Chapter 06 :Cytokines and Cancer-Related Research at the University of Pittsburg (late Eighties)
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Description
In this chapter, Dr. Tweardy traces the evolution of his work from the early stage of purifying and cloning cytokines (see Chapter 05) through the discovery of the relationship between STATG and STAT3. He begins by noting his interest in participating in the groundbreaking work on cytokines because of the further discoveries it promised. He talks about his move from the Wistar Institute to the University of Pittsburg, occasioned because of his wife’s career (Ruth Falik, MD; married 21 January 1982), then discusses his work with a library of bacterial RNA to discover mechanisms for producing cytokines, shifting to studies of neutrophils.
Dr. Tweardy then explains that his work at the new cancer institute at the University of Pittsburg enabled him to shift his focus to cancer and leukemia. He explains leukemia creates abnormalities in GCFS [granulocyte colony-stimulating factor?] its molecular signaling. He explains how he collaborated with an ENT surgeon to discover mechanisms of the role STAT3 serves in squamous cell proliferation and later work on how to block its function. He discusses how this work contributed to differentiating the roles of STAT3 and STATG.
Identifier
TweardyDJ_02_20190320_C06
Publication Date
3-20-2019
City
Houston, Texas
Interview Session
David J. Tweardy, MD, Oral History Interview, March 20, 2019
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Overview; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; Personal Background; Discovery and Success; Inspirations to Practice Science/Medicine; Influences from People and Life Experiences; Technology and R&D
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey. A. Rosolowski, PhD:
All right, our counter is moving. It is about 13 minutes after 2:00 on the 20th of March, 2019, and I am in the office of Dr. David Tweardy, and this is our second session together.
Tacey. A. Rosolowski, PhD:
And we were strategizing a little bit, or reminding ourselves where we were when we left off last time, and you were working with Jerry Ellner during your fellowship at Case Western. And you were talking about how the impact of the results that you had gotten working with macrophage-activating factor, and where that led you next, though I’d also like you, if you will—I mean, your story of that research study at the end of last session was really dramatic and exciting, but were there other takeaways from that period, working with Jerry Ellner? So I want to get kind of the full picture of what you had in your toolbox when you moved on to the next challenge.
David Tweardy, MD:
Right. So I think the toolbox I had at that point included a great respect and excitement about cytokines, particularly ones that were recombinant, cloned, and purified. One of the major breakthroughs in cytokinology was the ability to purify and sequence a small amount of the cytokine, and then from the sequence of the amino acids actually obtain the cDNA sequence, what’s called the cDNA clone of that cytokine; and then take that gene, essentially, and put it into bacteria, and the bacteria would just make gobs of it. And so experiments might take years to do, because you had to keep purifying these dilute cytokines, or cytokines present in dilute solution, before you could do the next experiment. Now, you just—you went to the cytokine store (laughter), Genentech, in this case—and bought—they gave you the cytokine, or you bought it, and you could just do endless numbers of experiments. So it was a major breakthrough in molecular biology, and I was actually wanting to participate in that molecular biologic breakthrough. And it turns out macrophage-activating factor or interferon gamma, also, as it’s known, was cloned in this way I mentioned early on in the game of cytokines. This is one of the second or third cytokine that was molecularly cloned in this fashion. So I said, I want to clone a cytokine so I could then do these fantastic experiments, and discover new things about the cytokines that were heretofore unable to be really discovered. So that was—I ended—actually, this is where my wife now factors in, because she was interested in continuing her medical training. She matched to the University of Pennsylvania Cardiology Program. So I wanted to be together with her, and so we then searched for—well, I had to, really, in this case, search for a position in Philadelphia.
Tacey. A. Rosolowski, PhD:
Let me just ask you, because I don’t know if I did the last time: your wife’s name?
David Tweardy, MD:
Ruth Falik, F-A-L-I-K.
Tacey. A. Rosolowski, PhD:
Okay, and when did you guys get married?
David Tweardy, MD:
We got married in 1982, January the 21st.
Tacey. A. Rosolowski, PhD:
Why are you smiling? (laughter)
David Tweardy, MD:
Because I always think it’s in ’81, but I always have to realize there’s a two, not a one, at the end of that. And I—
Tacey. A. Rosolowski, PhD:
You’ve gotten corrected about that at the dinner table? (laughs)
David Tweardy, MD:
Yes. Well, not much lately. It’s deeply embedded, and I have it engraved on my ring. That’s why I always fidget with my—should I look? No, I think I can remember. Anyway.
