Vector consulted its many informants to find out which way the wind will blow in 2018. Here are their predictions for what to expect in genetics, stem cell research, immunology and more.
Gene-based therapies mature
We will continue to see successes in 2018 reflecting the maturation of gene therapy as a viable, generalizable platform for curing many rare diseases. Also, we will see exciting new applications of other maturing platforms, like CRISPR/Cas9 gene editing and oligonucleotide therapies for neurologic diseases, building on the success of nusinersen for spinal muscular atrophy. Some of these may even allow for truly customized treatments for children suffering from ultra-rare and even “n-of-1” diseases. We will see increasing FDA attention paid to genomic diagnostics, particularly those relevant to guiding precision medicine, including new standards and opportunities for faster approval of genetically tailored therapies. — Timothy Yu, MD, PhD, attending physician and researcher, Division of Genetics and Genomics, FM Kirby Neurobiology Center, Manton Center and Translational Neuroscience Center, Boston Children’s Hospital
DNA diagnostic testing will grow
The cost of DNA diagnostic testing will continue to fall, its clinical utility will increase and the rate of reimbursement by insurance payers will increase in 2018. Test volume will continue to accelerate, as indicated by genetic variants deposited into the national open-access database, ClinVar. — Joseph Majzoub, MD, Chief, Division of Endocrinology, Boston Children’s Hospital; Thomas Morgan Rotch Professor of Pediatrics, Professor of Medicine, Harvard Medical School
Micro repairs for genetic disease
A cellular therapy that employs programmable single base editing (not gene editing) that does not require DNA to be cut will be used to correct human disease caused by tiny point mutations. One such mutation, changing a G-C base pair to an A-T base pair, accounts for about half of the 32,000 point mutations known to be associated with disease; the new therapy would reverse it. — Joseph Majzoub, MD
Rare and common forms of genetic disease
We have traditionally thought about diseases as due to either a single genetic mutation or a combination of common polymorphisms that increase disease risk. While we have traditionally thought about these causes separately, we are increasingly finding disorders that involve a combination of both rare and common diseases. For example, craniosynostosis (a skull malformation that we see in pediatrics), is due to a combination of rare and common mutations. My prediction is that in 2018, we will begin to see many other examples of this. — Vijay Sankaran, MD, PhD, Division of Hematology/Oncology, Boston Children’s Hospital and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Assistant Professor of Pediatrics, Harvard Medical School
Gene and cell therapies: The price of progress
This year we can expect to see the rise of personalized cell and gene therapy, but also concerns about cost. Last summer, the FDA approved Kymriah, a chimeric antigen receptor (CAR) T-cell therapy that treats leukemia by revving up immune cells. Its price reaches up to $475,000. As more personalized gene/cell therapies emerge in the next few years, they will be associated with super-high prices. As Steve Miller, chief medical officer of Express Scripts, recently put it, “The healthcare system isn’t set up for this type of economic model.” We will have to find ways to make cell/gene therapies constantly successful and accessible to everyone. — Paolo Fiorina, MD, PhD, Division of Nephrology, Boston Children’s Hospital
Heightened concerns about designer babies
Late last year, researchers used gene editing to directly to modify DNA in a living patient for the first time, to repair the flawed gene causing Hunter syndrome. In 2018, germline correction of a human trait (probably a severe/lethal monogenic disorder) will likely be attempted outside of the United States, probably by CRISPR/Cas9-assisted gene replacement at the blastocyst stage in an IVF embryo. The attempt — which produces a permanent, heritable change in the genome — will be condemned by major scientific regulatory agencies. If successful, its ethical implications will be hotly debated. (A recent position statement from the American Society of Human Genetics deems any correction culminating in a pregnancy as currently inappropriate, but supports appropriate research uses.) — Joseph Majzoub, MD
STEM CELL RESEARCH
Stem-cell-derived treatments enter clinical trials
