This is part two of our interview with Dr. Stephen Kingsmore, MD, DSc, President and CEO of the Rady Pediatric Genomics and Systems Medicine Institute. Dr. Kingsmore spoke at the inaugural Precision Medicine Leaders Summit last summer. We spoke with him about his program for rapidly sequencing the genomes of sick children and what he’s looking for in the field of next generation sequencing and genomics. (Also see Part One of the interview.)
AllSeq: Driving down the cost of sequencing has been the biggest push for the NGS market up until now, whereas you seem to have been focusing mostly on speed. Do you feel these two areas are the ones that still need the most improvement, or are other factors becoming more important?
Dr. Kingsmore: Yeah, I think other things are bigger factors. At least in my mind they are. We still need costs to come down, especially genome costs and especially somewhat rapid genome costs. So that’s still a big issue. But now you know our focus needs to turn an awful lot to education and engagement of patients and their families and health care providers. The new bottleneck is that we don’t have trained personnel to deliver genome sequence information to patients, and we don’t have patients who understand genome sequencing to know whether to choose it or not. I think that the tools that we have work pretty darn well. Now we need to figure out how to make this better fit into traditional medical practice, which is wholly unprepared for this. From our electronic medical records, to our ways of getting reimbursement, to the practicalities of how any given patient in any given clinic be able to benefit from this.
AllSeq: What are the biggest factors preventing NGS from being more widely adopted in the clinic?
Dr. Kingsmore: I think mainly our immediate next big thing is getting health care providers comfortable with this. And that means going out talking to them and listening to them and providing some educational tools, and then making what we do much more understandable. Because right now it’s pretty arcane and medieval. Our genome reports are really tough for anybody to understand, never mind a busy health care practitioner. And then what do they actually do with that data? And there are only eleven hundred medical geneticists in the entire United States. That’s not going to work as a delivery solution. Those guys are plenty busy even before we’re in an era of genomes. There aren’t very many of them and they’re working pretty hard. So how do we take this into the medical mainstream? A lot then comes to figuring out other health care providers who can step into that gap. People like nurses, and social workers and other health care providers, and kind of a team based approach. Same with genetic counselors – there’s only two and half thousand genetic counselors in the entire United States. We need other people to be able to do genetic counseling. So these are the practical issues and the thing about genomic medicine, precision medicine, whatever you want to call it, is it’s almost entirely only done in tertiary academic medical centers. So if you’re not a patient at one of those, you don’t get in on this. And secondly, it’s almost entirely only done in white folks – wealthy white folks with health insurance – private health insurance and that’s a huge issue here in San Diego where fifty seven percent of our patients are Hispanic-Latino. Only three percent of the sequenced genomes are Hispanic-Latino. So there’s an immense issue with health disparity getting worse with precision and genomic medicine rather than better. So these are urgent things that we need to address and they’re not easy to fix. It means that we need every document and every tool to be in Spanish and we need bilingual people and we need them also to be ethnically and racially attuned to different communities and different learning styles. These are real practical problems. Honestly the bottleneck is not
“Gee, I need a better Illumina sequencer.” It’s all of these other problems in the health care economy that’s really struggling a little bit anyway.
AllSeq: In addition to the rare childhood diseases that you’re working with, NGS is starting to be adopted in the clinic for NIPT and cancer. Where do you think we’ll start seeing NGS adopted next?
Dr. Kingsmore: I have to admit that our focus is pretty much all on two of those areas of cancer testing and rare genetic diseases because the early evidence is that this works. But as I stated, the problem that we have is that only 0.001% of the population who need it are getting it, and so how do we fix that? So I honestly don’t really need a new application area. I need the ones that we’ve been doing for the last five years to get scaled up. I don’t want to do thirty-five babies in a NICU over the next three years. We have 3800 admissions every year, so we need to grow up one hundred fold in our throughput. In neuro-developmental disabilities, we need to go up probably a thousand fold from where we are today. And that’s going to create an awful lot of new issues and problems and solutions. It’s going to be very exciting.
AllSeq: When talking about clinical sequencing, people are thinking about the genome rather than the transcriptome. How would you rate the importance of the two for clinical applications?
