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Seeing the Cytoskeleton in a Whole New Light

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It’s been 25 years since researchers coaxed a bacterium to synthesize an unusual jellyfish protein that fluoresced bright green when irradiated with blue light. Within months, another group had also fused this small green fluorescent protein (GFP) to larger proteins to make their whereabouts inside the cell come to light—like never before.

To mark the anniversary of this Nobel Prize-winning work and show off the rainbow of color that is now being used to illuminate the inner workings of the cell, the American Society for Cell Biology (ASCB) recently held its Green Fluorescent Protein Image and Video Contest. Over the next few months, my blog will feature some of the most eye-catching entries—starting with this video that will remind those who grew up in the 1980s of those plasma balls that, when touched, light up with a simulated bolt of colorful lightning.

This video, which took third place in the ASCB contest, shows the cytoskeleton of a frequently studied human breast cancer cell line. The cytoskeleton is made from protein structures called microtubules, made visible by fluorescently tagging a protein called doublecortin (orange). Filaments of another protein called actin (purple) are seen here as the fine meshwork in the cell periphery.

The cytoskeleton plays an important role in giving cells shape and structure. But it also allows a cell to move and divide. Indeed, the motion in this video shows that the complex network of cytoskeletal components is constantly being organized and reorganized in ways that researchers are still working hard to understand.

Jeffrey van Haren, Erasmus University Medical Center, Rotterdam, the Netherlands, shot this video using the tools of fluorescence microscopy when he was a postdoctoral researcher in the NIH-funded lab of Torsten Wittman, University of California, San Francisco.

All good movies have unusual plot twists, and that’s truly the case here. Though the researchers are using a breast cancer cell line, their primary interest is in the doublecortin protein, which is normally found in association with microtubules in the developing brain. In fact, in people with mutations in the gene that encodes this protein, neurons fail to migrate properly during development. The resulting condition, called lissencephaly, leads to epilepsy, cognitive disability, and other neurological problems.

Cancer cells don’t usually express doublecortin. But, in some of their initial studies, the Wittman team thought it would be much easier to visualize and study doublecortin in the cancer cells. And so, the researchers tagged doublecortin with an orange fluorescent protein, engineered its expression in the breast cancer cells, and van Haren started taking pictures.

This movie and others helped lead to the intriguing discovery that doublecortin binds to microtubules in some places and not others [1]. It appears to do so based on the ability to recognize and bind to certain microtubule geometries. The researchers have since moved on to studies in cultured neurons.

This video is certainly a good example of the illuminating power of fluorescent proteins: enabling us to see cells and their cytoskeletons as incredibly dynamic, constantly moving entities. And, if you’d like to see much more where this came from, consider visiting van Haren’s Twitter gallery of microtubule videos here:

Reference:

[1] Doublecortin is excluded from growing microtubule ends and recognizes the GDP-microtubule lattice. Ettinger A, van Haren J, Ribeiro SA, Wittmann T. Curr Biol. 2016 Jun 20;26(12):1549-1555.

Links:

Lissencephaly Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Wittman Lab (University of California, San Francisco)

Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)

NIH Support: National Institute of General Medical Sciences


Biomedical Research Highlighted in Science’s 2018 Breakthroughs

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Science Breakthroughs of the Year 2018

A Happy New Year to one and all! While many of us were busy wrapping presents, the journal Science announced its much-anticipated scientific breakthroughs of 2018. In case you missed the announcement [1], it was another banner year for the biomedical sciences.

The 2018 Breakthrough of the Year went to biomedical science and its ability to track the development of life—one cell at a time—in a variety of model organisms. This newfound ability opens opportunities to understand the biological basis of life more systematically than ever before. Among Science’s “runner-up” breakthroughs, more than half had strong ties to the biomedical sciences and NIH-supported research.

Sound intriguing? Let’s take a closer look at some of the amazing science conducted in 2018, starting with Science’s Breakthrough of the Year.

