Welcome to a new STEMterview. Today we have Dr. Manasi Apte from the University of Tennessee at Knoxville in the US, and she wants to talk about her postdoc research project with us. And welcome, Manasi.

Thank you happy to be here. Yes. So do you just want to start by summarising your research project, what I’ve been working on? And what is what is so amazing about it.

So yeah, I mean, I can definitely go into my postdoctoral research work, but I just want to set up the background. So I’m originally from India, I did my bachelor’s and master’s training from India. And then I moved to United States for my grad school, where I did PhD from Wayne State University in Michigan. And then I moved to my first postdoc at the NIH as a postdoctoral research fellow, I was working at National Cancer Institute, which is one of the 27 research institutes that come under the umbrella of NIH. And I was working with a set, I was working with yeast cells for National Cancer Institute like how am I going to cure cancer by studying yeast? And that’s the question that many people ask me, so I want to explain a little bit for them. in STEM fields, many times when the research project is designed, we don’t really necessarily get a chance to actually work with the patients for, let’s say, ethical considerations or some sort of private personal financial considerations. And over the time, the science community or biology community have come up with very clever ways of studying the same things using some sort of a proxy organisms or proxy animal models or microorganisms. So yeast is one of that, because and this is possible because yeast and humans share a lot of DNA sequence, which is this string of genomic information only passed by your parents to you. And in my study, we focused on understanding these specialised e cells that have sort of come up with this novel means of living surviving, without the presence of a very important factor otherwise, and this is, again, relevant to cancer biology, because this is the component which generally attaches itself along with bunch of different machineries, at the end of your DNA strings and protects the DNA end from getting shorter and smaller, and protects you or your each cell from losing any genetic information i

It sounds very important. medical information,

absolutely. And these, this is called telomerase. It’s an enzyme or a protein that acts with a bunch of different components at the end of your DNA strings to really capture. You know, when we keep on ageing part of the reason we age is because the levels of this protein keeps on decreasing. And then the efficiency at which it can protect the DNA keeps on decreasing as well. So the DNA length gets shorter and shorter. And that’s what we call ageing in one camp.

So thus, we lose genetic information when we age.

Yes.

And we have an enzyme that protects our DNA from this from happening.

Yes.

Okay. Gotcha.

And if you think about cancer cells, they don’t really, you know, care about ageing, actually, their advantage is that they grow much faster than your normal cells, and they sort of dominate over your normal cell population. And that’s why you see this tumour which is like a big mass of unwanted cancerous cells, right? And how do they get that growth advantage many answers this enzyme telomerase, our reverse transcriptase and very technical jargony term. That’s why they can keep on continuing to divide that these cancer cells where normal cells are actually going to keep getting shorter and shorter. So that is sort of giving them growth advantage. So of course, we humans have to combat cancer. So many of the anti cancer therapies are targeted towards how to take out this overproduced production of this telimorase, make sense, but again, cancer cells are clever, so they have to come up with another brilliant strategy to overcome this barrier. They have to resist our attempts to cure cancer.

So they become resistant to our chemotherapies, right?

They do. And there are also a set of cancer cells, which don’t really rely on this overproduction strategy, they actually serve as independent ways. And people have been studying those cancers for a long time. And that’s partly because they are most aggressive ones, you don’t have any cure, because even if you put the anti cancer agents that are already in the field at these cancers, nothing is going to happen, because they don’t rely on those pathways don’t rely on these processes. So these cells that don’t respond to normal cancer therapy are called alternative they they are called alt cancer cells or alternative lengthening of telomeres cancers, okay? Now, telomerase, the protein that I mentioned before actually binds to this DNA end, which is called kilo mere. And in cells, we work with similar type of population of beasts that also use alternative approaches of keeping that kilo-meres long. And so it’s sort of like we are studying yeast cells as a model for all cancer cells. Okay. But now,

yeah, so wait, you have those kinds of cells that you can’t study. So instead, you go into the yeast because they have the same mechanical setup as all kinds of

I mean, you’re partially true. People have been studying actual cancer cells as well. Yeah. This yeast cell that I’m going to explain to you was sort of like a novel discovery in itself. Because, or our lab found this type of specialised yeast population, nobody in the world knew that these kinds of yeast cells could even survive. So in 2010, my postdoctoral research lab published a nature paper, actually describing the discovery of this specialised population for the first time, people probably have seen those type of populations before. But they couldn’t thought that it was an artefact, some artificial thing that is happening in their experiment, so they didn’t really study them. And these specialised cells, what we call them, they’re called hottie cells. And in Hindi, means a big mammal, our favourite mammal elephant, okay. We call these cells hearty cells for two reasons. One is because they are giant as our big mammal, elephant as cells, okay? also seem to have a great memory just like, you know, great memory of elephants.

cells have memories.

