I want to wish everyone a Happy New Year! Hope your 2018 is off to a great start.
Over the holidays, the journal Science published its annual, end-of-the-year list of research breakthroughs, from anthropology to zoology. I always look forward to seeing the list and reflecting on some of the stunning advances reported in the past 12 months. Last year was no exception. Science’s 2017 Breakthrough of the Year, as chosen by its editors, was in the field of astrophysics. Scientists were able to witness the effects of the collision of two neutron stars—large stars with collapsed inner cores—smacking into each other 130 million light years away. How cool is that!
Numbered prominently among the nine other breakthroughs were five from biomedicine: gene therapy, gene editing, cancer immunotherapy, cryo-EM, and biology preprints. All involved varying degrees of NIH support, and all drew great interest from readers. In fact, three of the top four vote-getters in the “People’s Choice” category came from biomedicine. That includes the People’s 2017 Breakthrough of the Year: gene therapy success. And so, in what has become a Director’s Blog tradition, I’ll kick off our new year of posts by taking a closer look at these biomedical breakthroughs—starting with the little girl in the collage above, and moving clockwise around the images:
Gene therapy success: It was a banner year for gene therapy, a treatment strategy that has faced many challenges over the past 30 years. The top image shows 5-year-old Faith Fortenberry. She was born with spinal muscular atrophy (SMA), which is caused by mutations in a gene called SMN1. These mutations cause a deficiency of the SMN protein, leading to an untreatable degeneration of neurons in the brain and spinal cord, and progressive muscle weakness throughout the body.
Last November, researchers published the results of an innovative clinical trial to help Faith and other kids born with SMA . The treatment used is called nusineren (Spinraza™), and it’s not your typical drug. Nusineren is made up of single-stranded bits of DNA that, when injected into patients as a form of gene therapy, trick neurons into making the SMN protein. It’s a complicated process that I highlighted on the blog. Most of the children treated in the study had noticeable improvement in their mobility and well-being. In fact, based on the study’s earlier preliminary results, the Food and Drug Administration (FDA) approved nusineren in 2016 as the first drug to treat SMA. But what’s more, a different gene therapy approach using a viral vector to deliver a normal copy of the SMN1 gene, has also shown dramatic promise in infants who would otherwise have a very poor prognosis.
In another important gene therapy study, also highlighted on the blog, 15 infants with SMA had the genetic defect responsible for the condition corrected. The correction came from a one-time infusion of a modified virus that was engineered to carry a good copy of the SMN1 gene to affected neurons. The babies that received the highest dose of this gene therapy showed remarkable improvement in their movements. Further studies are in the works.
SMA was far from the only gene therapy success in 2017. In August, FDA approved the first CAR-T cell immunotherapy for kids and young adults with B-cell acute lymphoblastic leukemia (ALL)—the most common childhood cancer in the U.S. The drug, called tisagenlecleucel (Kymriah™), is a form of gene therapy in which a person’s own immune cells are genetically modified outside the body and then reinfused to target and kill cancer cells. In October, FDA approved a second CAR-T cell immunotherapy, to treat large B-cell lymphoma. The drug, called axicabtagene ciloleucel (Yescarta™), got its start right here at NIH. Then, in December, FDA approved a pioneering gene therapy approach, voretigene neparvovec-rzyl (Luxturna™), to treat children and adults who have potentially blinding degenerations of the eye’s retina associated with a specific inherited gene mutation .
Pinpoint gene editing: Gene editing has generated lots of attention for its potential to correct the one-letter misspellings, or point mutations, that underlie many rare genetic conditions. Progress has been most notable with the CRISPR/Cas9 gene editing system. However, most of this research has been performed in cells grown in lab dishes. In 2017, researchers made progress in applying gene editing in living systems to correct disease-causing mutations.
The image of scissors snipping DNA comes from my earlier post describing how NIH-supported researchers developed a CRISPR/Cas9 gene editing strategy that in mice reversed the effects of Huntington’s disease. In this case, they edited three bases, or units, of DNA that are repeated to cause Huntington’s disease.
But the ability of CRISPR/Cas9 to edit a point mutation accurately and reliably remains a work in progress. That has led to the development of additional gene editing techniques that have great potential for pinpoint accuracy to fix single base errors. One technique, developed by an NIH-funded researcher, chemically converts a point mutation to the correct spelling, rather than cutting out the error . Also emerging this year was a strategy that edits RNA, gene transcripts that cells process into protein . In this case, NIH-supported researchers showed they could convert one DNA base into another. Because cells quickly process RNA transcripts, the edits aren’t permanent like those in the genome. With these new tools and ample progress reported in other labs around the world, pinpoint gene editing was the People’s third choice for 2017 Breakthrough of the Year.
