Thomas O’Halloran and Jonathan Licht work together at the Northwestern Physical Sciences and Oncology Center. Tom is the Principle Investigator and his background is physical chemistry and molecular biology. Jonathan is the the Senior Scientific Investigator and also the Chief of Hematology and Oncology at Northwestern University, specializing in the molecular biology of disregulated gene expression in cancer. They’ve also been long-time collaborators at the Robert H Lurie Comprehensive Cancer Center.
Jon begins by describing his experience with the PS-OC.
Jonathan Licht: Well, it’s been certainly eye opening. Certain types of theoretical mathematical modeling, evolutionary perspectives, have certainly been new to me, and have gotten me out of my own little environment, which is fairly reductionistic. Some of the math has been a little challenging, but it’s been stimulating. What I’ve been trying to get out of these things is, new frameworks to actually design specific experiments. And there is a lot of high concepts and I haven’t always been able to translate them into experiments, but I’m still hoping.
FUTURE CLINICAL IMPLICATIONS
Pauline Davies: What about your clinical practice? Has that changed at all?
Jonathan Licht: Not yet. I think that from a physical science perspective the biggest change has been the application of technology towards detection of specific gene mutations that affect the types of cancer we see and the drugs we’ll use and not use. In terms of things such as the microenvironment, the stiffness of the microenvironment, which we can’t measure in patients, there are a lot of concepts here that are laboratory phenomena that we haven’t yet translated, but we are all thinking of how to do that.
Pauline Davies: Thomas how about you, how has the clinical perspective influenced you?
Thomas O’Halloran: So, I coordinate a lot of different research groups, that work across the biomedical engineering, molecular biology, cell biology and chemistry; very fundamental basic scientific groups. These groups are constantly pushing the edge in detection limits and the ability to measure very small perturbations in biological molecules that affect their structure and function. So what’s intriguing is that these groups of people keep pushing the envelope of our physical understanding of how a cell works, but they don’t really have a concept, or a grasp, of the challenges that the oncologists, the physicians, face as they treat patients; this is a much more complex world. So the PS-OC is an opportunity to bring these teams together, to learn each other’s languages, learn the challenges, learn how to apply breakthroughs in emerging physical methods to understanding clinical disease, early diagnosis. And one of the things that has come out of the Northwestern PS-OC is really a new physical method for probing for perturbations in cells in the body before really there's any sign of the cancer; in the site origins for instance, in colon cancer, these can be probed now by what's called ‘the field effect’ by some of the engineers and physicists in the group. And this is just one example of how pulling physics, chemistry, basic scientists and teaching them cancer problems and challenges the way in which Dr. Licht’s group does for the physical scientists, provides a common ground for understanding development of new clinical applications.
NEW DIAGNOSIS BREAKTHROUGHS
Pauline Davies: Right, so you introduced an idea there - measuring new types of perturbations. What sort of things you looking for?
Thomas O’Halloran: So this is looking for changes in the order of, and interaction of the different compartments within a cell. So these are organized at the nanometer scale; so when you use different types of radiation to interrogate the cell, you can find out if there is some more disorder than in a typical normal cell. When that extra disorder shows up in terms of the way light is scattered in the solid, the nanometers level, that's turned out to have a high prognostic value in saying that there's cancer that's in this patient's body. And that actually, that physical method, has now gone through clinical trials. So it's moved from concept, through physical methodologies up into the clinic now and we're very excited to see how that's going to advance and perhaps help us really discover colon cancer, lung cancer, in a variety of other types of cancers much earlier than we ever had the chance before.
INTERESTING IDEAS PRESENTED IN THE MEETING
Pauline Davies: Well, it sounds very useful. What have you thought of this meeting so far Jonathan?
Jonathan Licht: Well it’s been very of provocative, I've enjoyed the discussion about the idea that cancer genetic mutations might unleash some primitive preprogrammed state that might be akin to an early metazoan organism. I think that's a very interesting idea, it’s a very interesting simile, if you would like, or an analogy. However I have to think about how to take that idea and turn it into a set of experiments that will be testable to prove that the cancer cell is something like these types of organisms. Is there some lower phylum of organism that we can actually study is a new kind of model system? We learned about a very primitive sponge from the Great Barrier Reef and I was looking at its genome sequence to look for conservation of some of the genes we study, but I’m not sure how to quite study that model organism. I read it doesn't reproduce well in the laboratory. If were going to take some of these the ideas from the evolution development point of view, we need to think about reducing it to practice and so that's what I've been thinking about the past day.
COMMERCIAL DECISIONS – A BARRIER TO TREATMENT DEVELOPMENT
Pauline Davies: And what about the last session that we just heard about: this treatment of cancer by the metronomic therapy - giving low doses of chemotherapy over an extended period of time - do you think this has significance for your practice, perhaps?
