Sickle Cell Disease: Gene-Editing Tools Point to Possible Ultimate Cure

Sickled red blood cell

Caption: An electron micrograph showing two red blood cells, one normal (right) and the other (left) deformed by crystalline hemoglobin into the “sickle” shape characteristic of patients with sickle cell disease.
Credit: Frans Kuypers:, UCSF Benioff Children’s Hospital Oakland

Scientists first described the sickle-shaped red blood cells that give sickle cell disease its name more than a century ago. By the 1950s, the precise molecular and genetic underpinnings of this painful and debilitating condition had become clear, making sickle cell the first “molecular disease” ever characterized. The cause is a single letter “typo” in the gene encoding oxygen-carrying hemoglobin. Red blood cells containing the defective hemoglobin become stiff, deformed, and prone to clumping. Individuals carrying one copy of the sickle mutation have sickle trait, and are generally fine. Those with two copies have sickle cell disease and face major medical challenges. Yet, despite all this progress in scientific understanding, nearly 70 years later, we still have no safe and reliable means for a cure.

Recent advances in CRISPR/Cas9 gene-editing tools, which the blog has highlighted in the past, have renewed hope that it might be possible to cure sickle cell disease by correcting DNA typos in just the right set of cells. Now, in a study published in Science Translational Medicine, an NIH-funded research team has taken an encouraging step toward this goal [1]. For the first time, the scientists showed that it’s possible to correct the hemoglobin mutation in blood-forming human stem cells, taken directly from donors, at a frequency that might be sufficient to help patients. In addition, their gene-edited human stem cells persisted for 16 weeks when transplanted into mice, suggesting that the treatment might also be long lasting or possibly even curative.

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Creative Minds: Building the RNA Toolbox


Caption: Genetically identical mice. The Agouti gene is active in the yellow mouse and inactive in the brown mouse.
Credit: Dana Dolinoy, University of Michigan, Ann Arbor, and Randy Jirtle, Duke University, Durham, NC

Step inside the lab of Dana Dolinoy at the University of Michigan, Ann Arbor, and you’re sure to hear conversations that include the rather strange word “agouti” (uh-goo-tee). In this context, it’s a name given to a strain of laboratory mice that arose decades ago from a random mutation in the Agouti gene, which is normally expressed only transiently in hair follicles. The mutation causes the gene to be turned on, or expressed, continuously in all cell types, producing mice that are yellow, obese, and unusually prone to developing diabetes and cancer. As it turns out, these mutant mice and the gene they have pointed to are more valuable than ever today because they offer Dolinoy and other researchers an excellent model for studying the rapidly emerging field of epigenomics.

The genome of the mouse, just as for the human, is the complete DNA instruction book; it contains the coding information for building the proteins that carry out a variety of functions in a cell. But modifications to the DNA determine its function, and these are collectively referred to as the epigenome. The epigenome is made up of chemical tags and proteins that can attach to the DNA and direct such actions as turning genes on or off, thereby controlling the production of proteins in particular cells. These tags have different patterns in each cell type, helping to explain, for example, why a kidney and a skin cell can behave so differently when they share the same DNA.

Some types of genes, including Agouti, are particularly vulnerable to epigenomic effects. In fact, Dolinoy has discovered that exposing normal, wild-type (brown) mice to certain chemicals and dietary factors during pregnancy can switch on the Agouti gene in their developing offspring, turning their coats yellow and their health poor. Dolinoy says these experiments raise much larger questions: If researchers discover populations of humans that have been exposed to lifestyle or environmental factors that modify their epigenomes in ways that may possibly contribute to risk for certain diseases, can the modification be passed on to their children and grandchildren (referred to as transgenerational epigenetic inheritance, a controversial topic)? If so, how can we develop the high-precision tools needed to better understand and perhaps even reduce such risks? The University of Michigan researcher received a 2015 NIH Director’s Transformative Research Award to undertake that challenge.

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Imaging Advance Offers New View on Allergic Asthma

Healthy vs. Allergic Asthma Airways

Caption: OR-OCT images of the airways of a healthy person (left) and a person with allergic asthma (right). The colorized portion highlights airway smooth muscle, with thinner areas in purple and black and thicker areas in yellow and orange. Credit: Cho et al., Science Translational Medicine (2016)

You probably know people who sneeze a little when they encounter plant pollens, pet dander, or other everyday allergens. For others, however, these same allergens can trigger a serious asthma attack that can make breathing a life-or-death struggle. Now, two NIH-funded research groups have teamed up to help explain the differences in severity underlying the two types of reactions.

In the studies, researchers at Massachusetts General Hospital, Boston, used an innovative imaging tool to zoom in on a person’s airways safely in real time to gain an unprecedented view of how his or her body reacts to allergens [1,2]. The imaging revealed key differences between the asthma and non-asthma groups in the smooth muscle tissue that surrounds critical airways, and is responsible for constriction. In a complementary series of experiments, researchers also uncovered heightened immune responses in the airways of folks with allergic asthma. The findings offer important new clues in the quest to better understand and guide treatment for asthma, a condition that affects more than 300 million people around the world.