Yeah, does this member how they have survived from one generation to next generation and so on. They seem to remember that they don’t have the capacity of doing this overproduction of telomerase, okay, but they have to rely on retaining their DNA ends. And they keep on doing that very faithfully without any errors, every generation, every passing generation, well, we think that they have absolutely amazing qualities for us to study them in yeast, partly because he’s just so easy to grow. And, you know, it’s so easy to do experiments with, I don’t think I would have done the experiments in six years with human cancer cells, the as it would have been in yeast cells. That’s why I mean, I feel like model organisms don’t really get that much respect in biology, but they should, because most of our fundamental knowledge comes from studying these models, again, not really the actual systems in which people have been studying the problems. So that I mean, that’s sort of like a long route of telling me why I’m working while I was working in national cancer. But yeah, let me come back to hearty cells and what I did in my postdoctoral work, so when I joined the lab, we already knew the existence of hearty cells. And we knew that they are surviving by this alternative mechanism, we knew how to consistently You know, every time somebody does the experiment, we will get the same results, we will be able to produce this hottie population. And the way we do this experiment is that we take out the cells capacity of producing the telomerase enzyme completely

So you engineer the yeast so it can age Actually, yes, stop ageing, it can age. Okay.

So but we do Want to give it an opportunity to use telomerase at all. So we delete out the sequence or we take out the DNA sequence that actually encodes for the protein to still function, they will age over time, and there will be a payment, you know, life cycle, where they have lost that end piece completely end sequence complete, to me is completely and at that point a cell has to decide, so they have to survive the most proficient strategy in our laboratory conditions, how we have managed them to grow all this way, is by allowing themselves to grow by this alternative means. And what this alternative mean, involves is a very common biological process. So we were very surprised to know that, you know, these ends that they the cells have, they don’t look like any normal DNA ends, we actually have ribosomal DNA, the DNA that actually gives rise to a protein making machinery in your cells.

Okay, that was just mind blowing now. Okay.

Yeah, like Normally, you have this repatitive sequence of DNA letters that appears on the ends of all your chromosomes. And the sequence is always repetitive, exact sequence differs from species to species. So humans have different species level, numeric sequence, yeast has a specific sequence. But what we observed was in these heartbeat cells, when they lose complete telomeres and actually survived by hearty methods, they now replace that telomeric DNA with ribosomal DNA, so all the masoom and now have ribosomal DNA, they actually have six times more ribosomal DNA sequence than the wild type cell or not.

So what does it mean it’s gonna produce more ribosomes, then instead?

they will. And that’s probably why they could, they could get that growth advantage. But more importantly, what these ribosomal DNA sequences are doing are actually protecting the end sequence of this of the remaining chromosome, the placement of RNA-seq ribosomal DNA sequence is then aided by a machinery of any protection.

Okay, okay, so let me let me just get this straight. So the cells lose the telomerase sequence, so it’s not protected anymore. Instead, it puts up a different sequence for ribosomal DNA, right, but it doesn’t actually produce ribosomes. So just for our Can you just explain to our audience what ribosomes are, what do they do?

So these are sort of protein factories where the protein synthesis happens, that’s where different types of proteins are going to be produced in our cell, that they will go on to do different functions, one of them would be acting as an enzyme to you know, cut out things in the DNA, or some of them would be aiding, like transferring some molecules from one part of the cell to other parts. So these are all essential functions. ribosomes are just the place where they will turn that

so its the factory where everything happens inside the cell. Okay, so now, cells then produce more ribosomes as well.

