Anouncer:
Willkommen am Salk Institute Wo Heilungen beginnen podcast, where scientists talk about breakthrough discoveries with your hosts Allie Akmal and Brittany Fair.

Brittany Fair:
I’m here today with Dr. Reuben Shaw. He is a professor in the Molecular and Cell Biology Laboratory and the director of the Cancer Center at Salk. His lab focuses on harnessing our knowledge of metabolism and diabetes in order to target the fuel lines that cancer relies on. Welcome to Wo Heilungen beginnen. Dr. Shaw.

Reuben Shaw:
Danke.

Brittany Fair:
And just to get started here, can you tell me a little bit about your path to becoming a cancer researcher?

Reuben Shaw:
I was a biology major in as an undergraduate and I had the good fortune to work in a research lab that was starting to study some of the early genes that were connected with cancer. And one of the explosive, exciting new things that had come up in the eighties was that disease genes, single genes that were controlling and responsible for all kinds of inherited diseases like the breast cancer genes, BRCA1, BRCA2, too, other types of inherited forms of cancer, were just being discovered. These things were being discovered in real time. They weren’t even in the textbook yet. I couldn’t believe how exciting that was. They had had the good fortune of spending a couple of years while I was taking classes, but for work study, basically, I worked in a research lab for the last two years and for two or three summers while I was an undergraduate and then went from there, moved to Boston and started my graduate career.

Brittany Fair:
And you went to graduate school to work on cancer genes at MIT. Then you stayed in Boston for your postdoc in a lab at Harvard medical school. This time working on a brand new gene found to be altered in lung cancer.

Reuben Shaw:
Yes, so I was really had been to single-mindedly pursuing this main project that I had chosen to work on for years, but I could not technically figure out how to unravel, how to crack, how this one particular enzyme was working. The enzyme I was working on is a gene that’s altered in about a quarter of human lung cancers.

Brittany Fair:
And what was the name of the enzyme?

Reuben Shaw:
It’s called LKB1. It’s an enzyme has a particular activity called kinase activity. A kinase is a type of insight that passes a chemical group while the phosphate onto a specific site in another protein.

Brittany Fair:
Kinases are a type of molecular switch, some of which turn cancer on or off. Dr. Shaw continued his work to understand LKB1 during his postdoctoral studies.

Reuben Shaw:
I already was a postdoc four and a half year. So I either was going to crack what that enzyme did in the next year, or I would just never crack it.

I knew two other top labs in the world, and they were trying to crack it using different methods from when I was doing, but they couldn’t crack it at all either. It was just that this particular cancer fighting enzyme was elusive.

Brittany Fair:
So, were you able to crack it?

Reuben Shaw:
I was able to crack it. It was the discovery that the central thing that this anticancer gene was directly passing the signal to. And it was regulating was not an obscure, never thought about enzyme. It’s called AMPK and, separately, it was known to be turned on by the most widely used type II diabetes drug in the world Metformin. No one knew why Metformin worked at all. And this looked to be like, it might represent a major part of why Metformin was a good drug and continues to be such an important drug.

Brittany Fair:
So, you’re saying that this anti-cancer gene LKB1 and the drug Metformin both act as switches on the same metabolic pathway, meaning that you found a metabolic link between diabetes and cancer.

Reuben Shaw:
And I remember being in the dark room where you develop these films. And so it’s a red light. It’s less like, you know, it’s like a black light, but the lights only red. And I was sitting there waiting for it to come out. And at that point, you also it’s like four and a half years. So at any rate, the film came out and I looked at it and I just, I couldn’t believe the result. It was just one of the most black and white things that I’d ever found in my career. And I knew the potential impact of what was on that piece of film. And I actually stood there for a long set of minutes, making sure I was looking at it the right way, everything was lined up the right way. And then I, I kind of knew that day. I stayed in the dark and just saying that I’m like, yeah, this is true. Even if other people find it also like no one is going to believe it, no one is gonna believe this.

This cancer gene was regulating this metabolism, the anit-diabetes gene. And as I predicted that day in the dark room, people really hated this idea. We tried to publish it in a very prominent journal. And, uh, the reviews we got back were in fact, along the lines of this cannot be, I cannot figure out what’s wrong with this paper, but this is literally not possible that a card carrying, respecting a feed, a cancer-fighting enzyme is like regulating this metabolic kinase. Like absolutely not. And it turns out we couldn’t overcome that must-be prominent persons opinion. In the meantime, while we were trying to fight it too, they published in that journal. It came out into other smaller. And in fact, one of the world’s first online journals from a team of two different, uh, famous researchers in Scotland. So they also found it by a completely different approach.

Brittany Fair:
And what was it like then after all this time you had this amazing discovery that to then not be able to get published. And on top of that, have someone else publish what you had found?

