Episode 4: The Seekers

Andrew Becker:  Before we start, a quick note. The content in this episode should not be considered to be medical advice and no physician patient relationship is implied.

Dr. Chernoff: I have on my desk here, a collection of objects that I use both to remind myself of certain things and also for people to play with when they come and visit me. And it's about the pace of technological change.

Andrew Becker: On an early summer afternoon, Dr. Jonathan Chernoff, Chief Scientific Officer at Fox Chase, is seated in his office, set in the middle of a long line of laboratories. In front of him is a collection of strange objects.

Dr. Chernoff: So one of the oldest by far objects is a stone hand axe, a small piece of stone with a sharp edge that was dug up in Morocco and it's probably a hundred thousand years old. But the point of it is, this object was used... objects like it, virtually unchanged for several hundred thousand years. It was so perfect that no one needed to change it for millennia. And then in the middle, or just off to the side on my other desk a microscope, which in this case is my father's microscope, but is illustrative of microscopes at that time. And they had slow evolution, but anybody from 16 or 1700 could use my dad's microscope just fine. Now in the modern age, now in 2019, they're basically computers driving a light source. It's completely different now.

Dr. Chernoff: It's more computer than it is mechanical object by a long shot. But then on the furthest end of the spectrum are things like this little gene chip I have on my desk. So this thing is used to analyze arrays of RNA. It's got maybe 100,000 points on it. It's microscopic, you couldn't see all the little nodes on this chip, but it's half life as a useful object was maybe a year until it got replaced by a more dense chip. In the same way that computer chips are always getting smaller and more dense. So in this business, if I don't understand the workings of that gene chip, where there was modern microscopes, I'm going to be out of business myself, so I have to keep on my toes at all time and so does everybody else and that's a good thing. I'm not complaining about it. It actually makes life more interesting.

Andrew Becker:  Every day our waiting rooms, laboratories and clinics fill up with people searching for something. To take care of others, to find the next big breakthrough or maybe just to feel like themselves again. This is Connected by Cancer, the podcast of Fox Chase Cancer Center that's all about that search. I'm Andrew Becker. In each episode we explore these connections together.

Andrew Becker: Today we'll be looking at three different stages of a life in cancer research, from a newly minted PhD working in someone else's lab to a mid-career researcher leading the way against pancreatic cancer, to the keeper of a legacy that changed our understanding of the disease.

Alyssa Leystra: This is a pipetter that you can use to pipette liquids into multiple wells simultaneously. So I've got this plate...

Andrew Becker: Let's start in the lab of Fox Chase, Deputy Scientific Director, Margie Clapper who specializes in colon and lung cancer. This is where we find Dr. Alyssa Leystra who is wrapping up the second year of her postdoctoral fellowship. A training period that can last anywhere from two to five years.

Alyssa Leystra: ... some liquid, move it into the wells, expel it into the wells. And when I am finished I would then just get rid of these tips. So the work that I do is trying to understand how and why cancer arises in the colon and trying to determine what changes in the colon occur before tumors form so that we can detect them earlier so that we can develop new interventions to stop the formation of colon tumors. I've been studying how very minute changes within the colon of mice changes their risk of getting tumors. And it's great to work with mice because we can control so much more of their environment than we can with people.

Alyssa Leystra:  So we know what you eat makes a difference. We know your genetics make a difference. We know where you go during the day can make a difference and you can't just sit down a hundred people and say, "All right, you're all going to eat the same thing. You're all going to be genetically identical and we're going to figure out why some of you get cancer and some of you don't." So with mice I can do that. I can have a hundred mice and I can say you're all going to be the same, but some of you are going to get cancer and some won't. And then I can ask why.

Alyssa Leystra:  Well, certainly from the start of graduate school till now, there have been huge changes within the cancer biology field as a whole and also within studying colon cancer specifically. Those changes are largely in the tools that we have available. So a lot of people have heard of CRISPR now. It's a way that we can more easily edit the genes that we're working with in order to understand what they do. But also we are beginning to realize just how important the immune system is and the microbes within your body are for increasing or decreasing your risk of getting cancer and also for treating those cancers. So the fields of immunology and microbiology are becoming massively important to my research and that wasn't true five, 10 years ago.

