in 2016 Elizabeth Turner saw a need to increase access to genetic counseling. This was the inspiration for her to start advanced tele genetic counseling. Now during a pandemic. There has never been a better time to book a telehealth genetic counseling, consult cancer genetics is one of the many areas that A T. G. C. Specializes in their team of genetic counselors are specifically trained to help understand, interpret and navigate complex genomic information. All genomes have a story to tell. If you're ready to learn yours, head over to a T hyphen G C dot com to book your appointment with a genetic counselor today, I receive a lot of emails from listeners interested in genetic careers and I love connecting and providing resources. One of those is keck Graduate Institute genetics programs in southern California. K G I offers a Master's degree, Internet counseling as many of you know, but for those of you looking for something slightly different, kg also has a first of its kind graduate program in genomic data analytics. This to your master's program gives students the opportunity to work side by side with applied life scientists and future genetic counselors while gaining hands on experience with technology and information that are revolutionizing the future of medicine.

Learn more about the program of visiting k G I dot E D U slash DNA. Today. Again, that's K G I dot E D U slash DNA today. How is it that we find ourselves surrounded by such complexity, such elegance, the genes of you and me, jeez you you're all made of DNA. We're all made of the same category in a we're all made of being Hello, you're listening to DNA today, a genetics podcast and radio show. I'm your host. Kristine. On this show. We explore genetics impact on our health through conversations with leaders in genetics. These are experts like genetic counselors, researchers, doctors and patient advocates. My guest today is Dr Kat Arney, a fellow genetics podcaster. She is an award winning science writer, author, presenter, broadcaster and public speaker. Her voice will probably be familiar to you as she has appeared on radio and tv around the world, including BBC radio for the naked scientists and naked genetics podcast.

And more recently as the host of the genetics Unzipped podcast. She's written for outlets including the Times educational supplement, BBC Science Focus, the daily Mail, wired BBC online. The Guardian and new scientists. Dr Arne has authored three popular science books, herding Hemingway's cats, understanding how our genes work, how to code a human and her new book Rebel cell cancer evolution and the new science of life's oldest betrayal, which we're going to discuss in this episode. Oh and stick around to the end to find out how to enter to win your own copy of rebel cells. Before we bring Dr Kat Arney on the show. I wanted to thank all of you listeners again for your DNA Today nominations and votes that led us to the best 2020 science and medicine podcast award. I want to continue this momentum by getting listed on podcast magazines, Hot 50 list. All you have to do is go to podcast magazine dot com slash hot 50 and type in DNA today hosted by myself, Kira Deneen. Then just click cast my vote. We would so appreciate it.

And to make it easier. There's a link in the show notes to today's episode as well as the blog post on D. N. A podcast dot com. We're also going to blast out on social media. We need all the votes we can get since we are competing against a ton of other podcast from virtually every other category. This is a compilation of the Hot 50 podcast of every category. So we'd really appreciate your vote again. That's podcast magazine dot com slash hot 50. Thank you so much cap for coming on the show. I'm really excited to dive into all this and after hearing you for years on naked genetics, it's so exciting to have you on the show here. Well, thank you. It's nice to hear your voice as well, sort of direct to my ears. Yes, it is different from, I'm always listening to you now you're talking back so it's a little bit different here. Dream. It is. Yeah, definitely. And I really enjoyed your book Rebel Cell. It was so interesting that you explore cancer from an evolutionary lens. What makes this evolutionary perspective more accurate method to understanding cancer development. Then some of the more traditional ways of understanding it.

So there's kind of two different angles on that. I think one of the conventional ways of understanding has more been the public idea that perhaps cancer is a very new disease. It's modern disease brought upon us by our modern Western lifestyles. It's a human disease and it's maybe something that's visited on us because maybe something we've done wrong. So that's definitely an idea I want to challenge. Because I go into great detail in the book, you know, how old cancer is as a disease, how many different species across the tree of life could be affected by it. This is an ancient biological process that that happens to our bodies. But also the kind of I want to challenge in terms of how we think about treating cancer and think about what it is. But this idea that it's just something that starts from a mutated cells growing out of control, and then we just need to find the magic bullets, the drugs that we fire it, it will make it go away and, you know, to a certain extent that is true. But actually, that's not really helping us get really far down the road of understanding why does cancer start, where does it come from?

