00;00;10;08 – 00;00;48;19
维多利亚之声
Welcome to Beyond Lab Walls, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned research institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries in cutting edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it. Here at Salk, we’re unlocking the secrets of life itself and sharing them beyond lab walls.
00;00;48;21 – 00;01;14;28
伊莎贝拉
Hi everyone. Welcome to another episode of Beyond Lab Walls. I’m one of your hosts, Isabella, and I’m really excited today to be chatting with Jeff Jones. Jeff is a senior research associate in Professor Rusty Gage’s lab here at Salk, which is a neuroscience lab with some exciting recent projects focused on aging and Alzheimer’s disease. Jeff’s love of science came at a young age and was shaped by both his physical environment and family circumstances.
00;01;15;00 – 00;01;34;22
伊莎贝拉
He’s been all over the country refining his science skills, like how to use really sophisticated models for studying the brain, how to use gene editing tech, how to model diseases in the lab, all kinds of cutting edge stuff. And he uses all these advanced skills to study how cells age and how our differing genetics impact us over time.
00;01;34;24 – 00;01;43;27
伊莎贝拉
I think he had a really cool path to get to Salk, and I’m really excited to get started talking about it. So, Jeff, can we kick off at the beginning, where’d you grow up?
00;01;44;00 – 00;02;04;22
Jeff
Well, thank you for having me. I grew up in South Florida in a very rural part of Florida. I grew up on a dirt road and lived there most of my life. And I think that kind of closeness to nature inspired a lot of my influence into science. And just kind of looking at the different plants and animals out there.
00;02;04;29 – 00;02;19;27
Jeff
And I was really big into fishing, and so I liked going to my local pond and catching fish. And at the time I wanted to be a marine biologist. So I ended up going to the University of South Florida. I finally got out of the dirt roads onto some pavement.
00;02;20;00 – 00;02;22;13
伊莎贝拉
Did you have any scientists in your life at all?
00;02;22;15 – 00;02;42;12
Jeff
No, actually, I’m a first generation scientist, so neither of my parents went to college. And so I think the just the natural curiosity is what really got me into science. And wanting to be a marine biologist because of my love of fishing, really sent me down the path of a scientist, even though I didn’t end up doing that.
00;02;42;19 – 00;03;04;29
Jeff
I would say the thing that pushed me towards biology in particular was when I was in late middle school, early high school, my mom was diagnosed with breast cancer, and at the time I was just learning how to drive a car. So I was driving her to her chemotherapy appointments. And, I kept asking the oncologist, you know, what is cancer?
00;03;05;01 – 00;03;26;26
Jeff
And I kept probing them and just harassing this poor guy every time we’d go there. And eventually he was like, yeah, you should study this. And so that was my new major was going to be molecular biology, cell biology, and understanding what cancer is. Through a lot of just the way life goes sometimes, I didn’t end up studying cancer because I didn’t know anyone who studied it.
00;03;26;26 – 00;03;40;20
Jeff
I didn’t have any connections. And so I was, you know, cold calling professors, emailing professors, just trying to get into a lab. And as fate would have it, the lab that I ended up joining was an Alzheimer’s disease research lab.
00;03;40;23 – 00;03;41;10
伊莎贝拉
And where was that?
00;03;41;10 – 00;03;52;03
Jeff
And that was at the University of South Florida.
00;03;52;05 – 00;03;57;17
伊莎贝拉
So once you got into this Alzheimer’s lab, what was it like doing neuroscience for the first time?
00;03;57;19 – 00;04;18;00
Jeff
I loved it, you know, it can be very intimidating because you think, oh, neuroscience, the brain, it’s so complicated. And it is. But, you know, as a scientist, we kind of break down complex questions and sort of a reductionist approach. And so when you start to ask those simple questions about how do these cells work? What are the parts of the cell? It becomesless intimidating and more fun.
00;04;18;01 – 00;04;43;10
Jeff
I learned a lot in that lab and ended up going to graduate school in Wisconsin to continue on studying neuroscience and how cells work, and there I expanded my skill set a little bit and worked with embryonic stem cells and made neurons and other cell types of the brain. And then, ended up coming here to the Salk Institute because I wanted to get back to aging.
