Selected Podcast
Rare Disease Research
Dr. Raymond Wang discusses new diagnostic tools and technology that is helping to advance research in rare diseases.
Featuring:
Raymond Wang, MD
Dr. Raymond Wang is the Campbell Foundation Multidisciplinary Lysosomal Program Director and California Institute of Regenerative Medicine Alpha Clinic Director at CHOC. He is a board- certified clinical geneticist and biochemical genetics specialist. Dr. Wang is aware of the challenges faced by patients and families with rare diseases such as lysosomal storage disorders. His program provides treatment for the lysosomal disorders that have existing therapies; access to investigational treatment for patients with disorders that currently have no approved / effective therapy; and translational research vital to development of “next generation” treatments and cures for lysosomal storage disorder patients. As an undergraduate, Dr. Wang attended Stanford University where he was a member of the Phi Beta Kappa honors society and graduated with a bachelor’s degree with Honors and Distinction in Biological Sciences. He earned his medical degree from the University of California, Los Angeles (UCLA) where he was a member of the Alpha Omega Alpha honors society. He completed his internship and residency in medical genetics and pediatrics at Cedars-Sinai Medical Center where he served as chief resident in his final year of training. Dr. Wang completed his fellowship in biochemical genetics at the UCLA Intercampus Medical Genetics Program. Transcription:
Melanie Cole (Host): From new diagnostic tools and technology to advances in rare disease research, this is Pediatrica, a pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County.
I'm Melanie Cole. And joining me today is Dr. Raymond Wang. He's the Campbell Foundation Multidisciplinary Lysosomal Program Director and California Institute of Regenerative Medicine Alpha Clinic Director at CHOC, Children's Health of Orange County. And he's here to highlight rare disease research for us today.
Dr. Wang, it's a pleasure to have you join us. As we get into this topic, please tell us what are considered rare inherited diseases. I'd like you to sort of set the stage for us. Is there a practical definition or a designation for these?
Dr Raymond Wang: Thank you for having me and happy New Year. In general, a rare disease is defined as, in the United States, any condition where there are less than a hundred thousand people in the country affected. Within those, there are certainly acquired rare diseases. But my area of clinical and research focus are in inherited rare diseases.
Melanie Cole (Host): Well, thank you for that. So, how does knowledge about risk factors for rare genetic diseases have the potential really, Dr. Wong, to illuminate the biology underlying these diseases to improve the lives of patients through your new diagnostic and therapeutic possibilities and to shed light on related common diseases. Tell us a little bit about that.
Dr Raymond Wang: Yeah. So, the great physician, William Osler, actually said this really well. He basically said you can gain significant insights, and I'm paraphrasing, into the common by studying the rare. One example of that that comes off the top of my head, some of the work that I'm doing with regards to cardiovascular disease, we think of it commonly as cholesterol and lipids and heart attacks and that sort of thing. We're also hoping to illuminate some of the background in common cardiovascular disease by studying a condition called mucopolysaccharidoses or MPS, where a buildup of these polymers leads to inflammation within blood vessels and inflammation, as you know, as a part of cardiovascular disease. So, we can talk about that in more detail in the future, but definitely we can learn a lot about the common by studying the rare.
Melanie Cole (Host): That's so interesting. And, you know, this has been applied to cancer for a while. And I love that you are focusing on things like cardiovascular disease, because really we're seeing so many more approaches to this now. So, how have newer genetic testing strategies changed the diagnosis of some of these rare diseases? And when you're telling us about that, is there a difference in how you would approach something, a straightforward disease versus a more complex one?
Dr Raymond Wang: I would say that prior to the advent of what we call next generation sequencing techniques, unfortunately, a lot of our inherited rare disease families would have to go through something called a diagnostic odyssey, where they would see one physician either get dismissed or misdiagnosed with another condition, possibly even undergo treatments for that misdiagnosis, realize that wasn't it, and just keep seeing physician after physician without actually getting to the bottom of things. And these journeys would often take years. And I think in this day and age, we are thankful to have access to what's called next generation sequencing, where instead of looking at the spelling or the sequence of one gene at a time, which is time-consuming and expensive. Technology allows for looking at multiple, hundreds, sometimes even your entire, what's called an exome, all the genes that are expressed in your body, which is like 20 something thousand. That's extremely powerful and has yielded many diagnoses, as it's been implemented over the last five to 10 years.
I also think that the advent of newborn screening for some of these rare conditions that have therapies has really also revolutionized the care of rare disease patients where instead of spending years and years, trying to secure a diagnosis, and then only then could you get treatment, newborn babies are being identified, which allows for implementation of treatment right away. And that's really changed the face of rare disease treatment over the years.