Tacey. A. Rosolowski, PhD:
It’s like forgetting your kids’ names and their birthdays, yeah, yeah, yeah.
David Tweardy, MD:
Yeah, that’s different. I get forgiven much more easily for that. The names, no. Birthdates for them, yes. Our anniversary, never. I—
Tacey. A. Rosolowski, PhD:
Isn’t it funny how the brain retains certain details easily and not others? Yes. (laughs)
David Tweardy, MD:
Yes, perhaps out of requirement, insistence or whatever. But, yeah, in fact, we—
Tacey. A. Rosolowski, PhD:
Okay, so you guys are in Philly.
David Tweardy, MD:
We’re—well, we were in Cleveland, because we were an intern romance that ended up favorably, (laughter) positively, and—
Tacey. A. Rosolowski, PhD:
I’ve never heard that phrase before, “an intern romance.”
David Tweardy, MD:
Yeah. Oh, these are high—these have high failure rates. Intern romances generally don’t work out, but it was really a very cool story. But at this point, because we were interns together, I stayed on to do my infectious disease fellowship, and actually she had already gone to Philadelphia, and so we were apart for a year. And so when I got able to—I was free, so to speak, to get a new position—I looked for a position in Philadelphia, and with the specific, I mean, laser focus on I want to clone my own cytokine. I want to go to a lab where I can learn how to do this. And I was very fortunate to find the laboratory of Giovanni Rovera in the Wistar Institute. And I interviewed, actually, in the end—and, interestingly enough, the Wistar Institute was far and away at the leading edge of molecular biology, this ability to clone cytokines, anywhere in Philadelphia, in Giovanni Rovera’s lab, and Carlo Croce’s lab, who is a member of our Scientific Advisory Board, actually.
Tacey. A. Rosolowski, PhD:
I thought I recognized the name, yeah.
David Tweardy, MD:
Yeah. These labs really were developing the technology in their labs, and so I chose, actually, Johnny’s lab, even though there was another lab in the Wistar Institute that I could’ve joined, but I think it just was very fortunate I joined Johnny’s lab, because Johnny wanted to clone a cytokine that impacted white blood cell growth. And so that was completely simpatico with my desire, because I had already been working with white cells and I wanted to do a cytokine, clone a cytokine, so it was a perfect arrangement. And so, at first, as I mentioned to you, the first thing you have to do to clone a cytokine is you have to purify it to essentially homogeneity, which means the only thing in that tube of liquid is your protein. Then you put that on a sequencer to get the amino acid sequence, and then you convert that amino acid sequence to a genetic code. Those nucleic acids --there are three per amino acid that code for that amino acid, and then you make a chain of nucleic acids around 21 to 24 nucleic acids long. You make it really hot, and then you use that to probe a cDNA library, which is a library that has all the genes—or all the RNAs, I’m sorry—copied into DNA from a cell. Now, probably this is—I’m going to do this anyway, even though I’m (overlapping dialogue; inaudible)—
Tacey. A. Rosolowski, PhD:
I know you—I never—microbiology people and molecular biology people always do this. I sit very patiently and hang on to what I can. (laughter) So go for it.
David Tweardy, MD:
Okay. So the cell that I used—and I was successful to getting to near homogeneity, but not quite, because then I was—we were scooped. Our laboratory was scooped on the process of cloning this white blood cell growth factor called G-CSF by two companies. One was Amgen in California, and the other was Chugai in China—I’m sorry, in Japan. And so I didn’t go that purification route in sequencing. I looked to see what they had, the actual sequence of the gene, and I made a small fragment of that to then pull it out of—the right clone out of a library. And I won’t go into the details of that library, but that library essentially is a bacterial library that has all of the RNAs that a cell—in this case the cell we were starting to purify—all the RNAs that that cell makes. And so included in that million-colony library were several copies of the RNA that made the cytokine that I was interested in. And because—it’s kind of like fishing, but it’s fishing in a medium-sized tank, and what you use as bait is you use this very hot probe that you know is homologous. In fact, it’s the same sequence as the fish you’re trying to pull out. And because of --just the nature of DNA is if you have a copy that is floating, and it sits, it can find the gene you’re interested. And if it’s hot enough that colony of bacteria that’s making that gene will light up, and it will show, and you can pick that, and now you have the gene.