The factors driving airway constriction in people with asthma have been poorly understood in part because, until now, there hasn’t been a way to view airway smooth muscle in action. As described in the journal Science Translational Medicine, Melissa Suter and colleagues adapted an established form of imaging called optical coherence tomography (OCT) to help fill this gap. Standard OCT produces an image by measuring the amount of light reflected back from body tissues, but such images aren’t sufficient to distinguish airway smooth muscle from other tissues.

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Cool Videos: Regenerating Nerve Fibers

If you enjoy action movies, you can probably think of a superhero—maybe Wolverine?—who can lose a limb in battle, yet grow it right back and keep on going. But could regenerating a lost limb ever happen in real life? Some scientists are working hard to understand how other organisms do this.

As shown in this video of a regenerating fish fin, biology can sometimes be stranger than fiction. The zebrafish (Danio rerio), which is a species of tropical freshwater fish that’s an increasingly popular model organism for biological research, is among the few vertebrates that can regrow body parts after they’ve been badly damaged or even lost. Using time-lapse photography over a period of about 12 hours, NIH grantee Sandra Rieger, now at MDI Biological Laboratory, Bar Harbor, ME, used a fluorescent marker (green) to track a nerve fiber spreading through the skin of a zebrafish tail fin (gray). The nerve regeneration was occurring in tissue being spontaneously formed to replace a section of a young zebrafish’s tail fin that had been lopped off 3 days earlier.

Along with other tools, Rieger is using such imaging to explore how the processes of nerve regeneration and wound healing are coordinated. The researcher started out by using a laser to sever nerves in a zebrafish’s original tail fin, assuming that the nerves would regenerate—but they did not! So, she went back to the drawing board and discovered that if she also used the laser to damage some skin cells in the tail fin, the nerves regenerated. Rieger suspects the answer to the differing outcomes lies in the fact that the fish’s damaged skin cells release hydrogen peroxide, which may serve as a critical prompt for the regenerative process [1]. Rieger and colleagues went on discover that the opposite is also true: when they used a cancer chemotherapy drug to damage skin cells in a zebrafish tail fin, it contributed to the degeneration of the fin’s nerve fibers [2].

Based on these findings, Rieger wants to see whether similar processes may be going on in the hands and feet of cancer patients who struggle with painful nerve damage, called peripheral neuropathy, caused by certain chemotherapy drugs, including taxanes and platinum compounds. For some people, the pain and tingling can be so severe that doctors must postpone or even halt cancer treatment. Rieger is currently working with a collaborator to see if two protective molecules found in the zebrafish might be used to reduce or prevent chemotherapy-induced peripheral neuropathy in humans.

In recent years, a great deal of regenerative medicine has focused on learning to use stem cell technologies to make different kinds of replacement tissue. Still, as Rieger’s work demonstrates, there remains much to be gained from studying model organisms, such as the zebrafish and axolotl salamander, that possess the natural ability to regenerate limbs, tissues, and even internal organs. Now, that’s a super power we’d all like to have.


[1] Hydrogen peroxide promotes injury-induced peripheral sensory axon regeneration in the zebrafish skin. Rieger S, Sagasti A. PLoS Biol. 2011 May;9(5):e1000621

[2] Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Lisse TS, Middleton LJ, Pellegrini AD, Martin PB, Spaulding EL, Lopes O, Brochu EA, Carter EV, Waldron A, Rieger S. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2189-E2198.


Chemotherapy-Induced Peripheral Neuropathy (National Cancer Institute/NIH)

Learning About Human Biology From a Fish (National Institute of General Medical Sciences/NIH)

Sandra Rieger (MDI Biological Laboratory, Bar Harbor, ME)

NIH Support: National Institute of Dental and Craniofacial Research; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke

Mouse Study Finds Microbe Might Protect against Food Poisoning

T mu in a mouse colon

Caption: Scanning electron microscopy image of T. mu in the mouse colon.
Credit: Aleksey Chudnovskiy and Miriam Merad, Icahn School of Medicine at Mount Sinai

Recently, we humans have started to pay a lot more attention to the legions of bacteria that live on and in our bodies because of research that’s shown us the many important roles they play in everything from how we efficiently metabolize food to how well we fend off disease. And, as it turns out, bacteria may not be the only interior bugs with the power to influence our biology positively—a new study suggests that an entirely different kingdom of primarily single-celled microbes, called protists, may be in on the act.

In a study published in the journal Cell, an NIH-funded research team reports that it has identified a new protozoan, called Tritrichomonas musculis (T. mu), living inside the gut of laboratory mice. That sounds bad—but actually this little wriggler was potentially providing a positive benefit to the mice. Not only did T. mu appear to boost the animals’ immune systems, it spared them from the severe intestinal infection that typically occurs after eating food contaminated with toxic Salmonella bacteria. While it’s not yet clear if protists exist that can produce similar beneficial effects in humans, there is evidence that a close relative of T. mu frequently resides in the intestines of people around the world.

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