is but anyway I turned over all my experiments and my

22:26data to Dr Carl Johnson’s lab and he worked on circadian aspects of Angelman

22:32syndrome and they actually found some fantastic stuff and we published a couple papers on that so it all worked

22:39out those experiments got done and then I joined this lab and studied Huntington and I’m still working with some of the

22:46people in that lab today that are actually working for Combined brain so that in fact was also a happy and lucky

22:54into that story and now if you fast forward an AngelmanAngelman Syndrome Treatments

22:59syndrome we have so many treatments coming down the pike and in fact other people while

23:07I was in the middle of making my stem cells and studying Huntington a lot of other people came up with fantastic

23:13treatment strategies for Angelman syndrome and so what it turned out by

23:19the time I graduated so these were the studies these were the the companies

23:25that were in the field when I graduated so it turned out by the time I graduated what we really needed were biomarkers

23:32and outcome measures we really didn’t need more drug Discovery in that seven years while I was buried under the hood

23:39the stem cell Hood in the lab all this happened but we still had to

23:45have biomarkers and outcome measures so uh I ended up being drafted by the

23:52two foundations which at that time hated each other and that happens a lot in the rare

23:59disease field but I tried very hard to stay in contact

24:05with both foundations and so they both hired me to run this thing called the

24:10A-bomb which was the uh Angelman biomarkers and Alka measures Alliance

24:16and what that was was uh uh

24:22um an opportunity to try to figure out how we could possibly measure

24:29whether any of those cool treatments that were coming down the pike would work or not

24:35so we had to convene everybody we could think of who were experts most of them

24:41who were competing with each other industry groups who were competing academics who were competing foundations

24:47who are competing we had to get them all to work together to try to come up with the best biomarkers and outcome measures

24:55so I did that for a couple years learned a ton and then decided to form combined brain

25:03and combined brain is the A-bomb on steroids

25:09so combined brain is everything we learned in the A-bomb only better

25:15so we’re trying to come up with outcome measures and biomarkers for 65 different

25:21disorders at the same time it sounds pretty crazy but it’s actually working

25:28and it’s working amazingly well so um first of all do I get to ask forWhat is CombinedBrain

25:35questions in the middle of this Olga or am I supposed to just go on and on for

25:41how long um you you can go through the presentation and then we’ll we’ll do the

25:46questions I think that might make it easier how much more time till should I because I have like 10 more minutes I

25:53want that’s fine you’re good you’re good okay so um this is basically a slide that sort of

26:01tells all the different things we do at combined brain so at combined brain

26:08the step one is the disorder has to have a gene identified

26:13actually we do have one disorder that doesn’t have a gene identified but they’re hot on the trail

26:20but normally they have to have the gene identified and once they have the gene identified

26:26then we have to find the patients so these are our all projects that we’re working on to find patients project find

26:34out we try to find kids under the age of 12 months which is actually really hard

26:40because a lot of combined brain disorders are like Angelman with my kid you know the baby doesn’t look quite

26:47right or might even have something like seizures and trouble eating or hypotonia

26:54or motor difficulties developmental delay but most the time

26:59doctors just keep pushing them down the road and say oh they’ll be okay they’ll be okay they’ll be okay they don’t get

27:05diagnosed right away so we’re trying we have project find out to try to find

27:10these patients under the age of 12 months we work with the beginnings project which is doing Universal newborn

27:18sequencing in San Diego and in Memphis Tennessee I’m in Tennessee now

27:24we moved to Tennessee about 16 years ago we also do all kinds of work to help all

27:32the different disorders and combine brain come up with ways to find repurposed drugs as fast as they can to

27:39find the cell models and then to test those drugs to see if they might work and so

27:47in low throughput screens that means like in a plate that only has a few cells on it or in Mouse models I’m going

27:55to talk about the buyer repository in a minute so let me get to that in a second because that that’s what I’m really

28:00going to focus on but we also do all kinds of rent-a-brain projects we have

28:08scientists on staff some that worked with me in the Huntington lab and some

28:13other ones new ones we have postdoctoral scientists we have grad students we have

28:18undergrad students everybody has to care about translational Neuroscience meaning

28:25they have to care about everything from the science to the kid who’s going to

28:30get the treatment and everything in between um so we help with all our different

28:36groups with whatever they need from a scientist’s perspective we also help our

