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Connecting ALS is a weekly podcast produced by The ALS Association in partnership with CitizenRacecar. We aim to discuss research and technology developments, highlight advocacy efforts, and share the personal stories woven through the community.
Jeremy Holden:
Hello, listeners. Before we get to this week's episode, a quick programming note.
On April 25th, the FDA announced it had granted accelerated approval to tofersen, a treatment for people with ALS tied to mutations in the SOD1 gene.
This is a significant victory for the ALS community and our efforts to make ALS livable for everyone everywhere, until we can cure it. We will have much more to say about the approval of tofersen in next week's episode.
In the meantime, let's get to the show.
Dr. Virginia Lee:
Some of them actually thought that my work was BS, this was when it first came out, and they didn't believe it, but now they're working on it, that shows this is one of the aspect of ALS that they cannot follow and examine.
Jeremy Holden:
Hello, everyone, and welcome to Connecting ALS. I am your host, Jeremy Holden.
Every year, the Sheila Essey Award for ALS Research is given to acknowledge and honor an individual who is making significant contributions to research. The award recognizes seminal research breakthroughs in the search for the cause, prevention, and cure for ALS.
Past recipients have used the funds to continue ALS research or to support promising young scientists on their research teams. Since 1996, the ALS Association and the American Academy of Neurology have jointly chosen recipients of the award.
The award is made possible through the generosity of the Essey Family Fund, through the ALS Association Golden West Chapter. The award is in memory of Sheila Essey, who battled ALS for 10 years and died from the disease in 2004.
Richard Essey, Sheila's husband, served as a national trustee of the ALS Association and is one of the founders of the Greater Bay Area Chapter, now the Golden West Chapter. The ALS Association and the AAN are deeply grateful for the unwavering commitment of the Essey family in continuing to support this important honor.
This year, the Essey prize was awarded to Dr. Virginia Lee. Dr. Lee is the John H. Ware 3rd-Endowed Professor in Alzheimer's research at the University of Pennsylvania Perelman School of Medicine. She is also the Director for the Center of Neurodegenerative Disease Research and Co-director of the Marion S. Ware Center for Alzheimer's Drug Discovery Program.
I recently caught up with Dr. Lee to talk about her contributions to the field and her celebrated career.
Dr. Lee, thanks so much for being with us this week on Connecting ALS.
Dr. Virginia Lee:
You're very welcome, yes.
Jeremy Holden:
Before we get into some of the nuts and bolts of your work, can you tell us a little bit about how you found your way into neurological research, generally, and ALS more specifically?
Dr. Virginia Lee:
Yeah, so this may take a few minutes.
Jeremy Holden:
Sure.
Dr. Virginia Lee:
I have a very interesting background, I guess. I was born in China, after the second World War, and then my family made our way to Guangzhou and then eventually, when the Communists came, we went to Hong Kong.
So in the early 50s I was in Hong Kong [inaudible 00:03:16] until 1962. Then my mother sent me to England to study piano, to study music at the Royal Academy of Music.
Jeremy Holden:
Oh, wow.
Dr. Virginia Lee:
And then I went because I just couldn't wait to get out of Hong Kong, it was just a small place. So I just was very keen to travel. So I went to London and then after about a year or so I realized that I don't really have any talent to be a pianist. So I decided to go into science because I was pretty good in science when I was in high school.
So I got my bachelor's degree, I got my master's degree in biochemistry. I didn't know what to do with myself, I said, "Well, if I get a job I wouldn't be able to support myself so well, and so maybe I should get my PhD." So I came to UCSF, University of California in San Francisco to do my PhD because my mother was living in L.A. permanently and I thought that if I lived in San Francisco, it would be a best compromise for me to see her regularly and not have to live with her.
Jeremy Holden:
Sure.
Dr. Virginia Lee:
So then I did my PhD and then I still wanted to travel, so I went back to Europe. I went to Holland for one year to do neuroscience, actually, but I did Holland because the way of working is very different from us in the U.S.
So then I decided to come back to the U.S. to complete my post-op. So I went to Children's Hospital in Boston and so I did my post-op, learning how to do animal models. So for my PhD, I actually did a lot of biochemistry. Actually, those are important because I actually was taking tissues and wind them up and then do biochemistry to isolate proteins. So that was my PhD.
