Molecular “Transformers” Switching Form and Function - A Conversation with Dr. Lauren Porter

Show Notes

Transcript

00:00:04:06 - 00:00:28:09
Yamila El-Khayat
I’m librarian Yamila El-Khayat and this is NNLM Discovery a podcast from the Network of the National Library of Medicine. This podcast series explores how the NNLM is engaging with communities to provide access to trusted information for the purpose of improving the public’s health. On our final episode of season one, we've decided to showcase another podcast series that's being produced at the National Institutes of Health.

00:00:28:21 - 00:00:43:13
Yamila El-Khayat
The podcast is called “Speaking of Science,” and it is produced and hosted by Diego Arenas, a Health Communication Specialist working to promote the NIH Intramural Research Program. Diego is here with me today. Hi Diego!

00:00:44:06 - 00:00:44:18
Diego Arenas
Hi Yamila!

00:00:45:08 - 00:01:02:14
Yamila El-Khayat
In our previous episode we featured an Intramural Researcher at the National Library of Medicine studying artificial intelligence, Dr. Sameer Antani, so the NLM has it’s own Intramural Research Program, but what is the NIH Intramural Research Program and what is its relation to NLM?

00:01:03:03 - 00:01:27:19
Diego Arenas
Great question. Many people might not know that the NIH doesn't just award grants for extramural research happening all around the country. It also boasts thousands of scientists conducting their own research inside the so-called four walls of the NIH, hence intramural. The National Library of Medicine has its own intramural research program, just like the other 26 institutes and centers that make up the NIH.

00:01:28:09 - 00:01:45:00
Diego Arenas
Each Institute, like NLM, creates its own research agenda and its own budget, but collectively we refer to all these programs together as the Intramural Research Program, or IRP for short. And I’m part of a team that showcases all the great research coming out of the IRP!

00:01:45:18 - 00:01:53:00
Yamila El-Khayat
And the NIH IRP started a podcast called, “Speaking of Science,” tell me about this podcast.

00:01:53:08 - 00:02:15:15
Diego Arenas
Yes, we launched the podcast in 2019, and it's been a great way to profile IRP researchers and share their findings with the community. There's a lot happening at NIH all the time. We have over 1100 principal investigators and 4000 postdoctoral fellows conducting research, which actually makes the IRP the largest biomedical research institution in the world.

00:02:16:07 - 00:02:25:09
Yamila El-Khayat
So, “Speaking of Science” created a podcast episode featuring an NLM researcher. I invited you on today to walk us through and share some clips from this episode.

00:02:26:02 - 00:02:32:13
Diego Arenas
Sure thing. The episode you're talking about features Dr. Lauren Porter And it is called Molecular Transformers.

00:02:33:18 - 00:02:35:21
Yamila El-Khayat
Transformers like the cartoon robots?

00:02:36:00 - 00:02:41:20
Diego Arenas
Yes, exactly. Dr. Porter is helping redefine the way we understand how proteins behave.

00:02:42:05 - 00:02:48:20
Yamila El-Khayat
So it's been a while since I reviewed this. Can you give us the basics on protein function before jumping into Dr. Porter's research?

00:02:49:05 - 00:03:10:22
Diego Arenas
Sure. So proteins are basically large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for structure, function and regulation of the bodies tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains.

00:03:11:07 - 00:03:18:06
Yamila El-Khayat
I'm having flashbacks to my high school science class. I remember the amino acids help determine the functionality of the protein.

00:03:18:13 - 00:03:41:19
Diego Arenas
You're right, the sequence of amino acids is unique to each protein and dictates how it will arrange itself in three dimensional space. The resulting structure or conformation is what then gives a protein its function inside the cell. Most proteins only adopt one conformation. Well, that is until they don't. Here's Dr. Porter explaining more.

00:03:42:13 - 00:03:55:14
Dr. Lauren Porter
It turns out that there is this emerging class of proteins called fold-switching proteins, which can actually change their folds and their functions in response to cellular stimuli.