28:42groups figure out how to collect Natural History what questions to ask on Natural History how to publish Natural History

28:51um we do disease concept models and we’re doing a disease concept model

28:56right now for syngap it just got started and uh in a nutshell disease concept

29:03model is a way to figure out what matters to patients and how do you figure that out you ask

29:11so we actually go to patients families to the parents of kids with sync app and

29:19we ask what is your life like what is your nighttime like what are meal times

29:26like what do you do for fun we we ask open-ended questions because we we want

29:32to know from your patient your family’s perspective what is your life like and

29:39that’s really important because from doing that we can figure out what we really need to try to measure what we

29:45really need to treat when we come up with the treatment strategy and then we help people get ICD-10 codes

29:52thank God you all have one already um we also then figure out let’s say we

29:58figure out well what you need to treat what you what’s really Troublesome to

30:04sync up families is communication and so that might be the end point for

30:11clinical trial that’s the most important so then we have to find out well is there a way to measure a change in

30:18communication an improvement so we took a a survey that was being

30:25used in Angelman syndrome because I steal as much as I can from the Angelman field and use it in all these other

30:32fields and that was called the Orca The Observer reported communication abilities measure it’s a survey and so

30:40we then try to expand it to 12 other combined brain disorders including

30:45syncope and we have a lot of other things like that too we found out that another thing that was really important to families is

30:52the toileting abilities is it is a kid able to use the toilet independently and

31:00if not what parts of toileting can they do can they tell you do a sign when they

31:06have to go to the bathroom all those things so we have a new measure that we’re developing to try to develop how a

31:13kid is progressing towards independent toilety which in my family’s life is

31:20really life-changing if my kid at 24 years old could completely toilet

31:27himself it would make it possible for him to go to different facilities to

31:32different programs to all kinds of different things right now he still

31:38needs help and so any Improvement in that would be fantastic and then we also

31:43help all the groups go to the FDA talk to the FDA talk to the NIH apply for

31:50Grants and then design their clinical trials so we do all those things that combine brain but

31:56our big project right now the big biggest project is the bio repository

32:03and I’ll tell you why let me see what my next slide is um

32:08my next slide is not exactly the one I wanted to tell

32:14you about so I’ll go back to this slide whoops and talk about the buyer Repository so

32:20the buyer repository what one thing we found out is that for all of our different combined brain disorders they

32:28might have stem cells at one University and they might have uh plasma at a buyer

32:38repository or they might have um early stem cells but not completely

32:45validated stem cells in a company that was going to do a clinical trial

32:51and they’re all over the place so if somebody wants to study syngap and maybe

32:58they might want to compare it to another synaptic disorder like stxbp1 or

33:05dlg4 mutation for example and so they might want to have

33:10um plasma from syngap1 sdx bp1 uh 6a1

33:17and dlg4 four of Our member disorders they might want to have those but to get

33:24those stem cells or plasma from all four of those disorders they might have to go

33:31to 25 different institutions they would have to sign contracts with each

33:37institution they would have to have IRB approval for each of those different

33:42things it could slow down research by years

33:48so what we realized is that if we created a buyer repository for Combined brain disorders we could actually

33:57make it one central place where researchers and Industry could get all

34:05the samples they need quite easily and what we wanted to do was make it so

34:12that all of those samples were actually uh governed by Your Own Foundation

34:18so you have a say and who your foundation has a say in who studies your

34:26disorder let’s say that one one professor in Toronto decided to study

34:35singap and they request every single one of your samples that might not be so

34:42good if we were just a regular by repository whoever came first come first serve

34:49could request those samples in this case your foundation can have a say and say

34:54no we can’t release all of our samples to one person we could release a few to

35:01that person and a few to somebody else and meanwhile we can go out and collect more and we also when those people end

35:09up paying the fees to be able to get those samples we return some of that to

35:14your foundation so that your foundation gets to decide how what samples they

35:21want to make and where those samples get distributed and then it goes back into your

35:29foundation so it’s sustainable so that you can keep putting more samples in the buyer repository so

35:36what’s really cool I’m going to stop sharing for a second about the buyerBio Repository Overview

35:41repository we started building it we only opened it not even a year and a half ago

35:48and luckily syngap was one of the first groups to put samples in the bar repository which is fantastic