Alyssa Leystra: Well, we don't think about our colons very often, but it is a very important organ. It's where most of the liquid absorption for your body happens. So proper function of the colon is important to avoid dehydration. For people who have diseases in the colon, life becomes very difficult. You become malnourished and dehydrated. If you have to have your colon removed because of cancer or a really bad inflammatory disease, your life is changed for the rest of your life. You have to have a colostomy bag on your stomach and you have to change it frequently and there can be accidents. It's embarrassing and it's difficult and people don't like to talk about it.

Alyssa Leystra: The colon is also home to billions if not trillions of microbes, most of which are good for you. They help digest things and absorb things. But when things go awry, say you take some antibiotics and maybe you kill off some of those healthy microbes, it becomes easier for ones that are bad for you to colonize your gut and cause disease. And it is becoming increasingly clear that the microbes in our gut make a huge contribution, not just to your risk of colon cancer, but to your overall health, to your immune system, to your risk of various other cancers. And that field's still very much in its infancy. So I am very excited to learn about how the microbiome interacts with the rest of your body and hopefully there are huge advances in that in the next couple of decades.

Alyssa Leystra: Personally, I just hope that I can make enough of a difference as a mentor and a scientist that several new scientists are born into the field. So the reason that breast cancer has made so many leaps in the last 20, 30 years is we've gotten better at admitting that breast cancer is a thing that exists and that needs to be studied and people are willing to talk about it and celebrities will say, I did this thing in order to reduce my risk of getting breast cancer. But other cancers like colon cancer are more taboo to talk about because it is an icky organ. We don't want to talk about our bowel movements. We don't want to say, "I saw blood in my stool. What does that mean?" So I think that just people getting more comfortable talking about these things will be important. Getting better at detecting some of these more difficult cancers will be important. And I hope both of those things happen over the next 20 to 30 years.

Andrew Becker: If Dr. Leystra dreams of one day charting her own course in research, at Fox Chase she's surrounded by excellent role models of what mid career success looks like, including this man.

Dr. Astsaturov: My name is Igor Astsaturov. I'm a medical oncologist. I am also a physician scientist. So I run a research laboratory with two postdoctoral fellows, a technician and a student. My interest in science and in the clinic is to understand the biology and find new treatment options for patients with pancreatic cancer.

Andrew Becker: As a teen in the former Soviet Union, Dr. Igor Astsaturov reinforced his conversational English by listening to pirate radio broadcasts on a short wave radio. Now a medical oncologist and physician at Fox Chase, Dr. Astsaturov's research lab is leading the quest to decipher a different sort of signal.

Dr. Astsaturov: In the pancreatic cancer field, besides that majority of tumors are very difficult to treat and the options are limited, there is the worst of the worst subset, which is called basal pancreatic adenocarcinoma. So that particular subtype likes to have low cholesterol levels and that particular subtype is up regulating or enhancing a TGF beta pathway signaling. So we're trying to understand how these metabolic and signaling systems interact with each other. Science is a difficult field because on good days when we have maybe 30, 50% success rate, that'll be fantastic. Oftentimes you have to work on failures and technical issues and solve sometimes very challenging experimental problems because we deal with live systems where we deal with live cells or live animals, trying to find solutions for a problem, so almost like in a darkness.

Dr. Astsaturov: Pancreatic cancer epitomizes the difficulty that we face in dealing with any solid tumor of any cancer in general for two reasons. It is one of the smartest cancers. George Sledge, maybe five or six years ago, provided this very intuitive classification of tumors. He called them either stupid or smart. So the stupid cancers happen to have mutations or mechanisms for which we have drugs. When it comes to pancreatic cancer, only maybe 10% are the stupid ones. The vast majority of pancreatic cancers are smart and they have very few vulnerabilities on which we can impinge in order to suppress their growth.