Jonathan Licht: Well, I think it remains something that has to be tested in clinical trials. I actually just corresponded with our Director of Developmental Therapeutics, and from his point of view, his short answer is very interesting; “Hard to get support for those types of trials.” It's not really particularly a commercial interest for tiny doses - or some firms would prefer a big dose and use it weekly but maybe not daily. There are challenges to mounting those clinical trials in that they require a lot of doses, a lot of monitoring, a lot of logistics. Just looking briefly at some of the literature today, there has been some comprehensive reviews in the literature saying that when it’s done is with known drugs, its safe. There have been studies here and there saying it may be more effective, so I think the jury is still out on it. I would not do such a thing off of a study. There are certain practices that we've done, for example, I've treated in the past, patients with breast cancer with low doses of a chemotherapeutic agent weekly, in part because the toxicity of a high dose given monthly is a lot stronger and I've been able to squeak out a lot of response from such patients by this. So in a way, maybe I’ve done metronomic therapy in the past. I do think that the idea that there is still stochastic variation in the inherent drug sensitivity or resistance of cells makes a lot of sense to me. We do know that there's a lot of noise or biological variation in any phenotype, and I think these theoretical models therefore have applicability. So, what I would try to do with this would be to try to think about opportunities in illnesses in our practice that might be amenable for clinical trials comparing a standard dose to a metronomic dose.
VALUE OF INVESTMENT IN CANCER GENOMICS
Pauline Davies: What did you talk about in your own session?
Jonathan Licht: I followed up on a long set of email exchanges to somehow highlight one part of the dialectic. There are some in this meeting who were quite disappointed in the large investment we’ve had in cancer genomics, but I do think that this investment is wise at this time. I do think that we need to completely categorize and understand the sets mutations that are characteristic of different tumors. And we can just say we've done that, we know what that is. Whether or not those mutations alone will just explain phenotypes is yet still unknown. There may be stochastic variation due to epigenetic mechanisms, just fluctuation biochemical states, but all that has to be analyzed in the context of what mutation really could be a bad actor that could be driving the cell to new states. I was saying that if you deeply sequence many cancer specimens and you categorize mutations, you also find networks of mutations suggesting types of pathways that might be important for cancer. By finding genes that are mutated together you can suggest that if you mutate this pathway “A” and pathway “B” this may cause a tumor. If you find sets of genes that are never mutated in the same tumor, those genes may be working in the same network and be redundant. And in fact this type of analysis is led to the understanding of new pathways and, I think, will continue to do so for the next 3 to 5 years.
MATHEMATICS BRINGS POWERFUL NEW INSIGHTS
Pauline Davies: And you Thomas, what have you gained the most from this meeting?
Thomas O’Halloran: I think it's really critical to bring these mathematical models together as we understand the fundamental way the biological switches work, and we understand the way information is decoded, not just from the genome but from the epigenome, from the stress-induced perturbation of balances of proteins and factors in the cell. All these are massive data sets and genomics happens to be the easiest and most routine way that we can get large amounts of information. It's the first tranche, so we can say, that next is can be the epigenome and the next is going to be the proteome. The question is do we have the tools to go in and understand how these fundamental biological switching events work? Once we do, can we model them using mathematical methodologies, new constructs, new approaches to connecting very complex phenomena that can't be defined by just a straightforward set of simple equations, when I can have more complex interactions? Can we then put those together to build or predict phenotypes? One of the most interesting things that I heard this morning, was that in a two-state attractor system there could also be an emergence of a third state, a rebellious group of cells, that then go off on a different trajectory. If that can be defined for some of the classic types of aggressive cancers, their responses to drug “A” and then be able to find ways to hit with drug “B” this rebellious group and channel the cells down one path desired, either the differentiation path or to cell death, then I think we have some really novel ways and novel insights of how to use combination chemotherapy across different cancers. I think those are the types of things that are going to emerge as the low hanging fruit from this first round of the PS-OC. We've really just begun to be able to communicate across many scientific languages and we’re really looking forward to the next several years as we make our advances.
Pauline Davies: Is that how you feel too?
Jonathan Licht: Very much so. I think that these models can be very powerful, but you can't let a little data get in the way of the good model, or can you get a little model in the way of good data! (laugh) Well anyway, we can’t worship at these models. We have to understand that they are based upon assumptions and they offer a framework for testing, and doing empirical experiments. I'm very much the experimentalist; I'm looking for clever new insights, I'm trying to glean that from some of my very smart colleagues at this meeting.
POWER OF THE PS-OC CONCEPT
Thomas O’Halloran: I have one final comment on the PS-OC, and the sociology of science. I've watched now, through this workshop, some very vigorous debate; one could say confrontational challenges to ideas both to way things are modeled whether they are oversimplified, whether there are semantic differences etc. What's remarkable is this is a crowd where there can be great scientific challenges without ego battles and this is perhaps in part because we come from such a radically different areas but it means we are starting to make progress in understanding how each of the different components can contribute to a better picture of cancer, its evolution, it's early diagnosis, and its treatment. I think this is exactly the kind of stimulus that you need. We all work in our own communities we referee each other's papers a review each other's grants, and train each others students in our small silos, or sometimes bigger silos, but what the PS-OC is about is bringing together a variety of different silos breaking down those barriers and having real fruitful progress at the interfaces, which is where all of the world real problems exist.
Pauline Davies: So again, thank you Thomas O’Halloran and Jonathan Licht.