35:56and we already have now 400 individuals represented in the buyer repository

36:03across a lot of combined brain disorders some of those are patients and some of

36:10those are their siblings or their parents so we have patience and controls meaning we have blood or stem cells or

36:18Plasma in the buyer repository from both patients and controls and the thing is

36:25it’s kind of like the Field of Dreams once you build it they will come and so

36:31what happened we started the buyer repository your foundation was one of the initial ones you put samples in you

36:39made stem cells out of those samples industry learned about those and the

36:45others and the fact that we had controls and we now have a biomarker study which

36:52will be funded so that in fact Your Own Foundation does not have to pay for it

36:59and yet you will actually get the data from that it’s not just for sync app it goes

37:07across 20 combined brain disorders and that’s fantastic because they can

37:15compare for example all those synaptic disorders the biomarkers to each other

37:21and they can also it makes it more accurate because if something is increased in sync up but decreased in

37:28STX bp1 and the same and and not changed in the sibling controls for example that

37:37shows you that it’s probably a pretty good biomarker so we have a biomarker

37:42study now we have another biomarker study that goes across every single combined brain

37:50member disorder all you have to do is donate your patient’s blood sample

38:00and hopefully also sibling controls because that they’re really important to

38:05have too age matched or right around the same age or from the same family

38:10go and do that donation and your sync app can participate in those biomarker

38:17projects so what’s really cool about this and I have another slide but I’ll I’ll I I

38:24don’t wanna waste time finding it so we’re calling it the bio repository Road Show

38:32so what we’ve gotten is permission from all these different foundations who

38:38happen to be having family conferences this year all around the country I think

38:44we’re missing uh the Seattle area but all the rest of the

38:50regions of the country are having a family conference and so we’ve gotten

38:56permission from all of those different groups to have the combined brain team

39:01go to the conference for free and collect samples from anybody in

39:08those cities who wants to come in for half an hour an hour give a blood sample we’d like you to

39:16bring some pee too if you wouldn’t mind and answer a survey you always have

39:22dancers survey uh the Vineland everybody’s favorite but

39:27you can do it from home a survey about seizures and a few things about your own

39:33self uh where you live socioeconomic ethnicity things like that that’s all

39:40you have to do and you don’t have to go far away you can do it in a city near you with the

39:46biorepository Roadshow and so by doing that you can participate in Combined

39:52brain um fire repository and in the biomarker projects and uh sync up one is highly sought

40:01after right now so that’s a really good sign it means

40:06that there are a lot of groups that want to do research and try to find a treatment for sync app

40:11so um that’s my spiel and I’d love to um answer any questionsInterview with Dr Michelle

40:21thanks Harry Joe um I really appreciate you doing this as as you guys probably figured out Terry

40:28Joe needed more things to do like she needed a hole in the head and I asked her to do this because a I I talk about

40:35her a lot and I wanted you guys to see her in person but B this this biomarker

40:40um well there’s three reasons a what I just said B it’s important to realize that we’re not figuring this out for the

40:47first time that people like Angelman and druvet and Rhett have gone before us and we’d be stupid not to

40:55follow right behind them and learn as much as possible and and I and by

41:00joining combined brain very early on we were one of the first one of the early early joiners

41:07um we we are doing that we are actively working hard to benefit from Dr

41:13Michelle’s generosity because quite frankly if we curious in gap in 20 years the odds of me starting a new

41:18organization to help the next hundred genetic diseases close to zero like there’s no there’s

41:23actually no chance of that happening so I very general very grateful um that Terry Joe has taken this on from

41:30what I can tell there’s there’s nothing in it for her but the third thing I really want to double click on this because Dr Michelle you just said so

41:36many important things there are com there are sponsored biomarker projects happening through

41:44combined brain this is huge right I want to be clear for the audience before this

41:49happened through combined brain people were coming to us and they still are and we might do the side project but asking

41:56for like significant amounts of money to look for a singap biomarker and it

42:02was like a major undertaking and it wasn’t just an undertaking of give this scientist a bunch of money it’s give

42:07assigned us a bunch of money figure out which platform to use those are two really big things and figure out the

42:13logistics of getting blood out of because you

42:18can’t do it with three patients right you need dozens of patients how are we going to get samples from 50 patients

42:23and their siblings in one place are we going to fly 50 families to one

42:29place and collect them are we going to fly someone around the country and I mean it’s a logistical nightmare that

