355 Early Molecular Detection of Colon Cancer with Dr. Erica Barnell
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Kevin Folta: [00:00:00] Hi everybody. And welcome to this. Week's edition of collaborates talking biotech podcast. Now over the last couple weeks, we've talked a lot about different medical interventions that really are laying in the future things that are going to happen that will radically transform the way we treat different diseases.

What about detection and in so many different types of cancers, early detection is the cornerstone of effective treatment. That many of our most insidious cancers are ones that simply evade detection. Sadly, a lot of people don't get the appropriate screenings that could actually save their lives. So what if there's a way to make these kinds of screenings?

A little more simple simply by taking a look at the, the stuff that comes through us. And today that's what we're going to discuss. So we're speaking with Dr. Erica Barnell she's the co-founder and chief science officer at Geneoscopy. And welcome to the podcast Dr. Barnell. 

Erica Barnell: Thank you for having me. 

Kevin Folta: Yeah, I'm really glad you're here.

I think this is really [00:01:00] neat and I love this kind of, uh, this kind of technology. And instead of like spilling the beans now, uh, let's just talk about the basic concepts of the cancers and the diseases that happen, uh, in the digestive tract. So we'll talk about that. There really are, uh, problems with digestive cancers, particularly of the lower GI and how many people are affected by these types of cancers and, and how, what do we normally think of them?

Erica Barnell: absolutely. So typically, um, when we're thinking about cancers, um, you know, most people know the big ones. Um, they know about lung cancer and pancreatic cancer and colorectal cancer. Colorectal cancer is the second leading cause of cancer related deaths in this country. and can typically have, uh, morbidity and mortality.

Um, that is very high. If these cancers are [00:02:00] detected late and what you'll find in the community is one in 20 individuals, um, actually know somebody or are infected by themselves by colorectal cancer. 

Kevin Folta: And what are some of the typical risk factors that we consider? When we talk about colorectal cancer?

Erica Barnell: Yeah. So family history is a big one. Um, if you know somebody or you have a loved one that has colorectal cancer, um, it's, it's probably affected your life and, and you know that you need to go get screening for this disease earlier. Smoking is a, a big risk. Risk factor for, for development of colorectal cancer.

And then there are a number of other, um, contributing factors like your diet, um, things that you do or don't do related to your health, um, can influence the development of, of these diseases. 

Kevin Folta: well, colorectal cancer and maybe other digestive cancers. They're [00:03:00] particularly interesting from a diagnostic standpoint, because if you catch them early, you, you can actually correct them with a very high degree of certainty.

And so the advice to, to, to avoid these problems is once you turn 50, uh, get a colonoscopy every five years. And why is that alone? An insufficient method for detect. 

Erica Barnell: Yeah. So the, the kind of premise behind colorectal cancer screening is what you're describing, which is prevention. So colorectal cancer is one of the most preventable.

But actually least prevented diseases because of the way that the biology of colorectal cancer is. So typically your entire colon starts off as normal tissue. And then over time as you, um, replicate the cells in your colon, there can be small. DNA changes, um, that [00:04:00] create these things called polyps or precancerous OMAS.

And then over time, these precancerous OMAS accumulate more changes in the DNA that cause it to become larger and more malignant and have a higher potential of, of creating a problem specifically becoming a stage one through four colorectal cancer. And this process happens over the course of years. So unlike other cancers where, you know, a single gene mutation can cause you from going completely normal to disease, um, colorectal cancer is very indent and takes a very long time to develop.

And so what we're finding is. Colorectal cancer screening programs that utilize that time, um, can actually detect these precancerous changes before malignant transformation of the lesion. And that allows us to [00:05:00] prevent people from actually developing colorectal cancer. So colonoscopies have been the.

Gold standard for colorectal cancer screening since about the seventies. And those are excellent at detecting these precancerous lesions as well as detect. Full blown, colorectal cancer. But the reason why it's, we shouldn't rely exclusively on colonoscopy is because patients are really non-compliant with that procedure.

