Hijacking the Cellular Code: eIF4E, Cancer, & the Quest against Drug Resistance with Dr. Katherine Borden

WEBVTT
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lost in the fog of a cosmic storm floating on
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whimsical wavelengths is the norm dancing through
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the stars chasing spectrums of light riding the
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waves that are just out It's season three, and
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I'm your host, Dr. Jeffrey Zurich, a volcanologist
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and geophysicist. Today, we're digging into cellular
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function, a protein called EIF4E, or just 4E.
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Either way, it doesn't exactly roll off the tongue.
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It doesn't have a name that would suggest importance,
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like dioxic ribonolic acid, or When you come
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across something really important, you expect...
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My name is Maximus Decimus Meridius. Sometimes
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it sounds like the vine of my first name. My
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name is Jeff. But it is important. 4E, as I'm
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going to be calling it, as I learn in the interview,
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wait for it, is the way they refer to it, is
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the rate -limiting gatekeeper for building proteins
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in a cell. It escorts genetic blueprints through
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the editing and transport so the cell's factory
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can manufacture them. When a cell needs to divide,
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blood vessel growth, repair mechanisms, basically
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if a cell needs to create a new biological scaffolding,
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proteins, and therefore, 4E is involved. And
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it's not... Just humans. This protein is so ancient
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and foundational that complex life cannot live
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without it. Today we will explore this protein
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and what effect it has. What happens when there
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is too little and too much. Hint. We're going
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to be talking about cancer. Before getting into
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the actual episode, science sausage making time.
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I need to call out a relatively new Canadian
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organization for science communication. It is
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also a direct way for me to find Canadian researchers
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and guests. The organization is the Canadian
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Sciences Speakers Network. It can be hard to
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fathom that science tasks like reviewing grants
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still works a bit like a word -of -mouth system.
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Being able to fill grant panels with qualified
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people is a requirement, but only those on kind
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of a personal list or roller decks gets called
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upon. It causes the system to not work at its
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full potential, causing delays and other unintended
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consequences. We can also look outside of specific
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disciplines. For instance, how science communication
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is conducted, like in the media. It is also who
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you know. If you're on a journalist contact list
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when something in your field comes up, there
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is only one person they will call. And if they
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know no one, they go through the word of mouth
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method to find someone. The Canadian Science
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Speakers Network aims to make that much easier.
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Myself and today's guest, Dr. Katherine Borden,
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are both members. You can see our profiles and
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all the wonderful, knowledgeable science communicators
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at C -S -S -N -R -C -P -S dot C -A. Be sure to
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look for that in the show notes. So today's guest
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is Dr. Catherine Borden, a professor in the Feinberg
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School of Medicine at Northwestern University.
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The Borden Lab is at the cutting edge of researching
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4E and how it hijacks genetic messages that are
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edited and shipped out to force cells into an
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aggressive invasive. cancer state. Dr. Katherine
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Borden, welcome to Whimsical Wavelengths. Nice
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to be here. I really appreciate the opportunity
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to be part of your great podcast. Aww. Well,
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as I was wrapping up Season 2, I came across
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you and the Canadian Science Speakers Network.
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First off, thank you, you and your team, for
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collecting some of the best science communicators
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in Canada into one spot. I gotta say, it's gonna
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make my job going forward much, much easier.
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second before we jump into the research, how
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about we just dwell on it for a second and what
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is it and what problem is it trying to solve?
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So we nickname it CSSN, just for listeners. And
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the problem that it's trying to solve is that
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Canada is a big country, and we have a lot of
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talent here, and it's widely distributed. And
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so in order to harness that talent more efficiently,
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we developed this website, which is searchable
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for any kind of scientific or academic fields
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that you might be interested in knowing more
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about. there so that the government, the public,
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the press, academic institutions, funding agencies,
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industry boards, all of those places will have
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a chance to be able to not just use word -of
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-mouth networks, but to actually have a high
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-end search engine in order to identify individuals
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that could benefit their organizations. That's
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really what we hope the site can be used for
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and is starting to be used for. And I also just
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want to throw in that the site is completely
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not for profit. It's run by academics for academics
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and for the greater good. So there is no other
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agenda other than allowing Canadians to be highlighted
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and found who are particularly talented in a
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certain area. I find something strange that you
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just said there. It's almost like us scientists
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are almost hardwired for that sometimes, especially,
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I guess, when you're dealing with cancer in the
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health field. When it's taken up by scientists
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who don't get paid for something, we almost feel
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like it's an inflective response that we have
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to mention it. I guess I just wanted to be sure
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that people didn't feel that there was some hidden
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agenda. And also, you know, as a scientist, I'd
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like to be able to be found as well. And as a
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researcher who's organized big meetings, I found
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that there was no Canadian resource that would
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help me organize a better meeting or to organize
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a better board. And so it's a real problem. And
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I think only those of us who are scientists or
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in allied fields of STEM in particular have to
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kind of... build this to help ourselves. And
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I think it's a crucial time for the public interest
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to really be able to reach out to understand
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from experts what the real science is behind
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the headlines. Yeah. And I think also I'm going
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to have a running theme as part of the season,
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perhaps, is turning science back into a human
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conversation. So it's just putting humans in
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front of the people who are looking for that
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information. I completely agree with that. So,
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we're going to get on to the episode, and like
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most episodes, this started with a peer -reviewed
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article. And I'm going to try to not butcher
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the pronunciation of things. The eukaryotic translation
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initiation factor ELF4E unexpectedly acts in
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splicing, thereby coupling RNA processing with
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translation in bio -SEs. To get from here to
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understanding the results, let's start with how,
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I guess, a healthy cell functions. Like, how
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about the situation where I was getting ready
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for this interview and I got a paper cut? What's
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happening at the cellular level to repair the
00:08:05.839 --> 00:08:08.879
damage? Well, I guess you provide a perfect example
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of how dangerous research can be. first of all
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just to say that that it's e -i -f -4 -e but
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we but you otherwise you said it perfectly but
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we nickname it 4e because that makes it much
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easier to say okay so if i'm going to use 4e
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for the rest of the so that way i don't have
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to go through exactly perfect exactly so A lot
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happens when you have your paper cut. A lot happens
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on the organism level and the cell level in order
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to heal that paper cut. Your body sends immune
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cells to clean up debris from the cut to get
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rid of damaged cells and to ensure that there
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is no infection. Then other cell types have to
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come and lay down a scaffold in order to heal
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the wound so that now it becomes seamless and
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you don't see, hopefully, your paper cut anymore.
