UAlbany biologist Paolo Forni discusses a recent discovery in his lab that challenges our understanding of a basic cell structure and how mutant proteins alter cell function. In this week’s episode, Paolo explains why “settled” science is rarely so, how uncertainty can be liberating and what his lab’s finding reveals about the evolution of living things.
In this episode, Paolo explained how mutations help living things become stronger and evolve over time. He said: “A wrong version of something might not be good today, but might be good for the world of tomorrow.”
In the full conversation, Paolo elaborated on this phenomenon using the new protein his lab discovered for context. The protein affects the functioning of a cell structure called the endoplasmic reticulum, specifically inside neurons – the cells that help us sense and respond to all manner of stimuli around us.
Host: You recently discovered a new type of protein which can carry a mutation. Does this mutation cause harm?
Paolo Forni: In mice that have the mutated endoplasmic reticulum protein, we ask, what happens? Are these mice wrong? The answer is, they're different. One of the results of the mutation is that it causes male mice to stop fighting with other males. That could be good or bad. It's probably bad if they are in the wild because they could not successfully compete with other males and would be replaced. But if the mouse that has the mutation colonizes an island where there are no other mice, it would create a new society of mice that has an ethology that is completely distinct. The population would evolve different behaviors and could still be successful.
Studying mutations can help us understand pathologies, but it is also a way to understand how we evolve. In fact, mutations are also how we started to see in three colors. Most animals don't see red, green and blue. By mistake, we made new version of molecules that allow us to detect a wider range of color spectra. And so that's a mistake that turned out to be a good mistake.
Paolo also shared more about the visual aspects of science and the singular opportunities it provides to see beauty that many people miss.
Paolo Forni: I think of myself as a very lucky person, and I think everybody that works in biology is very lucky because the moment you have the opportunity to see the world through a microscope, you realize that there is an incredible amount of beauty that we are not aware of. The structure of tissues, how the cell is organized and how molecules are organized within cells. It's mind blowing. I think having an artistic eye definitely helps to depict that beauty, but it also helps you to see. In science, the eye has always been very important. All scientists in the past were very good at drawing and depicting what they were seeing.
Let's remember that Santiago Ramón y Cajal, that is the father of neuroscience, was this man who didn't want to be a scientist. He wanted to be a painter. And then he wanted to be a war hero. Only because his father wanted him to be a medical doctor, he went to university and eventually became a medical doctor. But then, still, what he really wanted to do was to paint. He discovered the microscope and he started to look at tissues and liked depicting all the tissues. And he classified almost all the neurons we know about today. He was able to make these drawings that are famous in the entire world. People often start lectures in neuroscience with a drawing of Ramón y Cajal’s – all of which are still as accurate as these beautiful images that you take with immunofluorescence. Sometimes you can put a drawing of Santiago Ramón y Cajal’s next to the immunofluorescence image. Yeah. There are two different sets of colors. One is in black and white, the other one is colorful. But what is depicted is the exact same cell.
In this episode, Paolo broke down some hard-hitting neuroscience. If this is your jam, here’s the source material.
Interested in the true origins? This article features examples of early depictions of neurons drawn by Santiago Ramón y Cajal.
We also briefly mentioned a newly discovered system in the human body called the interstitium. Recent investigation suggests it might help explain, on a biological level, why acupuncture works.
Audio editing and production by Scott Freedman
Photos by Patrick Dodson
Hosted and written by Erin Frick
Host (00:03):
Welcome to The Short Version, the UAlbany podcast that tackles big ideas, big questions, and big news in less time than it takes to cross the Academic Podium. I'm Erin Frick in UAlbany's Office of Communications and Marketing.
Paolo Forni (00:16):
Most animals don't see red, green and blue. And by mistake, we made a new version of molecules that allow us to detect a wider range of color spectra. And that's how we started to see in three colors. That's a mistake that turned out to be a good mistake.
Host (00:38):
Maybe you tried something new at the gym, or maybe you just hadn't been in a while. Either way, the next morning you wake up with an unfamiliar twinge, having discovered a muscle you didn't know you had.
Now, imagine that kind of discovery in a lab, not a new ache, but a new molecule you didn't know about before. From the discovery of systems like the interstitium, which spans the entire human body, but was only first reported in 2018, to new interactions among molecules inside our cells. The more we know, the more we know we have a lot left to learn.
