Joseph Francis Costello received his Ph.D. at Loyola University in Chicago, Illinois where he and his mentor, Dr. Russell Pieper discovered aberrant DNA methylation of the MGMT promoter in glioblastomas, which has since become the most widely used molecular marker to predict patient response to chemotherapy. In 1995, he became a postdoctoral fellow at the Ludwig Institute for Cancer Research at UCSD, in Dr. Webster Cavenee’s laboratory. As a postdoc, he was supported by grants from Loyola University Neurosurgeon Howard Reichman, and by an AACR fellowship in basic research. In 2000, he became an Assistant Professor at the University of California San Francisco where his laboratory investigates the roles of epigenetic mechanisms in cancer initiation and progression, and also develops new methods for global epigenetic analyses. In 2005, he was appointed to the Karen Osney Brownstein Endowed Chair in Neuro-oncology, and promoted to Associate Professor.
EpiGenie Insight
Despite walking the halls of the Cancer Center at UCSF frequently for several years, I never made it into Dr. Costello’s office. I managed to catch up with him during a recent visit to San Francisco for a conference to see if he had a few minutes to go on the mic with EpiGenie. After sharing that I too grew up in Chicago, Dr. Costello acknowledged that “I must be trustworthy” and agreed. Even though he’s a devout White Sox fan we decided to run the interview anyway because nobody’s perfect!
Joe Costello Interview
EpiGenie: How did you make it out to Mt. Zion (UCSF)? ??
Costello: Well, it was – in my PhD program in neuroscience at Loyola University, and I grew up out there (Chicago), too, so I’m really attached to the area, and thought I might stay. But during the course of my PhD, I met a neurosurgeon that was interested in the work I was doing and talked to my advisor and a few other people, and offered me a lab there, when I finished my PhD. My first reaction was excitement, because I wanted to stay in Chicago. But then I was too immature for it. I knew that starting a lab then without a post-doc was a recipe for failure. I just wasn’t ready for it. So it was a very nice offer, and he said, “Well, all right. If we can’t get you to stay now, how about as incentive for you to come back, we’ll pay for your post-doc?” So it was really nice. It was salary, and I could apply to a lot of places that I hadn’t considered before, because they were pretty high level, and I wasn’t sure I was ready for them. But when you say you have your own salary, pretty much anybody will take you….. almost. So it just opened up a lot of doors. And so then I thought, all right, I’m going to stay in the neurosciences, but more the brain tumor area, because that will ensure that I have this job back in Chicago, where I actually want to be, with my family and friends. And so I got a really great post-doc because of that, in Web Cavenee’s lab in San Diego. I had a couple of different options, but that was – just seemed to be the perfect one, with a world-renowned cancer geneticist. And that seemed like a great learning environment. It was a much bigger lab than I had been in in my PhD.
EpiGenie: I bet it was tough for you to adjust to the weather.
Costello: Yeah. Yeah. Really rough.?? Rough winters there. No. It was fantastic. Yeah. You just cannot beat the weather in San Diego. Time passes so fast there to me because of the lack of change of seasons. Every memory I have, I’m in shorts, and it’s Christmas, and it doesn’t make sense.
EpiGenie: So what do you miss most about Chicago???
Costello: Oh, the people, for sure, and then all of the food, and the architecture. Chicago has just fantastic architecture. I grew up around a lot of Frank Lloyd Wright homes. I had a job painting during my summers in college. So I painted some of those houses, and really gained an appreciation for architecture.??
EpiGenie: I read a recent blog posting from you on Nature’s Journal Club where you discussed the early opportunity you had to work in epigenetics in a cancer molecular genetics lab.??You had drawn a comparison that working in epigenetics at that stage was “akin to being a Republican mayoral candidate in San Francisco.”?? How has it changed? I know there’s been a tremendous surge in interest in the epigenetics arena over the years. How have you seen it change since it wasn’t a buzzing area of research???