00;04;43;12 – 00;04;56;01
Jeff
And what is it about aging and the aged brain that makes us susceptible to all these neurodegenerative disorders like Alzheimer’s disease, but other dementias as well, that seem to correlate with aging above all?
00;04;56;03 – 00;05;11;10
伊莎贝拉
Yeah, that’s interesting that you started with neuroscience and then kind of zoomed in on Alzheimer’s and then zoomed a little bit back out into aging. And now you’re exploring aging at a really tiny, tiny molecular level. What’s that like?
00;05;11;12 – 00;05;37;01
Jeff
Yeah. So in the laboratory of Fred Gage, we are looking at, well, first of all, we can model aging in a dish. That was one of the things that really brought me to the Salk Institute was a pretty unique model system where you can take skin cells from people of any age, grow them up in a dish, and then, perform experiments on them where you can actually see that those cells maintain the age of the original person on the molecular level.
00;05;37;06 – 00;05;58;28
Jeff
So these are like genes that are transcribed and how the DNA is compacted. And we can actually take those skin cells and directly convert them into a neuron. And so in doing that, those cells maintain the original age of the donor. And so we can look into “what is age” in a neuron in a dish from a human.
00;05;59;01 – 00;06;19;03
Jeff
And so that model system is really powerful. And through the course of my career here at the Salk Institute, we have found that the way that these cells maintain their genome, changes over time as a product of them being specialized, unlike a lot of the cells in the body, as you may know, the brain has no ability to rejuvenate.
00;06;19;05 – 00;06;46;21
Jeff
There is adult neurogenesis that happens, and that’s largely to replace cells over time. But in, traumatic injury or in a disease, there’s not really a lot of regenerative capacity there. And it looks like, at least my data suggests, that when the genome is first formed, they can kind of patch up some holes here and there. But over time, they struggle with that process.
00;06;46;23 – 00;06;54;21
伊莎贝拉
Can you tell me why a lot of your research looks at DNA and what you like so much about DNA, and looking at these very basic building blocks?
00;06;54;23 – 00;07;16;08
Jeff
Yeah, I am a reductionist. And so I think the most important thing is the information itself. And that is what DNA gives us. It is the long term carrier of information. And so I think we can learn a lot by by studying DNA and why cells prioritize certain pieces of DNA over other pieces of DNA, especially when you’re looking at aging.
00;07;16;10 – 00;07;38;02
Jeff
If you find regions that are vulnerable across multiple aged people, then you can say, maybe these regions are regions we should focus on for aging. What is it about these sites when they’re damaged that correlates with aging? Is it causative, is it not causative? And then conversely, are there regions that never change with age, and why is that?
00;07;38;02 – 00;07;42;00
Jeff
Are they protective? And how can we use that information to slow aging?
00;07;42;07 – 00;08;05;14
伊莎贝拉
Yeah. What I find so cool about the model you’re talking about, which for the listeners are these little lab grown mini organs called organoids. And for Jeff, those organoids are brains. And what I find super cool about organoids now in the modern time, like this year, is we’re able now to preserve genetic information from real patients in those organoids.
00;08;05;17 – 00;08;17;07
伊莎贝拉
And I’m curious, Jeff, what other interesting models you’re working with in the lab, or if you have favorites. It seems kind of like this golden age of brain models right now.
00;08;17;09 – 00;08;40;13
Jeff
Well, my, I’m biased, but my my favorite is is the fibroblast to neuron conversion. And right now we, we just are starting to be able to use those in an organoid system. Traditionally they’re just a single layer of cells in a dish. And we’re also limited to just making a certain subtype of neurons because of the way the protocol works.
00;08;40;15 – 00;08;59;08
Jeff
But some avenues to explore in the future are, can we make other cell types from aged individuals? And how do those behave in age? Are they different from the neurons? And then of course, kind of what you’re alluding to: What if we put them all together? Do you have an aged brain in a dish at that point?
00;08;59;10 – 00;09;02;02
伊莎贝拉
What are fibroblasts?
00;09;02;04 – 00;09;26;00
Jeff
Oh, so fibroblasts are the kind of they’re sort of connective cells. They’re all throughout the body and they sort of fill in the gaps. And that’s not to say they’re not important. They’re basically supporting all of your organs. And in the skin, they they provide a bed for the skin to lay on and separate the muscle from the outer layer of dermis.
