Voiceover: Welcome to the Salk Institute’s 治愈的起点 podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.
Allie Akmal： At a small Institute like Salk, where most people know each other it’s always exciting when a new faculty member arrives. I think the lab is down here.
Brittany Fair: Oh, okay.
Allie Akmal： Hey, here’s Dannielle Engle.
Dannielle Engle: Hi you guys. How’s it going?
Allie Akmal： Good. How’s it going here?
Dannielle Engle: Pretty good. Welcome to our lab. We’ve got a few things going on here today that’s mostly set up. Let me introduce you to Christina. She’s my first hire, a first Engle lab member besides myself.
Christina: Hey guys. Nice to meet you.
Dannielle Engle: Yeah. The nice thing about having a new lab is that you start fresh. Everything is clean and shiny and probably my favorite part so far is opening boxes.
Christina: So far, a lot of tissue to make things not shake around.
Allie Akmal： We left Christina to her unboxing and Dannie Engle and I sat down for a chat about what it’s like to be a new Assistant Professor at Salk.
欢迎 治愈的起点, Dr. Dannielle Engle Ingle.
Dannielle Engle: Oh, thank you very much for having me.
Allie Akmal： You’ve joined the Salk Institute as a new assistant professor recently, but you’re actually not new to Salk. Can you tell us about that?
Dannielle Engle: So I actually went to graduate school at UCSD and so I was a PhD student in Geoff Wall’s lab here at the Salk Institute where I finished my dissertation in 2011 and so this is a little bit like coming home for me.
Allie Akmal： Nice. And what were you working on when you were here before?
Dannielle Engle: So as a graduate student, I was working on how cancer’s really an extension of development and the model system that I was working on was breast cancer and how that relates to embryonic development of the mammary gland in mice. So I learned a lot of the basic tools and strategies for studying cancer.
Allie Akmal： So you came to Salk to study cancer as well, but you’re not studying breast cancer anymore. What are you studying now?
Dannielle Engle: So my lab focuses on pancreatic cancer and basically every stage of disease that leads to pancreatic cancer. We focus on this transition between inflammation and the early stages of pancreatic cancer development. Pancreatic cancer is one of those really difficult problems. It is incredibly aggressive, but that’s not necessarily because it moves very fast. It is very aggressive because there aren’t any early warning signs. All the symptoms are very vague and by the time you start feeling those symptoms, it is often already too late. And for example, say you get indigestion or you have some abdominal pain, you don’t go and say, “Oh, my pancreas hurts.” You think that you have eaten something bad or you have the stomach flu. And by the time you actually work your way down the list to pancreatic cancer, you already have a metastatic disease.
Allie Akmal： 哇。.
Dannielle Engle: And so I think that one of the biggest challenges is whether or not we can come up with an early detection test for pancreatic cancer. And if you think about what we’ve been able to do for many other types of cancer, a lot of this revolves around early detection. So for colorectal cancer, we have colonoscopies and for breast cancer we have mammograms. And even for prostate cancer, we have a PSA blood test. And in each of those cancers, we’ve gone from diagnosing patients where their cancer’s already spread to diagnosing patients before their cancers become dangerous. And that has made a huge impact-to-patient survival and quality of life.
Allie Akmal： Well, why is pancreatic cancer so difficult to diagnose? Shouldn’t it be as diagnosable as any of these other cancers?
Dannielle Engle: I guess the best way to describe why it’s so hard to diagnose pancreatic cancer is that we don’t yet have the right imaging tools or diagnostic tests.
So if we start with imaging tools, by the time you’re able to see a tumor in your pancreas on say an MR or CT scan is usually about 0.75 to one centimeter in size. Once a tumor in your pancreas is that size, it already contains more than a billion cells.
Allie Akmal： 哇。.
Dannielle Engle: Right? And so that is a lot of cells and it means that it’s had time to grow and it’s also had time to spread. So once a tumor in your pancreas reaches that size, it has a 75% chance of already spreading to other tissues in your body.
Allie Akmal： 哇。.
Dannielle Engle: And so I think that one of the big problems is that we’re not able to get the resolution that we need in the pancreas. And that would really be helped by the discovery of new biomarkers that we can either use to help our imaging by a blood test or by turning it into a type imaging probe itself.
Allie Akmal： Okay. And so when you say biomarkers, you’re talking about maybe some sort of protein that you look for in a blood sample or some specific-
Dannielle Engle: Exactly.