A number of stem cell clinical trials are being planned for 2018 and will be among the first to differentiate stem cells into tissues and transplant them into diseased organs. One patient has already been treated with retinal cells for macular degeneration of the eye, derived from induced pluripotent stem cells. A Parkinson’s trial will initiate with transplanted dopaminergic neurons produced from pluripotent stem cells, through BlueRock Therapeutics. Another group, through FATE Therapeutics, hopes to turn pluripotent cells into natural killer cells that could be used to fight tumors. At Boston Children’s, we have a hope to transfuse stem-cell-derived platelets into patients who cannot receive normal platelet units because they develop antibodies against them. — Leonard Zon, MD, founder and director of the Stem Cell Research Program, Boston Children’s Hospital; Investigator with the Howard Hughes Medical Institute and the Harvard Stem Cell Institute
Longer-lived lab embryos
Human embryos will be cultured beyond the “14 day” limit self-imposed throughout the global scientific community, pushing the boundaries of bioethics. To date, human embryos have survived in the lab for up to 12-13 days. Those in favor of pushing the limit say the extra culturing time will allow a better understanding of early embryonic development, miscarriage and infertility, and perhaps enable new stem cell therapies. — Joseph Majzoub, MD, Chief, Division of Endocrinology, Boston Children’s Hospital; Thomas Morgan Rotch Professor of Pediatrics, Professor of Medicine, Harvard Medical School
The immunology of non-immune diseases
We will learn more about how manipulation of the immune system can influence diseases that are not classically viewed as immunological. For example, neurodegenerative disorders and heart disease are increasingly recognized to have an inflammatory component. As we learn more about the immune system’s role in these diseases, we will begin to see new therapeutic strategies to improve patient health. — Jonathan Kagan, PhD, Division of Gastroenterology, Boston Children’s Hospital; Associate Professor of Pediatrics, Harvard Medical School
Diversification of cancer immunotherapies
Much of the excitement around cancer immunotherapy has centered on the success of checkpoint inhibitors, such as PD-1 therapies, which stimulate cancer-killing T cells to do a better job of attacking tumors. Over the next year, we can expect to see additional strategies, such as those that stimulate inflammation within the tumor, or that stimulate specific signal transduction pathways triggering strong T-cell responses. — Jonathan Kagan
A reboot for rheumatology
Decades of research on autoimmunity have discovered genetic variants that contribute to disease risk, immune cells that initiate and propagate the misguided autoimmune response and cytokines and other factors that amplify the inflammatory cascade. Despite these advances, progress in developing new therapy for autoimmune diseases has been slow, in part due to the heterogeneity among patients with the same diagnosis.
Take systemic lupus erythematosus (SLE). A recent landmark study found that lupus patients can be stratified into seven groups based on longitudinal transcriptomic profiling of blood cells. The biological differences may explain why lupus medications work for some patients but fail to show overall benefit in large trials.
Going beyond traditional clinical/laboratory criteria, systems biology is beginning to unravel the complexity of autoimmune diseases and discover targeted therapy. One such effort is the Accelerating Medicines Partnership (AMP), created by the NIH together with the FDA, pharmaceutical companies and nonprofit organizations. This partnership has a special focus on rheumatoid arthritis (RA) and SLE, with the ultimate goal of defining disease pathways, uncovering novel drug targets and sharing available data with the research community. In the coming year, we anticipate similar initiatives for other autoimmune diseases. — Pui Y. Lee, MD, PhD, Division of Immunology, Boston Children’s Hospital; Instructor of Pediatrics, Harvard Medical School
Food allergy efforts turn to prevention
While many potential new therapies for food allergy are under investigation, including pharmacological approaches and oral, sublingual and epicutaneous immunotherapy, interest has more recently turned to prevention.
The groundbreaking LEAP study showed that introducing peanuts to infants at high risk for allergy at 4 to 11 months of age reduces the incidence of peanut allergy. The follow-up EAT study looked at earlier timing, introducing allergenic foods to exclusively breastfed infants at 3 months of age, versus 6 months at the parent’s discretion. The results did not show better efficacy of early introduction in preventing food allergy — except in families that closely adhered to the challenging protocol. A more recent study from Canada found that adding maternal peanut consumption while breastfeeding to direct introduction in infants’ first year of life resulted in the lowest risk of peanut allergy — consistent with our own study in a mouse model.