00:03:55:20 - 00:04:01:13
Diego Arenas
This would be as if your kitchen blender could all of a sudden turn into a toaster. With a flip of a switch.

00:04:02:03 - 00:04:14:04
Dr. Lauren Porter
The first time I saw that, I was like, “Whoa! There is some stuff we do not understand about proteins, because based on everything I’ve learned that should not be possible.”

00:04:14:04 - 00:04:23:21
Diego Arenas
Fold-switching proteins are reminiscent of Transformers, you know, those huge alien robots from comic books and movies that can change from one machine into another at the drop of a dime.

00:04:25:16 - 00:04:32:04
Optimus Prime
My name is Optimus Prime. We are autonomous robotic organisms from the planet Cybertron.

00:04:32:16 - 00:04:53:06
Dr. Lauren Porter
The analogy with Optimus Prime is good, because in one case, he's a robot, and in another case, he's a car, and you would never know that the robot could become a car, or vice versa, just by looking at it. So, some of these proteins really can shift completely, and you would never know just by looking at it.

00:04:53:16 - 00:05:02:14
Diego Arenas
How different are these changes? I mean are we talking small differences like a car to like a truck or something more stark like a car to a helicopter?

00:05:02:16 - 00:05:07:11
Dr. Lauren Porter
We're talking like a car to an elephant. It's a complete different change.

00:05:08:23 - 00:05:15:04
Yamila El-Khayat
So a car to an elephant, that's a big change. And what's the importance of understanding these switches?

00:05:15:08 - 00:05:27:08
Diego Arenas
It's huge. Understanding how even the smallest switch occurs could help scientists understand the molecular basis of certain diseases like cancer, autoimmune disorders, and bacterial and viral infections.

00:05:27:22 - 00:05:29:12
Yamila El-Khayat
And how is this being done?

00:05:30:05 - 00:05:54:21
Diego Arenas
Well, proteins exhibit two main amino acid arrangements, alpha helices, which look like springs or beta pleated sheets, which kind of look like a woven fabric. But both types of fold patterns are energetically stable, which makes them pretty rigid. So a switch from one to the other is very surprising to see. Here's Dr. Porter talking about how they're studying these switches.

00:05:55:03 - 00:06:32:08
Dr. Lauren Porter
And what my lab is looking for right now are samples of proteins that switch from alpha helix to beta sheet, because those are like the most drastic changes one can imagine. And so they are probably the easiest to find. Right now, we use machine learning based methods that classify secondary structures of proteins. And what we look for are when we change things about the sequence, like we shorten it or something like that.

00:06:32:08 - 00:06:49:21
Dr. Lauren Porter
Does the secondary structure prediction change or does it stay the same? And when we see substantial changes to secondary structure by altering the context of the sequence, that to us is a strong indicator that this protein might switch folds.

00:06:50:21 - 00:06:56:15
Diego Arenas
And what triggers those folds to switch from one state to another? Is it something in the environment?

00:06:56:16 - 00:07:23:00
Dr. Lauren Porter
So, it depends. Certain fold switching proteins actually sample both confirmations at the same time, but there are other proteins that do need to be triggered, and there are a number of different triggers; so changes in pH, binding a protein, changes in redox potential, any of those things and many more things can trigger the fold switching.

00:07:23:03 - 00:07:38:19
Diego Arenas
In our “Speaking of Science” episode we do go into greater detail about how this research is carried out and how it fits into the ultimate mission of improving human health. But, Dr. Porter’s research is really changing the way we think of something that we thought was fully understood for so long.

00:07:39:14 - 00:08:20:17
Dr. Lauren Porter
For sure, I’m definitely comfortable saying that fold switching proteins show that there are some stuff we don't understand, and it's important to understand it, especially because of how relevant towards integral biological processes. We recently wrote a paper basically showing that fold switching seems like a specific mechanism of regulation and being able to respond to the environment quickly is a much more effective way of of regulation than, for example, conditions change and now a whole new protein needs to be expressed.