So for my master's, for my postdoc, I wanted to learn about animal models. So I went and worked with Mike Schalaenski at Children's Hospital and to learn about animal models. And then I'd really, I had no mentorship whatsoever, so I didn't know what to do. And at that time I met my husband and he was a neuro pathologist and so I decided that Smith, Kline, and French, that's what they call at the time, tried to recruit me.
And John actually was amenable to go from MTA in Boston to Philadelphia to Penn because we had a very good program in neuropathology. And so we got here and then I worked at Certifi five for a year. I hated it. And then John Sparse, which was my boss eventually and told me that if you get some grants, you have a job.
And so this is important for people to hear because most of the time now that if you can get ones grants, then most places will give you soft appointment. And so I did. So I got two grants. So I was an assistant professor, but at the same time I was worried that I wouldn't be able to make it. So at this, I actually went and did a MBA at the same time at the Warland school because they have a weekend Wharton school.
So I did that and I did my science and I realized that at that time that if I could do both of them together, I should be able to make it in science. And so I decided to just go full time in science. And so basically at that time, it was in late in the eighties. So we started working together, John and I, but nothing about NuGen is the topic that we often about.
And so John taught me all the neuropathology that I know. And so I'm a biochemist. So with the neuropathology knowledge, then I can then go and isolate each of the protein. We actually decided that's something that we would do starting in the 80s to systematically give a molecular phase to all the pathology that you see in all of Neurogen diseases starting with tangles. And so the second in the tangles was easy because I was working on neuroforamina and people thought that tangles at the time in the 80s were comprised of neurofilament, and I knew that it was not.
So I actually went and proved that it's tau. And so since it was 1991 and then we decided to go after the protein in Lewy body in Parkinson's disease and dementia with Lewy body. So we ID [inaudible 00:07:28] and as the protein. And then finally we realized that there are this chunk of disease like with FTD and ALS, and we just didn't know what the protein was. They were ubiquitinated.
And so eventually I was able to show that it's a protein called TD before three. And I suspect that, no, I suspect, I know that PTB 43 made the biggest impact because it was something that nobody knew. So it really opened up an entire seal altogether.
And so I just kept working on animal models and doing, and human pathology, doing human pathology, really very important. And people don't recognize in the significance of it and all often they have no access to them.
And I was very lucky because I was married to a neuro pathologist whose job is willing to do diagnosis of these neuro degeneration diseases as well as other diseases as well. And so I can get my hands on brains that in fact what John did was to develop a brain bank and which other people can request brain tissue from our brain bank. So it's at your web base, so you can go into the web, you can search for patients with dementia, with lewy body for example.
And then you can even say that early onset and duration of disease and all of that and information would pop up. So it's really very useful. And so that's how I got started, how I did all the work and why that it was successful, particularly with the human and aspect of it, because of my relationship with my late husband. John Trichinowsky.
Jeremy Holden:
You mentioned the importance of grants in your world and the world of research in academia. You received or you're leading a team of researchers received a grant from the ALS association's Barnett drug Development Program. What can you tell us about that research about microglia and the novel therapeutic that you're looking into?
Dr. Virginia Lee:
So that grant was actually submitted by a former post-op. And from, she actually was from Australia. And so basically we did a study before she joined us and basically looked at all the genes that are changing in our animal model of als. And so there are these, you basically do transcript, transcriptomic analysis, and then you'll have a bunch of genes and then they're either go up or go down. Then you say, okay, and which one do I think it's more important? So she went for this gene called Axel, and so she applied to ALS foundation, she got the grant.
Unfortunately, she was not physically very well, so she basically started the project and she was not able to, the project is actually still ongoing until spring of next year. So I have another person who's a junior faculty and civil reporter, and she's had taken over that responsibility.
So the study had already initiated. So what Sylvia is doing is trying to and complete the study. And I don't think that we know the answer yet because I think that a lot of this time it's just you do a time course and you wait until there's some phenotype. We know that because we know that these two groups are different, but we just haven't know the scope of it. So I think that most likely by NextGen and Spring of NextGen, we'll have a conclusion, the study, then we'll see how important Axel is in terms of being a target and for ALS.
Jeremy Holden:
Yeah, we'll look forward to the results of that research and hopefully have you back on to us through what we learned. Thinking about what we've learned over the course of your time research and looking into ALS, beyond an understanding of TDP 43, how has the field changed over the course of your career?