So patients don't like doing the bowel preparation, they don't like taking time off work and who can blame them. Um, it's, it's not a, a procedure that should be taken lightly. There can be serious adverse events associated with the procedure. And most patients that undergo a colonoscopy actually don't have findings and will be instructed to come back 10 years later.

So our goal is to create molecular diagnostics that use. Samples that people just throw [00:06:00] away in the toilet every day. Um, and leverage that sample type to understand if patients actually need to go through this very invasive procedure of a colonoscopy to detect and remove a lesion. 

Kevin Folta: Yeah. You see, this is what I was hoping you had mention is that the colonoscopy is really good, but only if you get one only get one yeah.

And too many people find this, like, you know, the, like you say, the prep work and all that stuff. Frankly, I, I haven't really, uh, ever had a problem with it. I, I really enjoy the the day off and, you know, and knowing that I'm okay, especially because I've come back with, uh, polyps that they've, that they've pulled out.

And so I look forward to getting the next one, just because I don't wanna know that this preventable thing is being prevented. So, uh, I, I would like listeners who are in that age range to make sure that you do it, make sure your loved ones do it, but also think about these new technologies. Um, the, the other thing I'd like to drill [00:07:00] down on just a little bit for this particular audience, that tends to be a little more excited about the techno technological side is, are the details.

When we are talking about colorectal cancers, there seems to be at least five committed steps that your, that the cell has to go through before it becomes a malignant issue. And so could you tell us a little bit about what those molecular steps are like, how you go from maybe one to two, two to three, three to four, four to five that kind of.

Erica Barnell: Absolutely. So as mentioned, colorectal cancer is, is kind of an indent disease. So it starts off as a normal, healthy, um, cell. And, and then you start accumulating these DNA changes. So there's two different pathways that colorectal cancer can undergo. Um, Or there's multiple, but the two main ones are the canonical pathway where you have a specific set of DNA mutations that [00:08:00] accumulate, and that causes that normal tissue to become a precancer OMA.

And then that precancer adenoma has a higher growth potential. So it's replicating cells more quickly relative to the cells around it. and then that creates this little polyp. Um, that's either sitting flat on the wall or grows out into the lumen of the colon and then that polyp, um, will undergo more mutational changes to, um, become a, a malignant.

Um, lesion. And at that point, um, it, it needs to be resected or it will continue to grow and develop and become a larger stage to cancer. 

Kevin Folta: Yeah, that was always the part that I didn't understand about this particular process was that you have these five, you know, four or five different steps that happen.

One of them is loss of P 53, which is a tumor suppressor that we've probably talked about here [00:09:00] before other ones are effective in, uh, um, um, map kinase, signaling this kind of thing. But the, I always wondered why the latter steps always happened later. And that the early steps happened earlier that they didn't have to happen.

They seem to happen in a specific order that you never have the fifth step happening first. And I think that's because of this rapid growth thing that you talk about when you say you get more cell division to make the polyps, is that, that the cells and the replication machinery gets a little sloppy in the polyps.

Erica Barnell: And it's, it's the, the traditional pathway that I was describing. Typically it starts with APC mutations, um, which is the, which can cause germline predisposition for cancer. And then you'll accumulate a, a K RS activating mutation and subsequently the, the kind last steps are when you have a TP 53 variant.

So the APC gene is kind of the gateway to developing these. [00:10:00] Polyps, um, that launch the process. And when you look at the APC gene, um, relative to kind of the other genes in your, your genome, it's very large. Um, and it's a tumor suppressor. So pretty much any pathologic mutation along that entire transcript can induce this type of change.

Um, so you really have a high target in this APC gene to develop a precancerous poly. Um, when you're thinking about those later changes like activating K a mutations, it's a really specific. Um, variant that has to occur to activate, um, K a S, which is a, an onco target. So those, those, the difference in the biology between the types of transcripts and the types of DNA variants that are accumulated over time, um, is what [00:11:00] creates the underlying biology of how this disease takes 10 years to develop.

