Search for tag: "discoveries"

The following is a summary of this episode.

The scientific laboratory is the birthplace of new ideas, rooted in a fundamental understanding of how nature works. While impactful on its own, sometimes discovery is just the beginning. Translatingideas to interventions for improving human health takes added insight and dogged perseverance.

Achieving this milestone is a rarity, but within the past year, three clinical trials have begun testing disease treatmentsbuilt from basic science discoveries at University of Utah Health. It could take years to determine whether a novel therapy for the deadly amyotrophic lateral syndrome (ALS) and two for a familiar foe, acquired immunodeficiency syndrome (AIDS), could become broadly available. But without a start at the lab bench, these possibilities wouldn’t even exist.

In this episode, host Kyle Wheeler interviews Wesley Sundquist, PhD. Dr. Sundquist is the Samuels Professor and Co-Chair of the Department of Biochemistry at the University of Utah. He is also a member of the Cell Response and Regulation Program at Huntsman Cancer Institute.

Kyle and Dr. Sundquist discuss the ordeal of discovery and how a career’s worth of workcan lead to interventions. Additionally, they discuss Dr. Sundquist’s work on HIV that has led to Gilead developing a new intervention. Dr. Sundquist also shares thoughts on the impressive work on HIV done by the Michael Kay, MD, PhD lab.

For more on these discoveries and others from University of Utah researchers that have led to medical interventions, visit Pioneering the Future: From Basic Discovery to Bedside.

Don’t miss out on all the discoveries happening at University of Utah Health. Visit the Discovery & Innovation Digital Collection.

Interviewer: Headlines are talking about a discovery that could lead to a one-size-fits-all cancer treatment. Is it realistic or is it hype? We'll talk about that next on The Scope.

I'm talking with Dr. John Phillips, professor of hematology at University of Utah Health. Dr. Phillips, first of all, what was your involvement with this research discovery?

Dr. Philips: We have been involved with a group at Cardiff. I met the senior author, Professor Andy Sewell when he was a postdoc here at the University of Utah 25 years ago. And our collaborative relationship has extended the last 25 years, and we work together at solving complex biological problems. And we collaborate on a number of things, but in this case, Professor Sewell came to me specifically asking how to screen for molecules that were required for cancer recognition by these T-cells.

Interviewer: So since this paper has come out, what's been the response?

Dr. Philips: It's been sort of overwhelming in some regards. First of all, I have multiple emails every day since the last a week and a half from people around the globe really who are either scientists wanting to know exactly what methods we used in our screening process to individual people who have identified my email address and are sending me questions like I have a family member, a friend who has some type of cancer that they want to be treated with this therapy.

Interviewer: So I mean, a lot of excitement, a lot of interest. What is everybody excited about? What did this paper show?

Dr. Philips: Well, the T-cell that we are describing in this manuscript is a T-cell that can recognize an antigen presented on some types of cancer in the context of a molecule called MR1. And the interesting thing about this is all humans have nearly identical MR1, this is why people are saying that it's sort of a universal anti-cancer therapy.

Interviewer: The excitement is that this could lead to an immune cell therapy that could treat many types of cancer in many people, is that the idea?

Dr. Philips: So, yeah, the idea is so I think, there has been a lot of excitement recently in the sort of the last four or five years about engineered T-cells called CAR T-cells that are specifically manufactured from a patient to recognize a very specific molecule on a tumor type. And those cells are grown in culture, in a laboratory from the patient and then given back to the patient where they attack a very specific type of cancer. These have been very, very beneficial for people. And this is just another type of T-cell can potentially do the same thing but without that engineering aspect needed to be applied to it.

Interviewer: So what are the limitations of the CAR T-cell therapy that this work with this cell might overcome?

Dr. Philips: Well, right now, the, the majority of CAR-T therapies are directed towards hematologic malignancies, so leukemias and lymphomas of specifically of the B-cell origin. There are things certainly in the laboratory and that commercial entities are working on to sort of expand those CAR-Ts to more solid tumor types but right now it really is hematologic tumors. What the molecule that we're looking at is directed towards is it certainly will work on hematologic tumors, but it will also work on solid tumors which expands the scope really of the types of cancer that can be treated.

Interviewer: And so how did you go about, or how did this research team go about figuring that out? What was the work that, you know, kind of showed what this T-cell could do?

Dr. Philips: Well, the T-cell was actually identified several years ago and the team in Cardiff identified it as a cell that could kill cancer cells. They expanded the panel of types of cancer cells that they could assay in the laboratory and they found, you know, what types of cancers it would and would not kill.

And then they were interested in what molecule is being seen, where like, why does this T-cell want to kill this cancer cell? And that's sort of where I became involved using as in the title it says CRISPR-Cas9 screening method. So we used a CRISPR method which goes in and modifies DNA. So we went in and knocked out every single in the genome and then screened for cells that were able to escape being killed by this killer T-cell.