Melanie Cole (Host): That's fascinating and thank you for telling us where in this spectrum of research, that increased use of sequencing for detection, earlier detection, prenatal diagnosis, and even testing for disease predisposition fits into your approaches. So now, as you're telling us that, tell us about the state of treatment for some of these rare inherited diseases right now. As we've talked about diagnoses and looking at genetic capabilities, tell us about treatments that you've been looking at.
Dr Raymond Wang: Definitely. And this is ultimately one of the reasons why I went into the field. I won't date myself, but many, many years ago, there were only a small handful of treatments. And what really excited me and intrigued me about this field was the possibility that new treatments would be developed over the years. And I am a witness to these elapsing throughout my career. It hasn't been that long, and that's what makes it really exciting.
So, I think what I want to emphasize here is that, yes, definitely there have been significantly more conditions for which treatments have been developed and approved by the FDA. It's still a long and difficult process. And I would say that for every one rare disease therapy in my field, there are at least five and maybe even 10 conditions for which there aren't any treatments. And that really informs sort of the ethos behind the research that we're doing here at CHOC.
Melanie Cole (Host): How important is it, Dr. Wang? As you're talking about these genetic testing sequences and treatments, how important is it to look at those patterns of trait inheritance in families, getting the families involved, in addition to analyzing those so-called isolated populations, how are the families of patients, as you're doing your research, involved in this?
Dr Raymond Wang: Well, families are partners in this. We often can't arrive at diagnoses without the very careful observations of our families. You know, a parent is going to have that innate sixth sense that something's going on with their child. Something needs more attention. And I think, over the years, I've learned to listen to my family when they say that there's something going on instead of dismissing that or saying, you know, "It'll get better," to really pay attention to that. Sometimes it resolves and doesn't amount to anything significant. But oftentimes, it's these astute observations by parents who know their kids so well, that something needs more attention.
Also, in terms of diagnostics, having family is often essential to resolving some of the findings that are found on these sequencing results. As you know, everyone's different. We carry many, many different variations within our DNA. And having both parents available is often essential to resolving which variants are just inherited from parents and not disease-causing, and which ones are actually the variants that are causing the children's disease. So, parents, family members are partners in rare disease diagnostics and treatment in many, many different ways.
Melanie Cole (Host): Well, they certainly are. And it's a great message for other providers. So, what's the next step in therapies? We're hearing more about targeted therapies. And while we said a little bit before, those have been used in oncology and such. But as we look at these rare inherited diseases, tell us a little bit about what's exciting in the future, an example of the research that you're working on. Where do you see this headed?
Dr Raymond Wang: I think that, as I mentioned before, there are so many conditions for which there are no existing therapies. And I went into medicine to be able to help families, help children. And it just absolutely breaks my heart when we are able to come up with a diagnosis, but then when the families ask, "Okay. So, now that we know what our child has, what can we do?" And it absolutely guts me to say, "I'm sorry, but there's no therapy. There's no treatment that can reverse the symptoms." And many, many of the conditions that I take care of are degenerative, and that's absolutely heartbreaking.
Now, I'm not somebody that is happy to just say, "Oh, there's nothing we can do." I want to be able to participate in the research so that I can tell families, "Okay. Well, there's nothing that's approved now. But, hey, you know what? We have a clinical trial for that here at our hospital." And if there isn't a clinical trial, "Hey, my laboratory and my scientists are working on a therapy," whether it's replacing the gene that the children are missing. That's one of our clinical trial foci.
The other is gene editing. So, many of our conditions are caused by changes in the genetic information. Well, we can actually use something called gene editing to specifically find the change that causes disease, at least in cells right now, and revert them back to the proper sequence. And in these cells, we've been able to see that the protein or the enzyme that the cells are missing are being made again, that whatever's building up in these cells is being digested and broken down when it wasn't before.
And so, I'm very, very excited at the prospect of bringing these, translating our lab findings to actual patient care. It's going to take a little bit of time. But I think what really excites me is that we're getting there, so that we can one disease at a time and one child at a time be able to give hope to our families and their children.
Melanie Cole (Host): What important work you're doing, Dr. Wang. And I hope you'll come on and update us as you learn more. As our last question here today as we wrap up, what role do you feel clinicians should be playing or can play in helping to establish a rare disease diagnoses? How can primary care clinicians, because they're sometimes that first line that the parents will go to, best collaborate with patients and experts like yourself in diagnosing and managing rare diseases?