42:35honestly I was stuck on and then combined brain rocks up and they’re like we have all these members we’re gonna have all these conferences we’ll just

42:40collect samples everywhere Terry Joe I can’t believe you didn’t say it this past weekend in Boston grin had a conference we collected samples from

42:47three singapians that’s three steps Closer by the way the goal is at least

42:5250. it’s my goal and and we’re gonna get there so I I think the um

43:00I think this was billed as um learn about the buyer repository so I

43:06would encourage questions on the buyer repository and the takeaway is just in case you want the right answer for the

43:11quiz at the end is find a way to get you and your loved ones to a place where you can give samples and Terry Joe we should

43:18talk about why it would be good to go to a combined brain collection as opposed to just the

43:26quest in the back of Safeway down the street yeah that’s a good idea yeah so theseBiomarker Studies

43:31biomarkers studies they’re done on blood which is really good because before that

43:37we had to do biomarker studies on cerebral spinal fluid which you have to get from a spinal tap and nobody likes

43:45that so these uh studies are from blood but you have to spin the blood down

43:50immediately you have to separate it into plasma and you have to flash freeze it so we have

43:56to do that within an hour and you have to do it all the same way which is why we have our combined brain teams going

44:02to these conferences so that we’re processing it all exactly the same way

44:07so the biomarker studies they don’t work as well if you

44:13don’t do it right like that so we have to do all of that that’s why we need you to walk into one of these combined brain

44:21conferences and do it there I see a hand up from Olga

44:26go ahead Olga yes Terry hi quick question um if we can we get a list maybe to to

44:34promote this as to all the different locations you’re at just because I know I know we have our family conference in

44:39December but like if there’s something going on in Houston maybe it might be easier for me to get everybody there

44:46we do have a list it is a working list because we’re still getting the final

44:52formal permissions from some of the different uh foundations to be able to

44:57collect at their conferences but you all will get the list so that you can put it

45:03on your own website so you can put it on this in-gap research fund website and so

45:08that you all can send it out in your own newsletter or your own materials we’ll

45:14be sending it out too but um the list today isn’t fully complete

45:21um but you will have a list really soon and in fact once you have it if you have

45:26this website post if you have this webinar posted um you could just put it right under

45:33this webinar we’re definitely going to do that but the the the big Point here is

45:39um these this is a very precious study this is going to happen

45:45sometimes towards the end of the year maybe early next year and it’s really this is the year for sample collection

45:51so when we do post this list try to get yourself to a collection site

45:57um definitely you should be coming to our conference anyway if there’s a collection site near you and you’re coming to our conference I’m

46:03just I’m just taking a flyer here go to the go to the conference near you because for two reasons a get the sample

46:10processed in the biobank ready for sharing right and B

46:16we have one of the last conferences of the year right before AES I’m actually thinking that our collection room is

46:22going to be pretty crowded I think a lot of people are going to figure this out and um as in Orlando a lot of people are

46:28going to bring their kids oh just go the srf conference that’s fun anyway so I would strongly urge every family

46:34watching this figure out when the nearest collection to you is as soon as possible and get it

46:40done as soon as possible because those samples we’re going to take plasma we’re going to put them into at least one

46:46maybe multiple biomarker screening projects and we’re gonna try to find a biomarker for syngap

46:53I have a speech on this but since we have Dr Michelle why just could we go one-on-one here like why does the buyer

47:00marker Matt what is this buyer who cares what is this it’s just science that’s a great questionHow do you know if a treatment is working

47:06um so here’s the thing you treat singap let’s say

47:12you give a gene therapy and it works

47:18how do you know if it’s working or not so hopefully your kid with singap will

47:25jump up ask to pass the salt go into the kitchen

47:30and wash all the dishes right but it’s usually not like that

47:36usually what happens is that it’s a very slow progress if it’s working

47:42What You Won’t See Is some miracle the day of the first treatment

47:48what you hope to see is slow steady progress

47:53so if you’re a pharmaceutical firm you’ve invested all this money in this

47:59treatment you have to know is it actually doing what it’s supposed to be doing so you

48:07the family have to report on is your kid or the adult within Gap

48:14doing something better or worse but hopefully better than they were doing before you have to report that that’s

48:21really crucial but it might take a while it might take a really long time it might take months