And once we had identified those cells, we can then look at what molecules on the surface are being recognized and that sort of that work was all done in collaboration with this team at Cardiff.

Interviewer: And so, you know, there are a lot of exciting implications, but we're actually a long way from getting to an actual treatment that can be applied to patients. Can you talk about that a little bit? If you had to talk to some of these patients who are emailing you and who are hopeful that this will lead to something, what would you tell them?

Dr. Philips: Well, so we've done a lot of work in the laboratory where we sort of have characterized the molecule and the interactions with the T-cell, we've even translated that to a mouse model but that's really about as far as we've gone. What we now need to do now is we need to figure out how to translate that preliminary animal work into like a phase one study in humans.

We have not done that, you know, working with academic partners and commercial entities. We hope to sort of move that forward in the near future but during this conversation that really has not occurred yet. And so this will take quite a bit of time, I won't give you a number of days, weeks, or years that it's going to take, but this will take a significant amount of time in order to sort of move forward to actually go from a laboratory observation to a clinical trial and then sort of a commercial cure for certain types of cancer.

Interviewer: And so if this treatment were to come to fruition, what would that look like do you think?

Dr. Philips: Well, so I think in this case, what it would be is there would be a manufacturing facility that would expand this type of T-cell. And we would do clinical trials to say, if we gave you, you know, 10 to the 10th of these T-cells, they would be sufficient to kill a tumor burden of, you know, a certain size or mass. And I think it would take, you know, several trials to figure out, you know, what's the optimal dosing, what's, you know, do we want to give multiple rounds of these cells? So I think, you know, again, because this is really a laboratory observation and hasn't made it to the even in the phase one clinical trial stage, we need to be a little bit cautious in what we say as far as what this is going to look like as an eventual therapy.

Interviewer: Sure. Nevertheless, are you excited by what's come out so far in the research?

Dr. Philips: Absolutely. I think this has been very exciting. I mean, I think, you know, I have published quite a few papers in my scientific career. I don't think any publication that I've been a part of has had global response that this has had. You know, I'm getting email from truly from people across the globe, when I look at the metrics associated with this manuscript in "Nature Immunology," this has gone, I guess mainstream very, very quickly. And, as of you know, as of this morning, there were 128 articles that were sort of written in other media outlets regarding this. This certainly is the biggest impact paper that I've been a part of.

Interviewer: Well, very good and congratulations. Is there anything else you'd like to say?

Dr. Philips: Well, I think this once again illustrates that science today is very collaborative. It's these big discoveries, you know, they're really team-based discoveries. And, you know, I was just a small part of this as were people in my laboratory and that without sort of this collaborative effort, it's difficult to make these discoveries.

Interviewer: Very good. Thank you very much.

Announcer: Examining the latest research and telling you about the latest breakthroughs; The Science and Research Show is on The Scope.

Host: Aids is one of the most significant public health challenges worldwide. My guest, Dr. Sundquist researches how HIV infects the body, with the goal of finding ways to stop it. His outstanding research contributions recently earned him a seat on the prestigious National Academy of Sciences.
You investigate how the human immunodeficiency virus, HIV, the retrovirus that causes AIDS infects people?

Dr. Sundquist: Yes, the thing we're most interested in right now is how the virus interacts with the host cells that it infects. So viruses are fairly simple replicating machines. In the case of HIV they only make 12 proteins and that's as compared to 20,000 proteins that a human cell would make. And so one of the interesting aspects of viruses is that they have to use host cell machineries and pathways to replicate and that's something that interests us.

Interviewer: Why does that interest you? What do you hope to gain by learning that information?

Dr. Sundquist: I guess there are a series of reasons to do it. One is a simple curiosity, I think; understanding the world around us is a valuable goal. But of course we would expect that understanding leads to important spin-offs. And two, areas where one can envision such spin-offs and that have been realized in a number of cases, one is in therapy, so of course HIV is still a very important biomedical research problem. There are literally more than 20 million people who are HIV positive worldwide and so that's a huge health problem, and drug resistance is an increasing problem. And so we need to understand new vulnerabilities of the virus and we can only do that by understanding how the virus replicates.
But maybe a less obvious but still very important aspect of this type of work is that we can learn a lot of cell biology as well. So viruses, because they use host cells pathways, are actually the ultimate cell biologists, and so if we follow them we can learn a lot about cells work. And that's been famously, for example, oncogenes, which are the genes that go awry when people get cancer were discovered by studying retroviruses and understanding how they transform cells. And so this is something that keeps happening again and again is that we study a good model system and make fundamental discoveries that have impacts in other areas that we couldn't have predicted.

Interviewer: So can you talk about one area of your research, what are you focusing on?