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So at the cellular level, As I said, many different
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types of cells have many different things to
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do in this sort of very basic scenario that you've
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brought up. And these cells receive signals that
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something went wrong and that they might have
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to move in and fix things up. So many of these
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signals turn on programs at the DNA level. But
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where 4E is cool is that it can disconnect the
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DNA signals to produce the actors in the cell
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called proteins with altered functions that can
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respond much more quickly to this sort of wound
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scenario, adapt to these stressful situations.
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And so that's kind of an overview of what's going
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on there. Describing that 4E is part of the process
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by... allowing the cell to quickly adapt and
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produce other proteins to help fix the problem
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of a paper cut? Yes, exactly. 4E plays many roles,
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but by being able to reprogram DNA signals in
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order to adapt to the stress, it allows these
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much faster responses. It works through something
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called RNA, which many of your listeners may
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be familiar with because we had the COVID mRNA
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vaccines. But the message from DNA is called
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messenger RNA. And that message is supposed to
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be instructions the DNA sends into the part of
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the cell known as the cytoplasm. where that message
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gets turned into these protein actors I was referring
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to. And what proteins like 4E can do is modulate
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those instructions. So they change the instructions
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to adapt to stress, or sometimes they can get
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hijacked by a cancer cell, and then they're doing
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things that they shouldn't be doing. Okay, so
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if I'm looking for how our understanding of this
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protein has changed over time, I suppose that
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we didn't always think of it this way. What did
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we think about it when it was discovered in the
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1970s? So in the 1970s, it was able to disconnect
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the signals from DNA to protein by allowing...
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more protein to be made out of every single strand
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of messenger RNA you have. And so it was allowing
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an amplification of the signal. And so back in
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the 70s was when this protein was actually discovered
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to bind a really important part of the messenger
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RNA known as the methyl 7 -guanosine cap, or
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we'll just call it the cap for the purpose of
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our conversation. And this modification allows
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4E to be able to interact with RNAs. And what
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we've found since the sort of foundational studies
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of the 70s is that FORE can also do things that
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not only amplify the message through both this
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increased translational efficiency or increased
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efficiency of getting more protein out of a single
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RNA, also by rewriting the message or editing
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the sort of the RNA code, as it were, allowing
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big chunks to be shuffled in or out of the RNA.
00:12:05.960 --> 00:12:08.769
And this can... cause proteins to be made from
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that RNA, they can actually even have opposite
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functions to what the original instructions were
00:12:13.450 --> 00:12:16.690
that was sent. So for instance, a protein that
00:12:16.690 --> 00:12:19.289
might tell a cell, you're really damaged, you
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need to die now for the good of the organism,
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in a process called apoptosis, this same protein
00:12:25.710 --> 00:12:28.490
can end up or the instructions can be modified
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so that protein actually rescues cells from apoptosis
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or cell death. And that can obviously, in the
00:12:35.289 --> 00:12:38.090
case of a cancer cell, allow the cancer cell
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to keep on going when it should have listened
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to the signals to die. You know what? I'm going
00:12:44.309 --> 00:12:47.029
to skip all over the place here. So is there
00:12:47.029 --> 00:12:50.009
any other protein besides 4E that does a similar
00:12:50.009 --> 00:12:55.169
job? Yeah, there are other proteins. So what's
00:12:55.169 --> 00:12:59.720
being... sort of known today as opposed to when
00:12:59.720 --> 00:13:02.659
those studies in foray started in the 70s, is
00:13:02.659 --> 00:13:06.200
that the foray can affect many of the different
00:13:06.200 --> 00:13:09.820
chemical changes that RNA have to undergo in
00:13:09.820 --> 00:13:13.299
the process of called RNA maturation, allowing
00:13:13.299 --> 00:13:17.820
different also... kinetics for the capacity of
00:13:17.820 --> 00:13:20.419
the RNAs to move from the nucleus to the cytoplasm
00:13:20.419 --> 00:13:23.259
to be available to the machines that make proteins
00:13:23.259 --> 00:13:26.639
out of the RNA, as well as this capacity to make
00:13:26.639 --> 00:13:31.320
more protein out of any RNA. So there's other
00:13:31.320 --> 00:13:34.440
proteins that can work at some of these steps,
00:13:34.659 --> 00:13:38.799
but 4E seems to be one of the few that actually
00:13:38.799 --> 00:13:41.919
can act at all of these steps. And that's...
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really based on the fact that FORE can bind this
00:13:44.710 --> 00:13:47.210
central cap modification I was talking about
00:13:47.210 --> 00:13:51.169
before. That's the little module that FORE recognizes.
00:13:51.529 --> 00:13:55.929
And then FORE sort of changes which other partner
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cofactors at each step of the processing and
00:14:00.330 --> 00:14:03.690
then protein synthesis production scenarios.
00:14:04.950 --> 00:14:08.590
So is that the thing that's changed the most
00:14:08.590 --> 00:14:11.090
from the 70s? It's like, okay, we found this
00:14:11.090 --> 00:14:14.019
protein. does some pretty cool stuff. And then
00:14:14.019 --> 00:14:17.200
kind of fast forward into late 80s, 90s today,
00:14:17.299 --> 00:14:20.500
we're starting to understand just how integrated
00:14:20.500 --> 00:14:23.620
this is within the whole machinery from start
00:14:23.620 --> 00:14:27.460
to finish. Exactly. And what's very special about
00:14:27.460 --> 00:14:31.940
4E is that it also doesn't affect these chemical
00:14:31.940 --> 00:14:35.759
modifications to the RNAs or their export or
00:14:35.759 --> 00:14:38.559
their production into protein. It doesn't treat
00:14:38.559 --> 00:14:41.639
all RNAs equally. It has the specificity and
00:14:41.639 --> 00:14:44.259
a lot of the RNAs that it's specifically changing
00:14:44.259 --> 00:14:48.139
are RNAs that are involved in cell division,
00:14:48.440 --> 00:14:51.360
so creating more cells in a process we call proliferation.
00:14:51.740 --> 00:14:54.960
In cell movement in particular is a big one.
00:14:55.100 --> 00:14:58.240
So as we know, for instance, those cells that
00:14:58.240 --> 00:15:00.799
we talked about during your paper cut, we had
00:15:00.799 --> 00:15:03.789
to have cells be able to walk into the... into
00:15:03.789 --> 00:15:06.090
the paper cut and help start to clear out the
00:15:06.090 --> 00:15:08.570
debris. So cell movement is a normal function,
00:15:08.710 --> 00:15:11.309
which ends up being hijacked by cancer cells
00:15:11.309 --> 00:15:13.370
in the form of what we know, you know, disease
00:15:13.370 --> 00:15:16.409
spread and metastases. And also this capacity
00:15:16.409 --> 00:15:20.429
of 4E to be able to affect RNAs involved in making
00:15:20.429 --> 00:15:24.110
the choice of cells being able to survive a stress
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or cells listening to what they should listen
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to and die. So those... The specificity is something
00:15:32.750 --> 00:15:36.049
that's come through the years. But the biggest
00:15:36.049 --> 00:15:38.529
thing, I think, is the fact that it can affect
00:15:38.529 --> 00:15:42.629
so many different steps of this sort of protein
00:15:42.629 --> 00:15:46.350
production pathway. All right, now the pivot.