48:27it might even take years to really kick in so if that’s the case why would the

48:34company stick with it because if they can’t see immediately immediate results

48:40if the kid doesn’t jump up and say pass the salt then how do they know if it’s actually working

48:46well how they know is because they could see some marker some biological thing

48:53that says the gene settled in it’s making more sung up

48:58the gene is doing what it’s supposed to be doing now we just have to wait for

49:03the brain to kick in for everything else to start working so if you have a

49:09biomarker that shows that the gene is doing what it’s supposed to be doing

49:15even if you can’t see a big Improvement right away in the patient you can stay

49:22the course because you can see that the gene is doing what it’s supposed to be doing and that means hopefully it should

49:30in the end improve your life that’s why biomarker is important

49:36thank you [Laughter] any any other questionsQuestions

49:42I have one more in mind just out of curiosity um with the international epilepsy

49:48Society overseas is that something we can do across the pond or is it just

49:53within the U.S right now that’s a really good question and I’m sorry to say right now is only in the

50:00United States we have our uh we have our site set on

50:07overseas and right now especially Europe but uh we it’s not going to happen this

50:16year all of the collections for these pre-comb these biomarker projects have

50:21to be done by December they have to be done by December it doesn’t mean there won’t be another

50:27experiment after this but the ones we’re talking about right now we’re doing them all by December in

50:33January we ship them off so everybody’s got to get them this year I think there was another question maybe yeah I just I

50:40just gave her permission to talk we have um we have another parent here who’s a fellow PhD level scientist Julia you

50:46want to just ask your question yes absolutely well first of all thank you so much this was fantastic thank you

50:53very inspiring and you know we all need hope so I have one quick question if

50:59there is no sibling um do you collect from parents what is that an issue

51:04uh no it’s not because we can use age match controls from other families to

51:10match the the person with syngap but we would like to collect from the parents

51:15as well we won’t use every project won’t have the same controls so we might not

51:23use the parent samples right away but we don’t want you to think they’re a waste because those controls are also very

51:30important so um if you could give parent controls that would be good too your

51:36foundation will end up covering the cost of storage for those samples but it’s 10

51:42cents a month per tube so I think you guys could raise sell enough brownies to pay for that all day long okay all day

51:50long sorry Mike I have another question this one’s small audio then the answer is

51:57probably no but I’m really curious about the measurements that you will be you know collecting and analyzing is at

52:04least available by any chance or what are you going to be yeah so in these two projects that are

52:11coming up now they’re looking at plasma so they’re looking at various uh plasma

52:19markers um which if you have studied this you

52:25know would either be protein expression or gene expression okay wow

52:32so all these big kind of omics studies send that’s something along those lines

52:38yes let’s talk one-on-one yes yes sorry okay no no no apologies I just there are

52:46a variety of ndas in play let’s let’s talk okay

52:51okay somebody else Lauren oh

52:57Lord Peterson is wondering if we happen to have a gathering of a bunch of syngap families how many would be enough to get

53:04a combined brain team to visit to collect samples

53:09we would rather you have that gathering at one of the places that’s already

53:15having the conference okay because if you do that we’ve already got a space there we’ve already

53:21got permission to do the collections there we’ve got a phlebotomist whose

53:27whole job is to you know so if if you want to do that though you can

53:34uh and I think Mike I’ve already given him a bid on that for how much it would

53:40cost and we can Circle back but if you plan your gathering at a conference the

53:47cost is zero and and because there are some sponsors who have

53:53already agreed to cover X conferences right so I think that the audience needs to understand you know as we need a

53:59phlebotomist we need we need an IRB we need um a room we need somebody who’s trained

54:06to stick kids and adults we need someone else who’s PhD level scientist who then takes the samples and Spins them down

54:12right and then we need it flash frozen and then we need a big fat shipping label to send to the big fancy lab where

54:20combined brain has a part that there’s a huge amount of complexity here that all costs money and the beautiful thing

54:26about combined brain is industry is sponsoring big chunks of this so our

54:31cost is very low there is a cost to collection there is a cost to supplies there is a cost of storage an srf

54:37happily covers all these costs and we also happily encourage you all to do birthday fundraisers and all the

54:43different fun thank you dude keep doing the fundraisers but like I want you to understand one of my agendas here is for