Dr. Virginia Lee:
I think that it's actually ALS is particularly interesting compared to Alzheimer's and Parkinson's. The reason being is that people are desperate. A illness is a bad disease. It's really, it's the worst disease and particularly for people who don't have the disease, they see people with a disease.
So basically it's obvious. I think that if you have Parkinson's, you shuffled a little bit and with Alzheimer's, as long as don't open up your mouth and ask a question, people don't know that you are demented. But with ALS it's just so obvious because she has such physical impairment and people just can look at you and they feel so bad for you. And so because of that aspect of it, the trial have the same tone in the sense that the urgency, and particularly these people don't live very long. So a lot of physicians basically said, okay, he has a new draw, we just give it this other.
And so basically it's not out of hand, but I think that if we don't watch out, it would be out of hand. And because these patients have gone through many different draws, but they're just nothing there and they gone on the draw for a year or half a year or whatever and they die and they eat, maybe, I don't even know whether there's any kind of benefit to some of these strokes. They're are being used right now for treatment of ALS, whether they, for example, delay the onset a little bit. And so that the impairment is not as bad. And I don't know whether there are a lot of information on that either.
Jeremy Holden:
Are you hopeful that the field is on the right track that we've made progress in terms of understanding the disease and identifying targets for potential treatments? Have you seen that the community's moving in the right direction?
Dr. Virginia Lee:
I think it's just slowly encompassing everything. So for example, a few years ago, one of the major hypothesis for ALS is non-cell economists and mechanisms. In other words that it's, even though the neurons are when they're dying, but it's not them they're causing the disease is actually something else. So I think that some investigator that glial cells may be important.
But I think that turn out to be one of them, maybe one of the mechanism but not, definitely not the only one. So they're just multiple ways in which people are looking at the disease and I think that the glial cells will be important. And studying the pathology within a neurons, it's important because if you don't have the pathology and then the neuron will die, at least for neurogen diseases, we always were able to demonstrate that there's the onset is [inaudible 00:13:56] by the presence of the pathology.
And then when the pathology got bad, then the cells die. And when the cells die, you have loss of function. And so depending on whether the neurons are, so you get movement disorder or you could, you get dementing illness depending on where the cell loss is, if it's an hippocampus, then you lose your memory. If it's the motor neuron and you can't walk.
Jeremy Holden:
It later this month, the AAN is going to be honoring you with the Sheila Essey award for ALS research. Congratulations on that great achievement. What does it mean to earn, to be honored in this way?
Dr. Virginia Lee:
I'm obviously very pleased because I think that it's always good to be recognized for the work that you've done. And so I think that TDP 43, it's an important finding for the field of ALS and because we actually, we discovered that in 2006 I believe. And so it's been like 15 years long, 16, 17 years. It's just really a lot of activity.
And so the ALS field, as I mentioned that is there's a lot of personality in the field and some of them actually thought that my work was BS. This was when it first came out and they didn't believe it, but now they're working on it. So that shows that they realized that this is one of the aspect of ALS that they can not follow and examine that because contributory the disease as well.
Jeremy Holden:
You mentioned that we're 15 years removed from the discovery of TDP 43 and then 15 years into our understanding of how it works and its role in disease onset and progression. What would you like to see in the next 15 years in the field of ALS research?
Dr. Virginia Lee:
So I want to go back one step.
Jeremy Holden:
Sure.
Dr. Virginia Lee:
To tell you that ALS is unique in the sense that an FTL D TDP treat, they're unique in the sense that they have TDB 43 as the pathological protein. And while you know it an Alzheimer's and Parkinson's, those proteins are [inaudible 00:16:05] , even though they're very abundant, they're brain specific, more or less brain specific protein.
They're very abundant and yet they're not so important for the survival of the animal because if you knock it out or knock the pound knock that the animal, they're alive, they don't care. They may not have the same and lifespan, but they're fine. But TDP is an RNA binding protein. It's got a very important function. It regulate RNA. And so because of that, you knock it out, you have a dead mouse, you over express, you have a dead mouse.
So it's much more difficult to work with for TDP. But the thing is that a lot of very smart people, the same people that I say that they sometimes missing the boat, but they're also very smart and they're now on the right track. So there's more people working on. That's really the key is that if you have really a lot of bright people working on a problem at some point and something will show up. And if you ask me, I know that the direction is trying to understand and how TDP 43 cause of disease, but it may be hard to do and how to come up with a drug that will counteract the effect of TDP. That may be hard too.