00:15:46.629 --> 00:15:49.909
I know it's a little bit of a cliche. What was
00:15:49.909 --> 00:15:53.549
the eureka moment or data or stack of moments,
00:15:53.629 --> 00:15:55.700
which is usually... more often the case, that
00:15:55.700 --> 00:15:59.100
kind of forced that rethink of 4E and put it
00:15:59.100 --> 00:16:00.679
on a path to today's understanding with respect
00:16:00.679 --> 00:16:05.620
to cancer? So I think for many, many years, it
00:16:05.620 --> 00:16:08.460
was considered to be very important in this role
00:16:08.460 --> 00:16:10.419
in protein synthesis, and that was considered
00:16:10.419 --> 00:16:12.960
its only role. So as we said, understanding these
00:16:12.960 --> 00:16:18.120
different roles really required the first observation.
00:16:19.360 --> 00:16:21.620
to be that foray was in the nuclear compartment
00:16:21.620 --> 00:16:24.679
of cells because the protein production part
00:16:24.679 --> 00:16:27.679
of cells is all in the cytoplasm. And so foray
00:16:27.679 --> 00:16:30.139
was considered to be only there and thus could
00:16:30.139 --> 00:16:32.980
only do things related to that compartment. In
00:16:32.980 --> 00:16:36.620
the 90s, some work by other groups had shown
00:16:36.620 --> 00:16:40.289
that that 4E could actually be in the cell nucleus
00:16:40.289 --> 00:16:44.710
of mammalian cells, so human cells, and also
00:16:44.710 --> 00:16:47.490
in yeast cells. And later studies even showed
00:16:47.490 --> 00:16:50.529
it in plant cells. So it seems that 4E being
00:16:50.529 --> 00:16:53.450
in a nucleus is actually quite ancient when we
00:16:53.450 --> 00:16:55.990
think about, you know, when was the last time
00:16:55.990 --> 00:17:00.269
animal plants and yeast were all sort of similar
00:17:00.269 --> 00:17:02.190
or, you know, derived from a similar organism.
00:17:02.710 --> 00:17:06.940
So the eureka moment for us. was I was working
00:17:06.940 --> 00:17:11.099
on actually a project related to viruses, completely
00:17:11.099 --> 00:17:13.759
unrelated to EIF -4E. In fact, I hardly even
00:17:13.759 --> 00:17:16.119
knew what EIF -4E was. And I just started my
00:17:16.119 --> 00:17:20.500
own lab. And we were using EIF -4E as a control
00:17:20.500 --> 00:17:22.980
because it was easy to buy antibodies for it,
00:17:23.000 --> 00:17:28.880
to be honest. And it turned out that in the control
00:17:28.880 --> 00:17:31.380
experiments, when I looked down the microscope,
00:17:31.500 --> 00:17:35.180
I saw 4E all over the nucleus. And I was like,
00:17:35.549 --> 00:17:38.069
What's that? And I started to look and there
00:17:38.069 --> 00:17:40.750
was only like two or three papers showing that
00:17:40.750 --> 00:17:42.569
that Fourier was in the nucleus. And it was sort
00:17:42.569 --> 00:17:44.890
of like, huh, we don't know. But it was there.
00:17:45.210 --> 00:17:49.190
And so we started to to dissect, you know, what
00:17:49.190 --> 00:17:52.210
could it possibly be doing there? So so really,
00:17:52.329 --> 00:17:55.109
it was completely serendipitous, as is a lot
00:17:55.109 --> 00:17:58.849
of research. And I guess as as we are both researchers,
00:17:58.990 --> 00:18:01.450
I think we understand that we write these very.
00:18:01.950 --> 00:18:04.730
tightly knit grants. But it's important to have
00:18:04.730 --> 00:18:07.569
the latitude to be able to to take one of those
00:18:07.569 --> 00:18:10.609
eureka moments and be able to build on it. Yeah,
00:18:10.730 --> 00:18:12.609
you never know where the research is going to
00:18:12.609 --> 00:18:14.730
go. And neither do the funding agencies that
00:18:14.730 --> 00:18:16.869
fund it. That's why you fund general science.
00:18:17.109 --> 00:18:19.130
And yeah, it's a little bit of a hope for the
00:18:19.130 --> 00:18:21.069
best. But at the same time, what you get out
00:18:21.069 --> 00:18:24.990
of it in the long run is just pretty amazing.
00:18:25.029 --> 00:18:27.049
Like the understanding the way it goes towards
00:18:27.049 --> 00:18:34.019
new drugs or new technologies or Etc. Okay, so
00:18:34.019 --> 00:18:37.299
one of the things that I found when looking this
00:18:37.299 --> 00:18:40.740
up and trying my best to understand it is an
00:18:40.740 --> 00:18:46.859
analogy to E4E being like a micromanager of the
00:18:46.859 --> 00:18:49.740
entire process. Is this kind of a fair representation?
00:18:50.539 --> 00:18:53.640
I thought it was a really cute analogy that you
00:18:53.640 --> 00:18:57.599
made. And for the RNAs that it affects, I think
00:18:57.599 --> 00:19:01.019
it's pretty true. because it's affecting so many
00:19:01.019 --> 00:19:05.319
steps where people, yeah, I like the analogy.
00:19:06.920 --> 00:19:11.279
Okay, so perhaps we'll go to an old saying to
00:19:11.279 --> 00:19:14.000
kind of look at this a little bit more. Too many
00:19:14.000 --> 00:19:16.259
cooks spoil the broth, or perhaps too few and
00:19:16.259 --> 00:19:17.940
we go hungry. So let's start with the later case.