Dr. Astsaturov:  The key here is to find these vulnerabilities in other cancers that are seemingly impervious at this point. I think we're going to flip this page and we'll get there. It just requires a better understanding of their biology, how they interact. Not only how they live by themselves, but also how they interact with the surroundings, with the microenvironment, the stromal cells and how they evade immune recognition. These are fundamental questions that are still not fully answered, but there are some early basic science inroads that will ultimately lead to development of clinical breakthrough therapies.

Andrew Becker: Treating patients while running a lab can be a lot to balance, but Dr. Astsaturov says it's good for both his patients and his research.

Dr. Astsaturov: I think without this interaction with real patients and taking care of real illnesses and real problems of cancer sufferers, I would not be as motivated or as insightful about what we do in the lab. These two parts of my professional life, they feed into each other.

Andrew Becker: Science can require a steely objective point of view, but Dr. Astsaturov's work is rooted in a painful personal loss.

Dr. Astsaturov: I didn't think that I would be doing pancreatic cancer from the very beginning of my research career, but just happened that I had to, because my wife was diagnosed with metastatic pancreatic cancer. She passed away in 2013 and since she was diagnosed, I really thought that I could come up with some treatment option for Elena. Her cancer had a rather unusual combination of mutations in KRAS and P53 and another gene that was amplified, named MYC, which made her cancer super aggressive. We basically started a whole new program deriving her tumor tissue, putting it in mice and getting cell lines out and getting what's called avatar model of her tumor.

Dr. Astsaturov: Unfortunately we could not finish the task while she was still with us, but finally it was published three years after she passed away. And we found actually an interesting option for patients with MYC amplified tumors. They're very susceptible to activity of a drug called Triptolide. And now this compound, also known as Minnolide, is now being tested in clinical trials. So we were late to help her, but I think this knowledge may arm other physicians and patients to fight this lethal disease.

Andrew Becker:  We'll be right back.

Andrew Becker:  Cancer advice from someone who knows.

Speaker 5: [Tula Aris inaudible 00:00:13:17], breast cancer survivor. With cancer, where you go can be the most important decision in your life. If you do not get the best medical care, nothing else matters. This is why I tell people, go to Fox Chase.

Andrew Becker:  Where you start matters. Fox Chase Cancer Center, 888 Fox Chase.

Andrew Becker:  This is Connected by Cancer. I'm Andrew Becker. If researchers like Alyssa and Igor are currently working long, hard hours to make a difference and make a career, Alice Hungerford has experienced what it's like when all that work leads to a true breakthrough.

Mrs. Hungerford: I will tell David's story until my last breath.

Andrew Becker: Mrs. Hungerford is a retired lab technician and the widow of Dr. David Hungerford.

Mrs. Hungerford: David was an incredible person, brilliant. Other scientists of the world had said he was probably the most brilliant mind of his generation. He was an incredible guy, really was. He knew everything about everything and people would ask him, just come into our lab. And those days you could sit in the lab and eat. We had this table and I so wish I had this table now, but it's probably radioactive. It was this great soapstone top table because all the lab benches were made out of soapstone. It was easy to mill. It was heavy, it was non-reactive and all labs had soapstone countertops. Now they're all, who knows what they are? anyhow, we had this great table in the lab and we sat and we all had coffee and David smoked, we all sat and smoked and ate in the lab. I mean, nowadays, oh my God, you can't do that.

Andrew Becker:  Her husband who died in 1993 spent more than 30 years at Fox Chase and along with Dr. Peter Nowell from the University of Pennsylvania, Dr. David Hungerford made the first landmark discovery at Fox Chase, the Philadelphia chromosome.

Mrs. Hungerford: How the Philadelphia chromosome got its name is an interesting story. Originally it was the Philadelphia and a super numeral one chromosome. So in those days, so we're talking the late fifties, early sixties, most of the science came from Europe, England, France. That was where the hotbed of discoveries was coming from, particularly, at least in genetics, Edinburgh. The paper was sent to the Edinburgh group for review. Now, they had already looked at all the known leukemias of the time using the techniques that they used. Not David, Pete's and Paul Morehead's technique, but their techniques, which were fine and what most people were using at the time. And they didn't see anything. So they wrote back and they read the paper. They did the technique the way David, Pete and Morehead had suggested doing the technique with the culture and the slides. And sure enough, they saw it too. Well, they quick wrote a paper off to Nature, which was the mouthpiece over there, where sciences are mouthpieced.

