In this podcast celebrating the 50th Anniversary of the Johns Hopkins Kimmel Cancer Center, Bill Nelson and Ashi Weeraratna look back at her experiences as a cancer researcher and forward to where research at Johns Hopkins is heading.
Bill Nelson: This is Bill Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and on the occasion this year of the 50th anniversary of the Cancer Center, we’re getting a chance to catch up with Ashi Weeraratna.
Ashi has been involved with the cancer center for many years. She was here as a trainee for some period of time, was across town as a colleague and collaborator at one of the National Institutes, in this case, the National Institute of Aging, then was in Philadelphia for a while, has come back to be a department director in the School of Public Health, and is as of this year the new research director for the Comprehensive Cancer Center.
I thought, actually, what we could talk a little bit about is how we’re anchored in the last 50 years, but where things are going to go. So start out with one that you know very well, which is, there was a distinct human biology orientation to the laboratory research that was done historically here—people, starting with the Clayton Fund that systematically collected human biospecimens from colon cancers, polyps, and whatnot.
From that, there were studies of acquired gene defects, acquired defects and gene functions. We call it epigenetics and genetics. A lot of that was built in a culture, so a laboratory sort of reconstructed out of a supermarket, Brown’s supermarket. And you were present down there as this started, what were your reflections on that time? Was it unique? There was a lot of excitement, a lots of activity in many different directions. What are your memories of those early days?
Ashani T. Weeraratna: I was there during the time the p21 gene was being discovered and named, and so I got to listen to Wafik El-Deiry out how he was going to name that gene. It was such an exciting time to be there. I was only 20 years old. I had just graduated from college. But to be surrounded by the intellect there, but also people who were just so down to earth and so practical was an amazing experience for me as a student.
But what I will say is that in this tiny little building that, as you said was a former grocery store. Bert Vogelstein always says he did his best work in the frozen vegetable section, right? The probable dynamism, if you will, of the science, was really just amazing. I mean, you had Vogelstein in there, you had Stephen B. Baylin in there, you had Paula Pitha-Rowe there.
You had all these amazing names that everybody recognizes. Even as a student who was completely naive, and didn’t really know much about the cancer research world, you felt that you were part of something special.
BN: At that time—of course, we knew then, as we still recognize now, that all cancers are fundamentally disorders of acquired defects in genes, and these acquired defects drive the cell that should ordinarily be doing something useful, into duplicating itself too often and growing in the wrong place, undermining organ function, ultimately threatening life.
In those early days with the technologies that were present, even with the bias to studying cancers out of human beings, which was really present in this cancer center from the get-go, it took forever, if you will, to find each individual gene that was affected at some frequency in any individual cancer.
To find that gene amidst 3 billion base pairs in the genome, to go find the address of the gene, and the gene itself, one of 19 to 20 some-odd-thousand genes, to say “This gene is the one that’s defective in this cancer.”
Each individual gene, when that was discovered, those were worth several papers, lots of excitement. They were titanic discoveries. Now of course, we have technologies that can sequence all the DNA, all the genes in any cancer patient at any time in any biospecimen.
How is the world going to change with this technological approach? What do you see going forward in the next 50 years? We’re not going to be discovering gene by gene by gene anymore because that’s largely done. What are we going to do with these powerful sequencing technologies?
AW: One of the things that is happening now and will continue to expand is the way that these genes relate to each other in real time, like through spatial transcriptomics, between both the sequencing and the imaging capabilities that we have now, and that we’ll continue to expand over time.
We’re going to understand more and more not just what genes are responsible for driving what cancer or what disease, but how they interact with other genes ,and not just within the tumor and not just within the heterogeneity of the tumor, but also how those genes work with other genes in the microenvironment of the tumor. I have a huge bias towards that.
BN: One of the things that you’re arguing—and I think you’re right, that’s going to continue to evolve fairly systematically, is the recognition, which was clear within the last 50 years, that the intrinsic properties of the cancer cell, the defective genes that caused it to behave abnormally were not the only conspirators present in the cancer that ultimately threatened their life.
That these rogue cancer cells had co-opted other cells, many other types of cells, to their nefarious purposes and were exploiting some of their properties to do some of their dirty work.
Back 50 years ago with John Isaacs, John collected a number of experimental data, very similar to what Isaiah Fidler had done, where he took model cancer cells from a rat, and these were cancers that spontaneously arose in a rat and ultimately threatened the rat’s life, could be transplanted and whatnot.
There wasn’t an immune barrier because the rats were all genetically identical, but he was able to find and study cancers that systematically, no matter where he stuck them, would metastasize to one place versus another place.
Obviously, that’s not an intrinsic property of the cancer, they were all clonal originally, but that was a property they had acquired, the way they interacted with the environment around them.
What you’re saying is now that we can tease apart who exactly is in that environment, and ultimately what might they be up to, that understanding of the complexity of that environment, perhaps even generating targets for us, the early ones were angiogenesis or something. You think that that’s got to be a fruitful area to study and perhaps provide new therapeutic targets?
