AudioHelicase Special: How foundational research takes medicines from lab to shelf

In this episode of AudioHelicase, we sit down with three Whitehead Institute researchers driving breakthroughs in disease treatment. Join us as we explore some of the toughest challenges they're overcoming to move transformative therapies from the lab bench to your medicine cabinet.

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Transcript:

Shafaq Zia: Swallow, inhale, inject, apply. Treating an illness has never been easier. Take a look inside your medicine cabinet — there’s aspirin, Sudafed, Tylenol, even some medicated bandages, ready for use. It’s quick and easy. But behind this convenience lies a tale of perseverance.

Zia: This is AudioHelicase, the podcast of the Whitehead Institute. Here we unwind the science and the people behind some of the Institute’s most exciting discoveries. I’m your host Shafaq Zia, and today we’re taking you down the long and grueling road to developing better drugs. While translational research — the process of applying biology to real-world problems — often takes center stage in moving therapies from lab bench to bedside, we're shedding light on an unsung hero: basic science. This foundational detective work uncovers the very essence of disease and lays the groundwork for potential treatments. Take Cisplatin, for example — a commonly-used drug in cancer treatment. Its origins trace back to basic scientific discoveries that revealed how it could halt cancer cell growth by damaging their DNA. Come along to learn about the formidable challenges Whitehead Institute researchers are overcoming on their path to developing transformative medicines. But before we dive into the details, let's rewind the clock to where every medicine's journey begins: the lab.

Zia: That’s Whitehead Institute’s Valhalla Fellow, Lindsey Backman. Her lab studies bacteria that live on our skin, inside our mouth, and deep within our gut to understand how they break down nutrients in the human body for growth and survival — and why some infectious species like E. coli and C. difficile are able to outcompete even the most powerful antibiotics.

Lindsey Backman: I really think of human biology as the background for what I see as the main players, the bacteria. They've grown with us; they've evolved with us. And we have a lot of them within us.

Zia: Backman is talking about a specific class of bacteria called anaerobes that emerged billions of years ago, before oxygen filled Earth’s atmosphere and oceans.

Backman: The most basic organisms really lived off of small carbon molecules or they worked with gases, such as hydrogen and nitrogen. They didn't actually require any oxygen. And as things evolved, there are different forms of metabolism that arose. You would have some bacteria that actually use sulfur species as their way to generate energy and you even had some bacteria at one point that were photosynthetic.

Zia: Some of these different types of metabolism were made possible by an important family of proteins, called glycyl radical enzymes, that can kickstart tricky chemical reactions, as long as they are not exposed to oxygen molecules. Today, many pathogens like E. coli use the same group of enzymes to fuel their growth and spread infection.

Zia: In fact, a number of antibiotics available on the market kill off bacteria by disrupting their metabolism. This is how that process works — when we fight off infections, our immune system kicks in, which causes inflammation and high levels of oxidative stress. This stress can damage glycyl radical enzymes so badly that bits of them literally fall apart.

Yet, some strains of E. coli are able to handle this pressure. Why? Backman says it's because they're really good at adapting their metabolism. And that's why her team is trying to understand the nitty-gritty of how these bacteria pull off this feat, so new drugs can target those defenses.

Backman: Antibiotic resistance is a huge global health issue. One of the strategies that these species have evolved — it's really clever — is basically developing a spare part protein.

Zia: She uncovered this mechanism during her PhD research in Cathy Drennan’s Lab at MIT, while studying the activity of E. coli in low levels of oxygen. She helped explain how these microbes carry an extra protein in their back pocket that binds to the damaged glycyl radical enzyme, restoring its function in a snap.

Backman: This is kind of like how when you think of your car and you get a flat tire, you would not replace the car, you would just replace the tire.

