Dr. Stephen Kingsmore a vision for transforming medicine with rapid genome sequencing

Transcription

1 Dr. Stephen Kingsmore a vision for transforming medicine with rapid genome sequencing Dr. Stephen Kingsmore, MD, DSc, is the President and CEO of the Rady Pediatric Genomics and Systems Medicine Institute. Shawn Baker CSO of AllSeq spoke to 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. 24 AllSeq: What prompted your move to combined with $10 million from the layes Rady Children s Institute for Genomic Family to study pediatric neuro-oncology, have When you have an acutely ill newborn, there Medicine? allowed us to recruit a world-class team of is a narrow time frame to save a life or improve researchers and secure the latest technology. the outcome. Speed is so critical because Our location is also an advantage as we are genetic diseases are the leading cause of death surrounded by innovation with 800 life-science in neonatal and pediatric intensive care units, companies and a number of prestigious and in infants in general. To make a diagnosis research institutes that make San Diego the of a genetic disease using standard tests takes nascent genomics capital of the world. In this an average of 90 days. We are able to take dynamic ecosystem, we are forging strong a blood sample and deliver a provisional local research partnerships that are key to fast diagnosis in as little as two days. We ve been scale up. This is the first community where the offering rapid whole genome sequencing to idea of employing genomic testing as part of patients at Rady Children s Hospital-San healthcare is becoming mainstream. Diego since July We ve sequenced almost Dr. Stephen Kingsmore: I believe the future of pediatric medicine is being transformed by the ability to decode the genomes of acutely ill infants to deliver precise diagnoses and targeted treatment. I came to Rady Children s Institute for Genomic Medicine because of the unique opportunity to advance healthcare for children through the application of rapid Whole Genome Sequencing at scale. We are at a pivotal moment of a revolution in waiting. At the Institute, an array of advantages and When you bring this all together, precision resources come together to help us transform medicine is no longer an academic exercise, precision medicine. it s becoming a reality for patients admitted Our institute is embedded within the largest children s hospital in California. Rady Children s Hospital-San Diego provides care for 91 percent of the children in a three-county region and is ranked among the top children s hospitals in the country in nine specialties by U.S. World and News Report. Hospital leadership, doctors and Institute staff are eager to bring genomics to the bedside and make it a standard of care in the neonatal and pediatric intensive care units (NICU/PICU). The remarkable generosity of Ernest and Evelyn Rady, who gave $120 million to establish the Institute, at Rady Children s Hospital-San Diego. It s possible for us to do things here at the Rady Children s Institute for Genomic Medicine that you just couldn t do anywhere else in the world. AllSeq: You ve been using NGS in the clinic in a very specific way applying rapid whole genome sequencing to the diagnosis of rare childhood diseases. Why is speed so critical in these cases and what are you doing different from other hospitals that are sequencing patients? 200 genomes. Our diagnosis rate is over 40 percent. In about half of those cases, the change in care is dramatic. We ve had babies who have received immediate, life-saving organ transplants, babies who are the youngest ever to receive targeted treatments for rare genetic disorders and infants who have avoided unneeded, high-risk surgeries. These are the cases that our team specializes in. We measure success one life saved at a time. The most exciting thing right now is that we re about to begin offering rapid whole genome sequencing to intensive care units in other children s hospitals. When we return the results, our expert physician-scientists work in tandem with the doctors caring for the sick

