DODI: Conor, have you ever heard the phrase 'put it on ice' when you want to preserve a topic but will return to it?
CONOR: Are you going to tell me that we should talk later?
DODI: Well, let's talk now. We're going to talk about putting things on ice in the literal sense, cryopreservation of biologics to overcome challenges of safe drug delivery for CAR-T therapy. Our guest is the illustrious scientist, John Morris.
CONOR: Ah, so this is the fellow from our most recent 'Pioneers and Visionaries' docu-series am I right?
DODI: Does anyone want to guess where you can find a link to that series?
CONOR: I do. I'm going to guess. Is it in the show notes?
DODI: Correct!
CONOR: Yay! Okay, so real podcast, real show notes. So pioneering and visionary science must be what matters on today's episode of Discovery Matters.
JOHN: I came to Cambridge as a post-doctoral student in the mid-1970s and I worked on very exciting work on freezing of T cells, mainly for diagnostic uses and immunological applications. You know, this was predated CAR-T by many, for many years and we published high-profile papers which were generally ignored until five or ten years ago, but it was a very exciting time to work in freezing.
DODI: You are hearing the voice of John Morris, PhD, former CEO of Asymptote, which was acquired by Cytiva, and John still consults with us. To John, Cambridge is where cryopreservation was invented.
JOHN: There was a community of people who understood about freezing. So, it's a very, very exciting time. I worked on freezing cells.
CONOR: But why cryopreservation? Why did this spark John's interest?
JOHN: I just got very interested in freezing, trying to understand what happens during freezing and what happens to the cells during that freezing process. I was offered a Ph.D. in, in from the Medical Research Council. They have an institute where they were interested in freezing cells for medical applications which were of interest at that time. So, it was freezing blood cells, platelets, and lymphocytes.
DODI: As he mentioned earlier, during his PhD, they published around four papers in Nature, one of the most eminent scientific journals on freezing T-cells. These papers are still being cited because of how important it is in relation to CAR-T cells.
CONOR: But by the sounds of it, he didn’t go straight from the work of his PhD to his work related to CAR-T cells.
DODI: There were a few examples where people had done clinical trials with new products and those trials failed because they didn't manage to control getting the material to a patient.
CONOR: And that was like a known challenge at the time. People were trying their best to freeze properly, and if they could, it would allow safer delivery of products.
JOHN: When we exposed it to people in cell and gene therapy, it was disruptive. I think, as you know, it was something they hadn't heard of.
CONOR: So, this is what we know as autologous cell therapy, you put the cells back into the patient that they came from. If you put those back into the wrong patient, first you lose the cells, which is a therapy for somebody else, and secondly, your patient could be even more ill.
DODI: Exactly, and this is where John's expertise really came in.
JOHN: The current CAR-T workflow is that you take cells from a patient, freeze them, ship them to a manufacturer the manufacturer grows a CAR-T from them, freezes them, and then ships them back to the patient. This can be in different continents and it's critical to be able to just ensure that the right cells are coming back and there's no mixing up. We've been instrumental in developing a cold chain with equipment and software so that we can ensure the right sample is followed at every stage. And so, you can check the sample has been frozen correctly.
DODI: Also, you can check that it's been thawed correctly and stored correctly. This ensures that the patient will get the best quality material for treatment. There was a need for cryopreservation to help scale up.
CONOR: And what was his vision when he set out to create a cryogenic cold chain?
JOHN: The vision was to be able to digitally track, a sample from the patient, right the way through to the manufacturing process and back into the patient. And know that it was optimum for treatment.
CONOR: And if we look back now at all that's been achieved and all of John's contributions, they've been absolutely foundational here. If it weren't for the cryo cold chain, then the potential of CAR-T therapies may not have happened for another 10 years.
DODI: Imagine all those patients.
CONOR: Exactly.
JOHN: Many companies in the world now manufacture CAR-T therapies, they've been applied to tens of thousands of patients with very, very good success, especially if, you know, they're administered to patients who failed with many of the other treatments. So, in the long term, they could be frontline treatments.
CONOR: John mentioned that it was a multidisciplinary beginning for him with many engineering and different sciences colleagues . How was the cryo cold chain then influenced by this collaboration?
DODI: The team started small with only eight people. They encountered a common problem for companies of that size.
JOHN: We were manufacturing the equipment and doing everything, and we had a lot of interest from the major people in selling gene therapy. But we had commercial problems about getting them to take the product on because we were too small a company to sort of support it in their view.
DODI: Because of their small size, they would struggle to manufacture the sheer quantities of the product required without the infrastructure. They just couldn't scale up. All that changed when they were acquired.