Reuben Shaw:
That was a tough fall. I’m not going to lie to you. That was a very, very tough fall. So I just thought, yeah, okay, that’s fine. Like this is, this is a huge discovery. It really is true. And so I’m going to keep trying to test and prove all the ramifications of this. If this is true, the LKB this cancer-fighting enzyme turning on this diabetes-fighting enzyme, does that mean that the anti-diabetes gene has anything to do with cancer? And conversely, could it be that this cancer-fighting enzyme as anything to do with diabetes and metabolism? And so the next thing that I discovered, while I was still in Boston, was using mice, we could isolate the tumors and study them, but I started looking at them specifically in liver and in muscle, the same way that people in the diabetes or exercise physiology field would do to see, is it true that this cancer-fighting enzyme has anything to do with exercise or diabetes? But I found the answer and it was a resounding yes. And that paper came out in an important journal. So I went on the job market one year later.

Brittany Fair:
And what brought you to Salk?

Reuben Shaw:
The reason I came to Salk was very straightforward. It was that idea of cutting across disciplines and cutting across different types of knowledge to pursue, uh, the answers by any means necessary. So knowing these kinds of details of how cells survive starvation and survive different types of therapeutic attack, that’s a major focus of my lab now, which stems out of some 15 years later, us continuing to decode deeper and deeper how this AMPK enzyme and other enzymes like it reprogram the cell to adapt to different environments. And then trying to find ways to develop new therapies, to turn up or turn down those key pieces at the right time to fight both cancer and diabetes. That’s what keeps me waking up in the morning is knowing that we are going to discover things that no one knows, and some of these are going to lead to new therapies.

Brittany Fair:
You’re also the director of the Salk Krebszentrum. Can you tell me a little bit about that?

Reuben Shaw:
Yes. So, um, the salt is one of seven so-called basic research dedicated NCI cancer centers. So, the NCI is the National Cancer Institute. That’s the arm of federal funded research, biomedical research, that is dedicated to cancer. Being the director means that you oversee are in charge of corralling and maintaining interest around certain areas dedicated to that broad topic of cancer. It is very hard to receive and maintain this NCI designation. This is the good housekeeping seal of approval. So the Salk, we were actually one of the first designated cancer centers in the entire country. When this system was first created by then president Nixon in 1971. The newspapers famously said, “Nixon declares war on cancer.”
Nixon Recording:
“I will also ask for an appropriation of an extra $100 million to launch and intensive campaign to find the cure for cancer. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease.”

Reuben Shaw:
So, we’ve had NCI Cancer Center funding now for 46, almost 47 years. So now I’m carrying the torch to make sure that Salk’s efforts at cancer and cancer research remain at the forefront for the coming decades. That’s really my mandate.

Brittany Fair:
And are you also guiding the Initiative zur Überwindung von Krebs?

Reuben Shaw:
I am. That’s another new specific, uh, scientific initiative. We are going to take on five of the world and the countries deadliest forms of cancer. And we are specifically both fundraising, but raising awareness about what the current treatment options are for those five. Uh, and then really trying to accelerate and enhance our research efforts and our partnerships to go after those five forms of cancer.

So those are pancreatic, glioblastoma, triple negative breast cancer, ovarian cancer, and lung cancer. But the reason that we set aside those five, uh, is because the, um, percentage of deaths from those has not really notably improved very much compared to some of the other forms of cancer for which there has been at least modest progress. One of the bigger problems is that there’s no detection. You have no way of knowing it. And you actually have these tumors within your body for often more than a decade before you have any symptom whatsoever.

What we are set about to do though, is to take a multidisciplinary approach to attack these specific types of cancer. We can take advantage of our knowledge decoding these starvation biochemical pathways to attack cancers and attack unique metabolic needs, effectively food needs, uh, that the tumors have another one of the approaches is to fight inflammation, which is a hallmark of many types of cancer, especially certain forms of breast cancer, especially colon cancer. And another approach which Salk has had great historical success in is in decoding the genes that underpin different forms of cancer. Finally, a newer approach, which is very exciting within cancer, uh, is the discovery in the past decade, really of, uh, concrete ways to harness the immune system to attack tumors themselves. It turns out though that cancer cells evolve mechanisms to deliberately prevent that, uh, self-disclosure of the tumor cell to the immune system.

Brittany Fair:
Hmmmm they’re hiding.

Reuben Shaw:
Yah. It’s stealth. What Salk does is this is really a think tank where people with different expertise in a small environment, overlooking the Pacific Ocean come together and brainstorm and do experiments at the intersection of fields. But I think that is what the Salk does best is just pursues the scientific questions to their fullest end, and then crosses the boundaries. That’s where we just go tripping over those lines, jumping into the next field and hiking the next mountain. That’s what we do. And that’s what we will continue to do. So, I am excited for the future of the Salk Cancer Center and I am extremely excited for the next couple of years in the Conquering Cancer Initiative. Well, thank you so much,

Brittany Fair:
Thank you, Dr. Shaw, for sharing your story of how you became a scientist. And thank you for telling us about your lab and the Conquering Cancer Initiative. Um, I’m really excited to see what comes of everything.

Reuben Shaw:
Thank you so much. Take care.

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