Tacey. A. Rosolowski, PhD:
Wow.
David Tweardy, MD:
It’s a very—yeah. Oh, I mean, I still have vivid memories of when I was sitting on the other side of the developer, and what you’re looking for, you have a plate. You made multiple filters, each having maybe a thousand bacteria on them, and you maybe did a hundred plates, so you have 100,000 colonies, and you collected—you put them all out, and you put the film on, and you put the film into the developer, and you’re waiting on the other side of the developer for a plate that has—or a circle, which represents the plate that has a black dot on it. And I still vividly remember seeing black dots on some of those films, and I got very excited because, indeed, I’d been able to clone the cDNA for G-CSF. Now, as I say, I was the third to do it, but we were able to then do some very nice experiments with that gene. We were able to find out where that gene mapped on the human chromosome, all the human chromosomes, and then we were able … And, actually, while we never were able to do massive numbers of experiments that the ability to have the clone would allow you to do, because by then Amgen was selling it—they beat us—I at least learned a very important technique of molecular biology, and then moved me into other techniques, such as gene mapping. In particular now, because of the important—in fact, we, by virtue of having that cytokine available, we were able to really demonstrate that it is, of all the hormones that affect hematopoietic growth and development, G-CSF was the most important for producing in the body white blood cells called—have many names, but it’s polymorphonuclear leukocytes, or PMNs, and these are the major infection-fighting cells. So that got me moved away from macrophages, which --monocyte macrophages-- which I think was the cell that I told you about when I was working with Jerry, to the neutrophil, or PMN. Then I moved from Wistar to Pittsburgh with my first grant, and I started really working on then how does that cytokine --now that it was cloned and available-- how does it, when it binds to a cell that has a potential to become a neutrophil, how does it signal the cell to become a neutrophil now? I became very wrapped up into that, and that’s how I got into the STAT3 field, because STAT3 was a critical signal that was activated inside the cell when G-CSF bound to the surface of the cell.
Tacey. A. Rosolowski, PhD:
So let me just say, to connect some date dots there, that you were at the Wistar Institute July ’84 to December ’86, and then began at the University of Pittsburgh—
David Tweardy, MD:
Right, my first ac—
Tacey. A. Rosolowski, PhD:
—in ’87.
David Tweardy, MD:
Yeah, that was my first academic appointment, right.
Tacey. A. Rosolowski, PhD:
First academic position, yeah, okay. So you established your own lab, had grant funding for that.
David Tweardy, MD:
And I established my own lab there. I had two grants. I was—
Tacey. A. Rosolowski, PhD:
Wow, okay.
David Tweardy, MD:
—ready to go. The Wistar Institute was a fantastic place for me. It was pretty concentrated, two and a half or so years, but I was able to achieve that incredibly critical—make that overcome that incredibly important barrier of funding. I mean, if you want to be a scientist, that’s good and great, but show me the money. Give me—
Tacey. A. Rosolowski, PhD:
Now, why did you select the—I’m sorry, yeah—University of Pittsburgh?
David Tweardy, MD:
Yeah, well, again—that’s a good question—it was, again, related to my wife. She had finished her fellowship; I had finished my work with Giovani Rovera, and we were both looking for jobs, and we both found positions at Pittsburgh. She found a position with the University of Pittsburgh at the VA there, the Oakland VA, which was part of the University of Pittsburgh’s teaching and clinical venue, and I found a job at the newly formed Pittsburgh Cancer Institute, yeah, which was very interested in the kind of work that I was interested in doing; that is, understanding growth factors and the signaling events that impact on white blood cell function.
Tacey. A. Rosolowski, PhD:
Well, that’s interesting from two perspectives. I mean, first of all, a great opportunity personally to have two career couples. (laughs) Yikes.
David Tweardy, MD:
Yes, always a difficult—and I’m very sympathetic for everybody who is in that situation now.
Tacey. A. Rosolowski, PhD:
Yeah, it’s very tough. And then good home for your research, but then also being part of a new institution—
David Tweardy, MD:
Yeah, yeah.
Tacey. A. Rosolowski, PhD:
—developing—offers often some really—opportunities.