In any biology textbook, you'll find a generalized diagram of an animal cell. It looks like a tidy sphere with a nucleus in the middle, surrounded by colorful structures and organelles with names like “mitochondria” and “ribosomes.” It looks complete; settled. What we're learning is that it actually isn't.
That matters because countless diseases remain untreatable and some haven't even been fully described. Solving them starts with understanding the basics, but even the basics, like what cells and their components are made of, can still hold surprises.
UAlbany's Paolo Forni is a professor of biological sciences and a researcher in the RNA Institute. His lab studies neurons — the cells that allow us to sense, perceive and respond to the world around us.
Recently, his team discovered something new about one of those neatly labeled cell parts, the endoplasmic reticulum, a.k.a. the cell's protein factory.
For decades, scientists though this protein factory was largely the same in every type of cell, but by studying specific types of neurons in mice, Paolo's team found something more bespoke.
The endoplasmic reticulum is not a standard part, but instead varies extensively across neurons. This suggests that a cell's specialized functions depend not only on the genes it expresses and the proteins it produces, but also on the machinery required to process them.
When one of these factories produces a misfolded protein, the result could lead to cellular malfunction and disease, but a differently folded protein could also be a happy accident that leads to a new trait or ability that helps an organism thrive.
Understanding that each cell type houses a unique protein factory changes the way we think about how mutations, both good and bad, come about.
In this week's episode, Paolo explains what his lab found, why in biology “wrong” doesn't always mean “bad,” and what it feels like to discover something that challenges established science.
Here's our conversation.
Host (3:12): I understand your research focuses on cellular diversity, the nervous system and the function of structures that make up cells. Through this work, you recently discovered something brand new about fundamental cell biology that we didn't know before. So, I'd like to hear about that. And for starters, I'd like to hear about the cells at the center of this discovery.
Paolo Forni (03:32):
The thing we try to study in my lab are neurons. And first, what are neurons? So, neurons are a type of cell, but actually are many types of cells. And these are cells that are able to do something that other cells don't do. They detect signals of different types. They transform these signals, they compute, and they transmit these signals to other neurons.
And for example, in humans, we have about a hundred billion of this type of cell that interconnect and enable us to perceive the world, all the stimuli that's around us. Then we arrive to represent in our brain images that are our sensation and then react to these sensations with actions. So, the question that we have here is, if we have a hundred billion neurons, how different are these neurons in the genes that they express and how, specifically, can a mutation in a gene affect one neuronal type versus another?
Host (04:40):
So as part of your research, you study something called the vomeronasal organ, which is a structure found in many animals, including mice. What is it and how does it help a mouse or other animals survive in its environment and ultimately succeed?
Paolo Forni (04:54):
This vomeronasal organ is a system that has the ability to detect molecules from the environment that trigger a number of behaviors like mating behavior, maternal behavior, avoidance of predators and so on. And in order to respond to the stimuli in the environment, in this vomeronasal organ, we have many neurons that differ in their ability to detect a specific molecule in the environment. And so, if we go back to this idea, diversity is determined by the genes that the specific neurons express. And one of the differences that we found across these neurons are molecules of the endoplasmic reticulum.
Host (05:38):
What does the endoplasmic reticulum do and how did your latest discovery change longstanding assumptions about this structure?
Paolo Forni (05:46):
Genes are the instructions that define what the cells can do, but cells do things using proteins and proteins are little molecular machines. They're able to do all kinds of things. They're able to produce energy, they're able to detect signals and so on and so forth. So, proteins are made starting from the DNA. These specific molecular machines need to be assembled. And in order to assemble these proteins correctly, we have an organelle in the cells called the endoplasmic reticulum.
If we make an analogy, let's think about each cell type as a specific factory that generates specific products. In each factory that makes, let's say, a car or a dishwasher, we need to have different machinery to assemble this product correctly. Similarly, we have the endoplasmic reticulum that is the factory that has different machinery inside to modify the product properly. And so, what we noticed is that these neurons in the vomeronasal organ that are able to detect different signals from the environment have differences among them in the endoplasmic reticulum.
And this was something we did not expect and that actually found very exciting. And by analyzing this, we identified a protein in the endoplasmic reticulum that was never studied before in mammals, never.
Host (07:22):
Can we assume from that, or can we hypothesize that that's true of different cell types beyond the one that you looked at — that perhaps the endoplasmic reticulum in this factory is a different factory inside each cell type?