Allie Akmal： Thing like that.
Dannielle Engle: So a biomarker, in this case, would be some sort of signal that we can measure in the blood or by a positron emission tomography scan, a PET scan.
Allie Akmal： And have you had any luck so far finding these kinds of biomarkers?
Dannielle Engle: So if you think about looking for biomarkers, it is this age-old problem of looking for a needle in a haystack. And traditionally what people in the past have done is look at the blood and look at the tissue itself and see if we can find something using unbiased profiling approaches. Now the problem is if you think about, for example, the blood, this contains signals not just from your pancreas but from every tissue in your body. And so you spend 99.9% of your time trying to exclude signals that are not informative. So you’re not really looking… You spend most of your time in the hay, in the weeds, is a good way of putting it.
Allie Akmal： Another approach you’re taking is using organoids. Can you talk a little bit about what are organoids and how are you using them?
Dannielle Engle: Sure thing. So when I actually started my project as a postdoctoral fellow, I was really focused on early detection. And one of the confounding parts about early detection is that you have to focus on not just telling the difference between somebody who’s normal and healthy, but also somebody who is suffering from some inflammation or also has cardiovascular disease or has some other GI infection. And it turns out that when you have some sort of inflammation in your gastrointestinal tract that can look very similar to cancer and you can’t really risk confusing the two with an early detection test.
Allie Akmal： 好的.
Dannielle Engle: You have to be able to tell the difference. And so when I started this project, the reason why I originally made the CA 19-9-sugar mouse model was so that I could look for biomarkers using the mouse model.
At the same time we developed a new culture technology called organoids and it was very revolutionary, not because we were growing cells in three dimensions, but because we could grow both normal proliferating epithelial cells that are very similar to what you see in an inflammatory process as well as each stage of cancer.
Allie Akmal： And so how does the process begin? Do you get a sample from a pancreatic tumor from a patient or do you use cell lines that laboratories produce?
Dannielle Engle: So organoids are always derived from a patient, so they never actually go through any intermediate. And I think that’s part of why they work so well. So we can actually make organoids from autopsy samples as well as from biopsies and surgical resections of patient tumors. And so we can actually grow organoids from many different stages of diseases that we were unable to access previously.
Most other models require that you have access to a lot of material. So that really restricted our ability to grow models only from patients receiving surgery. And that’s only about 15 to 20% of patients.
Allie Akmal： So then in a sense they’re like miniature versions of somebody’s pancreas or somebody’s pancreatic tumor. Is that correct?
Dannielle Engle: That is correct. We like to call them patient-derived models or sometimes in the field we also refer to them as avatars. So using these organoid cultures, we can basically expand them quite dramatically. So we can do these really intense experiments, but we can also do drug testing, we can look at their genetic vulnerabilities. And so they really open up the field to studying the entire gamut of pancreatic cancer progression in patients in a way that wasn’t really previously possible.
Allie Akmal： So you had a paper come out recently in the journal 科学 that has some very exciting results about pancreatic cancer. Can you tell us about that?
Dannielle Engle: A lot of what we use in the pancreatic cancer field to follow patients is this biomarker called CA 19-9 and I did just say that there are no early detection tests. And unfortunately this biomarker CA 19-9 cannot be used for early detection because it is also elevated in other types of disease. So it is not specific.
Allie Akmal： 好的.
Dannielle Engle: And so what we were very interested in understanding is why. Why does CA 19-9 fail as a biomarker and what can we understand about what it is doing during inflammation in cancer? And so one of our big frustrations in the field was the fact that while people make CA 19-9 none of our models, none of our models that use mice or any sort of rodent can make CA 19-9. So we created a mouse model that enabled elevation of human CA 19-9 and we noticed something very odd. And that was that as soon as we turned on CA 19-9 in the mice, they were getting severe pancreatitis. And pancreatitis is this type of inflammation in the pancreas that is thought to be necessary for tumorigenesis. So in mice without pancreatitis, they will never get pancreatic cancer.
Allie Akmal： So it’s sort of a precursor to cancer.
Dannielle Engle: Exactly. And so it’s very important for controlling that gateway to transformation in the pancreas. And so as soon as we observe this, while the first thing that we did was try and see if we could ever block it or turn it off. And so we used different antibodies to CA 19-9 to block those signals. What we found is that we were effectively treating pancreatitis using these CA 19-9 inhibitors. And this is very important because most of our treatments for pancreatitis patients really only address the symptoms and aren’t really able to walk the patients back and reduce the severity or the recurrence.
