HOW LUCK – AND THE COURAGE TO LOOK WHERE IT LEADS – DRIVES THE DIRECTION OF SCIENCE AND SCIENTISTS AT CU AND BEYOND

Say what you want about Dennis Rodman, but you can’t deny the dude knew how to grab a basketball. Like game six of the 1996 NBA finals against the Seattle Supersonics, when Ron Harper put up a fourth-quarter 3-pointer that bounced off the backboard right into Rodman’s hands for an easy put-back – he was just lucky to be in the right place at the right time. A 2011 interview in the Detroit Free Press with his Pistons teammate, Isiah Thomas, sheds a little light on this luck.

When an unexpected result shows up in the petri dish, it takes confidence to see it as a discovery instead of a mistake.

“We were standing in the lay-up line, warming up and shooting,” Thomas says, “and Rodman was standing back and watching everybody shoot. I said, ‘Hey, come on, you have to participate; everybody’s shooting lay-ups, you have to shoot lay-ups, too.’ And he said, ‘I’m just watching the rotations on the basketball.’ That’s how far Rodman had taken rebounding. He knew the rotation of every person that shot on our team. He had
rebounding down to a science, and I never heard anyone think or talk about rebounding and defense the way he could break it down.”

The point is that what looked like luck was actually science. On the other hand, what looks like science is sometimes luck. There’s the famous story of Raytheon engineer, Percy Spencer, experimenting with radar equipment in 1945 when he realized the chocolate bar in his pocket was melting – leading to the invention of the microwave. Or the story of Charles Goodyear spilling rubber, sulfur and lead to invent vulcanized rubber. But the thing about luck is Spencer had to realize that something more than his body heat had melted the chocolate bar. And Goodyear had to poke and prod the mess on his stove before just throwing it all out.

Cancer science is the same way. Often scientists create their own luck. When a lucky door opens, it takes courage to step through. And when an unexpected result shows up in the petri dish, it takes confidence to see it as a discovery instead of a mistake. Call it luck, call it science…we call it serendipity. Here are just a handful of the serendipitous experiences, straight from our researchers’ mouths, that have helped to push cancer discovery forward at CU.

ANDREW THORBURN, PhD

Professor and Chairman, Department of Pharmacology, CU School of Medicine

In the mid 1990’s, my lab was starting to look into how normal cells and cancer cells die. In an early experiment, my wife, Jackie, who is also my lab manager, separated a prostate cancer sample into tumor cells and healthy cells, which we hoped would let us search for something that would kill tumor cells but not the normal cells. Part of the experiment required adjusting a certain protein in the cancer cells so they wouldn’t commit a kind of cellular suicide before we could do our “real” experiments. By that point, hundreds of scientists had used this same technique on cancer cells, tweaking this protein to keep them alive, but because we hoped to compare the results of sub-sequent experiments to our controls, we had to treat the healthy cells in the same way. What happened was odd: This protein worked exactly as we expected in cancer cells, stopping them from dying. But it did the exact opposite in healthy cells – it killed them.

Now, this was just the control experiment and we didn’t actually want to kill normal cells anyway, so most people might have just ignored this weird result and concluded that they had mixed up the samples or something like that. But Jackie was smart enough to look into it further. Over the next few years we discovered that this protein had a very unique ability to kill only normal cells, not tumor cells and when it did so, it seemed to be associated with the activation of a process called “autophagy,” which is a bit like a cellular recycling program.

It changed the entire direction of my lab’s research, encouraging us to focus on autophagy. Now my former postdoc, Jean Mulcahy-Levy, MD, a pediatric oncologist over at Children’s Hospital Colorado, is deliberately manipulating autophagy in patients to improve therapy, with promising results. It all came from Jackie getting the opposite result from what you’d want—killing normal cells but not cancer cells with the thing that was supposed to actually block cell death.