And then like how do we treat advanced cancer more effectively? We've become really sort of reductionist about the genetic decision medicine idea that if we could just find all the mutations in cancer will really understand it will be able to treat it. And we sort of ignored all the evolutionary context of a cancer is an evolving system within a complex system of the body and also that there's more to it than just the cells, it's interacting with its environment. There's an ecology there. So taking this sort of wider, broader, more grandiose view, I think, provides a lot of enlightenment about helping people to understand what cancer really is and then a more realistic view of them. Okay, so what do we actually do about it? And there's an interesting idea presented in the book where you talk about the origins of cancer all the way back to when multicellular life was beginning to evolve. Could you share with us what we know about so far back of this origin of cancer and what we've been able to figure out from all the way back then did this really stunned me when I started researching into the book because I knew that cancer wasn't just a human disease.

You know, my my first dog, absolutely much beloved Welsh Springer spaniel died of cancer, You know, I've always known that it's not just human seats, but starting to really dig into it and seeing the extent across all branches of the tree of life that is affected by cancer, there's a couple of really notable and very weird exceptions comb jellyfish, no extent cases of cancer reported. And also sponges really weirdly resistant, but pretty much everything else can get cancer. And there's a book, it's edited by a researcher called the Outage Bari And there's like, you know, 20 pages of tiny, tight listing all the different species where council has been found everything like fish to birds, bats, to to Wales to combat everything. And so you realize that this is this goes deep. And What really blew my mind back in 2014 when the paper came out um from thomas Domestic Low show and his colleagues showing that they found a tumor in a tiny hydra.

I don't know if you know anything about hydro's, but they're basically these tiny animals that live in the water and they're basically a tube with tentacles, they're millimeters long. They're tiny and completely spontaneously. So there wasn't anything weird they've done to these hydra, but they found a spontaneous tumor in this organism that is basically a tube with three different types of cells. So that tells you like if something as simple as that all the way up to something as complex as a human or an elephant or a shark. Yeah, sharks do get cancer can get cancer. This is just a, this is just biology. And then I started to really get interested into, well why? And you realize that basically if you're going to be multi cellular cancer is the price of multi cellular charity, it's the price of multi cellular light because once you have cells that live in a community, a multicellular organism, once they're doing their jobs only multiplying when they should, they're dying when they're meant to not taking too many resources, they kind of made this social contract to be part of a multi cellular organism.

There will always be cheats that emerge in that system and become cancer cells and cheats emerging all systems in all groups of organisms in human societies and animal societies in cellular societies. And like this is kind of almost inevitable. And it's the natural. So that was that really blew my mind realizing like that the intimate origins of cancer are basically tied into the origins of of multi cellular life and looking at such simple life forms that can develop cancer. Like, as you're saying, just being such a surprising finding, are we seeing correlations between species cancer development that are more closely related to one another in terms of evolution. Is there any correlations there? Does it seem like as you said, most species are getting cancer so most species can get cancer. But the rate at which they get cancer does differ. And we have this idea like maybe humans are uniquely exquisitely and more prone to cancer.

But actually in the grand scheme of things kind of in the middle because the other things to factor in our evolutionary trajectory of your species. So you get animals that basically live fast and die young, they lived for a short time, They reproduce a lot. Their individual lifespan is very short. They are at high, high risk of developing us. So things like rodents, short lived rodents will spontaneously develop a lot of chances. They don't, they haven't evolved very protective mechanisms on the other end of the scale, you consider some of the massive, long lived organisms like like whales and like elephants. Right? If you think about it, kind of logically, you think, okay, an elephant has loads and loads and loads of cells, it lives for a very long time. You would expect an elephant to be riddled with cancer because you've got a lot of cells proliferating lots of chances for cells to go wrong and out of control. But actually elephants are remarkably cancer proof. They have evolved mechanisms that enable them to live so long.

And it's come at a cost of things like potentially, you know, wound healing and all these kind of things. But it's all a trader between your your lifestyle as a species, your evolution like how your cells and your tissues behave in order to control the innate tendency of cells to like want to want to buck the system. Um, so I think that that's fascinating and humans are kind of in between. There are things that we do in our lives that there are things in the modern world that do increase the risk of cancer. And we absolutely know that there are sort of basal cancer rate. It's kind of somewhere in the middle uh in in the ground sort of tree of life. And looking at human specifically, scientists are sometimes able to sequence DNA from fossilized skeletons. And so this give insights on the evolution of cancer in terms of overtime in humans. Because if we can go back in time almost and look at how cancer was back then compared to now. I mean, have we made any insights from being able to look at the DNA from fossilized skeletons?