54:49everyone in srf understand the Staggering well I’m staggered because I’m not a scientist but the complexity

54:55of getting this stuff done is can really I and and this combined brain is such a

55:02gift because it takes on a lot of that complexity by bundling us and Terry Joe raises money and she hires great people

55:08Kristen and Anna and all these incredible Souls so I just want you guys to understand the whole chain here but

55:14David your point is taken I’ve asked the same question and and if we do have a big West Coast Gathering or something

55:22um I we will bear the cost of flying a couple people out paying a phlebotomist covering all those costs but the the

55:29real push is to get us to and frankly crashing other rare disease conferences is kind of cool because you sit in the

55:36back and you’re like why aren’t we doing that and then you you know and and Terry Joe I Wanna while I’m doing just random

55:43unsolicited advertisements I have recently gone on the mission

55:48um so you know within our community like so many there’s the protein truncating variants who are nonsense and frame

55:54shift we know that therapies work for them and there’s the missense variants and

55:59it’s less clear what we need to do a lot of work to understand what missense mutations are doing right and so in

56:05addition to collecting the blasma the blood banking the plasma making it available for buyer samples the

56:11partnership with combined brain allows us to make stem cells and isagenic controls and one of the things I say to

56:18families Ad nauseam is you don’t know how lucky you are to be able to just raise ten thousand dollars 10 11

56:25whatever to to make a stem cell and an isagenic control like this is pretty recent and 10 or 11 is a kind of a

56:33screaming deal agree disagree it’s really true I mean when I started

56:40my PhD you know making a stem cell line was fifty thousand a hundred thousand

56:47bucks um recently very recently it was like a year ago it was always fifteen thousand

56:54bucks we’ve gotten because we’re doing a lot of them we’ve found a way to do it uh with

57:02certain Labs that is a whole lot cheaper and so what also happens is that if you

57:10get an extra tube drawn the day that you come in to draw the blood for the

57:15biomarker projects or for the buyer repository if you get an extra tube drawn and you put that in the buyer

57:22repository your foundation can decide if they want to process it into different

57:28parts so pbmcs is one of the parts and if you freeze down those pbmcs you can

57:35decide anytime in the future whether you want to make stem cells out of them or not so if people need stem cells in the

57:42future you would already have those pbmcs in the freezer in the bar

57:47repository ready to make stem cells that’s another really amazing thing to

57:53do um this year while you’re donating to the buyer repository donate an extra

58:00tube like that if the foundation is willing to do that so then if you make

58:06stem cell lines from all these different patients with all these different mutations and maybe different phenotypes

58:14like some people more severe than others maybe you can actually figure out why is

58:19it that some people with the same mutation are doing better than others and maybe you can actually use those

58:25stem cell lines to try new drugs and new technologies and new uh treatments so

58:31yeah it’s really I’m really really proud of what we’ve done here in a short space

58:37of time a combined brain and uh we’re getting requests for those stem cells

58:43that are made every day yep and I we anyone paying attention at

58:50srf knows that we had we made a bunch of cell lines of rare base that face has happened we are now making all our cell

58:57lines with combined brain and I have said on my podcast repeatedly scientists

59:02and Industry meets us they hear we have cell lines they do not look at the list they do not finally analyze they see how

59:08many cell lines do you have I say we have six at rare base and three over here and four over there and they say yes I will take them all

59:14because remember Guys these are not unlike plasma so plasma is is precious

59:21right we draw it we use it up and test it’s gone cell lines you make them

59:27and then you they’re Immortal and they’re re and they’re expandable is that the right word so you can make more

59:33out of the line you give so once you give and create once we create a style us ipscs from your patients we can then

59:43reproduce them and make as many as we need right industry pays like small change to get these things but we

59:48use that money to expand them into more and more and more and we not only make a sell line but we make an isogenic

59:54control which is where we use crispr to take the mutation out so so in a

1:00:00personal example we make Tony’s cell line which has Tony’s mutation and then we crispr out Tony’s mutation and we say

1:00:07this is what it would look like if Tony was normal so we can do some things

1:00:12if Tony were in a dish so yeah Tony in a dish it’s it’s so

1:00:18I really encourage families give blood to the buyer repository we

1:00:24need the plasma in 2023 that’s the headline by the way you could also have

1:00:30an opportunity to give an extra vial yeah whatever it costs we’ll spin those down so that when you realize oh my gosh