Kevin Folta: And that's really illuminating. That helps tremendously because if people understand that this is a process of different events that are happening at the molecular level, now it starts to make sense of why the prevention is even more critical. And it also really sets the table for your technology. And that's an excellent setup for us to discuss the way in which your company Geneoscopy is using stools to do diagnostics, to identify these different molecular events that have occurred to really be able to catch this nice and early.

So this is the talking biotech podcast by collabora, and we'll be back in just a moment. And now we're back on the talking biotech podcast. We're speaking with Dr. Erica Barnell, she's a co-founder and chief science officer at Geneoscopy. And we started out the conversation today by talking about colorectal cancers and their prevalence in society.

And the reason that [00:12:00] these can be, uh, at least avoided if caught early the molecular, uh, steps that happen in an iterative way, that lead from a benign type of lesion into, uh, an aggressive malign. Uh, cancer. And so the question now is how can we enhance the ability to detect this early in the absence of a colonoscopy that the sigmoidoscopy, that that is occurs is good, but not everybody gets it.

And so the question now is are there ways to catch this early? The other thought is too, is that if this kind of assay is so good, it may completely. LA sigmoidoscopy, at least in the beginning. And maybe just the folks who get some morning signs need to go get it checked out, but we'll talk about that. So your company has developed a method to detect evidence of this commitment to this cancerous progression.

And, uh, you're looking at gene expression in the gastrointestinal tract by looking at stool material. How exactly does that. 

Erica Barnell: Absolutely. So stool [00:13:00] samples are a combination of, you know, the, the waste that you produce when you eat things. Um, as well as kind of some of the cells that are lining the intestinal track of the colon, those cells are sloughed off.

Into the school stool and excreted as waste along with the other byproducts, um, of what you ingest. And so what we're interested in is kind of collecting those cells that are sloughed from the lining of the colon. And looking at them to see if any of those cells would signify that you have, um, a cancer or a precancerous change in the colon that would require a colonoscopy for lesion removal.

Kevin Folta: And are you looking at those DNA predispositions, like mutations that are inherited from your family? Or are you looking at changes in gene expression? Like when you mentioned APC mutations that may show. 

Erica Barnell: [00:14:00] So what's unique about Geneoscopy is that we're actually looking at the RNA transcriptome that's associated with both adenomas and colorectal cancer.

I think traditional companies have looked at DNA, either variants or methylation, um, somatic variants, because DNA is much more stable and it's easier to pull out of samples. um, but what we've seen is that RNA is a much more informative biomarker relative to DNA. It can provide you information about the universal molecular signature that is associated with all dysplasia and all advanced anos in all cancers.

And you're not just trying to pick out specific variant. That might be associated with an individual. So when you're looking at RNA changes, we have an improved sensitivity or an improved detection for these precancerous and [00:15:00] cancerous lesions relative to companies that are looking at DNA, variants or DNA methylation.

And what we've done that's been very successful is we've been able to preserve and isolate. And quantify this really informative RNA biomarker in stool samples and prevent it from being degraded over time. Um, to allow us to look at this, this very important signature in the GI tract. 

Kevin Folta: Uh, let's talk about that a little bit.

If you don't mind, it's that, you know, we learn in biology class, that RNA is cool stuff because it's transient and it's a message that breaks down fast and there's enzymes everywhere that want to take it apart. And it seemed like those would be just loaded in a stool. I'm just a guess. And so how do you keep a signal intact so that you can have faithful replication of a diagnostic, uh, positive if it's really.

Erica Barnell: And that was a very long process. Um, so that was really the, the technology that, that we [00:16:00] developed at Geneoscopy to, um, allow us to use these really important dynamics, signatures, um, that indicate disease and, and, and leverage that for our diagnostics. So it's a part, it's a two part process. Um, we use our own collection kit that has stabilization buffers, that preferentially degrade.