David Tweardy, MD:
It did, and it kind of—my research clearly tended towards cancer, particularly leukemia, because the hypothesis that supported my first grants in—not the very first grants but my second wave of grants, while I was in Pittsburgh—were centered on the notion that a molecule like G-CSF, that drives a cell to differentiate to a terminally-differentiated cell that no longer proliferates, that leukemia, which is a disease which is marked by impaired differentiation and continued proliferation, maybe G-CSF signaling was screwed up in those cells. So that pathway of driving differentiation to terminal differentiation could be altered in leukemia, and may explain why leukemia cells are abnormal. So that drove the first five or so years of my research there.
Tacey. A. Rosolowski, PhD:
And what were some of the outcomes for that?
David Tweardy, MD:
Well, the major one that really is long-lasting was that G-CSF stimulates, or activates, a second messenger inside the cell that tells the cell—I initially thought it told the cell to differentiate, and that signal was called STAT3. And I was very excited. It turns out that—there were some biochemical and molecular biologic experiments that kind of under—and really drove me to get my first R1—that said, hey, if you don’t have a full-length G-CSF receptor, and you don’t fully activate STAT3, the cells can’t differentiate. And actually, we even—and there was actually a naturally-occurring, truncated form in the G-CSF receptor that doesn’t have the ability to activate two STAT3s. And so in that isoform, if you will, a G-CSF receptor was up-regulating leukemic cells, so we had the beginning of a pretty cool story. In the end, it turns out that story was only partially true, in that STAT3 was essential for the differentiation of the cells, but it didn’t drive its differentiation. What it did was maintained the cells viable so that other factors could mold its actual phenotype down towards a neutrophil. And actually, right at the time we discovered that, we discovered a nice little, very important story that complemented that finding in myeloid, or hematopoetic cells. And this was in a type of cell that causes—well, that is, in fact, head and neck squamous cell carcinoma. And in that tumor system, we definitely showed that STAT3 was critically important to keep those cells growing as well. So we abandoned the notion that STAT3 drove differentiation of myeloid cells, and went whole hog with the concept that STAT3 drives proliferation, and maintains survivorship, or survival of cells, and then flipped our thinking that we shouldn’t try to augment STAT3 to drive differentiation, but rather we should start targeting STAT3 to inhibit growth and to get cells to die. And that was a very—that was pivotal. And we did that—we came around that in ninet—
Tacey. A. Rosolowski, PhD:
Yeah. Talk about paradigm shift. (laughs)
David Tweardy, MD:
It was. It was, and it was because—this is really where it’s—I’m a very collaborative person, and in part just by nature, perhaps. Maybe—we talked about my large family, and how I like working with people, just because I think it reminds me of that good time I always had with my family, and my brothers and sisters. But I also realize that you never know where science is going to lead, so I actually brought—had somebody—actually, a very successful ENT surgeon—enter my lab very early on—I think it was the first year I was at the Pittsburgh Cancer Institute—saying she wanted to work on cancer of the head and neck. And so we went to the textbook—I’ve forgotten the name of it, classic textbook on oncology—and every chapter of a cancer system—breast cancer, lung cancer, prostate cancer. You start with the epidemiology, or the clinical disease, and then the next is pathogenesis, like how does the tumor develop, what’s our understanding at this point in time. Well, if you did that for head and neck cancer, that section was missing. Nobody really knew how head and neck cancer developed. There were very —I mean, we knew at that time that alcohol and tobacco use predisposed, but we didn’t know why, and what that did to the cells, normal cells lining the upper airway, how that made that one cell or two cells, whatever, become malignant. And so I had been working, still in the AML field—this is mid-1990s—thinking of the fact that growth factors, like G-CSF or GM-CSF, could actually be produced by the cancer cells to drive their own cancers, their own proliferation. And so I said to Jennifer Grandis—actually, her name was Rubin then—I said, “You know what? Look into how do squamous cells of the upper airway, how do they grow? What drives them to grow?” And so that began just a remarkable series of experiments, where we found out that TGF alpha and EGF are the major growth factors, in fact --I didn’t find this out; this was known already, and she dug it up out of the literature—are the major growth factors for cells of this origin. And so then she was able, with the help of a very great collaborator, Theresa Whiteside at Pittsburgh, to explore 16 to 20 human squamous cell carcinoma cell lines. And the first thing I think she demonstrated was that those cells produced TGF alpha, and they produced a lot of it. So the first part of this, autocrine loop, having a cell make a growth factor that allows it to grow, checked that box, right? So the next thing is, okay, does it have the receptor? And is it their normal amounts or lower amounts? Turns out blazing; they all made lots of it. And this is where, actually, we were really—I brought to Pittsburgh something that many of the surgeons, even, and others liked about me, which is I had