00:19:18.019 --> 00:19:21.099
What happens if there's not enough 4E and the
00:19:21.099 --> 00:19:24.319
kitchen is empty? Is that even possible? So there
00:19:24.319 --> 00:19:29.690
are... There are examples, especially in neurology,
00:19:29.690 --> 00:19:34.589
where the loss of 4E can be associated with reduced
00:19:34.589 --> 00:19:40.069
activity of the neurons. I'm not an expert on
00:19:40.069 --> 00:19:42.950
neurology or neuroscience, but they impact the
00:19:42.950 --> 00:19:45.609
capacity of the neurons to send their chemical
00:19:45.609 --> 00:19:49.970
signals. by reducing the amount of the right
00:19:49.970 --> 00:19:53.849
proteins that are being made, so the right cofactors
00:19:53.849 --> 00:19:58.210
that need to send these signals. So yes, although
00:19:58.210 --> 00:20:00.069
I'm much more familiar with the cancer case,
00:20:00.230 --> 00:20:04.170
it has been observed. And also in neurology,
00:20:04.170 --> 00:20:08.910
there are cases where EIF -4E can be overactive.
00:20:09.559 --> 00:20:12.440
as is the case for diseases like Alzheimer's.
00:20:12.539 --> 00:20:16.339
But again, for that particular example, 4E can
00:20:16.339 --> 00:20:18.400
contribute, but there's also a whole plethora
00:20:18.400 --> 00:20:21.480
of other proteins that are really important to
00:20:21.480 --> 00:20:24.960
RNA biology as well and can also disconnect the
00:20:24.960 --> 00:20:27.720
sort of DNA instructions from the ultimate signal.
00:20:28.019 --> 00:20:32.579
So it's complicated, but definitely having too
00:20:32.579 --> 00:20:36.559
little is not good. There is very much a Goldilocks
00:20:36.559 --> 00:20:40.890
zone for 4E levels. And in fact, as an example
00:20:40.890 --> 00:20:43.470
of that in the lab, oftentimes to investigate
00:20:43.470 --> 00:20:49.349
the importance of a given factor to, say, survival
00:20:49.349 --> 00:20:54.309
of an organism is to make out mouse knockouts.
00:20:54.349 --> 00:20:58.250
And it was impossible to make a mouse knockout
00:20:58.250 --> 00:21:03.269
of 4E. So you mean remove the gene that would
00:21:03.269 --> 00:21:06.549
create 4E and then therefore the mouse was...
00:21:07.430 --> 00:21:10.250
In other words, it would just automatically die
00:21:10.250 --> 00:21:17.349
in fetus? Yes, as an early embryo. Like a couple
00:21:17.349 --> 00:21:20.869
of divisions and then it just, it's gone. So
00:21:20.869 --> 00:21:24.190
you can reduce it by about half and the mice
00:21:24.190 --> 00:21:26.650
are completely fine and don't seem to have any
00:21:26.650 --> 00:21:30.430
problems at all. But completely removing it was
00:21:30.430 --> 00:21:35.269
a no -go. Okay, so what... Your lab primarily
00:21:35.269 --> 00:21:38.890
deals with leukemia and cancer. So what happens
00:21:38.890 --> 00:21:42.829
to the micromanagers in these cases? What happens
00:21:42.829 --> 00:21:46.470
to our machinery? So it turns out that 4E can
00:21:46.470 --> 00:21:49.160
be elevated in a lot of cancers. be familiar
00:21:49.160 --> 00:21:51.819
with like prostate, breast, lung cancer. Not
00:21:51.819 --> 00:21:54.480
necessarily in every case, usually in a subset
00:21:54.480 --> 00:21:58.059
of patients will have this elevation. So it's
00:21:58.059 --> 00:22:00.039
not homogeneous, if you see what I mean, for
00:22:00.039 --> 00:22:03.059
each cancer. And that's also true of acute myeloid
00:22:03.059 --> 00:22:05.440
leukemia or AML, which is leukemia I work on.
00:22:05.500 --> 00:22:08.180
So there's a subset of patients that have elevated
00:22:08.180 --> 00:22:13.180
4E. And that elevation of 4E predicts poor outcomes.
00:22:14.000 --> 00:22:18.109
So obviously having... Too much 4E in the cancer
00:22:18.109 --> 00:22:22.769
cells is not serving the organism very well.
00:22:23.029 --> 00:22:26.690
So my lab, first of all, wanted to understand
00:22:26.690 --> 00:22:30.609
how is 4E causing, elevation of 4E causing disease?
00:22:30.930 --> 00:22:34.309
And secondly, like, could we target it? So to
00:22:34.309 --> 00:22:37.269
answer the first question is kind of I alluded
00:22:37.269 --> 00:22:40.509
to before, is that 4E really, through all of
00:22:40.509 --> 00:22:44.940
these different... modifications to the RNA and
00:22:44.940 --> 00:22:48.559
to the impacts on protein synthesis can make
00:22:48.559 --> 00:22:52.240
factors that allow the cells to ignore signaling
00:22:52.240 --> 00:22:56.000
that says that you should die. They allow the
00:22:56.000 --> 00:22:58.880
cells to move through the body more readily,
00:22:59.119 --> 00:23:02.000
escaping from the bone marrow and being found
00:23:02.000 --> 00:23:05.420
even in the central nervous system or the skin.
00:23:05.619 --> 00:23:11.880
So very large capacity to be able to move. I
00:23:11.880 --> 00:23:14.380
think understanding the molecular basis of those
00:23:14.380 --> 00:23:17.720
was really important for setting up a sort of
00:23:17.720 --> 00:23:24.559
plan in order to try to target in patients. And
00:23:24.559 --> 00:23:27.220
in the patient side, we developed a strategy
00:23:27.220 --> 00:23:32.279
that was, I guess, 15, 20 years ago was the first
00:23:32.279 --> 00:23:37.779
clinical trial was 2009. And we found a small
00:23:37.779 --> 00:23:40.200
old antiviral drug, which is actually kind of
00:23:40.200 --> 00:23:43.240
based. on the virus I originally was looking
00:23:43.240 --> 00:23:46.460
at when I first found that 4E was in the nucleus
00:23:46.460 --> 00:23:49.259
and could... You came full circle. Yeah, so we
00:23:49.259 --> 00:23:52.099
came full circle. So it was the only treatment
00:23:52.099 --> 00:23:55.339
for that particular virus called ribavirin. And
00:23:55.339 --> 00:23:58.640
this old antiviral drug has been known for...
00:23:59.180 --> 00:24:02.039
since the 70s to be completely safe. So we had
00:24:02.039 --> 00:24:04.619
this really nice position. It's also a generic
00:24:04.619 --> 00:24:07.160
drug, which can lead us into a completely different
00:24:07.160 --> 00:24:10.960
conversation about how drug discovery and clinical
00:24:10.960 --> 00:24:16.359
trial funding works in the independent investigator
00:24:16.359 --> 00:24:19.740
versus big pharma worlds. But anyways, what we
00:24:19.740 --> 00:24:22.380
found was really striking. We took... AML patients
00:24:22.380 --> 00:24:25.740
that had previously failed their chemotherapy
00:24:25.740 --> 00:24:28.420
or they never responded to the original chemotherapy.