00;09;26;03 – 00;09;44;11
Jeff
So they’re alive, unlike the outer layer of your skin, which is basically just dead keratin material. So when we get a skin punch from these individuals, it’s pretty deep. And it requires a stitch. So it’s, you know, we take this seriously. These are really valuable resources, especially when we’re talking about aged individuals.
00;09;44;14 – 00;09;54;25
伊莎贝拉
Yeah. So, what would be the alternative to create a model with like human cells? Would it be stem cells? What is the difference there? What’s the advantage of using fibroblasts?
00;09;54;28 – 00;10;20;08
Jeff
That’s a great question. So yes, stem cells would be one other option. And in particular, the idea of induced pluripotent stem cells that word induced means you take, traditionally it is a fibroblast from the skin, and you reprogram it back to a state that only occurs in the very early embryos. And pluripotency means that it can turn into any cell of the body, “many potencies.”
00;10;20;10 – 00;10;47;29
Jeff
And so when you do that, when you convert it back to this early embryonic state, the information associated with the age of the original person is wiped away. This is sort of like a rejuvenation. There’s a jellyfish called the Medusa jellyfish. And these these jellyfish are thought to be immortal because at a certain point in their age, they can revert back to their embryonic state and go throughout their whole life one more time, or many times.
00;10;47;29 – 00;11;10;25
Jeff
We don’t actually know how many more times. Yeah. And so, that’s a metaphor to describe how you can take a somatic cell, like a fibroblast from your skin and rejuvenate it back to this embryonic state. And those cells are immortal as well. But when you make a, a cell like a neuron from an induced pluripotent stem cell, it’s a baby neuron.
00;11;10;28 – 00;11;28;05
Jeff
In fact, it’s basically an embryonic neuron.
伊莎贝拉
是的。.
Jeff
And so we we can use it to understand a lot about human development and neuroscience.
伊莎贝拉
是的。.
Jeff
But it’s it’s impact for understanding the changes that happen over a long periods of time with age are pretty limited.
00;11;28;08 – 00;11;37;09
伊莎贝拉
That’s super interesting. And how new is doing that? How new is that ability to create neurons out of fibroblasts? Is that a super new technique?
00;11;37;12 – 00;12;00;09
Jeff
It’s been around for about 12 years I think now, but it’s a pretty challenging method. So it hasn’t really been widely adopted. And I think that’s why this is a unique space at the Salk Institute, where we have this model working.
00;12;00;12 – 00;12;07;00
伊莎贝拉
So what kinds of questions are you able to ask with these models? What are you actually looking at and asking in the lab?
00;12;07;02 – 00;12;28;22
Jeff
So we are very fortunate to be able to ask, you know, what are the molecular changes that occur with a, as a product of age? And as you can imagine, you can’t just use one person’s skin cells to answer that question because you and I age at different rates. And beyond that, likely our organs age at different rates even within our body.
00;12;28;22 – 00;12;50;23
Jeff
So depending on environmental factors and genetics, and so this is all to say that I think we need a lot of people. And here, across the street we have the University of California, San Diego, and they have an Alzheimer’s disease research center there who does a great job recruiting patients from a broad spectrum of age, from 0 to 94 years old.
00;12;50;26 – 00;13;23;24
Jeff
And this includes people that are totally healthy and cognitively normal and dementia patients, Alzheimer’s disease in particular. And so they have, about 100 different fibroblast biopsies. Now, they probably have more patients than that, but only a subset of their patients, consent to having their, their fibroblasts donated. And so we have many in the lab I think we have upwards of 60 fibroblast lines, from people representing the entire human lifespan, cognitively normal and Alzheimer’s disease.
00;13;23;27 – 00;13;30;04
Jeff
And so when you look at those in aggregate, you can start to see some of these changes in the way they maintain their DNA over time.
00;13;30;09 – 00;13;45;12
伊莎贝拉
So what are the kinds of therapeutic innovations that could potentially come out of the understanding that you’re getting from these cells, especially as they get closer and closer and more representative of a real person and what’s actually happening in the body?