I think this is such an interesting area. And there is this conception that cancer in the ancient world was very, very, very rare. And that's because there aren't that many ancient human remains that turn up with cancer. And I kind of want to like poke at that a bit because we don't dig up perfectly time matched series of bodies. You know, you kind of when you're coming to doing H and archaeology, you kind of get what you get. And there are lots of reasons why cancer might not be so represented in ancient humans. But I think almost the fact that we find it at all. And we can find some examples. For example, very rare childhood tumors in ancient remains, mummified remains, fossilized remains does tell us that if cancer maybe wasn't as common as it is now, it was certainly there. And really we have no idea how common. Uh and also of course that in in the olden times there were many, many more things that could kill you before you got to an age where cancer started to become a problem. Because again, going back to our evolutionary trajectories, species, humans, we tend to have a significant increase in our risk of getting cancer Through our sort of late 50s and 60s, remarkably low risk in young life and middle age.

So there is something very protective about our human bodies up until that point. And also when you're looking at ancient specimens, The likelihood that you're going to find a statistically significant population of people over the age of 60 represented their aging skeletons is very very hard. Um determining like whether they did die of cancer. And if so what sort is also very very hard. There's not representative populations. But I think there are some interesting questions and it certainly seems like the more people are looking for cancers in ancient human remains of ancient animal remains, the more they're finding. And just this week too late. But just this week, um we're we're talking in august There was the announcement that they found a 77 million year old dinosaur fossil with an austere self paper tumor. So, you know, this stuff is old and I think the fact that we find any of it is really suggested that it was it's not massively prevalent reasonably prevalent in the past.

That's an exciting finding. And that we're seeing again in different species, but also from so long ago and obviously as you said, there's a lot of limitations when it comes to getting D. N. A. And looking at it with skeletons because of just how old it is and what are you finding? But as you said, just being able to say oh it looks like this person did have cancer and so long ago that is valuable in itself. And I'm interested to explore if there's a relationship between the genes that are correlated with cancer and many of them we know of in the field and how long those genes have existed in terms of are these genes being highly conserved across species? Are these cancer genes seen throughout the animal kingdom or are we seeing more like there's human cancer genes and then there's other genes and other species. So the basic what we would consider to be cancer genes are the kind of the drivers of life. So they're the genes that are involved in cellular proliferation are the genes that are involved in like overriding cell death.

Their genes that are involved in metastases moving cells around. And so I think those are the same across all species because ultimately, you know, we all came from one cell with the same fundamental set of mechanisms that make cells multiply, you know the cell cycle is incredibly conserved all the way down to the east. There are similarities bacteria and archaea and all these effects and these are the genes that we find dis regulated in cancer. What's interesting is when you start to tie this into the ideas of multi cellular charity because there's some really interesting work from Peter Good and his team in Australia, Peter Matt cancer center in Australia that when they start analyzing tumors and looking athlete, the evolutionary age of the genes that are dis regulated. So they find that a lot of cancers are up regulating kind of really ancient old jeans. These are ones that are associated with almost uni cellular processes just proliferate at all costs.

Move around. Take what you need from the environment and the genes that are down regulated are the genes that are associated with multi cellular lot. So things like um sticking cells together, communication between cells differentiation. And there are some people who said oh this is because cancer cells are trying to get back to some more primitive way of life. So well what? Probably not. But they're certainly tapping it to the genetic processes that are there in all human cells. I mean we all start with one single cell got to make a lot of cells, you've got to differentiate them. I've got to move them around. All these processes are there? They're they're in unison, cellular cells that use different ideas there there all species of like variations of its genes. And so cancers kind of tap in to the more ancient genes, the cell cycle genes. The things that really make you proliferate and they start to ignore the genes that control that society and how you interact with the cells around you and your environment around you.