Those materials that you're describing that are attacking are signal. And then subsequently when the stool sample is received in the laboratory, we go through a series of, of steps to, um, isolate the cells, isolate the RNA, preserve the RNA, and then quantify it effectively, um, to get a robust signature that we can look at to assess for disease.

Kevin Folta: and you mentioned something about transcriptomes earlier. So are you just doing transcriptome sequencing of what's left after you do this, you know, preservation step or is there an amplification step just to do, you know, a specific PCR targets just with traditional PCR? [00:17:00] 

Erica Barnell: It's a, actually a combination of the two.

Um, so the, the reason why we've been successful, um, is because there's been massive advancements in the ability to, um, Evaluate and quantify the RNA signals and samples. Um, so people have been able to use kind of single cell sequencing or digital PCR, um, which leverages it, you know, kind of a amplification approach as well as those kind of traditional PCR methods.

And we've done something similar. So our platform for the CRC screening assay is a digital PCR approach that leverages amplification. but it's contained within droplets. Um, so it provides an absolute count of this, of the RNA signature that we're looking 

Kevin Folta: for. Oh, I see. So you have a quantitative ability to do this, right?

That's because can you learn more about the progression from the quantity of the target RNAs that are 

Erica Barnell: present? [00:18:00] That's correct. So we use a, a quantitative approach to understand if, if the RNA transcript is too high, Um, or too low, um, we can find a signature that we know is associated with disease, and that informs our decision to send an individual to a colonoscopy or not.

Kevin Folta: It still seems remarkable to me because just, you know, as a scientist, who's worked with RNA for years and who understands these things a bit and UN, and does transcriptome work? It seems like if I was pulling RNA out. A human stool or any stool, it would seem like the vast, vast, vast majority of RNA I would get would come from bacteria.

And so how are you able to really separate how you know, or basically the question is, how do you find the needle of the haystack? 

Erica Barnell: Yeah, again, that's that's, that was a long time, um, that we spent in the laboratory to kind of preferentially amplify the youcar or human signal [00:19:00] relative to the bacterial noise.

I was working in a, a laboratory, um, that was funded by the mil Melinda gates foundation grant. And that was kind of my task at the time was to see if we can, um, differentiate the cells in stool sample and kind of map out which ones are you carry, map out, which ones are bacterial and then separate them effectively.

During transit while it's coming into the laboratory. And then after we receive it in the laboratory. And so that was the basis for the, the technology that Geneoscopy uses, um, to degrade that bacterial noise and amplify the human signal, which is what we use to detect disease. 

Kevin Folta: Well, Geneoscopy seems to be, uh, you know, and this is just my guess kind of a, a newer player in what is already a, uh, uh, a, an industry that does some sort of stool-based detections.

And how is your assay different [00:20:00] from say other companies that have been working in this space? 

Erica Barnell: Yeah, I think there's two different types of, of companies, um, in the colorectal cancer screening space. So there's exact sciences, um, who produced ARD in 2014. and they leverage DNA methylation in some variants to detect cancer, um, and some precancerous changes and then there's blood based biopsy approaches.

Um, that kind of look for a universal cell-free DNA or circulating tumor cell, um, to detect disease. I think, you know, we haven't really seen any, um, Blood based biopsy approaches, obtain FDA approval for colorectal cancer screening application. So really the only player in the field right now is, is Cologuard.

And I think where they kind of don't do as well, [00:21:00] um, is the detection of these precancer lesions. So while they have a 92% sensitivity for colorectal cancer, Um, they, they only detect 42% of precancerous adenomas. They do a, not a great job at preventing cancer development. Because we're looking at RNA changes in the stool sample.

Um, we have the ability to dramatically improve the accuracy profile regarding the prevention of disease through OMA detection. And I mentioned that we're looking at that kind of universal signal that all adenomas create in the transcriptome. And that's how we improve our sensitivity. Relative to, to other diagnostic tests.