But now I think that some of the investigators are looking downstream, so they basically, they manipulate TDP, they actually show that these set of genes change if you change level of TDP. So those not becoming targets. So if we build the pathway pathway that mediated by TDP.
Jeremy Holden:
Your work is focused on animal models, a critical part in drug development and in scientific research
Dr. Virginia Lee:
In human, I think that the understanding what went wrong in the human brain is very important. I want you to communicate that and to be able to study the human brain, most importantly to from clinical perspective and also from the pathology and so on. Because once what's goes wrong, at least you can recapitulate the pathology or if all ALS patient have the same pathology. So the pathology become important.
Jeremy Holden:
Sure.
Dr. Virginia Lee:
So somebody has to study that. So that's basically, and what we go by and yes, they were these other people, they didn't think that TDP was so important. They thought that that other proteins are more important. That's right. So they actually identified Texan two, something downstream from TDP is something important. A.
Nd so they actually did a lot of work and Texan too, which basically works and worked some in, but they made, we don't know, is still a bit too early. Whether or not Texan will be, if they can provide Texan or modulated so that they will be normal, whether or not the patient will all be normal, we don't know that. But I think all of those are being done right now. They need to go downstream and instead of doing TDP, whichever downstream that is important, they can focus on that as well. That would be logical next step for the next 15 years.
Jeremy Holden:
I was going to ask, we talk about the upstream and downstream when we're thinking about the kind of biological pathways of disease, and I was going to ask about the importance of focusing on all aspects of the stream, looking at downstream impacts, but also looking at upstream.
Dr. Virginia Lee:
So we like to do that. So I think that to particularly for upstream, you more or less have to go the genetic route because you don't know who's going to get als. But if particularly if they have a mutation and on the gene there's [inaudible 00:19:45] and so you will get the disease. So if you have a mutation that in, you get the disease so that you can go upstream, you can say, okay, these people will get the disease. How do we slow it down so that they can get the disease later or not at all? So we're not quite there yet, but I think that people are definitely working on that aspect as well.
Jeremy Holden:
And as you said, very bright people working on all those aspects. The last question I have for you Dr. Lee, is do you still play the piano?
Dr. Virginia Lee:
No, actually it's very sad. I just didn't have time and now I have a little bit more time. My fingers don't work as well. I had a little bit of arthritis and in sad, and this is at the end, it's not so bad. So I have this wonderful baby grand Steinway in my living room and which was not play much at all, and I didn't know what to do with it. I didn't sell it back to Steinway.
And they don't said that now you know that this maybe your audience would be interested. Now people don't like the little girls and boys to play piano as much as they used to. So there's a lot of secondhand piano in Steinway. He said it has a thousand of them that he didn't know what to do.
Jeremy Holden:
Oh, wow.
Dr. Virginia Lee:
So he would give me less than what I paid for, much less than what I paid for and to buy the piano back. So finally I'm moving for my house right now. So I'm living in a three-story townhouse, but I'm moving to a one level because I'm getting to the age in the next 20 years. I want to be able to move around, not have to be limited by the stairs. And so the place where I'm moving into and they actually want to take the piano and put it in the lobby. Yes.
Jeremy Holden:
Oh wow. So it'll be there
Dr. Virginia Lee:
Now. There's a big black bird there. And so the manager of the building, when I told her about the piano, I thought she could put it in the recreation room or whatever and she said, no, we're going to put it downstairs in the main entrance.
Jeremy Holden:
Yeah, that's great. Great. That's a nice little bow tie on the end of that story. Yeah. Well, Dr. Lee, thanks so much for your time in sharing your insights with us today.
Dr. Virginia Lee:
You're very welcome.
Jeremy Holden:
I want to thank my guest this week, Dr. Virginia Lee. If you like this episode, maybe go back and check out our conversation with the 2022 Essey prize winner, Dr. Matthew Kiernan.
Also share this episode with a friend. And while you're at it, please rate and review connecting ALS wherever you listen to podcasts. It's a great way for us to connect with more listeners.
Our production partner for this series is Citizen Race Car Post Production by Alex Brower, production Management by Gabriela Monte Keen, supervised by David Hoffman.
That's going to do it for this week. Thanks for tuning in. We'll connect with you again soon.