So you know the the original book uh the original name, my book was was selfish monsters. So you know this kind of selfish cheating cell that are up regulating the genes that make them do their own thing down regulating the genes that make them live in their selling their society and starting to cause trouble. And it really it goes back to that as your as we keep coming back to the evolutionary perspective of saying, let's look at how cancer does of all that, you know over time, but also within the same person of you know what a process it is for cell to become cancerous from that normal. I mean what pattern of genes are we seeing that have changed to actually become cancerous? So there's sort of two angles on the evolution of cancer within the body of an individual. So almost like the books of two hearts, the first half of the book looks at cancer as an evolutionary process within species and how that ties into like evolutionary trajectory of the species.

And then the book kind of changes gear and starts to look at the evolution of cancel within the body from where it arises. So this idea that um you know, we're familiar with the idea that like cancer starts when a cell picks up mutations, it starts multiplying out of control. And eventually like it picks up enough mutations are kind of genetic bingo card and then it's like a metastatic tumor, right? And I started to look into this and then there's you see the work from Phil jones and integrate martin corona at the Sanger Institute. It's a Campbell where they start to look at normal adult tissue, like the tissue that just looks normal, it looks healthy under the microscope is not cancerous, everything's fine. And they chop it into tiny tiny bits and do genetic sequencing and they find that even normal tissue is a patchwork of mutation and I can in normal esophagus, by the time you're getting too late middle age, like up to half of your esophagus is full of clones, groups of cells that are expanding with mutations that if we found them in a cancer, we would say that is a cancer gene, that is a cancer private.

And that really like blew my mind because then you're like, okay, if loads of our normal healthy tissue is full of what we would call camps and mutations, but for any individual person, you might only develop one, maybe two cancers in your entire life type. What is stopping those cells from growing out of control. Because if all yourselves are a bit kind of sad if they've all got various mutations and they're all expanding and bumping up against each other sort of these patterns of clonal expansion in our tissues. What is the trigger tips a cancer into, you know, becoming really problematic. What makes a sad cell bad sell? And it seems to be, I think that the real tipping point is chromosomal instability. So most of the sort of the clones that we're expanding in our body there, picking up individual hits and individual genes here and there or they placed. But what seems to make a a clone of cells really go for it is when you get this large scale chromosomal rearrangements so big deletions cutting pasting chromosome patients when something is still wrong in division, you end up with a double set of chromosomes.

Um Thanks for getting chopped and changed around whole chromosomes getting shattered, stitched back together. That seems to be really potent fuel for the evolution of these sad cells to really become bad cells and start accelerating that evolutionary process towards becoming an aggressive and invasive tumor. And then ultimately a metastatic cancer where we have to see extreme changes of not just a few genes that have been mutated along the way, but as you said, I mean, we can see that chromosomes could be like shattered and kind of put back together in very, very haphazardly way. And it was so interesting as I'm reading this book, You talk about a very important paper by Peter Noel called the clonal evolution of tumor cell populations which proposed all the ideas we've really been talking about, of looking at cancer from an evolutionary perspective. And it was published 40 years ago, which when I read that I had to stop and I was like, wait a minute. You know, this seems to be like such a new perspective that you're offering and and saying, let's look at cancer in a different way than we normally do.

I mean, 40 years ago, I was like, why are we just starting to talk about this? I mean, why do you think that we are just starting to talk about it? And and that there are other ways of thinking about cancer that really became much more popular. So, you have kind of rumbled me there that this is not a new idea. Um and particularly I do want to like highlight the work of knoll but also Mel Greaves at the Institute of Cancer Research in Sutton in London. He's been kind of banging this drum. The cancer is an evolutionary process. It's rooted in our evolutionary history as a species and it evolves within the body. And if you treat it, you're just buying selective pressure that if it doesn't feel it, it's going to make it worse. He's been banging this drum for years. And, you know what? It did really surprise me researching the book, seeing papers like Knowles paper, you know, back in the 70s, the idea of the Stellar Society, really focusing on how cancers emerge out of the micro environment. All of these are old old papers, you know, so some really, really beautiful writing about this concept of where cancer comes from as this sort of almost dark side of development or this emergence cellular species out of the body and loads of it just I think got subsumed or superseded when we got genetic sequencing technology and could just like here's a bit of tumor, let's mash it up that sequence all the genes.