Mrs. Hungerford: David was a man of incredible language skills. He knew his words. He chose his words very carefully. When you don't talk a lot, you choose your words carefully. And they wrote a letter and said that they were very happy to have read their preliminary paper on their findings from the Edinburgh group, but perhaps they saw their abstract in science, which had been published in September of 1960, which noted that they had seen in some cases of acute granulocytic leukemia, this minute chromosome and further study is underway, which is what more or less the abstract says. Well, the Edinburgh group quickly pulled their paper, did not ever get published, and they proclaimed when Hungerford and Nowell's paper, Nowell and Hungerford's paper, was published, that it should now be called the Philadelphia superscript one chromosome because the thought was that there would be an Edinburgh two and a Chicago three and a Atlanta four and every city, wherever the discovery is made, would have their little claim to fame by having the chromosome named after them with a super numeral.

Mrs. Hungerford: Well, that was fine except that it stood as the only chromosome abnormality associated with a specific cancer for 25 years. So that didn't happen. At about 10 years, everybody kept looking because they thought for sure they were going to find something. A, they didn't have David's eyes. They didn't have his determination and you can look for so long and then nothing. So for 10 years nothing really happened. So that was '61 to say '71 and that's about when banding started to come in, in the early 70s and from then on it was a watershed. People had sort of lost interest in human chromosomes, but when banding came in, it opened up a whole new chapter and people were now doing the banding of these chromosomes and they could see things that were not obvious before when you just had a single stained chromosome.

Mrs. Hungerford: The Philadelphia chromosome, because it was the first chromosome associated with a specific thing, cancer, it was actually the first chromosomal abnormality that is really a genetic change. And the basis with the banding techniques, they could finally see where the breaks occurred and the re-fusion of the two chromosomes. Many people misquote Nowell and Hungerford's paper and they say that Nowell and Hungerford said that it was a deletion of the 22 and it was not. David, as I said, was very, very precise in his language and it was very careful in the paper. They noted that a loss of genetic material of that amount would be lethal and those were their words, lethal for the cell and the cell would not be viable. So the Philadelphia chromosome in essence created a fusion gene, which in turn made people develop the chronic granulocytic leukemia.

Mrs. Hungerford:  The Philadelphia chromosome became the first instance of targeted gene therapy with the development of Gleevec and Gleevec was cleared for use by the FDA in 2001 which was 40 years to the year from the discovery that David made under the microscope.

Andrew Becker:  If you love her storytelling as much as we do, look for an extended version of The Hungerford Story as a bonus episode soon.

Andrew Becker: The Philadelphia chromosome, which they discovered in 1959, established the first clear association between a genetic mutation and a form of cancer. It took decades for the scientific community to catch up. When that finally happened about 20 years ago, the field of targeted cancer therapies was born.

Andrew Becker: Our research episode could have made an entire series on its own. Fox Chase is home to the discovery of the Hepatitis B virus and a vaccine to prevent it along with critical breakthroughs in identifying and characterizing tumor suppression, cellular signaling, reprogramming tumor cells, genetic cancer risks, advances in radiation therapy, and many others. Our researchers have earned two Nobel prizes, the Kyoto prize, the Lasker prize, and more medals of honor and lifetime achievement awards than I have time to name. The small campus in an urban neighborhood far from downtown Philadelphia has truly changed the cancer world.

Andrew Becker: Connected by Cancer is the podcast of Fox Chase Cancer Center. It's produced and edited by Joel Patterson and me with help from Jonathan Pfeffer. Thanks this episode to Alyssa Lystra, Igor Astsaturov, Alice Hungerford and Jonathan Chernoff for sharing their stories with us. Thanks also to Blue Dot Sessions who helped with some of the music in this episode and to Rocket Summer Productions.

Andrew Becker: Subscribe to Connected by Cancer at Apple podcasts, foxchase.org or wherever you listen. And remember, the content of this episode should not be considered to be medical advice and no physician patient relationship is implied. I am Andrew Becker. Let's stay connected.