Season 4, Ep. 2

Jade Varineau: I feel like doing fundamental research is multifaceted in that you’re looking at what’s happening with the molecules, OK, what’s happening with the cells and the tissues and then what’s happening in the organisms. 

[“Something Elated” begins]

Eva Frederick: Thanks for tuning in to BioGenesis, where we get to know a biologist, where they came from, and where they’re going next. I’m Eva Frederick from Whitehead Institute—

[“Something Elated” fades out]

Raleigh McElvery: And I’m Raleigh McElvery from the MIT Department of Biology. This season, we’re talking to grad students who are conducting curiosity-based research with the potential to transform our every-day lives.

Frederick: Today is all about Jade Varineau. She’s investigating what goes wrong when errors in genetic code confuse the cells that form facial structures. Down the line, her research could inform treatments for craniofacial disorders.

McElvery: She’s not working in a clinic, with patients, or even in a particular organism. Instead, she’s analyzing cells in a dish to glean a fundamental understanding of how mutations can disrupt development.

[“Cran Ras” begins]

Varineau: My name is Jade Varineau. I’m a third-year graduate student in the Calo lab at MIT. So I was born and raised in Grand Rapids, Michigan. Both my parents are classical musicians. That was a big part of my childhood, sitting in the corner of rehearsals and practice sessions. My mom is a pianist and my dad is an orchestra conductor and a clarinetist. I played cello and piano growing up until I was 18. Classical music was kind of the backdrop to most of my childhood.

For a while, I was really interested in earth science and meteorology and geography. I don’t know exactly why those were my first interests. I think my first official biology class was my sophomore year of high school, and that was really interesting to me. And unlike previous science courses, I didn’t lose interest in biology a couple of months after that class had ended.

[“Cran Ras” fades out]

Growing up being interested in both science and music is a really good balance, in terms of just like how you’re thinking and what parts of your brain you’re using. I don’t know if I took anything from music into how I approach science, but I think growing up in high school and middle school, going to orchestra and then going to biology class was a really nice duality that I think helped me in school.

Frederick: With her days of meteorology and geography behind her, Jade was set on pursuing biology when she started at the University of Michigan.

[“Cornicob” begins]

Varineau: Pretty early on, I decided I’d go the biology route. So cellular and molecular biology. University of Michigan is unique because they have such a huge medical campus that they have lots of very specific biology majors, but the vast majority of students there are premed. I think there were 115 people in my major, and I know maybe two people who went on to grad school in biology.

McElvery: Jade herself preferred discovery-based research that allowed her to get to know specific cells and their contents rather than individual patients.

Varineau: So my first research experience was in a biophysics lab doing some computer modeling of immune system proteins. And then after that, I moved into a Drosophila genetics lab, where I was looking at a specific protein at the neuromuscular junction in Drosophila, and how it works and how depletion of that protein affects how the Drosophila function. I was looking at Drosophila larva crawl across agar plates to see if we get rid of this protein, do they crawl slower? And I really enjoyed that experience just because it was a longer two-year experience, and I was able to really develop a project there. Ultimately, I realized maybe I was less interested in neurobiology and looking at neurons and maybe in more molecular-based, cellular-based experiments.

So I was happy, especially in the Drosophila lab that I joined, that I was able to do some molecular biology as well as some organismal work with flies. But I knew eventually leaving undergrad that I was going to be able to tailor my interests a little bit more to what I was interested in based on classes I had taken in undergrad, or just general interests I had from papers I had read.

[“Cornicob” fades out]

Frederick: It was these general interests that spurred her to apply to a specific type of biology PhD program called an “umbrella” program.

Varineau: So an umbrella program is a program that everyone in a singular program has interests throughout biology and sometimes into chemistry, whereas other programs will have their biology program subdivided into genetics and cell biology and biochemistry. And because I didn’t know exactly what I want to do, I wanted to go to a program that really allowed me time to experiment with what field I want to pursue, as well as a program that was really open to me coming into grad school not knowing particularly what I wanted to pursue.

And so MIT drew me in because it is an umbrella program and they seem very, very accepting of people who come in saying, “Hey, you know, I’m interested in lots of different things. I’ll take this first semester and a half to figure stuff out.” And I think MIT is one of the stronger umbrella programs. Also, the size was appealing to me, in terms of a decent number of grad students but the department as a whole is very small, which appealed to me as opposed to maybe some of the other very large programs.

Frederick: The small program made it easy for Jade to connect with her colleagues, even outside the lab.