This is what's driving it. And we've become really obsessed with the kind of the genetic shopping lists of mutations find that develop drugs against them. And and you know, that that sort of goes out the window a bit when you discover that loads of normal tissue is full of what you'd consider to be these cancer mutations. And it also goes out the window when you realize that all these fancy targeted therapies are not bringing the cures that we were promised. And there's been a really sort of misleading thing here is that um there's a drug called lee back which is really famous. It's been absolutely transformative in chronic myeloid leukemia and Gleevec is a very famous story about its discovery and it's all written about in the book the philadelphia chromosome because these cancers are driven by a single genetic rearrangement. It's basically where one bit of one chromosome gets kind of cut and pasted onto another bit of another chromosome. It creates this hybrid gene that drives the cancer cells to proliferate.

And so researchers discovered this connection. They discovered the faulty molecule that's made from this hybrid jeep and they developed a drug that specifically locks into it stops it. And that is Gleevec. And I think Vivek is probably the most successful cancer drug of all time, arguably Come Fight Me. Um but it really misled us. It's transformed the outcome, chronic myeloid leukemia and a couple of other cancers where you find this change. But it really misled us on the idea that if you could just find these mutated genes just find the right drug, then we will be able to treat campuses with the same degree of success and that has not materialized because dae bak, it's such an outlier in the evolutionary process. Most of the cancers we're trying to treat with these drugs are really advanced and they are really heterogeneous. There's so much genetic heterogeneity in cancer. But when you step back and think logically, it's like yeah, of course if you try and treat with one drug, there's going to be cells in there that have evolved resistance and at some point they're just going to come back and in the book there was a line that I particularly um loved because it really changes.

I think people's perspective on this and it relates to this heterogeneity that you're talking about that not all your cancer cells are the same. They're not necessarily clones of each other. You're right. It could be argued each person's cancer represents one or more entirely new species. And I think that just highlights exactly what you're talking about here that it's not. I mean Gleevec was amazing and just the research behind it to that they were able to come up with this magic bullet as people call it so quickly because of this one genetic change. But I mean most cancer is just not that simple. Yeah. And that was really highlighted it as a transformative paper from charlie Swanson and his state published in the New England Journal of Medicine a few years ago and they looked at a patient in the book. I pulled them E. V. Because they're kind of name was E. D. 001. They were on a trial of a drug called anonymous and they took tumors from this patient and cut them into small sections and did genetic sequencing and also the metastases. They chopped metastases up and found mr metastases when it's first had surgery and showed the incredible extent of the heterogeneity in there.

And that you could draw evolutionary trees very style of Charles Darwin to demonstrate the evolutionary uh kind of routes where the mutations have been picked up that part of this tumor at this mutation part of this. Um I had a different mutation. And if you treated that cancer with this drug you are only ever going to knock out a certain number of cells and and it really started to focus people's minds on the extent of heterogeneity and charlie and his team have done a lot of work, looking at this issue of chromosome or instability, looking at all employee where you have multiple sets of chromosomes and the role that that place is really getting captains going. And that kind of did lead me to the idea that you say is like, so what makes a species? So humans, you compare humans and chimpanzees are D. N. A. Is pretty similar at the sequence level. Our chromosomes are different. So chimpanzees I think have uh oh God, I'm gonna get this wrong. So I don't know. I just I just read it in your book.

So I think they have one extra chromosome, right? Because our chromosome two is two of theirs together. Exactly, yes. So they have 48 chromosomes, 24 pairs. We have 23 because our chromosome two is it's too chimp ones stuck together. And you start to look at the incredible extent of chromosome or heterogeneity like doubling weird weird weird things going on in tumors. And you like a cancer cell is chromosomally so different from a human cell. And it starts to really make you think these are like species evolving within the ecology of the body and they're responding to the selective pressures that are being put on them. Whether that's drugs whether that's sort of the environment within the body, Whether that's inflammation, whether that's the hormones that are circulating in your body, all the sorts of things that you do. Cell cancer cells are little species and are going off on their own, choose your own adventure. And there is sort of an interesting diversion heal ourselves. The cells that were taken from Henrietta lacks the constipation in the fifties, very famous that they've been written about by Rebecca's suit in her book, the immortal life Henrietta lacks and someone has actually proposed because these cells have being grown out of the lab and have evolved and changed and they are so chromosomally different from human cells but maybe they should be pulled a separate species and have their own name.