We don’t think so because most of this, that’s what I was saying, like, yeah, the role of this newly placed Reimu ribosomal DNA sequence is actually to protect the ends of the DNA and not really to produce more ribosome specific Orca, the way they can regulate that function is by changing the environment in which this DNA is wrapped around. So normally, our cells have two types of environments, one where it’s more open and accessible to different types of machineries to get entrained. And do you know allow downstream processes, where those processes can, involving your or making two copies of your DNA or making proteins. But then there are parts of your DNA sequence, which are guarded from getting duplicated, or from getting entry to any of these protein machines. And this is done by setting up you know, an environment of different again, different protein driven molecules going and binding to the DNA, how the DNA is wrapped around, again, around different protein molecules and interacting with different up acids, and setting up this sort of a dark and garment like where nobody can get entry into a closed environment where nobody can get entrained to And this environment in biological term is called heterochromatin. And so heterochromatin is what is maintaining the ends of the DNA to normal to not allowed to go through this open environment, they are always disclose environment. So in the our DNA sequence replaces the kilometric sequence, okay, that is also guarded or protected by this heterochromatic. Closed. And so, that is one thing. But now, that also raises a question. So, does that mean all these six times more rd copies that we have all of them are going to be heterochromatic? And the answer is Yes, they are. Yeah, so, we found that these were actually heterochromatin amplification that is what is called. So you have more than what the normal cell would be a lot more heterochromatin in your cell. But at the same time, is protecting the ends of DNA that is the purpose of

exactly yeah. So, yeah, it could basically basically be any sequence of DNA at edit to the secret to the DNA just to have something at the end, and there’s no loose ends. Is it more or less how I understand

interesting that you ask, you say that because it cannot be any sequence. So far, we have only seen the capacity for two types of repetitive sequences. What and most predominantly, it’s the rDNA sequence that count. And that also comes that also brings us back to the main question I was interested in, like, how do these rDNA is get to the ends? And why is it only rDNA? Can it be any sequence? And the short answer to that is, we now know more details about how this process happens. And this happens by a process called recombination. It’s in normal terms, what I can explain the recombination process is just think about swapping things with type of any sequence section can occur by different ways. Sometimes it relies on a joining region of the DNA, which is very similar between spot a and spot B, then similar agents get together and they help swapping reaction. Sometimes there is literally no similarity between those two spots. And that’s exactly what is happening. In our case in our T cells, the kinematic sequence and rDNA sequence, do not share any similarity when it comes to their sequences. Okay. Neither is the there is any similarity in the adjoining regions. But still, for every time this happens, we see that all these six chromosome ends are now decorated with rDNA sequence,

So something else, must basically find some on a ribosomal DNA and put it to the DNA.

Yeah, I mean, we thought of it as a step-wise, you know, this can’t be this is so rare, right? This is very complex to find two random sequences and then swapping it out every time precisely, you know, in that limited time that the cell has to divide and finish this process. So maybe it is a stepwise process, this rare thing only happens once, maybe, you know, what happens is by what we call ilegitimate recombination, not based on any similarities between the sequences that are getting swapped out. That’s why it’s called illegitimate. The first fair thing happens where you know one of the rDNA sequence. So normally the rDNA sequences are located on a different chromosomal ends. And the telomeres are, of course, on all chromosomes. Right? Now, once you lose the telomeres, the first step, what cell probably does is to lock which is at the right next to the telomere Actually, yeah, on one of the chromosomes or DNA strings, pass it to one end. Now in Bz cells that I’m studying, there are six chromosome ends, there are only three chromosomes to study. Okay? That also is a very important point, humans have 23 chromosomes, two copies of each. So if I were to do this recombination process and study this, I have to keep track of 46. Right? Very simple haploid cell one copy of each chromosome, just three. So I can just track six ends

that will make studying yeast as model organism a lot more efficient? Yeah, following 46 strings of DNA, you just follow 3. Okay.