A drug for many cancers: Cancer researchers have been working tirelessly to bolster the life-saving potential of immunotherapy. In this treatment strategy (as noted above with the CAR-T cell therapies), a patient’s own immune system is empowered therapeutically to control and, in some cases, even cure the cancer. However, despite many dramatic stories of response, immunotherapy doesn’t work for every cancer.
As highlighted in the purple image of immune T cells (red) attacking a cancer cell (white), NIH-supported researchers figured out in 2017 how to identify a particular subset of cancer patients that are likely to benefit from immunotherapy. The work builds on the previous discovery that an immunotherapy drug called pembrolizumab (Keytruda®) works best in tumors with defects affecting the “mismatch repair” pathway. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If mismatch repair is defective in a tumor, the number of abnormal proteins produced is increased, making a more visible target for a revved-up immune system. The latest results are so encouraging that FDA recently approved the expanded use of pembrolizumab for people with any solid tumor that is deficient in mismatch repair.
This marks the first cancer treatment ever approved to treat tumors based on a specific genetic feature, not where they arise in the body. So impressive is this advance, it ranked fourth in the People’s Choice category for 2017 Breakthrough of the Year.
Life at the atomic level: The microscope is one of the oldest tools in biomedicine. Yet recent technological refinements with an established microscopic technique called cryo-electron microscopy (cryo-EM), could bring life at the atomic level into its highest resolution ever. The promise of seeing how things work at the atomic level is captured in the white, middle image above, showing the structure of the cystic fibrosis transmembrane conductance regulator. It’s a protein channel that regulates salt and water balance in the lungs and other parts of the body. It’s also a key target in learning to treat cystic fibrosis even more effectively.
Cryo-EM had a big year in 2017. Three of its pioneers—including NIH grantee Joachim Frank, Columbia University, New York—were awarded the 2017 Nobel Prize in Chemistry. Meanwhile, researchers continued to smash previous size barriers in cryo-EM, capturing the physical structures of proteins previously thought to be too small—or too large—to image with the technique. Included among the achievements in 2017 were the detailed physical structures of the tau filaments and amyloid fibrils that are seen in excess in the brains of people with Alzheimer’s disease [5-6]. Both will have major implications for drug discovery and development for this dread disease. So important is this technique to the future of research, NIH is in the process of establishing a network of cryo-EM centers across the nation. Details about these centers will be announced in the near future.
Biology preprints take off: This brings us to the final image, stamped “preprint.” Though sharing preprints, or draft manuscripts, has been commonplace in physics, it’s not previously been common in biomedicine. Tradition dictated that sharing ideas and data that hadn’t undergone peer review would be premature—and might diminish their chances of final publication. But that tradition is now being challenged. The vast majority of journals now will accept manuscripts that have been previously posted on a preprint server. And in May, NIH changed a longstanding policy and now allows researchers to include preprints in their grant applications. This new cultural change is intended to help speed the dissemination of information among researchers and push biomedicine forward faster toward the major discoveries that will improve health and change lives. NIH is also working with other research agencies across the globe to explore the feasibility of establishing a centralized service for preprints.
While Science magazine selected five biomedical breakthroughs in 2017, tremendous progress was seen all across biomedicine. Some of my favorites include discoveries that I blogged about last year, such as curing sickle cell disease with gene therapy, research to revitalize the aging brain, and monitoring health with wearable devices, with its reminder of this spring’s planned launch of the All of Us Research Program to advance a future of precision medicine. So, let’s get started on all of the exciting advances to come—many of which will likely be in the running for Science’s 2018 Breakthrough of the Year!
 Nusinersen versus sham control in infantile-onset spinal muscular atrophy. Finkel RS et al., N Engl J Med. 2017 Nov 2;377(18):1723-1732.
 FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. FDA News Release, Dec. 19, 2017.
 Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Nature. 2017 Nov 23;551(7681):464-471.
 RNA editing with CRISPR-Cas13. Cox DBT, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F. Science. 2017 Nov 24;358(6366):1019-1027.
 Cryo-EM structures of tau filaments from Alzheimer’s disease. Fitzpatrick AWP1, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW. Nature. 2017 Jul 13;547(7662):185-190.
 Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli RBG, Tusche M, Lopez-Iglesias C4, Hoyer W, Heise H, Willbold D, Schröder GF. Science. 2017 Oct 6;358(6359):116-119.
NIH Support: These breakthroughs represent the culmination of years of research involving many investigators and the support of multiple NIH institutes.