Allie Akmal： 好的.
Dannielle Engle: And so we are very excited because this could be a way of preventing that transition to cancer.
Allie Akmal： Wow, that sounds like a pretty big deal.
Dannielle Engle: I think it is. I think it’s a pretty big deal because whenever you identify a new vulnerability it gives you the option to take that to the clinic. And so what I want to focus on in my laboratory is really this bench-to-bedside transition so that our work can be translated to impact patient care. And I think this is really exciting because there are antibodies to CA 19-9 that are able to block those signals that have already passed safety trials.
Allie Akmal： 哇。.
Dannielle Engle: And so this is something where we could actually move very quickly and we’re pursuing that work now.
Allie Akmal： That is really exciting. Stepping back in time a little bit, did you always want to be a scientist?
Dannielle Engle: I actually had a roundabout route to become a scientist and so when I first went to college it was actually for music and I was preparing to become a professional musician. I had trained for it since I was eight years old and that’s really kind of where my trajectory was taking me. I was lucky though that my father was always challenging me and questioning me and at some point we had this really poignant conversation where I was telling him about some of the work I was doing in AP Bio and he was asking me about like, “Well, do you want to become a doctor or do you want to become a scientist?” Because the scientists are who make the discoveries and it’s the doctors in the hospitals that apply the discoveries. I’m like, “Yeah, I want to make discoveries and I want to be a scientist.” And I switched everything and started doing research and college and I realized that this is what I’m really passionate about and I changed my major and yeah, I graduated with a BA in biology.
Allie Akmal： Wow, that’s a wonderful story. Was your father a scientist or a physician?
Dannielle Engle: Oh no.
Allie Akmal： No?
Dannielle Engle: Yeah, no, he was a basically a computer scientist. But he was in the military and I remember we had a lot of conversations where he just convinced us that whatever we were passionate about in life, they would make it happen. We would be able to accomplish anything.
Allie Akmal： You actually have a very powerful motivation in terms of wanting to translate your science into the clinic. You’ve had some family members, close family members with pancreatic cancer. Can you talk a little bit about that?
Dannielle Engle: Yes, so I’ve had some, it gets me every time. Sorry. All right.
Allie Akmal： And thank you for sharing this story with us.
Dannielle Engle: Of course, it’s always hard to talk about, but I think it’s important that people know that scientists have these human feelings and motivations.
Allie Akmal： 是的。.
Dannielle Engle: All right. So when I was finishing college, I was about to graduate with my bachelor’s in biology. My father was diagnosed with pancreatic cancer. This was both terrifying and very frustrating. As a scientist in training, I figured, “This is a perfect opportunity to use what I’ve learned and figure out what can we do, what are the clinical trials, what’s available, what are our options?” And what I was able to figure out is really there wasn’t anything, there were no options. There were really no available clinical trials at the time. He had really, what it left me feeling like was there is no hope.And my dad was lucky in that he had jaundice. This is a yellowing of the skin. And so he was diagnosed with an early stage of pancreatic cancer. And what that means is that you’re eligible for surgery and surgery is the only possibility of a cure. But the vast majority of these patients still die from metastatic cancer because our imaging is not able to pick up when the cancer spreads and is very small. And so my dad passed away 14 months later and he was lucky. He was considered incredibly lucky because the median survival is usually only a few months.
Allie Akmal： My goodness.
Dannielle Engle: And I just remember how hopeless and frustrating that experience was. And so at this point I was studying genetics and fruit flies and I decided to switch fields as a graduate student and focus on cancer. And 10 years later I am doing my postdoctoral fellowship work in pancreatic cancer. And you would think that the situation would have changed. Unfortunately, at this point, my uncle is diagnosed with pancreatic cancer and passes away three months later.
Allie Akmal： 哇。.
Dannielle Engle: And it was the same, in other words, no options. There were no early warning signs and he was diagnosed with metastatic pancreatic cancer and was gone. And so I think. the only thing you can do to change the situation is start from the ground up, understand the problem, make the discoveries and translate it to the clinic. And that’s what I decided to do. I decided to really focus on starting my own laboratory and hopefully making those discoveries that make a difference to patients and families.
Allie Akmal： We’re so glad you did.
Dannielle Engle: Oh, thank you.