00;13;45;14 – 00;14;11;16
Jeff
Yeah, so many I think importantly, the field is the aging field is pretty new, when it comes to actually modeling human age. And then you know, in the dementia field, Alzheimer’s disease is fairly limited in the treatment options. There’s a few new ones on the market. The the effectiveness is up for debate. But given that it’s treating people and you still have Alzheimer’s disease, maybe we should also consider some alternative therapies.
00;14;11;16 – 00;14;36;24
Jeff
And so, having this model system, we can start to test some of these things. And one of the pathways we’re looking at is how we can modulate these neurons to, make more of the building blocks of DNA. It seems they have a shortage. And this shortage seems to be something that correlates with age. So if we use some, some drugs to stimulate that pathway, can we fix the the shortage and rescue the phenotype, the cells?
00;14;36;27 – 00;14;59;00
伊莎贝拉
Yeah, and to get back into the nitty gritty of the science, you look a lot at DNA but also at metabolism and the process of metabolism. And I think what a lot of people hear metabolism, they think, you know, eating a sandwich and digesting it. Can you kind of explain what metabolism is from the molecular standpoint and what that looks like in your research?
00;14;59;02 – 00;15;21;06
Jeff
Yeah, that’s a great question. So it’s all about, I think when you think about metabolism, you think about energy, right? And even biologists tend to think along those lines. But in my opinion metabolism is much more than that. It’s the, the the making of substrates, the making of stuff, the biomass you need to make your cells and function right.
00;15;21;08 – 00;15;41;15
Jeff
And so typically these are all coming from your diet, sugars. Your liver will break down the food you eat into simple nutrients. And then the individual cells will take those up, usually in the form of glucose, which then can be processed to make many things within the cells. One of those things are the actual building blocks of DNA.
00;15;41;18 – 00;16;04;08
Jeff
So that’s a process of breaking down sugar into into DNA building blocks is called de novo synthesis. But on top of that, the liver breaking down your food also supply some actual nucleotides themselves. From the plants that we eat that have natural DNA in it. And so it becomes a question of absorption and the ability to make these things from sugar.
00;16;04;16 – 00;16;16;15
Jeff
And so I think metabolism is the kind of sum of all of those things. How well can you absorb the food you eat? And then how well can the cells actually process it and make the things they need from the substrates?
00;16;16;17 – 00;16;27;14
伊莎贝拉
Okay, so the trope of your metabolism slowing down as you age so you can no longer eat a large pizza with no consequence, that’s really a thing that’s happening on a cellular level to some degree?
00;16;27;14 – 00;16;42;15
Jeff
Yeah, to some degree they are. And yeah, in this case, we’re you know, we’re looking at one pathway and one cell type. But it does seem to be true that it slows down with age.
00;16;42;17 – 00;16;52;14
伊莎贝拉
So you’ve been working on this Keck Foundation-funded project on aging heart and brain cells. Can you tell me what that’s all about and how it’s going?
00;16;52;16 – 00;17;20;23
Jeff
Yeah. So that project is kind of centered around this idea that nucleotides and the ability of, of a cell to make the actual building blocks for its DNA, and how it changes over time are associated with certain types of cells. And, you know, I started this idea with looking at neurons and, we thought while we were, you know, starting these studies, what is it about a neuron that makes it susceptible to aging?
00;17;20;25 – 00;17;48;04
Jeff
And that is that it never divides. Once you’re born with this neuron, it ages with you throughout your life. And so it has to be able to maintain its, its DNA throughout your multiple decades of life. And one other cell type that also experiences a lot of problems throughout age are cardiac cells, cardiomyocytes. And they share the same property that once they’re born, they can never divide again because they have a function.
00;17;48;04 – 00;18;14;03
Jeff
And that function is to be in your heart. The neurons function is to fire in your brain. And so, we propose this idea that both cell types share this specialization and they can’t divide. And so the maintenance of their genomes and the metabolism to make those substrates becomes very important. And we’re currently investigating this. But one of the ideas, from that the grant is funding is to one quantify this in both cell types.
00;18;14;03 – 00;18;39;16
Jeff
How much is it happening? Are there regions in cell types that are susceptible to age in general? Are there heart specific regions, brain specific regions? And then we are developing a technology to visualize this, and it can start asking questions about the heterogeneity of aging. So beyond this the different organs, are there spots within the brain that are really susceptible to this type of aging?