00:08:21:02 - 00:08:27:23
Dr. Lauren Porter
The timescale on just switching a fold is a lot faster than on transcribing and translating a new protein.

00:08:28:19 - 00:08:39:01
Diego Arenas
Beyond understanding the dynamics of these fold, switching proteins. What is the goal when it comes to implications in human health? I know they're kind of integral in some diseases.

00:08:39:01 - 00:09:10:21
Dr. Lauren Porter
Yeah, so I think the first thing is we got to understand the biophysics of these proteins, like the dynamics and how they work. If we can get a better handle on that. My hope is down the road, therapeutics could be developed that target fold switching proteins and force them to stay in one conformation or favor one conformation. So like for example, the protein we study called RfaH, regulates the expression of virulence genes in proteins like E. coli.

00:09:10:22 - 00:09:35:11
Dr. Lauren Porter
On a basic level, what that means is RfaH plays an integral role of giving people food poisoning. And so if it were possible to force RfaH to not be able to switch between its two folds, that could dramatically reduce the amount of virulence proteins that bacteria could produce.

00:09:36:02 - 00:09:39:07
Diego Arenas
And effectively lowering the likelihood of getting food poisoning.

00:09:39:11 - 00:10:04:20
Dr. Lauren Porter
Yeah, so it may be possible if down the road to produce drugs that target these. On the flip side, a kind of tantalizing study in Journal of Molecular Biology came out a couple of years ago showing that amino acid change associated with a certain form of human cancer switched a secondary structure element in a human protein from an alpha helix to a beta sheet.

00:10:05:07 - 00:10:38:22
Dr. Lauren Porter
And so it could be possible perhaps to design some sort of therapeutic that targets that protein, you know, that has that amino acid change, so that maybe it could be restored to its native form, and then maybe that would help, you know, decrease the number of cancer cells that could grow or something. So, I think those are kind of the two ways that I imagine, you know, decades down the road, this research being useful in the clinic, and I hope to see that in my lifetime.

00:10:39:09 - 00:11:03:02
Diego Arenas
Yeah, well, that's what I think is so great about basic science. Yes, there's the thrill of discovering something new and the curiosity to really understand it at a fundamental level. But I think it also feeds into like the scientific imagination, you know what I mean? Like, it kind of opens the mind to a new world of possibilities, especially ones that can make an impact on a lot of people's lives.

00:11:03:13 - 00:11:31:00
Dr. Lauren Porter
Absolutely. Yeah. And that's, I don't think I could have pursued this without knowing that this really could make an impact downstream. When I was a Junior in college, my dad got diagnosed with stage four cancer and seeing how much he had to suffer to survive, like he had to have multiple rounds of chemo. He had a bone marrow transplant.

00:11:31:00 - 00:11:56:17
Dr. Lauren Porter
And it was really, really hard for him and for us as a family to watch. And so I remember thinking like, well, you know, I would love to do something so that, you know, down the road someone like me doesn't have to watch their parents suffer and their parent doesn't have to go through the suffering. And so that really helps me stay motivated.

00:11:57:18 - 00:12:05:13
Yamila El-Khayat
Diego, thanks for sharing this story on our NLM researcher, Dr. Lauren Porter. It's research like this that may change the future of science.

00:12:05:23 - 00:12:14:04
Diego Arenas
I think you're definitely right. The power of the NIH/IRP is that we're really thinking outside of the box and trying to reshape scientific thinking.

00:12:14:15 - 00:12:27:10
Yamila El-Khayat
We've included a link to the full episode of the “Speaking of Science” podcast, plus a short video about Dr. Lauren Porter's research in our show notes. Diego, thanks for coming in and having a little NIH podcast synergy with us.

00:12:27:23 - 00:12:32:18
Diego Arenas
Of course, And congrats on your first season. I look forward to listening to season two.

00:12:33:15 - 00:12:49:00
Yamila El-Khayat
Thank you. NNLM Discovery will return soon with new episodes. Subscribe to our podcast and follow us online, and remember to rate, share, and comment on our show wherever you get your podcasts. This is NNLM Discovery.