Varineau: There’s a great game called Charty Party, which is like cards against humanity, except for with graphs. So they’ll give you a graph and then you have to say what’s on the X or Y axis. And so, for all of us bio PhDs that’s a great game for us.

McElvery: Out of the 60 plus labs spanning 10 major research areas, Jade settled on Eliezer Calo’s group.

Frederick: The lab itself aims to answer a variety of research questions using a multi-tiered experimental approach, which Jade appreciated.

Varineau: It comes back again to wanting to do research on multiple different scales. So I liked the way the projects in the Calo lab are structured in that there’s maybe some cellular studies, some molecular biology, some organismal studies. And a singular project can have lots of different aspects.

Frederick: Jade’s project is no exception.

[“Lord Weasel” begins]

Varineau: So my project is looking at diseases of the cranial neural crest cells. So cranial neural crest cells are a group of cells in the developing organism that are multipotent, so they can give rise to many different cell types. So the cranial crest can give rise to the bone structures in the face, as well as some of the nerve structures in the face. So notably the lower jaw, the bones in the ear, sometimes the palate structure. And I’m looking at diseases that result in malformations of the cranial neural crest.

The individual disorders themselves are quite rare. That being said, craniofacial disorders are one of the most common developmental birth defects. So specifically, I’m looking at mandibular facial dysostosis of microcephaly, which I just call MFDM, because that is a tongue twister. Individuals with this disorder tend to have hearing problems, under-formed lower jaw, occasionally cleft palate, occasionally some mental difficulties, as well as maybe an overall lower cranial structure. There’s also some other ones. So there’s Burn-McKeown syndrome as well as Nager syndrome. In general, they have very similar symptoms to MFDM. Sometimes they have maybe some finger defects as well as some heart defects. And so it’s kind of a very broad family of diseases that all result in this very specific developmental defect.

[“Lord Weasel” fades out]

McElvery: Each stems from random genetic mutations that confuse a type of protein called a splicing factor.

Frederick: After DNA has been transcribed into messenger RNA, splicing factors cut out sections so what’s left can be joined back together. By dictating which sections are removed and which remain, splicing factors allow a single gene to encode multiple different proteins.

McElvery: But random DNA mutations can muck up a splicing protein’s ability to splice, which can then lead to irregular craniofacial structures.

Varineau: So we’ll have patients with smaller lower jaws, hearing defects because the bones in the ear are not formed properly, sometimes cleft palate. But for whatever reason, the problems with these splicing factors, even though they’re present in all the cells in the organism, we really only see defects in the cranial neural cells. So there’s something going on in these cranial neural crest cells that makes them extra sensitive to changes in splicing.

Eva: Jade’s goal is to pinpoint that intermediary step: How do splicing mutations misdirect neural crest cells, and why are the ones in the developing face thrown off so easily?

[“Caprese” starts]

As she delves deeper into these complex molecular processes, it’s becoming clearer that a ubiquitous — and seemingly omnipotent — protein called p53 is to blame.

Varineau: Yeah, p53 is kind of a “do everything” factor in the cell. It is mainly a transcription factor. A transcription factor is a protein that binds to DNA and activates transcription, so the reading of DNA and turning it into RNA of a specific gene. And so p53 is a transcription factor for many, many genes. It’s also a tumor suppressor. So in normal cells, its presence stops cells from growing. So we hear about p53 a lot in cancer in that, you know, in cancer we have p53 mutated. So it’s no longer present as much in the cell and then the cancer cells can grow out of control.

McElvery: In the case of cancer, there’s not enough p53 to curb uncontrolled cell growth, forming tumors. But the cranial neural crest cells that Jade studies seem to have the opposite problem: mutations in splicing proteins increase the amount of p53, and that ultimately kills the cells poised to form facial nerves and bones.

Varineau: Most other cell types can handle p53 activation and just develop normally. These cranial neural cells, for whatever reason, can’t handle the p53 activation. p53 says, “All right, time to shut this down.” And the cells undergo apoptosis and die before they can reach, like, the jaw where they would eventually differentiate into bone structures.

[“Caprese” ends]

And so I’m looking at what makes these cranial neural cells so specific to p53. They’re so sensitive to p53. In theory, the same thing should be going on in most cell types. p53 should be activated due to splicing problems. But we only see defects in the cranial neural crests. So we’re looking to see what makes these cells so sensitive to p53 and how could we maybe make it so they’re not as sensitive to p53?

Frederick: To answer this question, she began by looking at all the mRNA in the cranial neural crest cells to understand what goes wrong when a splicing factor is mutated. She found that the proteins that normally prevent p53 from being expressed (called “negative regulators”) were unable to do their job as effectively.