00:24:28.680 --> 00:24:30.700
And that's normally the patients that you get
00:24:30.700 --> 00:24:33.779
in clinical trials. So they can already start
00:24:33.779 --> 00:24:39.319
to have signs of drug resistance. So these trials
00:24:39.319 --> 00:24:42.019
are more challenging, I think, and make it harder
00:24:42.019 --> 00:24:46.740
to see signals. And so we were really excited
00:24:46.740 --> 00:24:50.380
that we had patients that had complete and partial
00:24:50.380 --> 00:24:53.700
remissions just taking ribavirin as a monotherapy.
00:24:54.220 --> 00:24:56.420
And you can take ribavirin as a pill so they
00:24:56.420 --> 00:24:58.880
could take it at home, which is like the ideal
00:24:58.880 --> 00:25:02.359
scenario, right? So we had about 30 % to 40 %
00:25:02.359 --> 00:25:05.299
of patients had this sort of really nice, strong,
00:25:05.359 --> 00:25:08.319
objective clinical responses. But eventually,
00:25:08.420 --> 00:25:10.660
all the patients would become drug resistant,
00:25:10.859 --> 00:25:14.660
which is common, particularly in monotherapies,
00:25:14.700 --> 00:25:19.470
but common in drug chemistry. generally. And
00:25:19.470 --> 00:25:22.230
most cancers are not treated with a single agent,
00:25:22.349 --> 00:25:26.269
right? So we wanted to find combinations that
00:25:26.269 --> 00:25:30.769
allowed us to increase the percentage of patients
00:25:30.769 --> 00:25:33.289
that had responses and also the length of the
00:25:33.289 --> 00:25:36.230
drug responses. So for instance, in the first
00:25:36.230 --> 00:25:39.450
trial, the standard of care of the time would
00:25:39.450 --> 00:25:44.099
give on average seven months survival. And we
00:25:44.099 --> 00:25:48.720
had patients out to two years. So that was definitely
00:25:48.720 --> 00:25:51.619
very promising, although these are all early
00:25:51.619 --> 00:25:54.180
stage clinical trials, right? So small numbers.
00:25:54.740 --> 00:25:57.740
But we tried some combinations and we were always
00:25:57.740 --> 00:26:02.000
sort of hitting the same kind of mark of we were
00:26:02.000 --> 00:26:03.900
getting responses, which was great, but the patients
00:26:03.900 --> 00:26:06.740
would become... drug resistance. So we actually
00:26:06.740 --> 00:26:09.059
decided to try to figure out what the resistance
00:26:09.059 --> 00:26:11.759
was, and then we could use that as a combination
00:26:11.759 --> 00:26:16.220
therapy. And we found that what was happening
00:26:16.220 --> 00:26:20.319
to the ribavirin drug in the leukemia cells was
00:26:20.319 --> 00:26:24.660
that there was a... a small sugar molecule called
00:26:24.660 --> 00:26:27.039
glucuronic acid that was covalently added to
00:26:27.039 --> 00:26:30.039
the ribavirin. And that made it no longer bind
00:26:30.039 --> 00:26:33.660
4E and it made the cells completely resistant
00:26:33.660 --> 00:26:36.579
to not only 4E, not only to ribavirin, but to
00:26:36.579 --> 00:26:39.880
many common chemotherapies. So we found that
00:26:39.880 --> 00:26:43.619
this drug resistance mechanism was really relevant
00:26:43.619 --> 00:26:47.519
to a broad range of drugs. And what was really
00:26:47.519 --> 00:26:50.900
striking was that that... had been previously
00:26:50.900 --> 00:26:53.259
considered that this form of adding this sugar
00:26:53.259 --> 00:26:56.140
onto the drug called glucuronidation could only
00:26:56.140 --> 00:26:58.640
happen in the liver. And what we were seeing
00:26:58.640 --> 00:27:01.200
is that the cancer cells had evolved the enzymes,
00:27:01.240 --> 00:27:04.180
or turned back on the enzymes that were usually
00:27:04.180 --> 00:27:07.660
liver -specific in order to now be able to evade
00:27:07.660 --> 00:27:13.180
this therapy. So if you're a Star Trek fan, they
00:27:13.180 --> 00:27:16.880
remind me of the Borg. So... Resistance is futile.
00:27:17.230 --> 00:27:19.289
Yes. I even wrote a review called Resistance
00:27:19.289 --> 00:27:23.589
is Futile. But yes. And they say scientists don't
00:27:23.589 --> 00:27:27.710
have a sense of humor. Thank you. Yes. So we
00:27:27.710 --> 00:27:31.250
went on to do a clinical trial in patients where
00:27:31.250 --> 00:27:33.930
we had figured out how to target the drug resistance,
00:27:34.269 --> 00:27:37.829
this form of drug resistance, in patients that
00:27:37.829 --> 00:27:40.650
were already had failed like three to four other
00:27:40.650 --> 00:27:43.269
types of therapy. So very... drug -resistant
00:27:43.269 --> 00:27:46.109
patients. And we could see some clinical responses.
00:27:46.269 --> 00:27:49.470
We even had a remission in our small group. But
00:27:49.470 --> 00:27:52.109
then those patients became resistant to the drug
00:27:52.109 --> 00:27:54.289
that we had used to overcome the resistance.
00:27:54.869 --> 00:27:59.269
So I know it's both sad and ironic because I
00:27:59.269 --> 00:28:02.549
think it's a big challenge in clinical trial
00:28:02.549 --> 00:28:05.349
development for these drugs because especially
00:28:05.349 --> 00:28:09.509
when you're treating heavily refractory patients.
00:28:10.519 --> 00:28:14.000
Their cancer cells have been trained to evade
00:28:14.000 --> 00:28:16.380
a wide array of drugs. Those are the survivor
00:28:16.380 --> 00:28:21.720
ones. So they're that much more resilient, unfortunately.
00:28:22.299 --> 00:28:26.359
But I am excited to say that we hope in the winter
00:28:26.359 --> 00:28:29.359
of 2027 at Northwestern, we're going to be starting
00:28:29.359 --> 00:28:32.220
a new trial, including ribavirin with the standard
00:28:32.220 --> 00:28:35.279
of care in upfront patients, so patients who
00:28:35.279 --> 00:28:40.019
haven't received any treatment yet. And I also
00:28:40.019 --> 00:28:43.240
should say one of the nice things that we did
00:28:43.240 --> 00:28:46.779
that a lot of clinical trials do not do, especially
00:28:46.779 --> 00:28:50.359
industry trials, is that we developed assays
00:28:50.359 --> 00:28:52.599
to check that the ribavirin was really targeting
00:28:52.599 --> 00:28:54.819
the 4E in the patients and that we could really
00:28:54.819 --> 00:28:58.299
correlate the 4E targeting with the clinical
00:28:58.299 --> 00:29:01.720
responses, which was very satisfying because
00:29:01.720 --> 00:29:04.980
we could see the resistance patients, the ribavirin
00:29:04.980 --> 00:29:07.519
didn't do anything to their 4E, the responding
00:29:07.519 --> 00:29:12.160
patients. we had nice impacts on 4E activity.