00;18;39;18 – 00;18;51;09
Jeff
And if we can visualize it, then we can ask questions like what happens to the cells nearby? Are they impacted by it? And then what if we can rescue that? Does that rescue the effect across the whole brain or the whole heart?
00;18;51;11 – 00;18;57;23
伊莎贝拉
Is that what you’re currently working on, or are there other projects in the works right now that are taking up more of your time?
00;18;57;25 – 00;19;22;21
Jeff
There’s so much happening right now. I think this is an area that’s been under investigated, which I’m very fortunate to, to be looking in this area. But it’s also a little overwhelming because there’s so many avenues to explore. So one, for example, is the actual protein itself that’s responsible for making these building blocks, it seems to be differentially expressed in Alzheimer’s disease.
00;19;22;21 – 00;19;28;16
Jeff
And so one avenue that I’m currently working on is, why is that? And then can we fix its expression?
00;19;28;22 – 00;19;52;23
伊莎贝拉
This is making me think about recent work from Sue Kaech’s lab about cellular nutrition and the metabolism of tiny bits and cell fuel, how that can change the way a cell’s genes are expressed. And in her instance, she was looking at T cells, which are some of the most abundant immune cells. It seems like there’s a real renaissance happening in metabolism research and understanding what nutrition and metabolism can do on a cellular level.
00;19;52;26 – 00;19;58;16
伊莎贝拉
It’s a really interesting new area it seems like we’re getting a lot of new depth of understanding in.
00;19;58;18 – 00;20;28;12
Jeff
Definitely. There was a, I think in the field of epigenetics, so that’s the study of gene regulation, not the information on the DNA itself. There’s a big anecdote from the famine and from the the dust bowl, where if a person starves for a period of time, the children of that individual have a change in their metabolism. And so I think it goes to show you that it’s not the actual genes that are changing, but these sorts of metabolic changes can be inherited.
00;20;28;15 – 00;20;37;20
Jeff
And it makes you wonder how through my genetics and your genetics and all these different cell types, how are their metabolisms different? And yeah, you’re right, it’s kind of a new area.
00;20;37;24 – 00;20;51;23
伊莎贝拉
Yeah. Very cool. Love all things epigenetics. I find it so interesting.
00;20;51;26 – 00;20;57;03
伊莎贝拉
And what do you like about San Diego outside of Salk? Do you have any time for hobbies outside of the lab?
00;20;57;03 – 00;21;18;26
Jeff
My hobbies outside of work are also kind of nerdy. I work with like electronics, small electronics, engineering them and writing code for microcontrollers. So I know it sounds nerdy, but this is a hobby I picked up during the pandemic, and it actually it paid off. So I have all these, like, temperature sensors in my house collecting data.
00;21;18;29 – 00;21;22;25
Jeff
I guess I’m still collecting data one way or another.
00;21;22;28 – 00;21;28;22
伊莎贝拉
That is funny. Well, thank you very much for being on the podcast. This was great talking to you.
00;21;28;24 – 00;21;35;27
Jeff
This was fun. Thank you for having me.
00;21;36;00 – 00;21;57;01
伊莎贝拉
As Jeff said at the beginning of our conversation, he’s got a real dedication to studying aging, and he’s asking a whole bunch of different questions, all based on his reductionist mindset and love of looking at the absolute, tiniest building blocks of life. He’s asking questions like, what even is aging? How do our cells age? How the two neighboring cells age differently from one another?
00;21;57;01 – 00;22;23;27
伊莎贝拉
And how do two people age differently from one another, just staring out at this new, unexplored area of aging research and asking questions that are all possible thanks to the new models and techniques that we have today. I’m really excited to see what he discovers as he continues getting to the bottom of aging, and how the future of neuroscience and human health may change in our lifetimes thanks to dedicated researchers like Jeff.
00;22;23;29 – 00;22;57;03
维多利亚之声
Beyond Lab Walls 是萨尔克传播办公室制作的一档节目。收听萨尔克最新科学故事，请订阅我们的播客，并访问 Salk.edu 加入我们新推出的独家媒体频道 Salk Streaming。在那里，您将看到我们的科学家访谈、近期研究视频以及世界知名教授的公开讲座。您还可以浏览我们屡获殊荣的杂志 Inside Salk，并订阅我们的月度通讯，及时了解这些围墙内的世界。.