Zia: The spare part protein could be one of many tricks anaerobic bacteria have up their sleeves, and it’s a race against time before they develop new ones. But the Backman Lab is up for the challenge — in fact, they’re already looking at investigating another protective strategy these bacteria might be using, which involves the bacteria putting oxygen-sensitive glycyl radical enzymes in protein shells called bacterial microcompartments. 

Backman: These might be a physical shield against oxygen, and in all honesty, we still don't fully know if that is what they do. But one thing that's really interesting about these bacterial microcompartments is that they're particularly abundant in pathogens, and so we do think that at least in mouse models, some of these systems appear to give pathogens — these infectious bacteria — a competitive advantage.

Zia: You can imagine these microcompartments as enormous, three-dimensional puzzles made up of countless protein tiles. Each tile acts as a building block, and collectively, they form a polyhedral structure reminiscent of a dice, with numerous flat faces and sharp edges.

Zia: Advanced, more effective antibiotics could target these structures by stopping them from forming in the first place. But for science to get there, researchers like Backman need to study anaerobic bacteria in a new light first.

Backman: So if you look at the CDC’s list of antibiotic resistant pathogens, 15 out of 18 of them are anaerobes. So, a combination of what we call the strict anaerobes and then facultative anaerobes that can be in oxygen or without. But we mostly study them as aerobic bacteria, especially those facultative ones because most of them can also live in oxygen. And so, we're really missing out on a whole aspect of their identity.

Zia: But now, the Backman lab has designed a new set of machinery to study metabolism in these bacteria, both with and without oxygen.

Backman: What this thing looks like is kind of a giant balloon, like it takes up the size of a room. Inside this vinyl bag, essentially, is a nitrogen and hydrogen environment — there’s no oxygen. And so, to do all of your experiments, you reach your hands through the gloves and then you are able to do your experiments oxygen free. But what's particularly unique about our setup is that we have a sub-chamber that allows us to flow controlled levels of oxygen through our anaerobic chamber. And so, we can grow bacteria at low levels of oxygen and start correlating some pathways giving bacteria a competitive advantage when exposed to oxygen by actually testing it at these discrete increments.

Zia: While Backman is busy rethinking antibiotics, her neighbor and another Whitehead fellow, Aditya Raguram, is tackling different challenges that could have a big impact on drug development. 

Aditya Raguram: My lab studies how to deliver large molecules like proteins and RNAs into living cells.

Zia: Why? So these large molecules can target and correct mutations in DNA that are at the root of a disease.

Raguram: Historically, you can develop drugs that basically alleviate symptoms of a disease, and those drugs work quite well. But if you can actually directly correct the root cause of a disease, for example, a disease like sickle cell anemia, which is caused by a single mutation that leads to these sickled red blood cells, then that would be a really powerful way to, in theory, really cure that disease.

Zia: Today, CRISPR-Cas9 technology has the capability to do just that, not just for sickle cell but a range of diseases. The Cas9 protein functions like a pair of molecular scissors guided by a small piece of RNA, called guide RNA. The scissors hone in on a specific location in the DNA where the mutation appears and precisely cut the strand. Once the DNA is cut, the cell's natural repair mechanism springs into action and mends the broken DNA.

Raguram: But still, the big challenge that limits those therapies is how do we actually get the machinery that needs to perform the edit inside the cells in the body where you want the edits to be performed? And that's really critical, of course, because all the DNA in our cells is protected inside the cell nucleus. And so, you really need some sort of method to successfully deliver these large genome-editing proteins into the cell nucleus where they can actually exert their therapeutic effect.

Zia: You can picture cells as tiny fortresses — they have a protective wall, called a cell membrane, that shields all the important components these cells need to function. Now, cells are pretty picky about what — and who — they let in through this membrane. Small molecules like aspirin and ibuprofen? They can slip through. But when it comes to larger molecules, such as whole proteins or RNA, it’s a much bigger challenge.

Raguram: It turns out that nature has already given us a really good solution to this problem in the form of viruses, because viruses have evolved to be really good at infecting cells.