00:29:12.720 --> 00:29:16.339
Let's go with, so you said that some cancers
00:29:16.339 --> 00:29:21.619
show an increase of 4E and many do not, but would
00:29:21.619 --> 00:29:26.559
trying to control 4E still potentially help those
00:29:26.559 --> 00:29:30.619
without an increase in 4E? Yeah, I think potentially
00:29:30.619 --> 00:29:34.460
it would. The clinical trials that we ran are...
00:29:34.920 --> 00:29:36.940
They were funded by the Leukemia and Lymphoma
00:29:36.940 --> 00:29:39.440
Society US and Leukemia and Lymphoma Society
00:29:39.440 --> 00:29:42.799
Canada. So a big shout out to them. And so the
00:29:42.799 --> 00:29:46.799
budgets in those trials are, you have to have
00:29:46.799 --> 00:29:48.920
a randomized group of people that have high and
00:29:48.920 --> 00:29:51.839
low 4E and be able to make some statistics. And
00:29:51.839 --> 00:29:55.960
in that sort of realm with these early stage
00:29:55.960 --> 00:29:58.710
clinical trials, we just don't have the... capacity
00:29:58.710 --> 00:30:00.710
to investigate that. But I think theoretically
00:30:00.710 --> 00:30:03.069
it could be really interesting. Is there any
00:30:03.069 --> 00:30:07.630
risk of giving this drug early or to someone
00:30:07.630 --> 00:30:11.210
who doesn't have cancer and then later the cells
00:30:11.210 --> 00:30:14.029
are resistant to it? Like it holds that memory?
00:30:14.450 --> 00:30:18.990
I think that we discussed that possibility and
00:30:18.990 --> 00:30:23.150
I would... I would say that it is possible. I
00:30:23.150 --> 00:30:24.890
don't think that I would give someone ribavirin
00:30:24.890 --> 00:30:27.109
as a preventative anti -cancer to take the rest
00:30:27.109 --> 00:30:30.150
of their life because of this. Also, what happened
00:30:30.150 --> 00:30:32.130
with this drug resistance is it caused cross
00:30:32.130 --> 00:30:34.049
-resistance, so it became resistant to other
00:30:34.049 --> 00:30:37.509
cancer drugs, these cells. So I think you'd really
00:30:37.509 --> 00:30:42.700
want to go in. when it's happening. Now, ribavirin
00:30:42.700 --> 00:30:45.980
is an old generic drug. There's no intellectual
00:30:45.980 --> 00:30:48.799
property on it or anything, right? So I'm sure
00:30:48.799 --> 00:30:51.000
that there will be drugs, and there are like
00:30:51.000 --> 00:30:55.339
trials going on using different strategies to
00:30:55.339 --> 00:30:59.099
also target 4E. And so some of these new means
00:30:59.099 --> 00:31:02.240
to target it may be better. Although I do have
00:31:02.240 --> 00:31:06.740
to say that the early trial data, for instance,
00:31:08.029 --> 00:31:11.470
4E can be modified by phosphorylation, which
00:31:11.470 --> 00:31:14.450
is an important aspect of its cancer -causing
00:31:14.450 --> 00:31:17.450
activities. But in heavily pretreated patients,
00:31:17.569 --> 00:31:20.490
there was no statistical clinical benefit, whereas
00:31:20.490 --> 00:31:24.630
ribavirin was giving remission. And there's also
00:31:24.630 --> 00:31:27.410
genetic ways to target 4E that have been tried
00:31:27.410 --> 00:31:30.950
in two different clinical trials using something
00:31:30.950 --> 00:31:34.349
called antisense oligonucleotides. That's a mouthful.
00:31:34.779 --> 00:31:38.019
Yeah, yeah. So it's a way to genetically reduce
00:31:38.019 --> 00:31:41.640
4E. And it works really well in mice and gives
00:31:41.640 --> 00:31:45.339
really nice response in mice. But in people,
00:31:45.460 --> 00:31:48.259
it doesn't cause any difference in their 4E protein
00:31:48.259 --> 00:31:51.500
levels. So thus, you're not surprised that it
00:31:51.500 --> 00:31:54.960
didn't cause any objective clinical responses,
00:31:55.019 --> 00:31:59.519
really. But there's a lot of interest now that
00:31:59.519 --> 00:32:03.230
people realize from our work. in people and from
00:32:03.230 --> 00:32:06.210
previous vast amount of work by many groups in
00:32:06.210 --> 00:32:10.369
mice, that 4E is worth targeting, that these
00:32:10.369 --> 00:32:13.569
companies may come up with new ways so that we
00:32:13.569 --> 00:32:15.269
don't have to worry about this drug resistance
00:32:15.269 --> 00:32:18.549
phenomena. I personally think, though, what we
00:32:18.549 --> 00:32:21.809
really need to do is probably to find the right
00:32:21.809 --> 00:32:27.210
combination of drugs to target 4E and some compensatory
00:32:27.210 --> 00:32:30.289
mechanism that may be turned on once you hit
00:32:30.289 --> 00:32:33.650
4E. And knowing that mechanism, those factors,
00:32:34.009 --> 00:32:36.369
then you could start to design another round
00:32:36.369 --> 00:32:41.809
of smart therapy, I hope. Sure. And I think something
00:32:41.809 --> 00:32:45.490
you said there about the potential for drug resistance
00:32:45.490 --> 00:32:49.309
is, sure, based on what you described, the drug
00:32:49.309 --> 00:32:51.470
works great, seems to have a really good safety
00:32:51.470 --> 00:32:54.529
profile. But at the same time, any intervention
00:32:54.529 --> 00:32:57.980
does have. changes and you have to make sure
00:32:57.980 --> 00:32:59.980
that whatever intervention whatever risks you're
00:32:59.980 --> 00:33:02.460
putting in is much smaller than what the result
00:33:02.460 --> 00:33:05.160
you're trying to get right absolutely patient
00:33:05.160 --> 00:33:09.220
safety first absolutely um so we've talked about
00:33:09.220 --> 00:33:13.500
all of this so far and you've kind of mentioned
00:33:13.500 --> 00:33:16.839
that it's cell division cell movement cell repair
00:33:16.839 --> 00:33:21.619
those are the things that 4e target right well
00:33:21.619 --> 00:33:24.250
so It targets proliferation a little bit. I did
00:33:24.250 --> 00:33:26.829
mention it, but really cell movement and rescue
00:33:26.829 --> 00:33:29.150
from cell death, I think, are the two major things,
00:33:29.210 --> 00:33:32.450
at least in leukemia cells, and differentiation.