Kevin Folta: I guess the other question would be, are other. Gastrointestinal cancers, adenoma based where this may be able to detect something like stomach or esophageal cancer. 

Erica Barnell: Yeah. So we're definitely looking [00:22:00] at cancers in the GI tract or GE tract that could leverage our extraction technology. So if we're thinking about just looking at stool samples, it's possible that we.

Be pulling down, you know, pancreatic cells or chal cells or hepatic cells, um, that are dysplastic and be able to detect those cancers. Um, we also have the ability to transition to other sample types like menstrual tissue or urine, and look at the transcriptome of the cells in, in that. Sample type. And we could detect other diseases like ovarian cancer, endometrial cancer, or bladder cancer, or kidney cancer, things like that.

So we're exploring both opportunities trying to see if we can go further up in the GI tract, as well as use O other waste material that people really just throw away, um, to inform ourselves about, [00:23:00] about human. 

Kevin Folta: Yeah. And that's what I really love about this is that it's the stuff we throw away that now we can test to get a, a reading as to how we're doing on the inside.

And that just seems to me to be the way we're going to do a lot of things in the future. And if you had to look at. You know, in your crystal ball, uh, at, uh, what these kind of noninvasive or minimally invasive cancer techniques, uh, detection techniques do, does it seem like, um, that this is going to be a, uh, that maybe, you know, that this will have a lot of.

Really deep diagnostic ability for us to, to even go into places like, you know, liver and that kind of thing. 

Erica Barnell: Yeah. I think that, you know, people are getting busier. I think that people are, have more autonomy over their health. I think people are more informed these days, um, and they want, you know, they want immediate.

Action. And they want immediate [00:24:00] data. And, um, you know, that's just kind of the way that people are, are moving. And so molecular diagnostics and specifically at home molecular diagnostics provide a way for people to understand and be informed about their health in a way that is congruent with their lifestyle.

And so I think the trend in healthcare is to move diagnostics out of the hospital, out of inpatient, out of outpatient, really, even, and into the home. And so you're gonna start seeing more of these molecular diagnostics, where were traditionally things were diagnosed with procedures in the hospital, or, you know, CT scans or MRIs or x-rays, and now we're gonna be providing patients, um, with those, those abilities to detect.

Their disease and do something about it. 

Kevin Folta: Yeah. I, I agree with you a thousand percent. I really think that this has another important fringe and that is cutting healthcare costs because we're not just going to [00:25:00] be, like you say, going in for an MRI or a cat scan to see if something's wrong, you'll be able to detect it long before you may even be able to detect it with a cat scan.

And so you're, you're in a, in a space now where the at home molecular diagnostic techniques. Which can be done at a fraction of what it would cost to go in for, you know, a cat scan or pet scan, whatever. Now you're able to, uh, and have more sensitivity. Um, it, it just seems like this has a real good opportunity to revolutionize healthcare.

Erica Barnell: I, I agree. I think, you know, when, when you discuss the, the colonoscopy, um, you. We are at a huge backlog for colonoscopies. Right now there's 150 million Americans in the colorectal cancer screening population. And that has just increased as we've lowered the age for recommendations, for screening and the number of.

Practicing GI docs has really not changed over time. [00:26:00] And so this is putting a huge burden on the healthcare community and on the insurance and, and the healthcare system to get people scoped for colonoscopies. So if we can use our tests to. Rule out individuals that are at very, very low risk for having a disease or having a lesion that requires removal.

It will help us improve the kind of flow, um, in the healthcare system and ensure that the individuals who need to get scoped are, are getting to their physician quickly. 

Kevin Folta: Yeah, and this is, this is a real personal edge for me because I got my first one at 50, which was five years ago. And they found like a billion polyps.

I mean, they really, it was a lot for them to remove. They said, we need to get you back here in five years at the most. And I called it three years and they said, well, come at five. And then at five years, I called and this was in February. And I got my appointment for, um, September for the first [00:27:00] appointment where they go in and tell me what junk to drink so that I can clear out.