Zia: Every virus has its own set of genetic instructions, kind of like a tiny blueprint, that it needs to survive and replicate. Now, to keep this genetic code safe, viruses wrap it in a protective shell of proteins. You can imagine it as a little capsule, called a viral capsid. On the outside of this protein shell, there are other proteins that act like tiny keys, helping the virus find and unlock the doors to its target cells. These proteins are called envelope proteins, and they bind to proteins on the surface of a cell, allowing the virus to start the infection process. Once the virus attaches to the cell, it gets engulfed into a tiny bubble called an endosome, or a delivery sorting area within the cell. Now, all the virus needs to do is release its genetic load and break free.

Raguram: So that kind of raises the question of, well, what if you could take all the good parts of viruses and have them sneak into cells or break into cells? But instead of delivering a viral genome to cause disease, it might be able to deliver, let's say, a genome editing protein, which then could actually treat a disease. In some ways, this would be like a Santa Claus who still breaks into your house, technically, but he does so in a very nice way and leaves presents behind.

Zia: Raguram calls these particles “virus-like” particles. To create them, researchers start by growing cells in a petri dish and guiding them to churn out the basic elements of viruses, like the capsid and envelope proteins. But here's the twist: instead of sharing the virus's genetic material with cells, researchers ask them to include a different protein — a cargo they want these virus-like particles to deliver. And guess what? Cells are surprisingly good at following these instructions and assembling a harmless “virus-like” particle that is to shuttle useful cargo.

Raguram: One application was a study that we performed in collaboration with the Palczewski lab at UC Irvine. They are experts in retinal diseases, especially genetic blindness disorders, where you might have a single point mutation in retinal cells that leads to a kind of a complete loss in visual function. And we now had these virus-like particles that could deliver genome-editing agents that might be able to precisely correct the blindness causing mutation, and therefore, restore vision in these mice.

Zia: Raguram and his colleagues at David Liu’s lab at Harvard produced these virus-like particles and shipped them off to researchers at UC Irvine. There, the researchers injected the particles into the retina of mice without causing damage. Just a few weeks later, treated mice showed partial restoration of visual function compared to untreated mice that had no improvement in visual function at all.

Raguram: The amount of rescue we saw wasn't completely back to the “normal” levels, but it was still a very positive step in the right direction. And we think, with further optimization, we can improve the delivery. And, most importantly, in this experiment, we noted that the treatment was safe in these mice.

Zia: Although the findings of this study suggested that these virus-like particles hold plenty of promise in disease treatment, Raguram isn’t committing to a single solution just yet.

Raguram: So, viruses are one of nature's solutions to the question of how we deliver things into cells. But it turns out, cells have another process called vesicular transport.

Zia: These vesicles work as shuttles between cells, allowing them to transport proteins and other molecules with ease.

Raguram: If you have a neighbor who's just delivering a present or a freshly baked pie, they can just knock on the door, and you know who it is. And cells kind of communicate in some similar ways where you have neighboring cells sending these vesicles filled with proteins.

Zia: But why these vesicles function the way they do is still unclear, and it’s one of the many questions the Raguram Lab is committed to answering.

Raguram: The goal is eventually to be able to have a delivery technology that is safe and effective in human patients for delivering therapeutic proteins into cells within the body. And whether that is a “virus-like” particle or a vesicle, or even some other type of delivery strategy, my lab is trying to take as many different approaches as possible to make progress on as many fronts as possible. We're really just trying to learn as much as we can about these systems and kind of push the boundaries of what they're capable of.

Zia: Much like Raguram, Whitehead Institute Member Richard Young has championed unique ideas in drug development since the beginning of his career. Here’s how his latest discovery came about:

Richard Young: My academic history is all about trying to understand gene regulation. And in 2016/ 2017, Phil Sharp and I were collaborating on two things. One is some science to understand how gene regulation works. And the other is teaching together here at MIT — we were teaching first-year grad students. And we realized that a set of mysteries in how gene expression is regulated were not yet solved, and students were asking us questions about them. So, we sat down to think, how could we solve these mysteries?