Dr Raymond Wang: Based on my experience, listen. Listen to your parents and their children. I feel like when somebody comes into your office, there's always a story that they have to tell and something that they want you to be able to address. And certainly, sometimes it can be reassured, but just really listen to them. And if they really, really have that concern, to pay heed to it, make a referral. Sometimes just give our office a call and just say, "Hey, this is a child and the complaint that they've brought to me. What should I do with that?" Sometimes taking that extra time can lead to finding a diagnosis and, at the very least, reassuring the families.
Melanie Cole (Host): Excellent advice, Dr. Wang. Thank you so much for joining us today, and thank you for listening to Pediatrica, a Pediatric Research and Innovation podcast presented by clinicians and researchers at Children's Health of Orange County. To learn more about Children's Health of Orange County and to refer your patient, please visit choc.org for more information. I'm Melanie Cole. Thanks so much for joining us today.
Melanie Cole (Host): From new diagnostic tools and technology to advances in rare disease research, this is Pediatrica, a pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County.
I'm Melanie Cole. And joining me today is Dr. Raymond Wang. He's the Campbell Foundation Multidisciplinary Lysosomal Program Director and California Institute of Regenerative Medicine Alpha Clinic Director at CHOC, Children's Health of Orange County. And he's here to highlight rare disease research for us today.
Dr. Wang, it's a pleasure to have you join us. As we get into this topic, please tell us what are considered rare inherited diseases. I'd like you to sort of set the stage for us. Is there a practical definition or a designation for these?
Dr Raymond Wang: Thank you for having me and happy New Year. In general, a rare disease is defined as, in the United States, any condition where there are less than a hundred thousand people in the country affected. Within those, there are certainly acquired rare diseases. But my area of clinical and research focus are in inherited rare diseases.
Melanie Cole (Host): Well, thank you for that. So, how does knowledge about risk factors for rare genetic diseases have the potential really, Dr. Wong, to illuminate the biology underlying these diseases to improve the lives of patients through your new diagnostic and therapeutic possibilities and to shed light on related common diseases. Tell us a little bit about that.
Dr Raymond Wang: Yeah. So, the great physician, William Osler, actually said this really well. He basically said you can gain significant insights, and I'm paraphrasing, into the common by studying the rare. One example of that that comes off the top of my head, some of the work that I'm doing with regards to cardiovascular disease, we think of it commonly as cholesterol and lipids and heart attacks and that sort of thing. We're also hoping to illuminate some of the background in common cardiovascular disease by studying a condition called mucopolysaccharidoses or MPS, where a buildup of these polymers leads to inflammation within blood vessels and inflammation, as you know, as a part of cardiovascular disease. So, we can talk about that in more detail in the future, but definitely we can learn a lot about the common by studying the rare.
Melanie Cole (Host): That's so interesting. And, you know, this has been applied to cancer for a while. And I love that you are focusing on things like cardiovascular disease, because really we're seeing so many more approaches to this now. So, how have newer genetic testing strategies changed the diagnosis of some of these rare diseases? And when you're telling us about that, is there a difference in how you would approach something, a straightforward disease versus a more complex one?
Dr Raymond Wang: I would say that prior to the advent of what we call next generation sequencing techniques, unfortunately, a lot of our inherited rare disease families would have to go through something called a diagnostic odyssey, where they would see one physician either get dismissed or misdiagnosed with another condition, possibly even undergo treatments for that misdiagnosis, realize that wasn't it, and just keep seeing physician after physician without actually getting to the bottom of things. And these journeys would often take years. And I think in this day and age, we are thankful to have access to what's called next generation sequencing, where instead of looking at the spelling or the sequence of one gene at a time, which is time-consuming and expensive. Technology allows for looking at multiple, hundreds, sometimes even your entire, what's called an exome, all the genes that are expressed in your body, which is like 20 something thousand. That's extremely powerful and has yielded many diagnoses, as it's been implemented over the last five to 10 years.
I also think that the advent of newborn screening for some of these rare conditions that have therapies has really also revolutionized the care of rare disease patients where instead of spending years and years, trying to secure a diagnosis, and then only then could you get treatment, newborn babies are being identified, which allows for implementation of treatment right away. And that's really changed the face of rare disease treatment over the years.
Melanie Cole (Host): That's fascinating and thank you for telling us where in this spectrum of research, that increased use of sequencing for detection, earlier detection, prenatal diagnosis, and even testing for disease predisposition fits into your approaches. So now, as you're telling us that, tell us about the state of treatment for some of these rare inherited diseases right now. As we've talked about diagnoses and looking at genetic capabilities, tell us about treatments that you've been looking at.
Dr Raymond Wang: Definitely. And this is ultimately one of the reasons why I went into the field. I won't date myself, but many, many years ago, there were only a small handful of treatments. And what really excited me and intrigued me about this field was the possibility that new treatments would be developed over the years. And I am a witness to these elapsing throughout my career. It hasn't been that long, and that's what makes it really exciting.