So sort of peel a site on carla I think is the host name and I'm not sure exactly where I land on this, but it really is this idea that these cells have gone off on a evolution in a microcosm or evolution in like a dumpster fire. I like to call it like they have gone on a journey and we have to acknowledge that and understand that and then try and use evolutionary strategies to control them better, particularly for advanced cancers. Um rather than just, oh yeah, here's a targeted therapy. Oh look, it only kills off some of the cells and and the cancer comes back. It's like, well we'll do. I mean, what did you expect? But this somehow seems to be a surprise. It's very, very interesting way of thinking about it. And I mean we could go on and on about the concepts in this book and it's it's just a fantastic read. Even when I was reading, I was really reading it in your voice and I was like, this is really like, you know, you write in a similar way of engaging people um just in in the way that you talk on podcasts and everything. So, I mean it's just a fantastic read and you just learn so much and you you write in a way of looking at it from kind of a story um perspective.

So it's not it doesn't read like a textbook for some people that um you know, sometimes it's hard for them to pick up a book, but it's it's fantastic and people can head over to our social media to enter a book of Away. Um and also go to Rebel Cell Book dot com. So, thank you so much for coming on the show. I mean this is just such interesting way of thinking about cancer. And I think as you said, it's going to lead us to more precision medicine and looking at cancer treatment in this way. So, thank you so much for coming on the show. It's been a pleasure talking to you. Thank you. It's it's just been wonderful as promised, you can enter to win your own copy of Rebel Cell by going to our twitter facebook and instagram, just search DNA today for further details about the giveaway. Learn more about the book at Rebel Cell book dot com and search genetics Unzipped in your podcast player To hear cat show. I was a guest on one of her episodes as well where she interviewed me about prenatal genetic counseling. So follow all of her exciting updates on twitter at cat underscore Arnie and genetics unzip. Don't forget to enter our giveaway. Just search DNA today on social media and buying that post where you can see Rebel Cell to enter, learn more about the show by going to D.

N. A podcast dot com. There is more information on this episode. Every episode has a blog post at DNA podcast dot com. There's also a contact form on the website. If you would like to ask a question to myself, cat or another guest on the show, please email info at DNA podcast dot com. Don't forget to head over to podcast magazine dot com slash hot 50 and vote for DNA today, hosted by myself. I mean we would appreciate all the votes we can get so that we can be in the top 50 podcasts for december 2020. Before setting off, I want to remind you about keck graduate Institute master's program in genomic data analytics. K. G. I. Is an innovative grad school that is a member of the Claremont colleges in southern California. Their name might sound familiar if you listen to the genetic counseling application episodes with Brennan who's on my friends. That's a student there. In addition to genetic counseling KG. I also offers this Master's degree in genomic data analytics. Students benefit from foundational coursework and human genetics cutting edge courses in the applied life sciences and an innovative human genomics curriculum that combines to prepare for the exciting field of genomic data analytics.

Upon completion of the program, students will be able to utilize their foundation and genetics and genomics along with the practical knowledge of data analytics to be able to translate patients sequencing data into actual clinical recommendations and also be able to bridge the gap between research scientists and clinical practitioners, graduates of the program will gain the ability to translate research into precision medicine, Learn more about kgs genomic data analytics program by visiting k G I dot E D U slash DNA. Today again that's K G I dot E D U slash DNA. Today Dr Kat Arney showcased how complex cancer genetics is. So it's understandable that people are often confused about the role genetics plays and their cancer or their family members. Cancer. That's where genetic counselors come in. We are trained healthcare providers in genetics to explain these concepts and help you navigate testing the genetic counselors over at advanced Teligent counseling specialize in areas of genetics like cancer. Their team is skilled in knowing common and less common genes. Think beyond B.

R. C. A one and two and these genes can predispose a person for cancer. So knowing more about these incredible variants or mutations in your genetic makeup can help you understand and manage your unique genetic risk. Their genetic counselors will also help guide you through the genetic testing decision making process. So if you find yourself having questions about your own genetics or want to learn more about adding the expertise of a T. G. C. Certified genetic counselors to help support your own practice, reach out to the advanced tele genetic counseling team through their website at 80 hyphen gcc dot com. Again, that's 80 hyphen gc dot com. Thanks for listening and join us next time to learn, discover new advances in the world of genetic genes. Genes. They're all made of DNA. We're all made of the same chemical DNA me and we're all made of being a