modern, up-to-date molecular biologic expertise. So there weren’t actually abilities to measure these things like protein level; the only way you can measure them is at the RNA level, and I was a master of the technique of measuring RNA, which is called northern blotting. It’s an interesting story, why it’s called northern, but anyway. So we were able to really answer that question very rigorously. Then she and I started publishing on squamous cell carcinoma drives its own proliferation through this autocrine cycle. And the reason that was important is that we both—when STAT3 was identified by Jim Darnell in 1991, ’92, both EGFR, the receptor that was massively upregulated, activated STAT3. And so the next question we asked was, well, is STAT 3 there? And yes it is. And that’s when we knew—and when we targeted STAT3, it inhibited the growth, that we knew that, along with the data I told you about myeloid cells, we knew that STAT3 was a growth promoter. And so by virtue of having that project running in parallel to my core program, we’re able to connect dots and make that, as you say, paradigm switch, like (snaps) that. We said, a-ha! And we were actually the first to describe STAT3 as an oncoprotein in a human malignancy. That was the first description of it, first evidence of it. And then, like I said—and then the other very fortuitous thing that occurred in 1998 was a group in Europe had crystallized STAT3 bound to DNA. So this was the very beginning of the era of structure-based drug design, where people would take the crystal structure, figure out the critical part of it that was important for its function—like in kinases, the actual kinase domain, and how all kinases bind ATP, and ATP is then—that phosphate, the last phosphate on ATP is transferred to the target of the kinase. And so all of them have pretty much a similar structure, slightly different, but the way all the kinase inhibitors, like Gleevec and John Mendelsohn’s [oral history interview] targets in kinase that he developed, Imatinib, the way they were developed was having the crystal structure of the kinase, and knowing, at a molecular level—atomic level, actually—that little pocket that the ATP bound into. And the idea is if you could put a molecule that’s not ATP into that pocket, you could inhibit the enzyme.
Tacey. A. Rosolowski, PhD:
You block it, yep.
David Tweardy, MD:
Yeah. And so that was the beginning of that era of what’s called structure-based drug design. So once—
Tacey. A. Rosolowski, PhD:
I’m sorry, structured-based?
David Tweardy, MD:
Structure-based drug design.
Tacey. A. Rosolowski, PhD:
Oh, okay, yeah.
David Tweardy, MD:
Yeah. And so we—
Tacey. A. Rosolowski, PhD:
Where it helps to think like an electron. (laughs)
David Tweardy, MD:
Yes, as I told you. That’s right. I’ve always had the ability (inaudible).
Tacey. A. Rosolowski, PhD:
Yes. No, no, I see it, I see it. How else is it going to get glued into that little pocket, right?
David Tweardy, MD:
Exactly, and so it’s the lock-and-key mechanism. If you can develop the key that goes into that lock, it blocks the other real key from going. And so I was very keen, and I said, wow, gee, now we have the structure, can we block the ability of STAT3 to, in this case, dimerize? Because one of the important things about STAT3, it has to partner with another member of its—partner with another molecule of itself to be functional. And there is a lock-and-key in that interaction. To lock that confirmation, it turns out there’s a phosphorylated tyrosine in one member that floats over and binds to the pocket, the phosphopeptide binding pocket in the other, and vice versa. It’s really cool. It’s actually like this reciprocal, tethered molecule. And so it gave us some insight into that. And it turns out that same region of the STAT3 that binds to its partner, phosphopeptide, actually before it even gets able to do that it actually gets recruited to an eGFR and a G-CSF receptor through a phosphopeptide in the receptor. And so it’s sitting around, floating around. The cytokine hits the cell. It could be TGF alpha. It could be G-CSF. There’s a series of phosphorylation events that occur. In the case of eGFR, the kinase is actually within the structure of the receptor. In the case of G-CSF, it actually kind of associates with the receptor, so it’s nearby. And that activates through—actually, the receptors kind of come together, and then they phosphorylate each other, as it turns out, and activate each other, and then start phosphorylating specific residues, tyrosine residues in the receptor. And it’s like all of a sudden these receptors develop Velcro, and they’re sticky, and they’re sticky for molecules like STAT3 that have a little hook. You know how Velcro works. They have the ability to bind to that fuzzy receptor, and then STAT3 gets phosphorylated by the same kinase that phosphorylated the receptor itself, falls away, and then does this homodimerization routine, binds to DNA. So there are two interactions that I was very interested—well, one interaction that actually mediated two steps in the activation, that I became interested in targeting. Once I then … Because of the work Jenny had done and we had done—and Jenny had done in squamous cell carcinoma, I had done in myeloma and myeloid leukemia—I said, I want to see if we can’t target STAT3, and understand how it works. Because this is still the beginning of the STAT3 field. It was started in ’91, ’92. And so the long and short of it is then, with the structure, we had a way to go forward, and we, in other words, developed small, fake keys that would block those two interactions, and then block STAT3 activation.