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3 child to tailor the course of treatment based on the genomic findings. Our goal is to make genomic medicine available to every baby in North America who needs it. 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 need to train people like nurses, social workers and other health care providers to step into the gap to help translate the findings of WGS in a clinical setting. AllSeq: Most of the clinicians we talk to wrestle with choosing between targeted panels and exome sequencing. For them, whole genome sequencing is simply out on speed. Do you feel these two areas are the ones that still need the most improvement or are other factors becoming more important? The other key obstacle is access. Genomic medicine is currently available only in medical research centers. So, if you re not a patient at one of those, you don t get in on this. When 26 of the question, primarily due to lack of reimbursement and difficult in analyzing the results. What makes your program different? There are three great advantages to whole genome sequencing over exome sequencing and targeted panel testing. First, WGS is faster, has many fewer steps and has much less technical complexity. This makes it easier to scale at rapid speed. Second, exome sequencing and targeted panel testing have to be performed in batches to be cost-effective. Waiting to accrue a batch of samples is a poor option for an acutely ill child. Third, the diagnostic utility of WGS is potentially far greater. We are interested in developing methods to identify structural variants, copy The total cost of clinical sequencing tests still needs to decrease if large numbers of patients are to benefit. However, other factors are becoming more important. The most important need is for education and engagement of patient families and healthcare providers. A key bottleneck is that we don t have enough trained personnel to deliver genome sequence information to patient families. In addition, most medical practitioners are wholly unprepared for implementing genomic medicine. The bottleneck extends from electronic medical records to formulas for reimbursement to the practicalities of understanding the benefits of genomic medicine for any given patient in any given clinical setting. it is available, it s typically only offered to people with private health insurance. In many parts of the country, that leaves out many minority communities who are underserved by insurance carriers. That s a huge issue here in San Diego where 57% of our patients are Latino. Yet only 3 percent of the sequenced genomes come from Latino patients. So there s an immense issue with health disparity that s getting worse with precision medicine rather than better. These are real practical concerns that we need to address and they re not easy to fix. Honestly the bottleneck is not Gee, I need a better Illumina sequencer, it s all of these other issues in the health care economy. AllSeq: In addition to rare childhood diseases that you re working with, NGS is starting to be adopted in the clinic for NIPT number variants, regulatory variants, deep intronic splicing variants and pathogenic triplet repeat expansions with clinical precision. At the Institute, we want to invest in core methods with at least a three-year useful life. I anticipate that exomes and targeted panels will no longer be optimal methods for rapid pediatric diagnosis by Also of great importance, the results of each whole genome sequence become a long-term resource that can be referenced for future analysis and clinical interpretation. It s exciting that our work will contribute to expanding the knowledge base of genetic diseases. AllSeq: What are the biggest factors preventing NGS from being more widely adopted in the clinic? We have to make genomic medicine much more understandable to health care providers so they are comfortable and competent with NGS-assisted healthcare delivery. This means going out and talking to them, listening to them, and providing educational tools. Right now our nomenclature is rather arcane and our reports are often difficult to understand. Busy clinicians need practical guidance to understand the results and then what do the data. There are only 500 practicing medical and cancer. Where do you think we ll start seeing NGS adopted next? Our focus is pretty much in the areas of neuro-oncology and all rare genetic diseases because the early evidence is that this has clinical utility. We don t really need a new application area because of the bottleneck that is limiting access to pediatric genomic medicine to only 0.001% of the population who need it. We want to expand our cases and scale up, probably a thousand fold from where we are today. And that s going to create a lot of new challenges and solutions. It s going to be very exciting. geneticists and 2,500 genetic counselors in the entire United States. So how do we take this innovation into the medical mainstream? We

4 AllSeq: When talking about clinical sequencing, people are thinking about genome rather than transcriptome. How would you rate the importance of the two for clinical applications? I think that s a great idea. The question of whether we can marry exome or genome sequencing with RNA sequencing is one I m exploring in an NIH grant study together with Michael Seldin, MD, PhD, a geneticist at UC Davis. If it works, 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. Looking at the RNA seems to be a very sensible approach in helping to make that decision. The issue is that each of these ideas takes 10, 20, 50 million dollars to 27 FIELD NOTES go from an idea to a practical, rugged reality 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 omic data in the clinic. AllSeq: Do you think the use of NGS will take off in the direct-to-consumer space? I do feel fairly strongly about this. I came to education and training for doctors in how the United States from Ireland in part because to interpret genetic results, there will be I believe in capitalism. We need commercial the temptation to bypass the expert analysis, companies to bring genomic medicine up apply clinical diagnosis and go straight to to scale. But the idea of direct-to-consumer treatment. That works well for common genomic medicine, especially for children, is conditions, but genetic information is something that gives me shivers. It really does incredibly difficult to interpret. Genomics concern me. I think that the medical system offers a new way to target diagnosis and is the proven primary route to bring medical improve management of rare genetic diseases. advances to meet public need. However, I But we will only accomplish this by affirming have a huge fear that the medical community a new partnership between the patient, the is wholly unprepared for putting the benefits physician, and those with genetic and of genomic medicine to use. Without technical expertise.

5 28 AllSeq: Have you actually heard people talking about wanting to use direct-toconsumer genomics in the pediatric space or is that just a worry that you have? There is certainly great interest in commercializing direct-to-consumer genomics in childhood diseases within private industry. In general this seems to reflect unhappiness with the slow rate of adoption of genomic medicine, relative to shareholder expectations. Implementation is being further delayed by lack of reimbursement for physician-ordered genomic testing. So there s huge pressure on commercial test developers to speed up market growth. Industry is anxious to boost public demand and then to meet that demand. The problem with that model is that it bypasses the medical mainstream. If that happens, the clinicians may never catch up and that opens up consumers to many risks. It s ethically very worrisome to think about children s genomes becoming the subject of direct-to-consumer marketing. 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? In complex diseases, there is immense opportunity today to save children s lives and alleviate suffering by using genomic sequencing. An unintended consequence of such effectiveness is increased interest by direct-to-consumer commercial laboratories. Newborns, infants and children are the most vulnerable members of society. When acutely ill, they are even more vulnerable. Parents of critically ill children need guidance as they navigate the medical system seeking help with a sick child. They tend not to be resource-rich. It is our goal to have genome sequencing and genomic medicine become generally available for all parents and children. It should become an easy-to-use new tool inside the medical mainstream, rather than making the whole system a bit more complex and a bit more fragmented. Shawn Baker, Ph.D., is the Co-Founder of AllSeq, a sequencing marketplace and genomics business consulting company. He has an extensive and broad experience in the genomics industry, ranging from R&D, product development, marketing, and business and scientific consulting. He can be reached at shawn@ allseq.com AllSeq is the Sequencing Marketplace, where researchers can get competitive bids on their sequencing projects and read informative articles on next generation sequencing.