ANDI DWYER

Co-Director of the Colorado Colorectal Screening Program at the University of Colorado Cancer Center and Program Director at the Colorado School of Public Health

Almost a decade ago, not long after I started working with the Colorado Colorectal Screening Program, I spoke at a 9Health event about the importance of screening and early detection in colorectal cancer. After the event, I was impressed but slightly jealous of all the attention that breast cancer received and I decided we had to do something proactive to raise awareness. When I chatted about my goal with a colleague at the
American Cancer Society, he told me that he was in a band with one of the producers of the TV show South Park. After speaking with the producer, he agreed to help us create a video, which we ended up titling “Jo Jo: Your Colon and You.” The irreverent video was picked up by NPR, played in movie theaters and shown in clinic waiting rooms across the country. Jo Jo also won the 2013 Scientific Health Messaging Award of the year for the American Public Health Association. Indeed this weird connection certainly helped us get the word out about CRC screening!

Cathy Bradley, PhD

Associate Director for Population Sciences Research, CU Cancer Center, David F. and Margaret Turley Grohne Endowed Chair for Cancer Prevention and Control Research at the Colorado School of Public Health

When I was first studying employment outcomes of cancer survivors, our computer system crashed and we lost a whole bunch of data. To guard against that ever happen-ing again, I decided we would start recording our interviews – then if there was another computer crash, at least we could go back and listen to the taped interviews to recreate our data. Interestingly, at the time we had been finding only a very modest effect of cancer on employment – most people who got cancer stayed employed and this made it seem like cancer may not have a dramatic effect on patients’ lives beyond their disease. One day I happened to be listening to the tape of an interview with a woman with breast cancer who was a school bus driver. She talked about how she got up early, took kids to school, went to get her chemo, and then went back to pick up kids at school to take them home. And she said something very important – she said that if she couldn’t keep that schedule, she would miss her chemotherapy before she missed work. Our interviewer asked a little more and found out that for this woman losing her job would mean losing health insurance. It turned out that the reason that cancer had such a small effect on employment is that due to concerns about health insurance, cancer patients often just had to keep working anyway. Now, I can’t tell you how many times we recorded interviews and ended up with information we didn’t expect. And the whole reason we started recording in the first place was due to a computer crash.

STEPHEN WITHROW, DVM

Founding Director of the CSU Flint Animal Cancer Center Distinguished Professor, Colorado State University

In the early 2000s, veterinary oncologists up here at the CSU Flint Animal Cancer Center started noticing something strange in our bone cancer patients – they got sur-gery, they got chemotherapy, and then about 40 percent of dogs with bone cancer went on to develop a bone infection called osteomyelitis. Now, infections are one of the most dangerous post-surgical complications, leading to deaths in both canine and human patients. But we saw that the dogs with this infection actually lived longer on average than dogs with no infection, actually on average about twice as long. When we looked into why, we found that elements of the immune system that were activated against the infection also helped to keep cancer in check. In 2010, we published the study in a journal for advances in human cancers and I presented our findings at a meeting for surgeons and oncologists. No U.S. researchers ran with our finding, but I got a call a few months later from an MD in England named Lee Jeys who had done a similar study looking into infection and survival rates in kids with bone cancer, and found that 10-year survival rates for infected kids was 84.5 percent compared with 62.3 percent of uninfected patients. How to implement this in a clinical setting is still an open question, but now researchers at CSU like Steven Dow, DVM, are looking into how we can use infection – which is usually a bad thing – along with other therapies to help fight bone cancer.

CHRIS LIEU, MD

Director of the CU Cancer Center Colorectal Oncology Program

When I was an intern at the VA, Steve Leong was a fellow at the same hospital and because we looked alike, we were always being mistaken for each other – people would be asking me for chemotherapy orders, which was way beyond my experience at the time, and asking him to handle a patient’s potassium replacement, which is an intern’s job! Through this ongoing case of mistaken identity, we got to know each other pretty well and talking with Steve helped spark my interest in hematology and oncology. When I was looking for a research mentor, Steve introduced me to his mentor, Dr. Gail Eckhardt, MD, here at CU who became my scientific mentor and helped propel me into a fellowship at MD Anderson. And that was my start! I like to think that Steve and I would have become friends even without people thinking that we were one person, but I’m really not sure where my career would have led without this lucky mix-up.