Tacey. A. Rosolowski, PhD:
Let me just—because I’m looking at dates here. So you came to Pittsburgh in ’87, and you said kind of this—by the time ’91 came around there was this critical mass of stories accumulating, understanding. So that’s a good five years of work, but that’s a huge amount of work, that you’re kind of shining the light in this area, and—
David Tweardy, MD:
Yeah, and that’s—and we were not the only ones—
Tacey. A. Rosolowski, PhD:
And I’m not saying it’s a long time. I’m just trying to get us a time map of how it’s progressing.
David Tweardy, MD:
Yeah, so it’s a very important question, is when do these things kind of come together. Well, we actually identified—so when I went to Pittsburgh, we knew that G-CSF bound to the receptor. We developed very early on in my stay at—my start at Pittsburgh-- antibodies to the receptor, so we could ask the next question: well, what does the receptor recruit for the next step of signaling? And that’s where we pulled down a couple molecules that—tyrosine kinases that we didn’t pursue. But this interesting third molecule --and that molecule, that we didn’t know what it was, because it hadn’t been identified yet-- and that third molecule turned out to be G-CSF. When we first published what it was, we called it STATG, because it had all of the functional behavior of, at that time, the early members of the STAT family, STAT1, 2, and 3. We thought it was most consistent with STAT3, but the only reagent that you could use to confirm did not react with it. It was a monoclonal antibody against STAT3, and it didn’t react. So when we published the paper, saying that G-CSF binds to T-CSF receptor, and activates a STAT-like molecule, we called it STATG. It turns out, in ret—now, very quickly we learned it was a what was called an isoform of STAT3, called STAT3 beta, and making us the first to identify STAT3 beta in humans. It only had just—in fact, again, papers that you read and get excited about. There was a paper that came out of Hopkins that talked about this truncated form of STAT, called STAT3 beta, in mice. And it turns out that isoform was missing the target of the only antibody that bound to STAT3. It was spliced away when—so, totally explained our data, so we quickly confirmed that, and so—
Tacey. A. Rosolowski, PhD:
And so that was around what time?
David Tweardy, MD:
Ninety—so ’87, so we’re talking probably that was ’90, ’91, when we published that paper on STATG. Took us a while just to get set up and publish the STATG paper. And wrote a few papers around regulation of G-CSF, as well as the other major hematopoietin called GM-CSF, writing hundreds of northern blots, because that’s what I could do when I started. So we published a bunch of papers around regulation of G-CSF and GM-CSF. And then the real focus of what was to be the focus of the lab, we started getting traction. So we published those papers around STATG and then STAT3 beta in ’91, ’92, ’93. Actually, I would say, no, ’93, ’94, ’95, because Jim Darnell had just published the finding of STAT3 in ’91, ’92, so it was within a year of that. We actually even—so, bottom line, that’s the timeline. And so mid-’90s, where we know that G-CSF activates STAT3, we test the hypothesis that I’ve mentioned that G-CSF drives differentiation through STAT3. We disproved that hypothesis in ’97, and then published the paper around STAT3 being essential for squamous cell carcinoma, head and neck growth in ’98. The crystal structure comes out in ’98, and we go full force into developing small molecules that can allow us to interrogate how STAT3’s really working, because … And so the project—and then I get a grant around that, and in ’99 I move to Baylor. So that’s sort of the history of that.
Recommended Citation
Tweardy, David J. MD and Rosolowski, Tacey A. PhD, "Chapter 06 :Cytokines and Cancer-Related Research at the University of Pittsburg (late Eighties)" (2019). Interview Chapters. 1388.
https://openworks.mdanderson.org/mchv_interviewchapters/1388
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