Dr. Sundquist: Sure, one of the things we work on fairly intensively is understanding how the virus exits cells. So if a cell is infected in order to spread the infection the virus has to leave that cell. And we're interested in how that happens. And we got interested in that in a collaboration initially with Myriad Genetics where we were able to show that by a tech company here in Salt Lake City. And together we were able to show that the virus uses a host cell pathway called the escort pathway to leave cells. And the interesting spin-off, that was just over a decade ago, the interesting spin-offs are that we now understand that almost all envelope viruses use the same pathway to leave cells, so this has turned out to have quite a global impact on our understanding of viruses in general.
But the other thing that's happened is that this pathway, which of course performs important cellular functions, the cell isn't making these proteins so they can be infected by viruses, but rather to do other things. It turns out that the most important function of this pathway we now think is in the final step of cell division. And so a lot of what we do now is study how cells divide, rather than how viruses leave cells, even though we got into the problem through our interest in viruses.

Interviewer: Okay, so the escort pathway actually is something that occurs in human cells, but the virus needs it to get out of the human cell so it can infect other cells; is that right?

Dr. Sundquist: That's exactly right.

Interviewer: Okay.

Dr. Sundquist: And that's fairly common; as I said HIV and other simple viruses have only a dozen genes and so they have to use host cell pathways and reprogram them in order to do many of the steps of viral replication.

Interviewer: Why do you think this work is so fascinating? I mean, you've been studying HIV biology...

Dr. Sundquist: Why can't we quit?

Interviewer: Exactly. Is it an addiction?

Dr. Sundquist: Yeah, it is a little bit of an addiction. I think that you have on the best days, and they don't happen very often, you have a feeling that you're seeing something you and your students and your post-docs are seeing things that nobody has ever seen before, and understanding things that nobody has ever understood before. And that's sort of an exhilarating feeling, and it doesn't happen so often. Much of what we do is quite routine, but I think the idea that you can discover something that hasn't been known before is quite exhilarating.

Interviewer: What are you most excited about right now, in looking at that...?

Dr. Sundquist: The thing that I'm most excited about right now? There's are a subset of machinery of the escort pathway that we think forms filament strings basically and that those strings act like a noose from inside the neck of a budding virus and pinch the membrane together so the virus can leave. And they seem to do the exact same thing when cells divide. So they sit at the region between the two dividing cells and pull the membranes together. And we have a very talented young faculty member in our department, Adam Frost, and together with Adam Frost our lab and people in our lab have been able to I think make real progress in understanding the structure of those filaments. That's quite recent; we haven't yet published that. And it gives us at least ideas about how the noose might work.

Interviewer: I know Adam Frost has come up with these really cool visualization methods for these machines and cells. Have you been able to see a picture of this noose?

Dr. Sundquist: Yeah, we have at least what we think is the first picture of what it looks like. And I should say that we have a long-time collaboration with another structural biologist, Chris Hill, who is also in the Department of Biochemistry. And between the two of them they've given us a huge number of pictures of how the escort machinery works.

Interviewer: It sounds like cliche, but a picture is worth a thousand words, right?

Dr. Sundquist: It is.

Interviewer: But what can looking at a picture of that structure do for you?

Dr. Sundquist: Yes, I think if you view this in analogy let's say to a car, you have no idea of how an engine works until you look at an engine and see what it's parts look like and how they all fit together. And that still doesn't tell you how it works. But it means that now you have ways of thinking about it in concrete terms, what a piston might do, and so forth. So I'm a big believer in structural biology and other ways of actually seeing what things look like. I think that often gives you clues about how they work.

Interviewer: You seem to not be afraid to collaborate with people who do different types of research than you do. Would say that's a fair assessment?

Dr. Sundquist: I hope that's a fair assessment. I think that one of the really fun aspects of science is that you have interesting bright people who are doing different but complementary kinds of things, and some of the most exciting science gets done when they get together.

Announcer: Interesting, informative, and all in the name of better health.

Dr. Lee: Good afternoon, everyone. Welcome to the show. I'm your host, Dr. Vivian Lee. I'm the Senior Vice President of the University of Utah Health Sciences. Today, we're going to talk about breast cancer. About one in eight women will develop breast cancer in her lifetime, and it is the second leading cause of cancer death in women.
One of the misunderstandings about breast cancer that we're just starting to understand now better is the fact that breast cancer is not just one disease, but it's actually many different diseases. That's a really important point to understand. Because breast cancer is different diseases, it means we have to have different treatments for women with breast cancer.
My guest today is Dr. Alana Welm, who's a researcher at the University of Utah's Huntsman Cancer Institute. Dr. Welm and her colleagues are making news all over the world because they have found a way to grow pieces of a woman's breast cancer in mice, and that's really going to transform the way we think about breast cancer treatment.
Now, I have read that your research means that we're going to treat women in a very different way where in the past we might try a treatment and it may work or it may not work. The women almost feel like they might be guinea pigs because we don't know how to treat them. Instead, your approach with these mice is almost like making a guinea pig for every patient. Is that a fair description of your work and its implication?

