Myron Ignatius, PhD, is assistant professor of molecular medicine and a member of the Greehey Children’s Cancer Research Institute at The University of Texas Health Science Center at San Antonio. Here he speaks about his research using zebrafish to track cancer recurrence, potentially leading to better treatment options for those who relapse.
Interview conducted by Ivanhoe Broadcast News in October 2017.
Behind you are ten thousand fish?
Ignatius: We have between seven and ten thousand zebra fish and when we’re at full strength we’ll be at about fifteen thousand.
These zebrafish… Usually you go into a lab and you see mice and rabbits, these guys here what is it that’s so special about them?
Ignatius: The value of zebrafish as a system to study cancer or even disease, in humans, is the fact that they’re really tiny and you can keep many fish per tank. Also, when they breed and they mate you get between fifty and two hundred eggs per mating and so if you count that we can mate maybe a hundred pairs of fish a day, we can have as many as many as five to ten thousand embryos to study. And so what this allows you to do is genetics because human disease is caused by mutations in genes and if you’re able to follow genes through genetics you can find a phenotype or a defect associated with a disease and then follow that up. And so that’s where the fish have really been instrumental because of numbers. We also can see through how embryo development happens outside the animal; so we can look at it under the microscope and follow animals for days, months and years. And then because of numbers we can follow cancer biology, for example, how cancers form. Finally, because fish are transparent we can look in the tumor and say, these are stem cells, this is a blood vessel, and ask what are they doing.
These guys are like tailored to show you what that cancer is doing? How do you look at them, through some sort of microscope or visually?
Ignatius: The way we study cancer in fish, some of the advantages are inbuilt, such as, the fish are transparent and so you don’t have to work on that. We can work on that a little bit because we can remove pigmentation. So zebrafish have stripes but you can have a mutation that removes stripes and the fish community named the mutant Casper for the ghost which you can see through. But that’s the inbuilt advantage. The other thing that we do is we make transgenic lines. And what I mean by transgenic is you can label fish cells with a color, a green florescent protein or a red fluorescent protein or a blue fluorescent protein. And if you label different components of the tumor with different colors you can actually follow those cells. Then, since they’re fluorescent we can put it under a fluorescent microscope and keeping the fish alive. The we can actually image in real time what the tumor cells are doing. We can take tumor cells to a sorting machine after we take the tumor out, sort the cells out and then re-transplant back into other animals all because you can see the colors.
Is this viable in primary tumors or just primarily for secondary tumors?
Ignatius: So in my research, the problem in the sarcoma which we study and with most childhood cancers is there’s a high cure rate in primary tumors. But it’s a cure five year survival rate. The five year survivor rate is about between sixty and eighty percent. In most tumors, the twenty percent of patients that relapse there is no cure and they do not respond to any of the primary treatments. And so there’s really an urgent need to discover treatments for relapse. And while this is common to childhood cancer, the problem with relapse is also common to adult cancers. So what we try to model is relapse in patients. We get primary tumors, but we use transplantation as a way to show how relapse occurs. And if you think how relapse occurs in patients, first the patients comes to clinic they get their tumors treated, if it’s a solid tumor by resection and they get radiation. And then they go back home and maybe get more treatments, but then they effectively are monitored for if a tumor comes back. And so when the tumor comes back, that’s what they doctors see. So what we do is instead of radiation, we do transplants. When we transplant the cells into another animal it has to survive in a very hostile environment. And so that’s what tumor cells do, they survive in a hostile environment when you treat them. And so transplantation mimics relapse and this is what we study.
Is the hope here that you’re going to be able to intervene in that process at an earlier point?
Ignatius: Sure, there are two aspects to our work. One is definitely we’re looking for genes that drive initiation of the bulk of the tumor because then we can maybe screen patients even before you know they’re patients and say if you have these genes you’re predisposed to cancer. But on the other end of the spectrum the problem really is we have children who have cancer for whom there’s no treatment. The hope is then we take our fish and model what’s causing that relapse. And if you can model what caused the relapse then maybe you can then start treating them with drug treatments that affect how their relapse occurs. And so the hope ultimately is when a patient comes in with the tumors, we know what mutations they have, they get treated and they go away. Typically tumors take a year to two years to come back and in those two years we can model what’s going to come up.