And I probably won't actually get the colonoscopy until November, December, maybe even 2023. . And so I, I wish that things like your, uh, products were, you know, freely available on the market. And my doctor could at least say, we're gonna do this screen just to make sure you're cool, because this is something we need to catch early if there's an issue.

So, you know, you're, you're not falling on deaf ears with, with, uh, with your thoughts on this particular concept. 

Erica Barnell: Oh, that's not an uncommon problem that we've, we've heard, not only are wait times in the GI space very long. Um, but patients, especially in rural areas or, or areas where they have lack of access to healthcare, it's, it's, it's nearly impossible for them to get the screening they need.

Kevin Folta: And, and also in, in the developing world where you may not have the same kind of hospital infrastructure and accessibility, this kind of thing, you would have accessibility. Absolutely. Yeah. So this is, this kind of technology has [00:28:00] this wonderful way to democratize science, which is really exciting too.

That's really cool. And it's really good that you can detect cancers. That's that's wonderful, but there's so many other conditions of the, uh, lower GI that we hear about all the time, whether it's, uh, whether. Whether it's, uh, things like Crohn's disease or inflammatory bowel disease or, uh, other types of chronic, uh, colitis.

Is there other types of diagnostic tools that can help shed some light on exactly what is affecting somebody in a lower GI disorder? 

Erica Barnell: Yeah. One of the really beneficial things about using RNA instead of DNA markers, is that we can look beyond oncology. So we're actively developing diagnostics to monitor mucosal healing for patients with I B D to predict therapeutic response.

Um, for those individuals we're looking at other inflammatory conditions of the GI tract, like IBS or Celia. [00:29:00] Um, we're looking at infectious causes and, and diseases and trying to understand, um, those. Disease indications more effectively and treat them better. So I think when you're, when you're thinking about the colorectal cancer screening space for us, that's a very busy space.

There's a lot of companies out there that are trying to develop techniques to prevent and detect cancer. Um, but there's also this very huge unmet need and clinical burden in the GI disease community in the inflammatory and auto. Um, space and we're, we're hoping to address that with our technology as well.

Kevin Folta: This is all very exciting. If people wanna learn more about what's happening at Geneoscopy or, uh, maybe the new products that are available, where would they look? 

Erica Barnell: Absolutely. So you can see our, our upcoming research and what we've been doing, and our press releases@geneoscopy.com. We're also very active on Twitter, [00:30:00] Facebook, LinkedIn, all the.

Social media sites and, and hopefully we'll have some very big updates coming soon. Um, so stay tuned. 

Kevin Folta: well, that's pretty exciting. So big updates coming soon, like 20, 22. 

Erica Barnell: 2022 soon. Um, we have a large pivotal study that we've, um, completed enrollment. And so we're gonna be releasing that data, um, very shortly.

Kevin Folta: Well, that's really exciting because there's so much that we can do that. If we can keep people out of the hospital and be able to make these diagnostic tests function wonderfully at home, it, it really does add to. Care arsenal. So Dr. Erica Barnell thank you so much for joining me today. I really look forward to future breakthroughs and hope you'll join us again as things progress.

Erica Barnell: Absolutely. It was a, a pleasure to be on the show. 

Kevin Folta: Thanks so much and to the listeners. Thank you very much for listening to the talking biotech podcast, uh, as always write a review on iTunes or share with others. The other day, I was telling my wife I'm 55 years old. And I said, I [00:31:00] got at least 45 more years of functional biology left in me where I plan to keep doing things as I'm doing 'em now.

And I really do believe that because the talking biotech podcast gives me interviews with people that really do give me hope. Um, I think that. It's great for people who suffer from these disorders, people with genetic predispositions, for these disorders, to know that there are scientists who are working hard to ensure their health and safety for years to come.

So this is the talking biotech podcast, and we'll talk to you again next week.