Yes. And again, the similarity lies in the fact that even in the human cells, are also located next to the telomeres, just like yeast. So what we think is the first step happens by, you know, it’s a rare thing to happen, but it just happens by illegitimate recombination. And from then it’s not really a recombination, it’s more of a copy paste, you know. So because now we have our DNA sequence At the end already. Yeah, then the next more about what is called Simple break induced replication. So this is a process by which many of the damages that are done in the cell by many different reasons get repaired. So let’s say your cells are continuously exposed to UV or some chemicals, harsh environment, and they are going to affect the integrity of your DNA strands, and that really deserve to double stranded DNA molecule, and the cell has come up with a strategy to repair it. There are a number of ways the cells can repair and one of the strategy that the cell uses is just repairing the brake and making sure that the gap is filled properly, by location process that follows or duplication process that occur. So what we think is happening is, once the first sort of swapping reaction happens, and our DNA goes from one chromosome end to the other chromosome end and establish a sort of itself as this end protection, new infection, then it doesn’t get very easily copied to other chromosome ends by this object or break induced replication process. Now, the details of how breaking this replication process happens is still unknown. Okay. So that’s going to be your next project. Yeah, project ended I worked on. Yeah, somebody is actually working on it. Right. So okay, I’m hoping we’ll know the answers to that. Okay. We’ll think about this all is we’ve, I found in my research 2 novel factors that were never implicated in such a recombination process before these factors are known forever. One is, again, a chromatin environment sensing and modulation sort of protein complex. Okay, and it’s called I know, 80 complex or inositol sensing complex are widely studied, like any biology textbook will have a mention of I know 80. And in a biology terms, it’s called a chromatin remodeler. So, it actually allows the cells to sense where the D in how the between different parts of the DNA perfect and it allows for different types of DNA repairs, you name the process and I know it is implicated okay. But nobody knew how you know, how it can play a role in you know, recombination process like that. And we actually found that when you don’t have I know 80 in the cell, so, if we take out genes in coding the annuity complex machinery, hearty cells cannot survive, okay. So, they need this perfect environment, it needs Yeah. The other important observation that was made prior to my study, but I also worked on it a bit further to understand is this machinery called RNA I RNA interference machinery, this is normally in all the eukaryotic cells and also the process by which many of the unwanted unpaired the RNA products that are formed from the DNA products get silenced. This is also again, a major regulatory process here. But we showed that if you delete or if you take out the DNA sequence encoding any of the components of RNA I complex, again, happy cells cannot survive, okay? And it’s not like 20% of them survive, or 20% of them don’t survive. It’s zero or it’s none or 100. It’s absolute. And it’s in case of both. It’s not like one or the other.

Okay, so now does this mean for cancer to at soundpoint treat cancer, we just have to inhibit these factors, these proteins, or is it more than that?

I think that is a premature statement for me to make. We still have in human settings if we were to, you know, take these observations and extend them to all cancer cells. But it definitely gives us more understanding about how possibly the alt environment is maintained in the old cancer cells. Now, I know at an RNA pathway, both are functional in human scenarios as well. So it’s great to see that the processes that are happening in yeast are parallely, and universally present in the cancer settings as well. So we can definitely extend these observations. But it’s far premature for me to predict that, you know, just by targeting some of these components, we are going to cure cancer, I think it’s a multi pronged approach, that will always be the more you know, practical approach for these cancers. Again, cancer as a as a whole, never, our most aggressive cancers of all, it’s never just one thing, and you take care of that one thing and you get cured. It’s multiple things in at multiple levels, and you have to take care of all of them together to cure. So But yeah, I mean, it’s been great time actually discovering this. I never knew going in that I was going to find something very exciting, I actually found that I know at is doing this role in hearty survival. In probably in my third year of my postdoc, and well, super excited, and I quickly realised that the experiment, even though I’m doing them in yeast, they are not as fast as other yeast experiments go. Because every experiment that I described, of identifying the role of any protein in this hearty cells, and for yeast biologist, it’s a long experiment. Normally, these experiments are like two days.

So they have to be patient in your field.

Very, very, like I mean, what hearty project has given me is like immense understanding of working with a very simple organism, but doing complex biology at a very, very patient pace. And I think that’s beyond just like scientific contribution to the publication. It’s bad that I think I’ll, I’ll take it forward. I’m actually really excited about this paper, because it just got accepted

Congratulations.