Zia: Young is talking about the mystery of how different proteins work together in a cell, a process that is essential for them to function smoothly.  It turns out, cells have a unique mechanism in place for fostering this collaboration — the creation of small membrane-less compartments, called condensates. You can imagine them as meeting rooms in a cell where proteins, nucleic acids, and other biomolecules gather to carry out chemical reactions.

Young: We thought that was an interesting concept and got together with a theoretical physicist, Arup Chakraborty, and the three of us published a perspective that proposed that the way that the hundreds of proteins that are involved in gene regulation work is they assemble into a body called a condensate, without a membrane. And it was met with pretty broad skepticism. But that's what new ideas are met with in the scientific community.

Zia: Young and his collaborators weren’t deterred, and it wasn’t long before they began thinking about the potential of condensates for not just understanding, but treating diseases. They thought:

Young: If this is the way cells are organized, and we don't fully understand disease, and we fail very frequently to develop new therapeutics where we do understand disease, might this be a concept that would be valuable for understanding disease and then developing new kinds of therapies?

Zia: They realized that while condensates are great for protein teamwork, they might also be blocking drugs from reaching where they need to go in the cell. Here’s how:

Young: When the cell creates all these compartments, each one might have a slightly different biochemistry. And if each one has a slightly different biochemistry, then when drugs enter a cell, they may not diffuse evenly throughout the cell and evenly access areas where their target lies. They may end up concentrating in these bodies.

Zia: Take Cisplatin, for example — the cancer drug we talked about in the beginning of this episode. At first, researchers thought it randomly binds to DNA in a cell to stop tumor cells from dividing. But they’ve since realized, it first gets concentrated in areas where cancer-driving genes are regulated, and that’s what makes it so effective at stopping cancer from proliferating.

Young: This new paradigm of cells having lots of different compartments, many of them forming and dissolving very dynamically in short time frames, allows us to think completely differently about how many of these drugs work, how they may get concentrated on target or get distracted from their targets and cause toxicity. So, it's really a radically different way of thinking about what diseases are and how you might develop a therapeutic hypothesis to counter all kinds of diseases, ranging from cancer to neurodegenerative diseases to muscle wasting disease — pretty much any disease you can think of that has an ideal target that has been identified.  

Zia: In championing condensates as an idea that’s worthy of scientific attention, and throughout his 40-year career at Whitehead, Young has learnt that foundational research is truly about laying the groundwork for tomorrow’s biggest advancements.

Young: I have been involved in forming at least half a dozen companies. Each one of those emerged from a fundamental basic science question where an answer to a mystery that we posed — with no idea toward understanding disease or treating disease —  led us to realize that there was a new path we could consider towards doing that. And on top of that, I think many of the people I've trained just in attacking fundamental biological problems, they have emerged, as I've come to discover, as great candidates for biopharma — from continuing to do fundamental research to actually helping file investigational new drug applications to the FDA and shepherding drugs into registration. So, to my mind, it's been far more productive for my lab to be focusing on basic questions when it comes to ultimately developing new concepts for therapies and actually executing on them.

Zia: To learn more about ongoing research at Whitehead Institute, go to our website at wi.mit.edu. This is also where you can find past episodes of AudioHelicase and tune in for new ones. Thank you for listening!

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Interviews, production, and hosting by Shafaq Zia.

Music and sound effects:

Crescent Bloom by Kai Engel (CC BY-NC 4.0)

OBJPlls-INT_Pills Rattling by Alessia Pultrone (CC  BY-NC  4.0)

Asthma Inhaler — Sprayed/ Dispensed 2 times by MutilatorBCB (CC0  1.0)

Velcro 7 by CassieTee (CC  BY-NC  3.0)

Illustration: DrawImpacts