Varineau: The missplicing events that occur make it so that they can no longer negatively regulate p53. And so because they can’t negatively regulate p53, there’s more p53 in the cell. And so, I found that, along with some other papers that were published kind of at the same time, providing that link between splicing and p53, which hadn’t previously been known.

[“November Mist” begins]

McElvery: Next, she wants to find out what happens to cranial neural crest cells before they undergo apoptosis and die from too much p53. This will help her determine why these cells in particular are so sensitive to changes in p53 levels.

Varineau: Different aspects of how these cranial neural crest cells behave make us think that it’s not just a straightforward “p53 causes apoptosis.” We think there’s something else going on in there. 

Frederick: Understanding what goes wrong in these intricate molecular processes could help researchers find a way to right them early in development.

McElvery: Despite the fact that craniofacial disorders are so common, at the moment there are still very few treatment options beyond painful surgeries. The Calo lab’s research could help change that.

Varineau: With just cleft palate, there are surgeries involved, but with MFDM and Nager syndrome with a bit more complex craniofacial phenotype, I have not seen any big treatment ideas besides just reconstructive surgery, which is expensive and I don’t think is a walk in the park at all. So, yeah, I’m mainly focused on studying what makes these cranial neural cells so sensitive to p53 activation. But if we can understand what makes them sensitive to p53 activation, we can, down the line, hopefully develop therapies that allow these cranial neural crest cells to migrate and differentiate properly into these structures so that we can help prevent these developmental disorders — hopefully maybe before they happen or in utero or something like that.

I don’t think I was planning on doing anything translational when I was coming into grad school. So while the translational aspect is really, really important, obviously, I’m much more drawn to just the fact that you can look at biology on so many levels when you’re doing translational research.

[“November Mist” fades out]

McElvery: Thus far, Jade has been probing the properties of cranial neural crest cells in a dish, in order to glean a basic understanding of what makes them so sensitive to perturbations. But she’s hoping to start studying them inside living organisms soon.

Varineau: And so I’m doing lots of molecular characteristics of what’s happening in these cells. So what are the splicing changes that are happening? What are the other changes on a cellular level happening? So lots of qPCR analysis. So looking at gene levels, some Western blots looking at protein levels. A little bit of computational work comparing the RNA sequencing of these cells to other published work.

So I like how I can look at what the cells are doing kind of on a broader scale as well as, OK, let’s look at this specific gene. How is it misspliced? And then while I’m currently not working with any organisms, I like the fact that there’s literature out there on these disorders that look into organisms, and fish models and mice models for these diseases. And so I like that even if I’m not doing organismal research right now, I can think about it on multiple different levels.

[“Sals Place” begins]

Frederick: She plans to continue leveraging the Calo lab’s multi-tiered approach even after she graduates from MIT, perhaps working in industry. It’s a mindset with utility beyond the craniofacial disorders she’s currently investigating.

Varineau: It’s not just one disorder, it’s multiple disorders. Looking at the basic principles of cranial neural crest cells development maybe could give us insight into other diseases even if they aren’t development-related. We may not even need to look at a disorder. Maybe it’s just like looking at the cranial neural crest cells itself. It’s an interesting cell type. We have parallels between development and cancer. So coming at it from a basic standpoint, that gives us a broader understanding of a cell type or something happening on the molecular level, allows us, if we want to apply it translationally to multiple different translational aspects than maybe just like a singular disease or a singular type of cancer or a singular drug. And I think starting at the basic level allows us to branch out more.

[“Sals Place” fades out]

McElvery: That’s it for today. Next episode, you’ll hear about a grad student who’s probing the parasite that causes toxoplasmosis.

[“Something Elated” begins]

Frederick: That’s right — the microscopic organism that’s known for lurking in cat poop! Subscribe to the podcast on Soundcloud and iTunes or find us on our websites at MIT Biology and Whitehead Institute.

McElvery: Thanks for listening.

[“Something Elated” fades out]

Produced by Raleigh McElvery and Eva Frederick.

Music for this episode came from the Free Music Archive and Blue Dot Sessions at www.sessions.blue. In order of appearance:

• “Something Elated” — Broke for Free
• “Cran Ras” — Blue Dot Sessions
• “Cornicob” — Blue Dot Sessions
• “Lord Weasel” — Blue Dot Sessions
• “Caprese” — Blue Dot Sessions
• “November Mist” — Blue Dot Sessions
• “Sals Place” — Blue Dot Sessions