AW: I exactly think that. But in addition to that, I also think that temporal changes in those relationships are going to be important as well. You take something like tumor dormancy, where you have a tumor cell that metastasizes from the primary site very, very early, and you may not really find mechanisms to stop that initial step from happening.
But it goes to the lung, or the liver, and it just sits there for years and years existing in an environment where you could potentially, with these technologies, see what genes are expressed, how they’re interacting, but then something changes over time and those cells come out of this tumor dormancy. They start to grow. They form avert metastases.
It’s not just the immediate relationships of the transcriptional changes between the tumor cells and their environment, but also the temporal and spatial relationships between them. Not just what organ are they in, but where do they sit in that organ.
We know with brain metastases and melanoma, you get them on the leptomeninges, as opposed to other sites like other tumors. It’s really fascinating, and I think understanding all of those types of relationships are going to be so critical to finding targets and overcoming metastasis.
BN: That whole notion of metastasis, which has a very long and wondrous history, how it works, has evolved substantially, too as a result of some of these new technologies. You’re pointing out the distinction of what some people are calling disseminated cancer versus metastatic cancer, in other words, the ability to found, at a distance site from where the cancer rose, found something that can grow and destroy the nearby environment and compromise organ function.
What we’ve learned because of this exquisite sensitivity of many of the new measurements we’re making is that dissemination is actually quite common, if not nearly ubiquitous.
I actually begin to wonder myself—if the cancer can invade through the basement membrane or wherever it’s at in terms of the ones on lining cells of the body. That’s the definition of a cancer histologic. If it can do that, it can get anywhere.
The issue then is, which by the way means dissemination may be more common than we ever thought, but fortunately, metastasis must be a reasonably inefficient process, although we have, as you mentioned, disseminated cancer cells that persist. They don’t grow, but they don’t die. They hang out.
Are there things that can happen in the future to activate, not even reactivate, to activate them and a counterproductive way? That’s a very novel thought, but the elements in the roots of those were back a number of years ago, weren’t they?
AW: Absolutely. You mentioned angiogenesis. That is one key way where these tumor cells who are just hanging out in an organ doing nothing and something changes and they’re able to generate their own blood supply from the nearby endothelial vessels.
That’s one major way in which cells come out of tumor dormancy changes in the immune system. I’m sure we’re going to get to discussing how important the immune microenvironment is in cancer biology. Changes in the immune system as you age or over time or even with therapy, can drive these different changes and proliferation capacities.
BN: Let’s talk about one aspect of it, because it’s something that you’ve thought up a fair amount, which is, 80% of all human cancers arise above the age of 60, 30% above the age of 80. Ssomething about the aging process is a contributor to cancer as it becomes to manifest and threatens life and health and happiness.
There’s an older argument that time is an event marker, that it’s an accumulation of exposures that damage things and whatnot. And the other, of course, is that there in the entire environment of the body for many different reasons, there are other things that aging changes like the microenvironment, something that you’ve been very specifically interested in. Tell us about that.
AW: A lot of our work has been in melanoma, although we now have new data in pancreatic cancer as well. And what we’re seeing is that there are changes specifically in two major cell types. Not to say that there aren’t changes in others, but in fibroblasts and immune cells, what we see is that those fibroblasts as they age, some of them become senescent, although the phenotype is not always completely dependent on senescence, but what we see is that as they age, they become senescent.
They secrete different growth factors that can affect the way tumor cells grow, the way they metastasize, they can affect the nearby endothelial cells, cause them to come in and form new blood vessels in the tumors.
It’s very fascinating because we had a study where we showed that there was an increase in angiogenesis, in tumors in older patients, but it was not dependent on VEGF. It was dependent on a completely different growth factor that is only secreted by aged fibroblasts and not by young fibroblasts.
There are all of these changes that happen during aging, secreted changes, changes in the biophysical matrix, and epigenetic changes as well, that can drive tumors to be more aggressive and more resistant to therapy.
BN: One thing to think about is you, in addition to being the research director for the comprehensive cancer center, you are a department director in the Bloomberg School of Public Health.
As the cancer center started, it started, the university charged the creation of a single department in the School of Medicine to operate the cancer center. They created the Department of oncology and said, you need to operate this cancer center.
The first reach outs, if you will, outside of the School of Medicine, were really to the School of Public Health in the form of four different departments. Very early on there was a great interest in the biostatistics capability, particularly as a clinical trial design.
That grew substantially, building biostatistics efforts in both the School of Public Health and in the Department of Oncology School of Medicine, in a reasonably coordinated way, actually is a remarkable story.
The second was in epidemiology, where people look at associations that might be cause cancer and whatnot, and that began to grow. That one took off a little bit slowly. The expertise in that group tended to be a little more towards cardiovascular disease than towards cancer.