CHRIS: We wanted to get it to the world in a bigger way, and we couldn't do it on our own that easily. So, we did need to get some sort of backing.
STEVE: We always felt like we were in the right place, and that the industry was growing quickly. There was a need for cryopreservation to help scale up everything.
DODI: These new voices are Chris Creasey, Hardware Engineering Operations Manager, and Stephen Lamb, Manager, Cryochain Mechanical Engineering, both of whom are our colleagues at Cytiva. They were with John throughout this time.
STEVE: All that hard work up to the acquisition felt like real hard work and the acquisition was that finish line. Couldn't be further from the truth. It really started after that point.
CONOR: This is what always fascinates me. You've got this amazing science and then in a situation like this, you've got this drive, which is shared by a team, because a patient or person is waiting.
STEVE: When we were dealing with companies, it was about enabling. You didn't always see the doctors or the patients, but occasionally I remember one company in Holland that was a university hospital. Yeah. When you walk, you walk through the hospital and the cancer wards to get to their premises and the guy’s saying they're the patients. And that's quite sobering.
DODI: Understandably, John is really proud of his contributions to human health.
JOHN: We're not responsible for the whole process but our equipment's used for saving lives and ‘how does that make you feel?’ Well very happy, you know, it is being used for many pediatric CAR-T therapies. So it makes you feel very good.
DODI: In the future, the developments are all about dry cells.
JOHN: From a preservation point of view, potentially, if you could move away from liquid natural temperatures to store material if you could dry cells or have other ways of stabilizing cells that would completely revolutionize what happens in certain gene therapies if it was a magic way of just stabilizing them so that they could be transported and not die or could be stored for a period.
CONOR: So, we've looked back 20 years today, but what does John foresee in the future?
JOHN: The other dream is solid gene therapy, it is very good with blood cancers but blood cancers are only 10% of all cancer deaths. So, it's solid tumors, you know, lung cancer, liver cancer, the dream is in the long term, those will be treated by cell and gene therapies. There are many people working on those, but it's not as well developed as the blood cancers.
DODI: So, a topic that is NOT put on ice is about properly putting cells on ice … do you like how that came full circle?
CONOR: That was deeply, delicately, and so carefully crafted. I'll just say, you've got it down to an art. Okay, amazing puns aside, bringing us full circle. What have you learned this week that – and no puns allowed – has opened your eyes a bit?
DODI: This is another podcast. There’s a reason that this podcast is, you know, so popular. It's called This American Life. The episode is called 'The Feather Heist' and is so beautifully put together. It is about rare feathers being used as fishing lures. It's just a great story. I don't want to spoil it. I recommend that you go listen to the episode of This American Life. It sent me down a rabbit hole of exploring rare bird feathers, their value, and why we humans are interested in them. And just a small factoid here, the most expensive feather ever fetched 4000 GBP at an auction. It came from the extinct huia bird from New Zealand.
CONOR: Who would have known that would ever have been a sentence? The most expensive feather ever.
DODI: Huia would have known. Did you hear that? Shall I repeat it?
CONOR: This is just terrible. You can't do this.
DODI: And yet we did.
CONOR: Public service announcement: we have to apologize.
DODI: All right, I dare you to bring a pun into what you learned Conor.
CONOR: So, from extinct birds to something inspired by the book that you last gave me 'Overstory' by Richard Powers.
DODI: Love the 'Overstory'.
CONOR: An absolutely marvelous book about the impact of trees on human stories. There is a study by Ohio State University, which has shown that the forest growing season in the United States has increased by a month. So, the growing period of hardwood trees in the east of the northern United States has increased on average by one month over the last 100 years as temperatures have risen. So, these trees burst into bud earlier their leaves fall in the autumn later. And this shows climate change’s impact on how our forests work. I'll let you judge whether that's a good thing or a bad thing to have trees growing for longer or more slowly. In a century's time, people will see it in the rings of the trees.
DODI: Well, you didn't bring us a pun so Conor could you knock me over with a feather with that fact?
CONOR: Oh, that's awful!
DODI: Come on. Next time I want you to bring your pun.
CONOR: Okay, I'm just going to say, 'insert hilarious tree joke right here' and let's bring this to an end. Our producer is Beth Armitt-Brewster.
DODI: Who blooms in her role.
CONOR: Editing, mixing, and supervision by Ulrika Swenson and Tom Henley from Banda Productions. Music from Epidemic Sound. My name is Conor McKechnie.
DODI: And mine is Dodi Axelson. Please do rate us on Spotify or whichever platform you use to listen to our podcast. We will catch you audibly when we return with another episode of Discovery Matters.
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