Thank you. So in print by next month, so we’ll say more in detail.

awesome. Yes, absolutely. Awesome. So this has been a very, very brief summary of your project. Awesome. So one can tell I don’t know you have some experience in communicating your science, your research to a broader audience, and you definitely like talking about which is amazing. So let’s definitely, that’s for sure. No, that’s, that’s good. Let’s maybe just touch on that, because you’ve been quite active in the science communication world as well. So how is it too? So first of all, what kind of projects are you working on? And then maybe second, like, how do you do both? Like being a scientist being like, in the lab, like, probably 50/60 hours per week plus doing some sci-comm on the on your free time? How does all of that work? I hope you seep

I do Sleep I Love sleeping. So I will never trade anything for my sleep. I okay, that’s that’s a good start. I’d like to hear learn more about Yeah, no, I think it’s more about balancing and time management. I have been doing science communication on the periphery more, more so than, you know, completely actively involved. Since my undergraduate days actually. I’ve always been involved in different initiatives around communicating science might be you know, just like poster presentations, doing leadership roles in science conferences, outreach activities, at that point are science education activities where you know, go out and mentor students. I continued that with my grad school experience as well. Because I knew somewhere, you know, at the back of my mind that I wanted to explore more opportunities, I wanted to be part of, you know, different communities that I have been exposed to, and is what it sort of keeps me driven, so to say, to balance out, you know, I will always take permission from my advisors before doing any of these so called peripheral or extra additional sci-comm things. But I would say, I’ve seen, I have done most consistent sci-comm work for the last seven or eight years, partly because I was a postdoc at the NIH, NIH is a place gave me lots of opportunities to do lots of different types of communications, education, engagement work, and NHS postdoctoral office is a great place for anybody who’s listening to this interview. I mean, I could, then I could folks who do those kind of activities and workshops, and actually keep on giving us postdocs chances and opportunities to you know, enhance our resumes, actually, to do all these things, along with your research. That’s just increasing your worth, and your, you know, overall personality at such. So, I, very early on, in my postdoc, I made a conscious decision of being very frank with my postdoc advisor and saying that, hey, I am going to be involved in all these initiatives. And it does take some time out of the lab, but I’ll make sure I won’t slack on experiments. And I was very fortunate about that, too. Like, even from even from my undergrad days, all my mentors have been super helpful, super supportive.

I will unfortunately was not in the same position, I really had to Yeah, kind of secret all my science communication projects that I was working on, because my supervisor, she did not appreciate me doing this. So yeah, that is very lucky.

I think of all these activities as the integral part of our training, and not really, you know, something that is wasting our time sort of zoned to say are, we are doing this, on their own time, are some big like to think. And, again, National Cancer Institute is a great place in terms of giving the postdocs opportunity to work on these aspects of your personalities. Again, we are made to keep up with our individual career plans or development plans every year. And I was fortunate to work with the director for last five years of my postdoc, well, he was very, very passionate about, you know, you going out of the lab and actually networking and communicating and doing all this stuff. So I feel like that you need to have some sort of a support system to get you through it. So my family and then, of course, all my lab colleagues, sometimes, if I have to leave for some, you know, workshop that I’m attending, if I had to rely on them, they were there. So even the support from the community that’s very important. And in terms of the current projects that I’m involved in, I’m doing a bunch of things. So in terms of creative writing, and content writing, I am currently partnering with a brilliant illustrator, a brand curator. And we are coming up with a coursework about how to tell inclusive science story. Okay. So previously, we already did one coursework, which was how to tell a science story, which was like a basic module for science storytelling, and this is more like an obese course of a sci-comm programme, which is offered by a company called lifeology. So that is one thing that I’m working on currently, I’m also involved in American society for biochemistry and molecular biology’s art of science communication coursework. I took that course myself back in 2016. And then they asked you if you would like to come back as a discussion facilitator or mentor for, you know, coming cohorts. So I’ve been teaching that course on and off for last four years. So I’m doing that again this summer. Last year, along with my friends, we came up with a new initiative or an organisation called istem care. And we actually recently launched our own podcast series. Related to this, our focus is a little bit different. Our intended audience mostly is Southeast Asian undergrads and masters level students. But of course, the content will be globally applicable. We are actually interviewing and having conversations with STEM professionals who have actually gone on to do non traditional career paths. And we are asking them, how did they choose that? How did that transition go? Why did they do it? And like, was there a support? And there is a lot of discussion about what kind of resources one can you know, look for? Or can they provide to the upcoming generation of STEM professionals?