1:00:36I want a stem cell line we can make it okay people are so sick of hearing me say

1:00:43that but I’m just going to keep singing so I I gotta say people a lot of times have

1:00:50questions about this I don’t know if your community does but we might as

1:00:56well answer them if we can but a lot of times people have questions like who’s gonna use my kid’s sample or why would I

1:01:05contribute to some company who’s trying to make a profit okay let me tell you

1:01:10something my kid I have written uh the same letter to

1:01:17just about everybody I write I say I renounce HIPAA I want no privacy I want

1:01:25everyone to know everything about my kid and me and my husband I don’t make all his siblings do that

1:01:32but because uh we want to find a cure and so yes if if a profit making company

1:01:40wants to use my son sells in order to look for a treatment for my son’s

1:01:45disease I hope they make it and make a great profit on it because I want them to have

1:01:53a great company that can be making that treatment for decades to come

1:01:58so that’s my opinion on it uh I know that other people have other opinions I

1:02:06I’m happy to hear them and talk about them and um so let me know if you have

1:02:11any questions about that stuff yeah yeah here here I mean a company

1:02:18that doesn’t make a profit is called out of business so you know this

1:02:23this nonsense needs to stop like we want and let me tell you the companies that

1:02:28are publicly working on syngap Stoke Praxis Regal others I can’t name

1:02:35um we’re spending a lot of money advancing syngap research right and or sponsoring this by repository that

1:02:42frankly we would we would have to do a lot of bake sales for so um or not the Spy repository this biomarker exercise

1:02:48so yeah I’m with Terry Joe all the way but the good news it’s not that binary though right Terry Joe like yes we

1:02:55should put these in a buy repository and encourage science both industry and academic to work on it but you don’t

1:03:01they don’t come with your kid’s name on them like we we go to Great Lengths to use industry rest practices to um

1:03:10but this idea that oh somebody’s gonna make money one day Hallelujah because if

1:03:15they’re making money they’re doing something people would pay for which is a therapy that our kids need right and and and so I I don’t want to

1:03:22conflate um I think there’s two conversations is industry bad no industry is desperately

1:03:29needed as my privacy protected yes your privacy is protected and those are two separate

1:03:35conversations but yeah anyone’s got questions yeah

1:03:41I definitely don’t want to make you think for a second that you would be identifiable because you would not your

1:03:48child your sibling control the parents are not identifiable once the sample

1:03:53goes into the bio repository it’s completely de-identified what we do attach to the sample is the variant so

1:04:01we know which mutation is there and uh we will attach some of the

1:04:08phenotype data meaning has the kid recently has had a seizure or how uh how

1:04:15many what are his abilities in terms or her abilities in terms of Developmental abilities so we would have those things

1:04:23but it’s not identifiable so very important that I didn’t muddy the waters

1:04:29there I got to make a plug for my next project that’s coming up okay the next project we have is going

1:04:38to be an EEG Repository and so here we are sticking blood and

1:04:44urine and whatever else you have in our bar repository and we’re going to be

1:04:51using that for a lot of experiments but we also need eegs in a repository

1:04:58and that might seem kind of weird but it’s very similar to having the blood in

1:05:03there because eegs themselves are a source of biomarker so for Angelman

1:05:12we ran this natural history study for 15 years and while we were doing

1:05:18that we collected so many eegs let me tell you from hundreds of kids all around the world

1:05:25and uh those eegs were in all different kinds

1:05:31of software they were in institutions all over the place and uh really for the first five or ten

1:05:39years hardly anybody ever even looked at them because it’s just so much data and

1:05:45so much to go through and nobody really knew how to handle it on a big scale and

1:05:51so they weren’t all put in one place once we got treatments coming down the

1:05:58pike Annie since all it goes Gene therapies repurposed drugs new compounds

1:06:04everybody needed a biomarker and people started looking at those eegs

1:06:10to see if they could find a pattern that was consistent among people with

1:06:16Angelman syndrome we had to do a hell of a lot of work we meaning the field not

1:06:23me personally to be able to make those eegs all uh analyzable by one kind of

1:06:31software or in one pile or by one researcher it took a lot of work

1:06:38but we did it and what we found in the end was there

1:06:43is a biomarker in those eegs a certain pattern it’s a Delta High Delta pattern