Costello: It’s just been fascinating to watch. Ten years before I was even in the field, a lot of researchers were studying epigenetics just kind of in the background and being noticed but nothing like how it’s been the past couple of years. It’s just been – it’s fantastic to see – to have seen how many of the – the scientists, personalities, especially the leaders in the field in the cancer side of things, like Peter Jones and Steve Baylin, Andy Feinberg, how their personalities have kind of helped shape the field, but also given it a lot of wider interest, a lot more exposure, to the scientific community, but then even coming out to the lay press.
EpiGenie: It’s great to have spokespeople for the field like the gentleman you mentioned.?? Do you think it’s pretty critical in terms of gaining traction and generating interest and research funding, to reach out to the public?
Costello: I guess I don’t understand the exact connections between those things, the public perception, public excitement about it, and how that really translates to funding, or if it does.
EpiGenie: I don’t either. I was hoping you did. (Laughter)
Costello: Yeah. I wish I did. But you know, NIH has just put in approximately $190 million into epigenetics research. They have felt that their cancer epigenetics portfolio was not bad, but that everything else, epigenetics in diabetes or brain health, drug exposures, alcoholism, anything like that, was really underfunded. ??And where did the excitement and where did the – where did the main stimulation come from? I worked with Peter Jones and others on this committee the past couple of years that partly was sponsored by the AACR, partly by NCI, to try to drum up more support for this.??But even before that, I think Andy Feinberg had started meeting with NCI and NIH. And so at least – those are the things I can identify that helped Peter Jones’ committees, and Andy Feinberg’s, and then eventually they joined. Those are mostly cancer-related researchers. But there was still a lot of activity going on outside of those meetings in other branches of NIH that were parallel in trying to build excitement about epigenetics.??And so at least – and that’s my understanding so far, that those kind of efforts really helped to bring the interest, NIH, and more funding.
EpiGenie: I know that your lab has used restriction landmark genomic scanning historically. What were the primary drivers for using that technique versus the multitude of other combinations of methylation sample prep methods that were available?
Costello: I started using that in I guess about 1995, when I was a post-doc with Web Cavenee in San Diego. His lab was very cancer genetics oriented, and having a little bit of knowledge in epigenetics, I had some ideas that I wanted to pursue, and he was open to it. So I had read in the literature a paper by Yoshihide Hayashizaki. So 1991, they published the RLGS method. And at that time, even in ’95, there were no methylation arrays. There was no good way to look at more than one or two genes at a time, at the methylation status. This was a great method. You could look at a thousand genes at a time. ???It was quantitative. You could look at single genes or a thousand genes. And I have to tell you; it was just the only thing available. So a tough technique to learn, but luckily, there was one other lab in the US, Verne Chapman, who had brought this technique over from Japan into Roswell Park. There was a post-doc there, Christoph Plass, who is now a very prominent epigenetics researcher, who just moved to – back to Germany. So that’s kind of how and why we started, I guess.??
EpiGenie: You can incorporate information about copy number as well as methylation state, right???
Costello: Right. Right.??
EpiGenie: I know in some of your papers, you highlight the importance of integrating genetic variation as well as epigenetic information like methylation data. Does the Costello Lab, have plans to use some of the next generation sequencing technologies to tie it together????
Costello: You know you can’t not try the next generation sequencer.?? There are a couple of publications out now. Steve Jacobsen’s group at UCLA. That’s a nice paper in Nature that published in the past month or two, doing shotgun bisulfite sequencing with the Solexa/Illumina platform. So yes. We’re definitely trying different variations of that. ??Yeah. I think there’s a lot to be explored there.
EpiGenie: We’ve heard a lot about the challenges related to the upstream sample prep for some of these methods. What sort of challenges do you see in terms of really harnessing the value of deep sequencing?