So, I think what I want to emphasize here is that, yes, definitely there have been significantly more conditions for which treatments have been developed and approved by the FDA. It's still a long and difficult process. And I would say that for every one rare disease therapy in my field, there are at least five and maybe even 10 conditions for which there aren't any treatments. And that really informs sort of the ethos behind the research that we're doing here at CHOC.
Melanie Cole (Host): How important is it, Dr. Wang? As you're talking about these genetic testing sequences and treatments, how important is it to look at those patterns of trait inheritance in families, getting the families involved, in addition to analyzing those so-called isolated populations, how are the families of patients, as you're doing your research, involved in this?
Dr Raymond Wang: Well, families are partners in this. We often can't arrive at diagnoses without the very careful observations of our families. You know, a parent is going to have that innate sixth sense that something's going on with their child. Something needs more attention. And I think, over the years, I've learned to listen to my family when they say that there's something going on instead of dismissing that or saying, you know, "It'll get better," to really pay attention to that. Sometimes it resolves and doesn't amount to anything significant. But oftentimes, it's these astute observations by parents who know their kids so well, that something needs more attention.
Also, in terms of diagnostics, having family is often essential to resolving some of the findings that are found on these sequencing results. As you know, everyone's different. We carry many, many different variations within our DNA. And having both parents available is often essential to resolving which variants are just inherited from parents and not disease-causing, and which ones are actually the variants that are causing the children's disease. So, parents, family members are partners in rare disease diagnostics and treatment in many, many different ways.
Melanie Cole (Host): Well, they certainly are. And it's a great message for other providers. So, what's the next step in therapies? We're hearing more about targeted therapies. And while we said a little bit before, those have been used in oncology and such. But as we look at these rare inherited diseases, tell us a little bit about what's exciting in the future, an example of the research that you're working on. Where do you see this headed?
Dr Raymond Wang: I think that, as I mentioned before, there are so many conditions for which there are no existing therapies. And I went into medicine to be able to help families, help children. And it just absolutely breaks my heart when we are able to come up with a diagnosis, but then when the families ask, "Okay. So, now that we know what our child has, what can we do?" And it absolutely guts me to say, "I'm sorry, but there's no therapy. There's no treatment that can reverse the symptoms." And many, many of the conditions that I take care of are degenerative, and that's absolutely heartbreaking.
Now, I'm not somebody that is happy to just say, "Oh, there's nothing we can do." I want to be able to participate in the research so that I can tell families, "Okay. Well, there's nothing that's approved now. But, hey, you know what? We have a clinical trial for that here at our hospital." And if there isn't a clinical trial, "Hey, my laboratory and my scientists are working on a therapy," whether it's replacing the gene that the children are missing. That's one of our clinical trial foci.
The other is gene editing. So, many of our conditions are caused by changes in the genetic information. Well, we can actually use something called gene editing to specifically find the change that causes disease, at least in cells right now, and revert them back to the proper sequence. And in these cells, we've been able to see that the protein or the enzyme that the cells are missing are being made again, that whatever's building up in these cells is being digested and broken down when it wasn't before.
And so, I'm very, very excited at the prospect of bringing these, translating our lab findings to actual patient care. It's going to take a little bit of time. But I think what really excites me is that we're getting there, so that we can one disease at a time and one child at a time be able to give hope to our families and their children.
Melanie Cole (Host): What important work you're doing, Dr. Wang. And I hope you'll come on and update us as you learn more. As our last question here today as we wrap up, what role do you feel clinicians should be playing or can play in helping to establish a rare disease diagnoses? How can primary care clinicians, because they're sometimes that first line that the parents will go to, best collaborate with patients and experts like yourself in diagnosing and managing rare diseases?
Dr Raymond Wang: Based on my experience, listen. Listen to your parents and their children. I feel like when somebody comes into your office, there's always a story that they have to tell and something that they want you to be able to address. And certainly, sometimes it can be reassured, but just really listen to them. And if they really, really have that concern, to pay heed to it, make a referral. Sometimes just give our office a call and just say, "Hey, this is a child and the complaint that they've brought to me. What should I do with that?" Sometimes taking that extra time can lead to finding a diagnosis and, at the very least, reassuring the families.
Melanie Cole (Host): Excellent advice, Dr. Wang. Thank you so much for joining us today, and thank you for listening to Pediatrica, a Pediatric Research and Innovation podcast presented by clinicians and researchers at Children's Health of Orange County. To learn more about Children's Health of Orange County and to refer your patient, please visit choc.org for more information. I'm Melanie Cole. Thanks so much for joining us today.