Dr. Kingsmore: We had a baby that we enrolled in our study yesterday who has one-half of their brain inflamed and is in a coma. And, yes, we’re decoding that baby’s genome. But we really are thinking to ourselves, “Wow, I wish we could get a brain biopsy and sequence the baby’s brain transcriptome. And also use RNA sequencing to look for pathogen signatures.“ So yes, it would be beautiful to do that. I, together with a guy called Mike Seldon at U.C. Davis, have an NIH grant which asks “Can we marry exome sequencing with RNA sequencing? Does it work, and does it help us?” It ought to really help especially with variants of uncertain significance where we’re just not sure whether what we’re seeing in the genome is enough to cause a phenotype. You know looking at the RNA seems to be a very sensible approach in helping make that decision. So I think that’s a great idea. The issue always is that each of these ideas takes ten, twenty, fifty million dollars to go from being an idea to being a practical, rugged thing that we can bring to bear. And I do wonder maybe whether the metabolome or the proteome might jump in there before the transcriptome as cheaper ways to get the same type of information. So it’s going to be a very, very interesting next five years as we start to marry different types of genomic data in the clinic.
AllSeq: Do you think the use of NGS will take off in the ‘direct to consumer’ space?
Dr. Kingsmore: I do feel fairly strongly about (this space). I came to the states from Ireland because I do believe in capitalism. I do believe that we need commercial companies to start to replace academic groups, because they just do things better at scale. But you know the idea of direct-to-consumer for genomic medicine, in particular for pediatric genomic medicines or decoding children’s genomes, is something that gives me shivers. It really does concern me. And not because the companies will do a bad job, but really because what generally can happen in that situation is that medicine gets bypassed. And if that happens then it never becomes mainstream medicine. It becomes alternative medicine and we’ve seen that with new exciting developments across society over the last fifty years. And I don’t believe in the long run it’s going to be in the best interests of kids with disease. I think that the medical system is the proven primary route to bring medical advances to meet public need, and I have a huge fear that medicine is wholly unprepared for genomics. And in this struggling and that vacuum there will be the temptation to just bypass the docs and take it straight to the patient, and that in the long run that’s not the happy marriage we want to see. Modern medicine works. Genomics offers a way to make modern medicine work better and that partnership really needs to be reaffirmed between the patient, the physician, and the technology guys. It’s worrisome for me – to the extent that we behave in competitive behavior, “Gee I want to be the first to do that.” The drive really is mainly because we recognize there is a vacuum. Only by continually making progress and getting it out there and making sure it’s anchored in the medical mainstream do we kind of prevent that vacuum becoming a real issue.
AllSeq: Have you actually heard people talking about wanting to use direct-to-consumer genomics the pediatric space or is that just a worry that you have?
Dr. Kingsmore – I think there’s a very active desire to do that on behalf of commercial entities. They have to justify to shareholder expectations, and clearly reimbursement is an issue. They’re not happy in general with the rate of adoption of tests and so there’s a huge, huge sort of pressure on them to speed the system up, and so it makes eminent logic to get the public to start to demand it, and then to meet that demand. And that results in greater sales of tests. The problem with that will be though that you by-step the medical mainstream and they may never catch up. There are just so many examples of that in the past, that that’s my fear.
AllSeq: Do you think that’s more likely to happen in the pediatric space or is that just your concern because that’s where you’re focused?
Dr. Kingsmore: Well I don’t feel quite so strongly about direct-to-consumer for adults, because adults are consenting individuals and, heck, if they want a genome, why shouldn’t they get a genome? Because a genome speaks to more than just disease: it can just be personally enriching to look through your own genome and ponder. It speaks to the essence of life. But for an acutely ill child, parents need all the help they can get. They find a medical system bewildering at times to navigate with a sick child. They’re not resource-rich. We want genomes to become a helpful, easy-to-navigate thing inside the medical mainstream, rather than make the whole system a bit more complex and a bit more fragmented. So I think they’re a very special case. And really, there is some kind of a need for custodianship. The idea of just letting loose an entire child’s genome and all of its information is also ethically worrisome, because we’re really focusing exclusively on “Your child is ill. I’m going to look in the genome only for something that could be causing your child’s disease. I’m not looking at whether your child is likely to have a high I.Q. or likely to develop alcohol dependence.” But that information is in there. It’s quite ethically worrisome to think about that just being liberated into the public direct-to-consumer market.