Dr. Welm: That's right. It's a science that's telling us now that breast cancer is probably more, like, ten different diseases. Currently, in the clinic, it's treated as though it were, really, three types of breast cancer. What we're doing is trying to personalize the therapy so that we can grow an individual person's tumor in a mouse and actually use that mouse or that tumor line as a way to determine what are the best therapies for that particular women are.

Dr. Lee: Well, if there are really ten different types and we only know about three, then what does it mean if a woman comes in now? If a woman comes into our clinic at the Huntsman Cancer Institute, how do we treat them now?

Dr. Welm: Currently, breast cancer is heavily over treated, believe it or not. So, we really are treating ten women for the benefit of three. We know that about 30% of breast cancer patients will go on to develop a relapse or a metastasis, and metastasis is what kills patients with breast cancer. Because we cannot determine which three women out of the ten will go onto develop metastatic disease, they are almost all getting treated with really toxic chemotherapies. So one of the goals of our study is to be able to use these tumors grown in mice to determine which ones are the most aggressive ones and then modify treatments according to that particular tumor.

Dr. Lee: One of the most interesting aspects of your work was that when you took these pieces of a woman's breast cancer and you put them into mice, the behavior of those tumors actually was just like when they're in people, right? They not only grew like breast cancers, but they also metastasized. What was it about how you did it that was different from what everyone else had previously tried to do and failed?

Dr. Welm: What we did was expand on an idea that we don't want to culture the tumors before we put them in the mice. So we don't want to put them in the lab on a petri dish like everybody had done before. Instead, we put them directly into the mouse breast tissue or the mouse mammary gland. This environment is so much like the human breast that it allowed these tumors to not only grow, but also to behave very similar to how tumors behave in patients.

Dr. Lee: One of the questions that came to my mind when I first read about this research was, won't it be easier to just take a piece of the breast cancer tissue, look at the DNA of it, and then figure out which of those ten types it is just from that?

Dr. Welm: We are doing that. We're examining the mutations in individual tumors. However, we believe that you have to combine some functional analysis of the biology of that tumor together with the genetic information. So just knowing that there's a mutation in a gene doesn't necessarily tell us about how that tumor will behave in terms of metastasis or in terms of response to therapy. Our idea is to really combine that genetics analysis with a functional assay of tumor biology and tumor behavior in order to make the best treatment decisions.

Dr. Lee: It's sort of, like, that old line that it's not just the genes but the genes and the environment? Just putting some of those breast cancer cells somewhere in the mice, but that didn't work but putting it in the breast tissue itself worked. So there's something about the genes and environment relationship that's important.

Dr. Welm: That's exactly right. The other advantage to using this type of an approach is being able to modify the genetics of a mouse in concert with asking about tumor biology gives us a chance to actually examine the interaction between the genetics, the tumor biology, and the host response to the tumor.

Dr. Lee: We have some questions from some listeners online. Laurie, in the West Valley asks this question. "The women in my family have breast cancer. My mother had it. Two of my aunts had it, and now my sister has it. What does that mean for me, and what does this research mean for people like the women in my family?"

Dr. Welm: We know that cancer is a genetic disease, meaning it can be hereditary. As you probably know, we made the original discovery of the BRCA mutations.

Dr. Lee: The breast cancer genes.

Dr. Welm: The breast cancer genes that are carried through certain families and contribute to a small proportion of breast cancer, but those patients who carry those genes have very, very high risk of breast cancer. That type of inheritance is what seems to be manifested in this family. Partly as a result of these kinds of discoveries in Utah, we have a fantastic high-risk breast cancer clinic that's directed by Dr. Saundra Buys at the University of Utah and Huntsman Cancer Institute. They can test people for these genes. They can provide genetic counseling as to how they might want to modify either their lifestyle or even take surgical precautions for breast and ovarian cancer in the case of BRCA mutation. They actually follow these patients. So rather than that just being the end of, you know, "Okay, here's mutation, and this is what it means for you," we actually want to be able to follow them with high screening.

Dr. Lee: Here's another question from Sandra in Murray. Sandra asks about men. "Can men get breast cancer?"

Dr. Welm: Men do get breast cancer. It's relatively rare. It's only about one percent of breast cancer that happens in men, but it is a problem, and it's not very well recognized.

Dr. Lee: Does it run in families the same way as women? We don't know?

Dr. Welm: We don't know. Yeah.

Dr. Lee: Since it's so rare, we just haven't done enough research in that. Well, Dr. Welm, thank you so much for being my guest today.

Dr. Welm: My pleasure.

Announcer: We're your daily dose of science, conversation, medicine. This is The Scope, the University of Utah Health Sciences Radio.