1:06:52there is a biomarker for Angelman syndrome okay so that’s cool we have a biomarker for Angelman Center but what

1:06:59if you make that better does it matter to the kid okay this is the really cool

1:07:06part you reduce that abnormal Delta it turns out

1:07:12you can also tell that kid is better the motor skills match so as that kid gets

1:07:19better as the motor skills get better the Delta power is going down

1:07:25so that Delta power is now a great biomarker for treatment for angelman’s

1:07:31syndrome we want to have that for all the disorders in Combined brain

1:07:37so what we need are hundreds and hundreds of eegs and we need them all

1:07:45collected in the same way and we are working on that right now with the working group this one will also be

1:07:51funded externally meaning that your your foundation will

1:07:57not have to pay for the collections we will be collecting these eegs at your

1:08:03house we will send the technologist to your house to collect the eegs

1:08:09we will also have to ask you the same old surveys you had to fill out for the blood samples

1:08:14and we will de-identify all of that and we will put that in a repository so that

1:08:21people can study those and see if they can find good signatures that are consistent maybe even consistent with

1:08:28the blood biomarker so that’s our next project called it’s the EEG Repository

1:08:37is that not exciting you’re not excited oh I’m so excited people just people know that I’ve been obsessed with EJ we

1:08:44need an EEG biomarker more than forgive the expression damn near anyone because I think a lot of these diseases have

1:08:49seizures that you can see and syngap seizures are hard to see so when we we’re not if but when we find an EEG

1:08:55biomarker for syngap I think it will um remove one of the major barriers to

1:09:00syngap and trials which is I mean we’ve already had I can tell you already um we had one company come and if you

1:09:08remember the SSB the Sleep seizure and behavior survey we did through citizen a company did a survey with us to test if

1:09:15there were enough reportable events and people did the survey and guess what there weren’t enough reportable events and guess what that company is looking

1:09:21at another disease now so it’s a it’s a very real risk for syngap that because we don’t have reportable seizures people

1:09:28don’t know what’s a measure and therefore will not pursue us now this was a repurposed drug that will hopefully come available for us later in

1:09:35life I’m watching it but is this a real risk and I think the EEG biomarker is a

1:09:40massive thing that like every other massive thing we should do I’m grateful

1:09:45we can do it in partnership with combined brain because we have Terry Joe bouchelle’s expertise her network and you know srf

1:09:53is a strong player and we’re stronger with combined brain

1:09:58thanks cool any other so that one’s not ready yet for prime time but it’ll be

1:10:03ready soon so do the blood this year do the eegs next year believe me

1:10:09yeah other questions I thought I saw some more coming in the chat but are you guys reading them out

1:10:16of the chat will it be in Denver um that’s just me okay

1:10:28there is yeah there is one in Denver and yes we will be in Denver we I I’m just a

1:10:34little worried because I I don’t know if we got the formal written permission yet so hold off okay find that until I give

1:10:42you the whole list okay okay um does somebody else have a question

1:10:50we’re out of questions thank you Terry Jay this was awesome Mike I’ll let you finish up and no no

1:10:58that’s it I gotta say one more thing sync up is hot

1:11:03and uh I’m telling you and part of the reason people ask me why

1:11:09is there so much attention towards syngap right now and uh because really you know you don’t

1:11:16have there are other disorders in Combined brain that have similar incidents there

1:11:22are other disorders in Combined brain that have similar symptoms most of them have similar symptoms

1:11:27so why is sync up so hot I’m going to tell you why sync up so hot because you guys have done a whole bunch of work to

1:11:34make it easy for people to do research on syngap I’m not kidding you all the

1:11:40stuff that you put at citizen all the stuff the natural history that you’re collecting the samples that you’re

1:11:47collecting the research that you’ve been funding it’s working people are noticing

1:11:53they talk to me and ask me about syngap a lot and by people I mean researchers

1:12:00industry members clinicians sync up is hot and it’s because you all have made

1:12:07it hot and it seems kind of weird to have to make a rare disease hot but I’m

1:12:13telling you the easier you make it for people to do research the easier though they will actually find a treatment for

1:12:20your kids and you’re doing it that’s all thank you I didn’t write that

1:12:28no you didn’t all right thanks so much y’all that that

1:12:34was fun and uh and I’ll be seeing you around okay thank you all right bye bye