Allie Akmal： Yeah, really powerful story. So is there a strong genetic component to pancreatic cancer?
Dannielle Engle: So there are many different risk factors for pancreatic cancer. It does include a genetic component. So individuals that have two or more family members with pancreatic cancer are at risk. And the more family members you have that have suffered from pancreatic cancer, the higher, even higher the risk you have. Also, if you have hereditary pancreatitis, pancreatic inflammation you have a lifetime risk of about 50% of developing pancreatic cancer. So there’s really nothing though that we can do for these patients in terms of surveillance and monitoring. So that they are diagnosed early enough that we can perform surgery or have an effective intervention.
Allie Akmal： Wow. It’s just really one of the deadliest cancers.
Dannielle Engle: It is the deadliest common malignancy.
Allie Akmal： Wow. Can you talk a little bit about… You talked about switching gears in college. Do you have any advice for other young people thinking about a career in science? Hopefully, they don’t have such a dramatic story, but maybe you’ve had some thoughts about that transition now.
Dannielle Engle: Definitely. So the path to become a scientist is not something that you have to lay out since you’re a freshman in high school. You don’t have to know that you want to become a scientist right away. It’s also not just for the super-smart or geniuses. I get this comment a lot. They’re like, “Oh, I’m not smart enough to become a scientist.” I beg to differ. I think if you have that scientific curiosity, that’s all you need and everything else you can work on it. You can become a scientist if you want. You just have to have that passion.
Allie Akmal： That interest and the willingness to work hard, it sounds like.
Dannielle Engle: Yeah. I think that this idea of making discoveries, if that gets you excited and if that’s something that really drives you, then that’s all you need.
Allie Akmal： Well, I’m curious to know what instrument were you going to play and do you find any parallels between studying music and doing science?
Dannielle Engle: Well, I think they’re both motivated by passion and so that helps a lot. So I would say I was training to become a virtuoso, which means that you are able to spontaneously also create music.
Allie Akmal： 哇。.
Dannielle Engle: And so you have that creativity, that spontaneity and also just thinking outside of the box, thinking outside of the music that’s written on the page in front of you. But taking what you learned at the same time and creating that into something new and something interesting. And I think that definitely relates to science. We can keep making incremental progress, but the likelihood of that actually impacting patient care is small. So at the same time, it might be more risky if we come up with these more creative, spontaneous ideas. That’s where we have the most potential for impacting the lives of our patients.
Allie Akmal： And do you play the violin still? Like for sort of relaxation or…
Dannielle Engle: So for me, I play a little bit, it does require a lot of work to keep up and so I’m definitely not going to have a career in music anytime soon. But it’s still something that I enjoy. For me, I think actually the thing I like most about music is I used to do outreach also for kids. I would get the same thing I do now about science, about, “Oh, I can never become a scientist.” So we basically, I pull out my violin, tuck it under their chin and we’d play Twinkle, Twinkle Little Star on the spot. And I’d convince them, “Oh, no, see? You can do it.” And you’d get that sparkle in the eye and you have a promising new musician or scientist or whatever they want to become. So I think that I’ve learned a lot from both, but for me right now science is definitely my number one.
Allie Akmal： That actually reminds me of Salk. So Salk attracts a lot of people who want to make a big difference, have big, bold ideas. And I’m just wondering if that’s one of the reasons you came back here.
Dannielle Engle: That’s actually the major reason why I came back to the Salk. I remembered that as a graduate student that it didn’t matter how crazy your idea was, you made it happen at the Salk and even if that meant reinventing who you are as a scientist or adopting this new approach that nobody’s ever tried before or calling in a scientist from someplace else in the country or the world to come help you figure how to answer your new question. That is basically, one of the… I would say the Salk is one of the only places in the world where you can do that.
Allie Akmal： Really?
Dannielle Engle: Mm-hmm (affirmative).
Allie Akmal： That’s remarkable.
Dannielle Engle: 是的。.
Allie Akmal： Well, Dr. Dannielle Engle, thank you so much for joining us today and telling us your powerful story. We’re really excited to see where your career and your discoveries take us.
Dannielle Engle: Thank you very much.
Voiceover: Join us next time for more cutting-edge Salk science. At Salk, world-renowned scientists work together to explore big, bold ideas from cancer to Alzheimer’s, aging to climate change. 治愈的起点 is a production of the Salk Institute’s Office of Communications.