Costello: I think just theoretically, there are a lot of issues. Complexity reduction, and then trying – if you’re doing a shotgun approach, trying to map back fragments to a genome, especially if you’re using something like the Illumina/Solexa, where you have 35 base pair or nucleotide sequence, and only three nucleotides, instead of four, mapping back is a tough problem.?? Steve Jacobsen’s lab used that approach, and we can look at their paper and see just how efficient it is, or inefficient. But it’s possible.??And they did a good job of that. I would say an incredible job of it. But they were dealing with the Arabidopsis genome, which is many times smaller and less complex. ??Mapping back still was a problem there, but that is going to be amplified in the human or mouse. But I’m sure different groups will try it. Lander’s group published a paper called “Reduced Representation Bisulfite Sequencing.” So then, they were not using the next generation sequencing. That was Alex Meissner’s work from 2005 or ’06 or so??.
EpiGenie: It’ll be interesting to see how that plays out.??
Costello: Very interesting. I agree.
EpiGenie: Can you share any hypotheses related to the role of DNA methylation and the other epigenetic mechanisms, or the genetic, within the architecture of cancer???
Costello: I would say just the facts that are out there that might lead to a new hypothesis are really interesting. I think there are experimental models that show that an initial genetic defect – and it’s been known for a long time, that that can lead to cancers. ??But the interesting thing from the epigenetics side is that even in the absence of a genetic alteration starting the cancer – that’s how many cancer researchers view cancers; just they start with a genetic mutation. ??But the Jaenisch lab has shown that epigenetic defects as the initiating event can start the formation of many different kinds of solid tumors and leukemias and lymphomas. So that I think changes the perception, at least from how we understand mouse models, and what they mean about real human cancers. But it’s saying that epigenetics can be the initiating event. ?
It’s so important, because so much – again, so much of the understanding of cancer outside of epigenetics has been very genetic oriented, and that’s – perhaps even all of epigenetics is a consequence of the genetic alteration, as opposed to the reverse or the interplay. ??So there are maybe three to five percent of all human cancers which are truly hereditary, and they’re caused by genetic mutations. And then there’s the other 95 to 97 percent of all human cancer that’s sporadic, that we don’t know the actual initiating events, in a lot of cases. In some cases, there are environmental insults that are so strong that we know – smoking, for example, that’s probably causing the cancers. Right? ??But then is that causing it through – initially through an epigenetic insult, or genetic, or both? Again, I’m coming back to that integrated approach, and that it really is both driving the process.
EpiGenie: I know that you happen to have some of the major thought leaders in the world in looking at genomic variation here with array CGH, and you’ve been interested in DNA methylation. You have actually called out the importance of looking at these mechanisms in concert.??What do you think it’s going to take before start seeing more widespread collaborations that integrate these types of data?
Costello: Well, partly, it’s what any small lab can do. Right? You can’t do too many methods and be an expert, so then you have to reach out to – like we did here. I mean, we really were just more focused on epigenetics, but I’m surrounded by the – some of the best cancer genetics researchers and methods in the entire country.?? Some of the methods are developed right here in the Cancer Center.??So it just seemed natural to reach out to and to try to collaborate with those groups. And so in one part, I think it’s just the spirit of collaboration. And also, the sense that – that by taking a very narrow track you often miss out, but then again, by taking the most wide track, you can’t really do anything conclusive. ??I’d say there’s a really good example of the NCI trying to stimulate – that’s putting $100 million into it, which is the TCGA project, The Cancer Genome Atlas. ??
I think many people attribute that whole project to Eric Lander, in the sense that he went around the country drumming up support for it, and convinced NIH, NCI, to fund this. And that’s labs all around the country studying-the first phase. They’re studying brain cancer, actually. So our department is very involved in that.?? But they’re using genetic and epigenetic methods, and they’re integrating data, and the integration is going to be really a big, important thing. Just huge amounts of data. And David Haussler, who along with his then-student Jim Kent, put together the Human Genome, and made a public face of that, is helping do the informatic side.
So there’s a great example of people getting out of their silos. And I think that’s certainly NIH’s theme, of team science.
Costello portrait courtesy of Mercedes McAndrew