In 2018 (and in the next decade), we can expect an increased understanding of the induction of food tolerance, further defining maternal–offspring interactions and the best “window of opportunity.” — Michiko Oyoshi, PhD, Division of Allergy and Immunology, Boston Children’s Hospital
Microbes and us: a clearer view
2018 will witness a continued interest in host-microbe interactions as they relate to infectious diseases, driven in part by the increasing threat of antibiotic-resistant bacteria. We will also learn new ways that our microbiota — the bacteria, fungi and viruses that inhabit our bodies without causing disease — contribute to our health. These microbes have emerged as important control systems in our bodies. The spectrum of physiological benefits that they confer and which microbes are most influential will become clearer this year. — Jonathan Kagan
Health tech escalates
Leading institutions and companies will innovate at the point of care by creating and using digital apps that connect to their proprietary electronic health records (EHRs), rather than simply modifying processes within the EHR. At the same time, clinicians and patients at home will begin to use validated digital biomarkers, recorded via patients’ mobile devices, to track disease activity and progress with therapy. Finally, I expect there will be a burst of peer-reviewed publications reporting on artificial intelligence being better able than human practitioners to quickly and accurately complete a variety of healthcare-related tasks. — Kenneth Mandl, MD, MPH, Director, Computational Health Informatics Program; Professor of Pediatrics and Biomedical Informatics, Harvard Medical School
Everyday objects become diagnostic
In the near future, we will be able to use not just watches, but objects like toothbrushes, toilet paper, contact lenses and more as diagnostic tools and health monitors. Our homes will essentially become small hospitals. Companies like Scanadu plan on selling simple appliances that can easily scan foreheads to determine a fever (or other symptoms) or analyze a blood or urine sample, like a hospital machine would. Objects that we use in our daily life, changed in this manner can have a great impact. This will help to reduce the costs of hospitalization. One company, Hospital at Home, states that thanks to the simple modifications they have for now, costs (and impediments) decrease for elders by nearly one third. — Paolo Fiorina, MD, PhD, Division of Nephrology, Boston Children’s Hospital
Everyone knows cell therapy is hot, but tremendous work is also being done on understanding and exploiting the therapeutic possibilities of sub-cellular structures. Organelles are being studied as potential therapeutic engines with functions and effectiveness beyond their native role within cells.
Mitochondria were once thought of as simple energy providers, but are now being seen as potent biological machines that can be harnessed for many purposes, from re-invigorating damaged tissue to drug delivery devices. An effort at Boston Children’s, led by Pedro Del Nido, MD, James McCully, PhD, and Doug Cowan, PhD, has shown the effectiveness of using mitochondria isolated from infants with heart disease to strengthen their heart tissue and has even helped some desperately ill infants come off extracorporeal membrane oxygenation (ECMO). Animal studies show an even broader set of potential uses for isolated mitochondria.
Exosomes are another example. These small vesicles, secreted by cells, are now being seen as therapeutic agents in their own right. In fact, there are at least 14 companies developing exosomes as diagnostic aids or therapeutic delivery vehicles. Sub-cellular organelles and vesicles may be the cell therapy of the future. — Irene Abrams, Vice President, Technology Development and New Ventures, Boston Children’s Hospital Technology and Innovation Development Office (TIDO)
2018 will bring exciting achievements in medical gases. Using a new microparticle engineered for safe intravenous delivery, our lab will test whether injections of oxygen gas can rescue the heart from cardiac arrest in large animal models. We will also explore the use of oxygen microparticles to sensitize tumors to radiotherapy, which requires the presence of oxygen to damage tumor DNA, and will begin testing a new laser device that monitors oxygenation of mitochondria to determine the health of heart tissues after surgery.
Finally, how’s this for an explosive idea: using small concentrations of inhaled hydrogen gas to protect the brain during infant heart surgery. Hydrogen, which acts as an antioxidant, has been tested in rat models for various forms of brain injury and for stroke in clinical trials in Japan. Boston Children’s Hospital may be the first institution in the United States to conduct human safety trials, planned for 2018. — John Kheir, MD and Brian Polizzotti, PhD, Co-Directors, Translational Research Lab, Boston Children’s Hospital Heart Center
Read our picks for the top 10 biomedical advances of 2017 at Boston Children’s Hospital.