That’s changed over time, particularly with strong and effective people like Elizabeth Platz, as a good example, although Kathy Helzlsouer was really the original person who was driving this out of the Department of Epidemiology, she’s also a trained oncologist—that made the interactions a little bit more seamless. She could do both.
Then there was environmental health sciences, which was a little bit, of what things in the environment cause cancer or carcinogens, can we study how they work? And that gave an avenue toward cancer prevention. John Groopman, Thomas Kensler, James Yager, many folks like that.
And then in the department that you direct, thinking back to things that even I did when I was younger with Paul T’so, we built a technology to go find cells circulating.
Oddly enough, it’s long since expired in terms of its timing, but we had a patent in that area. That’s one of my most cited works.
BN: One of the things that we discovered at the time that we were just talking about that was complicated for the world of cancer research to put its mind around, is that we were finding disseminated cancer cells very, very often
That shouldn’t be the case, but that’s what we found. And it turns out, of course to be true, like most data. So, now of course, the cancer center that you get to serve as the research director for encompasses five schools in addition there’s the 9School of Medicine, school of Public Health, there’s the School of Nursing, the School of Engineering, and the Krieger School of Arts and Sciences—35 departments, and an ever increasing value and effectiveness of bringing people together as teams. How is that going to work as we go forward?
AW: This is an area that is very, very rich right now—and actually on all of our radars right now because the president announced this new incentive to build this life sciences neighborhood in East Baltimore.
And the whole idea behind that is to bring people together in what we’re calling neighborhoods, so that you’re bringing people together from all these different schools, all these different disciplines, to work together to create a really multidimensional sort of soup to nuts approach to studying different aspects of biology in general.
And for us at the cancer center, I think we’ve been very proactive in encouraging people to put in collaborative grants and to work together. I mean, we have a grant that’s in submission right now that involves people from the school of engineering, public health, cancer center. So I think that this sort of collaborative approach is absolutely critical.
And when I came in here, one of my missives was you really need to build stronger bridges between your department and the cancer center, as well as the School of Medicine. So that’s been a ton of fun. You mentioned things like epidemiology. One of the areas of future research that is really taking off for us here at Hopkins, as obviously as you know, is the health disparities of cancer.
For example, we recently hired someone whose work is right at the face of public health and molecular biology. Her name is Brittany Jenkins-Lord. She’s a new assistant professor who studies the cancer health disparities of breast cancer, but from a molecular and genetic level.
And so I think that bringing all of these different disciplines together is a way for us to really get to the nuts and bolts of this disease and how to treat it and how in some cases, hopefully to prevent it.
BN: The other thing that you can clearly see shaping up in the future that’s very distinct from the state of affairs and the origins of the cancer center and some of its early successes is that the biomedical sciences at the time, particularly laboratory research, tended to be conducted in laboratories that would import techniques and technologies that they would apply systematically to research questions to try and generate answers to story and better insights.
Now, with the instrumentation and technologies that are present, measurement science is at a premium. Our ability to measure things has never been greater. And of course, we’re generating data for which the analytic aspects of it have become increasingly complex. And so in general, what we’re finding is that in these team science efforts, is that it’s not just that you bring people together around a problem, it’s bringing markedly different skills, expertise, and technologies together.
There don’t seem to be individual laboratories that can readily import everything they need to ask the most impactful questions, even now, much less as people think about it moving forward. And so how do you think we’re going to get our mind around that? I think we’re only in the beginning of constructing teams. We tend to construct teams out of affinity. Everyone who’s interested in the microbiome says, “We’ll work together.”
Really, what we need is somebody interested in microbiome, is interested in color vision, and is interested in something else, coming together. How are we going to do that?
AW: That is going to have to be something that’s super proactive, right? Bringing people to together in joint meetings and symposia that present completely different things for us.
We don’t do any engineering, but when we see what the capabilities of the bioengineers here are to make different sort of artificial scenarios of stiffness of the skin and that sort of thing, we can really capitalize on that.
For them, our work gives them a translational aspect to those really cool technological things that they are doing. And then you look at technologies like cryo-EM, and the capabilities of that for structural biology like we do in my department.
I think that exposing people, I had never heard of cryo-EM, but one of my faculties, Scott Bailey, was doing some work. I heard one of his students presenting on it, and I thought, wow, that’s so fascinating. What can we do with that?
Just being exposed to that, which I think is really one of the strengths of our cancer center and of Hopkins in general, is this wide variety of people and tool builders and toolmakers who are all within a close proximity to each other. Just being able to expose people to even understanding what the capabilities of those technologies are, I think is so important.
BN: We’ve been chatting with Ashi Weeraratna, the research director for the Kimmel Cancer Center, talking about how the cancer center grew up as a research engine over the last 50 years and where it seems to be headed—the trajectory it’s on for the next 50 or beyond, if we even need it. Hopefully we’ll cure cancer sooner than that. And with that, thank you all for joining us today.