Gene Editing: Gold Nanoparticle Delivery Shows Promise

Juip Family with Dr. Francis CollinsAbout a month ago, I had the pleasure of welcoming the Juip (pronounced “Yipe”) family from Michigan to NIH. Although you’d never guess it from this photo, two of the Juip’s five children—9-year-old Claire and 11-year-old Jake (both to my left)—have a rare genetic disease called Friedreich’s ataxia (FA). This inherited condition causes progressive damage to their nervous systems and their hearts. No treatment currently exists for kids like Claire and Jake, yet this remarkable family has turned this serious health challenge into an opportunity to raise awareness about the need for biomedical research.

One thing that helps keep the Juips optimistic is the therapeutic potential of CRISPR/Cas9, an innovative gene editing system that may someday make it possible to correct the genetic mutations responsible for FA and many other conditions. So, I’m sure the Juips were among those encouraged by the recent news that NIH-funded researchers have developed a highly versatile approach to CRISPR/Cas9-based therapies. Instead of relying on viruses to carry the gene-editing system into cells, the new approach uses tiny particles of gold as the delivery system!

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Regenerative Medicine: Making Blood Stem Cells in the Lab

Endothelial cells becoming hematopoietic stem cells

Caption: Arrow in first panel points to an endothelial cell induced to become hematopoietic stem cell (HSC). Second and third panels show the expansion of HSCs over time.
Credit: Raphael Lis, Weill Cornell Medicine, New York, NY

Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.

A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).

Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.

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Random Mutations Play Major Role in Cancer

Cancer OddsWe humans are wired to search for a causative agent when something bad happens. When someone develops cancer, we seek a reason. Maybe cancer runs in the family. Or perhaps the person smoked, never wore sunscreen, or drank too much alcohol. At some level, those are reasonable assumptions, as genes, lifestyle, and environment do play important roles in cancer. But a new study claims that the reason why many people get cancer is simply just bad luck.

This bad luck occurs during the normal process of cell division that is essential to helping our bodies grow and remain healthy. Every time a cell divides, its 6 billion letters of DNA are copied, with a new copy going to each daughter cell. Typos inevitably occur during this duplication process, and the cell’s DNA proofreading mechanisms usually catch and correct these typos. However, every once in a while, a typo slips through—and if that misspelling happens to occur in certain key areas of the genome, it can drive a cell onto a pathway of uncontrolled growth that leads to cancer. In fact, according to a team of NIH-funded researchers, nearly two-thirds of DNA typos in human cancers arise in this random way.

The latest findings should help to reassure people being treated for many forms of cancer that they likely couldn’t have prevented their illness. They also serve as an important reminder that, in addition to working on better strategies for prevention, cancer researchers must continue to pursue innovative technologies for early detection and treatment.

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Regenerative Medicine: The Promise and Peril

Retinal pigment epithelial cells

Caption: Scanning electron micrograph of iPSC-derived retinal pigment epithelial cells growing on a nanofiber scaffold (blue).
Credit: Sheldon Miller, Arvydas Maminishkis, Robert Fariss, and Kapil Bharti, National Eye Institute/NIH

Stem cells derived from a person’s own body have the potential to replace tissue damaged by a wide array of diseases. Now, two reports published in the New England Journal of Medicine highlight the promise—and the peril—of this rapidly advancing area of regenerative medicine. Both groups took aim at the same disorder: age-related macular degeneration (AMD), a common, progressive form of vision loss. Unfortunately for several patients, the results couldn’t have been more different.

In the first case, researchers in Japan took cells from the skin of a female volunteer with AMD and used them to create induced pluripotent stem cells (iPSCs) in the lab. Those iPSCs were coaxed into differentiating into cells that closely resemble those found near the macula, a tiny area in the center of the eye’s retina that is damaged in AMD. The lab-grown tissue, made of retinal pigment epithelial cells, was then transplanted into one of the woman’s eyes. While there was hope that there might be actual visual improvement, the main goal of this first in human clinical research project was to assess safety. The patient’s vision remained stable in the treated eye, no adverse events occurred, and the transplanted cells remained viable for more than a year.

Exciting stuff, but, as the second report shows, it is imperative that all human tests of regenerative approaches be designed and carried out with the utmost care and scientific rigor. In that instance, three elderly women with AMD each paid $5,000 to a Florida clinic to be injected in both eyes with a slurry of cells, including stem cells isolated from their own abdominal fat. The sad result? All of the women suffered severe and irreversible vision loss that left them legally or, in one case, completely blind.

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Creative Minds: Modeling Neurobiological Disorders in Stem Cells

Feng Zhang

Feng Zhang

Most neurological and psychiatric disorders are profoundly complex, involving a variety of environmental and genetic factors. Researchers around the world have worked with patients and their families to identify hundreds of possible genetic leads to learn what goes wrong in autism spectrum disorder, schizophrenia, and other conditions. The great challenge now is to begin examining this growing cache of information more systematically to understand the mechanism by which these gene variants contribute to disease risk—potentially providing important information that will someday lead to methods for diagnosis and treatment.

Meeting this profoundly difficult challenge will require a special set of laboratory tools. That’s where Feng Zhang comes into the picture. Zhang, a bioengineer at the Broad Institute of MIT and Harvard, Cambridge, MA, has made significant contributions to a number of groundbreaking research technologies over the past decade, including optogenetics (using light to control brain cells), and CRISPR/Cas9, which researchers now routinely use to edit genomes in the lab [1,2].

Zhang has received a 2015 NIH Director’s Transformative Research Award to develop new tools to study multiple gene variants that might be involved in a neurological or psychiatric disorder. Zhang draws his inspiration from nature, and the microscopic molecules that various organisms have developed through the millennia to survive. CRISPR/Cas9, for instance, is a naturally occurring bacterial defense system that Zhang and others have adapted into a gene-editing tool.

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