00:33:32.829 --> 00:33:35.569
FORE can also block the capacity of a blood cell
00:33:35.569 --> 00:33:38.769
to differentiate into a mature form, which makes
00:33:38.769 --> 00:33:42.009
sense because leukemia is all about having too
00:33:42.009 --> 00:33:45.569
many immature blood cells. So how does that...
00:33:45.799 --> 00:33:48.880
come together with the new cancer vaccines that
00:33:48.880 --> 00:33:50.619
we're seeing that's trying to teach the immune
00:33:50.619 --> 00:33:55.859
system to kill the cells instead of 4E to essentially
00:33:55.859 --> 00:33:59.940
tell the cell to die? Is there a difference of
00:33:59.940 --> 00:34:02.559
a way those two mechanisms, like obviously the
00:34:02.559 --> 00:34:04.279
two mechanisms are different, but can be they
00:34:04.279 --> 00:34:08.500
targeted the same way or differently? Yeah, I
00:34:08.500 --> 00:34:11.780
mean, I would require some more thought to answer
00:34:11.780 --> 00:34:14.480
that deeply, but I think it's important to remember
00:34:14.480 --> 00:34:18.190
here that like, We're talking about the cancer
00:34:18.190 --> 00:34:20.409
cell and what the cancer cell is doing, and we
00:34:20.409 --> 00:34:22.349
haven't really talked too much about its immune
00:34:22.349 --> 00:34:26.769
interactions. In one of the clinical studies
00:34:26.769 --> 00:34:30.030
I discussed, one of the PD -L inhibitors was
00:34:30.030 --> 00:34:34.329
used in combination with this drug that inhibits
00:34:34.329 --> 00:34:37.530
Fourier modification by phosphorylation. And
00:34:37.530 --> 00:34:41.489
unfortunately, the... drug company study didn't
00:34:41.489 --> 00:34:44.329
really do any molecular analysis. So I can't
00:34:44.329 --> 00:34:47.190
really speak to whether the targets were hit,
00:34:47.190 --> 00:34:49.949
if things worked as expected or not, which I
00:34:49.949 --> 00:34:52.849
think is so central to our understanding of building
00:34:52.849 --> 00:34:55.909
from clinical science to back to the lab and
00:34:55.909 --> 00:34:58.869
then back to the bench, right? Bench to bedside.
00:34:59.130 --> 00:35:01.230
So I do think it's important. And one of the
00:35:01.230 --> 00:35:03.329
things that's sort of interesting is some recent
00:35:03.329 --> 00:35:07.539
studies have shown that 4A dysregulation influences
00:35:07.539 --> 00:35:10.360
not only the cancer cell, but can influence what
00:35:10.360 --> 00:35:13.000
we call the tumor microenvironment. So those
00:35:13.000 --> 00:35:15.000
are the cells around the cancer cell, which can
00:35:15.000 --> 00:35:17.679
include immune cells that you alluded to. And
00:35:17.679 --> 00:35:21.719
that some of the changes that we've noted for
00:35:21.719 --> 00:35:25.039
you can do in the cancer cell, they can also
00:35:25.039 --> 00:35:28.260
happen in this tumor microenvironment, and they
00:35:28.260 --> 00:35:31.829
can make the tumor microenvironment more permissive
00:35:31.829 --> 00:35:34.210
of having a tumor there. Because normally the
00:35:34.210 --> 00:35:36.909
job of the tumor microenvironment is to, as you
00:35:36.909 --> 00:35:39.510
say, send out the immune cells and just clear
00:35:39.510 --> 00:35:45.670
this bad actor out. But in this case, it allows
00:35:45.670 --> 00:35:48.750
this permissive environment that actually can
00:35:48.750 --> 00:35:51.489
even not only just allow it to grow, but actually
00:35:51.489 --> 00:35:56.690
help them to grow. It's really, I think, the
00:35:56.690 --> 00:35:59.969
next big area for probably for 4E is to understand
00:35:59.969 --> 00:36:03.110
these sort of interactions. So it's part of the
00:36:03.110 --> 00:36:06.269
bigger picture of just what allows cancer to
00:36:06.269 --> 00:36:09.309
evolve and change and stay around, even though
00:36:09.309 --> 00:36:13.789
it really shouldn't be there. Yes. Yes. All right.
00:36:13.829 --> 00:36:15.610
So we've already talked a little bit about some
00:36:15.610 --> 00:36:18.489
big picture stuff with the fact that 4E is involved
00:36:18.489 --> 00:36:22.440
with a lot of other... potential diseases through
00:36:22.440 --> 00:36:25.880
neurology, dementia, Alzheimer's. But where is
00:36:25.880 --> 00:36:27.960
this all going? Like, get out your crystal ball.
00:36:28.139 --> 00:36:31.019
And I know it's always a bit of a lark to try
00:36:31.019 --> 00:36:33.920
to forward and future cast. But are we slowly
00:36:33.920 --> 00:36:36.559
learning how to control our own machinery with
00:36:36.559 --> 00:36:40.420
4E as an important mechanism? I hope so. I think
00:36:40.420 --> 00:36:43.159
that we've shown it can be controlled, that we
00:36:43.159 --> 00:36:47.179
can benefit from it. We've done a lot of... biochemical
00:36:47.179 --> 00:36:50.340
and molecular biology assays to really understand
00:36:50.340 --> 00:36:55.559
at the molecular level how these things are happening.
00:36:55.800 --> 00:36:59.579
And obviously, there's much more mechanism to
00:36:59.579 --> 00:37:02.760
dissect and understand. And understanding those
00:37:02.760 --> 00:37:07.880
mechanisms help us develop or see new crucial
00:37:07.880 --> 00:37:11.280
intervention points that could be potentially
00:37:11.280 --> 00:37:16.280
used to make foray inhibition more effective
00:37:16.280 --> 00:37:19.039
or maybe inhibiting something else in the same
00:37:19.039 --> 00:37:21.639
pathway might work better because we don't have
00:37:21.639 --> 00:37:25.599
compensation. So I think back to the basic science
00:37:25.599 --> 00:37:29.000
is always going to instruct how we move forward.