Paolo Forni (07:33):
That's a great question. In the last paper we published, we kind of end up with the question, is this an example of a difference that is true across different cell types? And so it's definitely important to start to look at the molecules of these organelles in a different perspective, because oftentimes there are things in science that we don't pay attention to because we think, okay, these are housekeeping proteins. These are the same across the cells, so they're not interesting. But noticing differences in the housekeeping tools can be very informative and tell us that the house is actually different and the house has different needs. So, it's very possible that these differences at different levels are true across different cell types. But what is also very intriguing is this. A lot of neurodegenerative diseases, and we talk about let's say Parkinson’s or Alzheimer’s or aging itself, we know they correlate with problems in the endoplasmic reticulum and in the ability of certain cells to process certain proteins.
And so, the question here is, can it be that some forms of degeneration or congenital defects might be associated with a specific mutation in molecules in the endoplasmic reticulum?
In the year 2000, a new technology appeared that is the single cell transcriptomic. What does it mean? Each cell has the same DNA. They express the DNA differently, meaning that different genes are turned into different proteins. So now we can isolate single cells from a tissue and you divide it in thousands of single cells. We have the ability now to check all the genes that are expressed in each individual cell. This new single cell sequencing technology is really reshaping our understanding and definition of what we're made of and therefore how defects in the components of what we're made of can manifest themselves in different pathological states.
Host (10:00):
You're seeing basically what might be going wrong in the factory that produces a faulty misfolded protein that leads to something going wrong, that manifests as disease.
Paolo Forni (10:10):
Right. And I want to say something about wrong. Wrong is something that decreases your ability to survive, but wrong can also be advantageous, meaning wrong is the basis of evolution. A wrong version of something might not be good today, but might be good for the world of tomorrow.
Host (10:31):
I really like that illustration, change that happens at the cellular level, not always leading to something bad could lead to good things too. I mean, we're just beginning to scratch the surface of understanding the processes that happen throughout the human body at all these different levels. Learning that we're still learning what we're made of is a pretty extraordinary thing.
What does it feel like as a scientist to make a discovery like this that sort of turns on its head something fundamental that we thought we knew about a particular structure within a cell?
Paolo Forni (11:01):
Every day is exciting. Every day you discover little piece. Like any discovery in life, you discover something, you start to see something you thought about in a certain way in a different way and makes it even more exciting because immediately you have new white canvases that you can write on.
I remember as a student when I was studying biology thinking why should I even study this? We already know everything. And the beautiful thing when you do science that you realize that you knew something up to a certain point and oftentimes that what you knew and what you studied is actually wrong and that's very liberating.
Host (11:42):
A part of what you're doing too is, as you say, you're creating these models, you're creating a blank canvas for not only your lab as a jumping off point, but also other labs around the world that might be following adjacent or parallel research strands. I'm wondering if you could talk about that a little bit, how what you're working on in your lab could be useful in other contexts.
Paolo Forni (12:03):
If this is paradigmatic, as I said before, of differences across other cells, we will definitely learn soon because this technique is out there and there are so many data that are available to everyone, and any student anywhere in the world can download this data and with a computer test immediately if what we said is true and can be transposed to other cell types. So, there is also this level of democratization through a format of data that makes my lab everyone's lab. Currently in the American system through the NIH, our discoveries are public and so everyone can access our reagents, everyone can use our primary data and investigate whatever they want.
Host (12:59):
I'd like to ask a bigger picture question about what this discovery means for the evolution of cell biology across organisms and across time.
Paolo Forni (13:11):
Every animal species has its own way to detect certain specific signals that are important for that form of life. Cells are able to do something or not based on the genes that they express.
So, we need to have proteins that are these little machines that evolve to detect something specific. Mice can detect pheromones that are these molecules that other mice produce that tell them if they're healthy, they're male, if they're female, if they are related, if they're not related and so on. So, they have cells that evolved with the ability to detect molecules that we do not detect.
During evolution, we diverge, occupying different niches, different part of the world, and we have different needs to be the best version of ourselves to fit the evolutionary pressure. We need to develop specialized cell types. To put our discovery in this perspective, that suggests when you, through genetic mutation, make a new form of a protein that has an acquired ability to detect a signal that was not available before, you might need also an endoplasmic reticulum to make that specialized form of protein available and to fold that in the way that gives to that protein the ability to do what is needed.