DANIEL POLLYEA, MD

Clinical Director of Leukemia Services at CU School of Medicine

When I was a first-year fellow in hematology/oncology at Stanford, fellows had to pres-ent journal articles at a weekly meeting, where faculty enjoyed grilling the presenter to ensure he/she understood the paper. When it was my turn, the paper I chose happened to be from the lab of Craig Jordan, chief of the Division of Hematology here at CU, describing a new therapy he was developing to target leukemia stem cells. I was intrigued by his idea that a small population of stem cells was the root cause of leukemia, in this case acute myeloid leukemia (AML), and that these stem cells, which could almost never be eradicated by conventional therapy, were a common source of relapse. Over the course of my preparation I learned that paper very well, and starting then, became fascinated with the biology of leukemia stem cells and the potential to target them in the clinic.

Years later, I came to CU as junior faculty in Hematology and Craig was recruited from the University of Rochester a few years after that to be the division chief. We immediately began to collaborate, and decided that the central theme of our Division would be the study of leukemia stem cells and the clinical development of targeted therapies to eradicate this population. Now, this interest that started when I happened to pick up one of Craig’s journal articles long ago has turned into a collaboration in which I get to help Craig test the drug venetoclax, which you can read about elsewhere in this magazine.

STEPHEN LEONG, MD

Associate Professor, Division of Medical Oncology, CU School of Medicine

A handful of years ago, I was the principal investigator on a phase I clinical trial of a new drug being tested to treat a range of advanced solid tumor types. One of the patients on the trial happened to have adrenal cancer, a rare, aggressive cancer that is most commonly diagnosed in patients in their 40s and 50s. Though the drug didn’t go on to earn FDA approval, this patient had a reasonably strong response and he posted
about his experience in a support forum for people with adrenal cancer. Suddenly we started getting calls from all over the country from patients who wanted to explore having their adrenal cancer treated here at CU. Now, very few centers are able to do research in adrenal cancer – there just aren’t enough patients at any one center to draw meaningful conclusions. But there we were because of this forum post all of a sudden
seeing three, four, even five adrenal cancer patients every week. With patients’ permission, we started banking tumor samples to use for experiments and our team here has become a real leader in the field of adrenal cancer research.

TRACI LYONS, PhD

Assistant Professor, Division of Medical Oncology, CU School of Medicine

In 2014, I had just learned I was getting my own lab and decided that I would focus part of my research on how cancer cells migrate through lymphatic vessels. To get up to speed, I decided to attend a research conference in Italy on lymphatics and happened to notice on the list of attendees the name Beth Tamburini. She and I had been in grad school together here at CU and I noticed that, like me, she was also still here. Out of the blue, I emailed her and said, “I’ll see you in Italy!” and we ended up spending the conference catching up. It turned out that Beth is in immunology, studying how lymph vessels work with the immune system. And I was studying how lymph vessels provide avenues for cancer metastasis. We kept in touch but we were both busy and it was another two years before we got back in touch…at another conference! This time when we talked, we decided on an experiment we wanted to do together. Basically, for various reasons, we wanted to see if a protein called Semaphorin 7A would make mouse models of cancer grow more lymph vessels. The idea was we would give some mice regular cancer cells and others cancer cells overexpressing Semaphorin 7A and then compare the growth of lymph vessels. But we accidentally put some cancer cells into mice with an antigen that activated the immune system – when these immune systems rejected cancer cells before tumors could grow, it looked like a failed experiment. However, it turned out that not all our cancer cells were rejected. The ones that had been engineered to overexpress Semaphorin 7A survived. We thought this pro-tein would result in more lymph vessels, but what we learned is that it dampens the immune system in a way that can help cancer grow. Now we have a grant from Cancer League of Colorado to figure out how. And we think that Semaphorin 7A – this protein whose effect we stumbled onto purely by chance – might actually be a marker for patients who will benefit from immunotherapy.

Computer crash. Mistaken identity. Experimental error. Roundabout personal connections. Unexpected results. Most scientists try to avoid these things that can derail the direction of their work. And for the most part, they’re successful – experiments usually go according to plan and careers are usually linear things driven by interests, talents and (very, very) hard work. When things go wrong, the focus is on how to make them go right and coincidental connections can seem like distractions. It takes a special scientist to follow coincidence into the unknown. But here’s the thing: The process of science can find answers to important questions, but sometimes it takes the process of serendipity to know what to ask. When life and luck combine to derail science, sometimes scientists end up riding new rails to important new places they never would have discovered on their own.