Something our STEMcognito team should listen to her?

Oh absolutely. We would love to hear feedback on that. We just dropped our first episode, where two of our hosts spoke to Dr. harshvardhan. Who coming from a plant biology background, then he went on to do a job in Citibank completely switched positions. And now he’s a postdoctoral research in artificial intelligence. So very, very diverse career paths. He’s managing it all and he’s done it really well.

Nice, perfect. Okay, yeah. Thank you so much for this overview. It was so good. So interesting to see someone doing so much so many science communication projects as well.

I didn’t get I didn’t get time to touch on all of them. But if you go onto my website, which, thank you, Sarah, for helping. So you can provide the link for the website,

we will include it Yes.

Then people can know more about it.

Okay, so now to the end. We always have like five kind of random question not too science related, that we would like to just ask you quickly, and from the top of your head. Okay. Okay. First question. What is your or what was your favourite subject at school?

languages? l

anguages. Okay. So it’s Yeah, it’s about talking. It’s about communication. Well done. Yeah.

Actually, it’s, it’s very funny because when I graduated from high school, everybody thought that I would go into linguistics because I was a topper for state level boards for one of the languages so everybody thought that I would do something in there. And I actually for a split second thought about it, because I really loved learning languages interacting with people. But very soon, I realised that there was not many career options, at that time, at least to go and become the best. So the second favourite subject or science.

okay, yeah, but now, as I said, as a science communicators, bring them both together, and yeah.

I can, yes, yes. Yeah.

Okay, next question. And one sentence, what are you truly passionate about?

Um, I am passionate about making connections, making connections between two abstract thoughts, abstract scientific concepts, 2 people 2 communities, 2 stories 2 characters, but the essence of it is making connections i think i love that is.

That’s good. I was really important as a science communicator. Perfect. Okay, what do you do in your free time?

Um, it changes it. In a pre-kid world. I used to do a lot more or now I have a kid. Most of my free time goes with, you know, around her schedule. But we Yeah, I mean, I do enjoy occasional paint by numbers. That just relaxes me. I do love listening to podcasts. I love listening to music. I actually love watching documentaries and period dramas. And I try experimenting with food but not that’s not really what I enjoy, but I just like to do it. That’s that’s like something that I enjoy doing with my daughter.

Okay, so that is actually our next question. What is your favourite Indian dish?

What’s my favourite Indian Dish?

What do you miss most from being a being away from home?

I miss Alphonso mangoes the most pickup in my opinion, they are the best mangoes in the world.

Okay, and ever lifetimes. Unfortunately, though, the ones that I am really passionate about in the United States, we can, but it’s a lot of processing to get them here. In terms of Dish, I feel like anything that my mom and my mother in law cooks is something that I love. They are both amazing cooks. And they have their own speciality. So I think I will always go back to their dishes rather than I, I do have some favourites of my own. And I can cook them pretty well, apparently. But I think that’s for other people to say.

Okay, and our last question, I love that question. What would you do if you were donated $10 million to your project?

Oh, whoo. That’s a lot of money. Yeah, so sorry. When am I getting that? Whenever there’s money in science. But I think jokes aside, I feel like if I were given that much money, I would definitely consider it for sort of putting together infrastructure where scientist and communicator don’t feel like two different and disparate roles. I would be a scientist where I will also be a communicator, and I don’t have to, you know, explain myself. In these dual capacities, I would definitely invest in a lot of resources for my group, could be a science group or a communication group to have access to the resources that they want. We would definitely attend a lot more conferences for sure.

that goes into your passion actually connecting the two communities. That’s perfect. That’s great. This has been so great when I say thank you so much.

Oh, thank you. Thank you very much. I hope I didn’t I didn’t go too tangential. But I love talking. So

That’s, that’s been amazing. So yes, thank you again. And we will keep in touch. Everybody should is going to visit your website because it looks beautiful.

Thank you. Thank you.

Okay, who don’t know, Sarah actually helped run a workshop few months back where she coached me and many, many fellow participants how to actually build a very beautiful looking and very functional website or portfolio blog. And thanks to Sarah now, I have a full website.

You and many other people. Yes. It’s been so good. Yeah, it was such a cool experience. I knew that workshop with you. It was awesome. Okay, thank you again.

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