Evolution determines if we are a good fit for the environment where we are. If evolution can reward mutations that expand the ability of an animal to detect signals from the environment and detecting those signals is advantageous for their survival. Okay, that's good. But to make that new version of a protein, you might need new machinery in the endoplasmic reticulum to fold that properly and to sustain the molecular needs to have that newly acquired ability to detect the signal. So what our paper suggests is that as cells become more specialized and they require new versions, they might have very idiosyncratic endoplasmic reticulum needs and therefore the endoplasmic reticulum has to evolve in parallel with mutation in genes that are advantageous in order to be able to sustain the making of those specific proteins.
Host (15:55):
What initially got you interested in science and in biology?
Paolo Forni (16:00):
I come from a family of scientists. Basically, my grandparents were doctors. My father is a famous professor in Italy and so on. And I didn't really feel like I was into science. I thought I was going to be probably a movie director or a photographer or a painter or a sculptor or something of that type. Then when I was about 19, I thought, oh my gosh, what if I become an artist and I run out of ideas? And so, I though, okay, maybe science is a safe choice. So, I did study biology and then one day I was studying with a friend of mine in the library of the institute where he was working and I met his boss and we had a conversation in English. I was in Italy. And then she decided that I had to work in her lab after that.
Host (17:02):
She decided that.
Paolo Forni (17:03):
Yeah. And so, I moved to her lab. I started working in her lab and that was incredible. We were doing very cool science back then in the '90s, making stuff that was very new. We're making new mouse models with point mutations. It was very interesting. After a few years, I decided to do a PhD with her and the lab ran out of money and so I had to find a way to sustain myself. And we had all these mouse models that we were working on to study muscle development and cancer. And I wrote a project for a fellowship in neuroscience where I proposed to use these mice we generated for something else to study the central nervous system, the brain, and I won this fellowship. And so suddenly, I started to do neuroscience in a lab that was studying muscle development and cancer. And then for something completely unrelated to science, I decided to move to United States because I met somebody that is currently my wife, and she was studying in the United States.
And then I applied for several labs at the NIH, and I started to work in a lab that was studying the development of the olfactory system and other neurons that form in the nose.
Host (18:20):
I'm wondering, do you keep up any of the kind of creative or artistic media that you mentioned?
Paolo Forni (18:26):
Yes. I like to organize symposia conferences and things like that. And the drive is really to make the poster. I usually first start with the poster, then organize the symposium. In the work as a scientist, you need to be also a graphic designer. You need to make illustrations all the time. You need to make beautiful photos, composites, and you need to be able to illustrate your work. What probably, when I was young, I thought was frivolous turned out to be a great set of skills that definitely helped me and still helps me to deliver my science.
Host (19:08):
What is your favorite thing to teach? What do you enjoy about working with students?
Paolo Forni (19:13):
Delivering a set of information that you need to deliver and that students need to understand and learn, it can be challenging. I like to become good at delivering complex concepts in a way that is accessible, that means I need to understand the concept very well and to develop tools, that could be depictions.
So, I like to make my slides or animations to deliver a concept as a series of simpler concepts that come together in something complex.
Whenever there is a discovery and the principal investigator, in this case me, is invited to talk about it, what we do, we actually talk about the work that has been done by others. And so, in this case, are my students and the work I talked about today was for the most part, the work of one student, Nick Matthias, that is actually graduating this week, but also it's a collective work from the lab.
And that is an exciting thing to have a group of students that go from not knowing anything to being the people that know of something more than anyone else in the world. And it's fantastic to see these metamorphoses and also what comes out of the interactions of these people.
Host (20:48):
That was Paolo Forni, professor in the Department of Biological Sciences and researcher at the RNA Institute in UAlbany's College of Arts and Sciences.
In this week's episode, Paolo explained how a recent discovery in his lab changes our understanding of a basic cell structure and what it means for the broader field of evolutionary biology.
To hear more about how molecular mistakes can actually be good, check out The Longer Version, in our show notes.
If you missed last week's episode with UAlbany researcher Sujata Murty on how her lab is using coral cores to recreate past climate and bolster resilience planning, be sure to check it out.
The Short Version would not be possible without contributions from many people, including for this episode, Scott Freedman, who provided audio production and editing from the UAlbany Digital Media Studio deep inside the podium tunnels.
We'll be back next week with another quick conversation about something interesting.
I'm Erin Frick at the University at Albany, and this has been The Short Version.
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