In terms of a time line you’re doing research, how soon do you expect this to be ready?
Ignatius: I tell people research takes time. And really what I just told you is the hope and that’s the hope of a lot of scientists like me who actually are in the field and know the problem. But cancer it’s a big problem and it’s going to take one gene at a time. I don’t think my research will benefit patients right away and that’s a false hope I’m giving to people if I’m saying that it will. But I know what we find will be useful to other scientists making discoveries who are trying to use what we do to then find cures that go into clinical trials.
What is the length of time on say a fish’s life and what do you do with these guys on a day to day basis?
Ignatius: In terms of the lifespan of zebrafish, they live as long as mice, so about two years. But they breed for about a year and a half. But our tumors come up in ten days so we inject the tumor causing gene and we get tumors by ten days. Between ten and thirty days most of our tumors come up. So our experiment is really thirty to sixty days. And then we can take those tumors transplant them, do all our experimental analysis. Our model ends up being one of the fastest tumor models around, we just got lucky. We use the same tumor causing gene and we get a tumor really quickly developing in the time frame a human patient would get it. And then we can follow the biology, so that’s the clear advantage of this model.
A guestimate, five years, ten years, what are you looking at?
Ignatius: I’m hoping to find gene pathways to target with all the new tools available. For example, when we take out tumors; we can sequence them, the sequencing that is being done with human patients’ tumors gives us a better idea what mutations they have. The hope is if there’s a drug currently on the market that works on a mutation or pathway, we can test it on our zebrafish cancer model and if it works we can bring it into the clinic immediately. Just to give you an example, I was part of a project with my friend Eleanor Chen (First author), now at the University of Washington in Seattle and we were both in Dr. Dave Langenau’s lab in Boston. So we did a screen for drugs that affect our tumor type. We can take our tumor and grow the cells up and put them in zebrafish, we transplanted about three thousand animals. Every week you do transplant about a hundred fish and screen about ten drugs. Now in a mouse, if you say have to screen a hundred ten drugs it would probably take about two to three years and probably cost you maybe a million dollars at least because it costs more. We screened a hundred and ten compounds in six months, it still takes time, but what was interesting from our screen is we found ten compounds. And of those ten compounds there was a group at Novartis who were doing a screen in cell culture, which is what pharmaceuticals typically do. They use plastic plates, but the cells growing on a plate they don’t have vasculature, they don’t have the other cells which are normally present in the body, so they found a subset which overlapped. One of the things we are finding in the fish, we’re also going to find what they find in the pharmaceutical companies. But additionally, we’re going to find things that affect the vasculature, because it’s the whole animal right, we are also going to find things that are in the normal body that influence how tumors grow. Which if you think about it, tumors don’t grow by themselves, rather they actually require normal non-tumor cells to make them grow better. And those are the things which other people working in cell culture just aren’t going to find.
How old is this study with the zebrafish, how long has this been around?
Ignatius: Some of the fish research was funded in the eighties by NIH. The big discovery is in the nineties, there were two big volumes of research papers published where we made a splash about what we could do in zebrafish. The first fish cancer model was published in 2004. People were studying mouse tumor models in the seventies and earlier. The first model was made in 2004, so we don’t have a whole range of zebrafish cancer models, so every time we find something new, it might just be a new model by which we can model another human disease. And so there are about ten to fifteen zebrafish cancer models now, we don’t represent all human cancer but the genes we’re pulling up are the same that are coming up in mouse and also in the human studies, so a lot more growth can be expected.
So for someone sitting at home watching this story right now and looking for hope what would you tell them?
Ignatius: My personal goal in life is to make a difference. If I can affect one patient, I think I would have done a lot, because cancer is a hard disease and it’s not one disease. Most cancers are different, blood cancers they’re different from neuroblastoma, which is a tumor of the sympathetic nervous system. But I think we have the tools to ask the questions. And if you can ask the questions and then screen for drugs, we can have candidates that can go for clinical trials. That’s hope, so I would say there’s hope.
END OF INTERVIEW
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