00:37:29.179 --> 00:37:31.960
And I think that now that we have this clearer
00:37:31.960 --> 00:37:36.880
view of 4E and all of its roles, and not just
00:37:36.880 --> 00:37:39.579
one of its roles, will help us, you know, all
00:37:39.579 --> 00:37:44.280
of its roles being the nuclear RNA. changes to
00:37:44.280 --> 00:37:47.480
the RNA instructions through the export and then
00:37:47.480 --> 00:37:49.260
into the protein synthesis, by understanding
00:37:49.260 --> 00:37:53.280
this as not just a single step, that our intervention
00:37:53.280 --> 00:37:56.460
needs to be considered more globally in terms
00:37:56.460 --> 00:37:58.960
of the impact. And by understanding the molecular
00:37:58.960 --> 00:38:01.139
basis of these, I think that that can help us
00:38:01.139 --> 00:38:04.300
not only understand cool RNA biology, which I
00:38:04.300 --> 00:38:06.880
think is worthy of understanding of its own,
00:38:06.940 --> 00:38:10.039
just like a... poet likes writing poetry, it's
00:38:10.039 --> 00:38:13.519
worthy of it, but also from the practical aspect
00:38:13.519 --> 00:38:18.360
to be able to come up with better clinical interventions,
00:38:18.420 --> 00:38:21.760
both for neurodegeneration and for cancer. Now
00:38:21.760 --> 00:38:24.880
that is a perfect way to end the science portion
00:38:24.880 --> 00:38:28.139
of it, because it wraps it all up. It's one big
00:38:28.139 --> 00:38:32.980
picture. It's great. I love that. Now it's time
00:38:32.980 --> 00:38:36.679
for call -outs. I don't know, future work, colleagues.
00:38:37.769 --> 00:38:41.010
Anything you want. I really wanted there's so
00:38:41.010 --> 00:38:44.050
many people to thank for all the work I did.
00:38:44.110 --> 00:38:47.789
And I apologize to to people who wrote the papers.
00:38:47.829 --> 00:38:50.550
I didn't have time to talk or give references
00:38:50.550 --> 00:38:54.599
for. But the biggest shout out is. patients and
00:38:54.599 --> 00:38:57.420
their families that they were willing to take
00:38:57.420 --> 00:39:00.719
this risk. When you join a clinical trial with
00:39:00.719 --> 00:39:03.639
advanced cancer, you're first informed that this
00:39:03.639 --> 00:39:05.880
clinical trial is probably not going to help
00:39:05.880 --> 00:39:09.460
you. You're helping the future. And so I'm, first
00:39:09.460 --> 00:39:11.820
of all, glad we were able to help some, but those
00:39:11.820 --> 00:39:14.280
people did the trial anyways. And I think, and
00:39:14.280 --> 00:39:16.179
they went through and they got samples that we
00:39:16.179 --> 00:39:19.239
could study that allowed us to understand the
00:39:19.239 --> 00:39:21.199
drug resistance, allowed us to understand a lot
00:39:21.199 --> 00:39:25.420
of the what's going on in the person. And so
00:39:25.420 --> 00:39:28.460
that was awesome. I also have to have a huge
00:39:28.460 --> 00:39:32.059
shout out to Dr. Sarit Asselin at McGill, because
00:39:32.059 --> 00:39:34.860
she ran the, she's a medical monitor. She's a
00:39:34.860 --> 00:39:38.579
hematologist and chief of hematology now at the
00:39:38.579 --> 00:39:41.260
Lady, at the Jewish General Hospital. And so
00:39:41.260 --> 00:39:43.699
without her, this work couldn't be done. I also
00:39:43.699 --> 00:39:46.179
want to thank Morris and David Goodman at PharmaScience
00:39:46.179 --> 00:39:49.300
in Montreal, because they provided us free ribavirin,
00:39:49.360 --> 00:39:52.349
which, you know. was a big, big help and also
00:39:52.349 --> 00:39:55.369
some free other drugs that we used and gave us
00:39:55.369 --> 00:39:58.210
some analytical chemistry support, which allowed
00:39:58.210 --> 00:40:01.210
us to further dissect the drug resistance mechanism
00:40:01.210 --> 00:40:04.210
I referred to. A big shout out to all my lab
00:40:04.210 --> 00:40:07.710
team members, past and present, the funders like
00:40:07.710 --> 00:40:10.489
the NIH, the Leukemia and Lymphoma Society of
00:40:10.489 --> 00:40:14.190
Canada in the US and CIHR, and also to Shira
00:40:14.190 --> 00:40:17.170
Dinner and Jessica Altman, who are the clinical
00:40:17.170 --> 00:40:19.730
leads for the new trial that we're about to embark
00:40:19.730 --> 00:40:23.269
on. Okay. See, it really does take a whole team
00:40:23.269 --> 00:40:25.289
and a group of individuals to conduct science
00:40:25.289 --> 00:40:28.829
at the highest levels. It really does. No other
00:40:28.829 --> 00:40:32.309
ways around it. But now, we're at the infamous
00:40:32.309 --> 00:40:35.510
last question here on Whimsical Wavelengths,
00:40:35.510 --> 00:40:38.769
where my guest tells us all their favorite science
00:40:38.769 --> 00:40:44.010
joke. Okay. It's pretty corny. That doesn't matter.
00:40:44.369 --> 00:40:48.489
Come on. Just embrace it. Why can't you trust
00:40:48.489 --> 00:40:53.219
an atom? I don't know. They make up everything.
00:40:55.400 --> 00:41:00.599
Well, thank you so much for coming on Whimsical
00:41:00.599 --> 00:41:02.360
Wavelengths and sharing your science with us.
00:41:02.760 --> 00:41:05.380
Thanks, Jeff, so much for doing this podcast
00:41:05.380 --> 00:41:08.199
and making science popular. I have never been
00:41:08.199 --> 00:41:11.139
accused of being popular, and maybe I'll actually
00:41:11.139 --> 00:41:13.599
succeed in making science popular. But you've
00:41:13.599 --> 00:41:17.039
been with me this long, so... by all means, subscribe.
00:41:17.179 --> 00:41:19.739
Leave a review. You have no idea how important
00:41:19.739 --> 00:41:21.400
those are. It doesn't matter which app you use.
00:41:21.579 --> 00:41:27.500
Please leave a review. Yeah. And that's Season
00:41:27.500 --> 00:41:31.300
3, Episode 2 in the books. I'll see you again.
00:41:31.659 --> 00:41:54.119
Two weeks. Swaying to rhythms as the galaxies
00:41:54.119 --> 00:42:19.829
fly by. J.