Development Cell by Cell: For millennia, biologists have wondered how a single cell develops into a complete multicellular organism, such as a frog or a mouse. But solving that mystery was almost impossible without the needed tools to study development systematically, one cell at a time. That’s finally started to change within the last decade. I’ve highlighted the emergence of some of these powerful tools on my blog and the interesting ways that they were being applied to study development.

Over the past few years, all of this technological progress has come to a head. Researchers, many of them NIH-supported, used sophisticated cell labeling techniques, nucleic acid sequencing, and computational strategies to isolate thousands of cells from developing organisms, sequence their genetic material, and determine their location within that developing organism.

In 2018 alone, groundbreaking single-cell analysis papers were published that sequentially tracked the 20-plus cell types that arise from a fertilized zebrafish egg, the early formation of organs in a frog, and even the creation of a new limb in the Axolotl salamander. This is just the start of amazing discoveries that will help to inform us of the steps, or sometimes missteps, within human development—and suggest the best ways to prevent the missteps. In fact, efforts are now underway to gain this detailed information in people, cell by cell, including the international Human Cell Atlas and the NIH-supported Human BioMolecular Atlas Program.

An RNA Drug Enters the Clinic: Twenty years ago, researchers Andrew Fire and Craig Mello showed that certain small, noncoding RNA molecules can selectively block genes in our cells from turning “on” through a process called RNA interference (RNAi). This work, for the which these NIH grantees received the 2006 Nobel Prize in Physiology or Medicine, soon sparked a wave of commercial interest in various noncoding RNA molecules for their potential to silence the expression of a disease-causing gene.

After much hard work, the first gene-silencing RNA drug finally came to market in 2018. It’s called Onpattro™ (patisiran), and the drug uses RNAi to treat the peripheral nerve disease that can afflict adults with a rare disease called hereditary transthyretin-mediated amyloidosis. This hard-won success may spark further development of this novel class of biopharmaceuticals to treat a variety of conditions, from cancer to cardiovascular disorders, with potentially greater precision.

Rapid Chemical Structure Determination: Last October, two research teams released papers almost simultaneously that described an incredibly fast new imaging technique to determine the structure of smaller organic chemical compounds, or “small molecules“ at atomic resolution. Small molecules are essential components of molecular biology, pharmacology, and drug development. In fact, most of our current medicines are small molecules.

News of these papers had many researchers buzzing, and I highlighted one of them on my blog. It described a technique called microcrystal electron diffraction, or MicroED. It enabled these NIH-supported researchers to take a powder form of small molecules (progesterone was one example) and generate high-resolution data on their chemical structures in less than a half-hour! The ease and speed of MicroED could revolutionize not only how researchers study various disease processes, but aid in pinpointing which of the vast number of small molecules can become successful therapeutics.

How Cells Marshal Their Contents: About a decade ago, researchers discovered that many proteins in our cells, especially when stressed, condense into circumscribed aqueous droplets. This so-called phase separation allows proteins to gather in higher concentrations and promote reactions with other proteins. The NIH soon began supporting several research teams in their groundbreaking efforts to explore the effects of phase separation on cell biology.

Over the past few years, work on phase separation has taken off. The research suggests that this phenomenon is critical in compartmentalizing chemical reactions within the cell without the need of partitioning membranes. In 2018 alone, several major papers were published, and the progress already has some suggesting that phase separation is not only a basic organizing principle of the cell, it’s one of the major recent breakthroughs in biology.

Forensic Genealogy Comes of Age: Last April, police in Sacramento, CA announced that they had arrested a suspect in the decades-long hunt for the notorious Golden State Killer. As exciting as the news was, doubly interesting was how they caught the accused killer. The police had the Golden Gate Killer’s DNA, but they couldn’t determine his identity, that is, until they got a hit on a DNA profile uploaded by one of his relatives to a public genealogy database.

Though forensic genealogy falls a little outside of our mission, NIH has helped to advance the gathering of family histories and using DNA to study genealogy. In fact, my blog featured NIH-supported work that succeeded in crowdsourcing 600 years of human history.

The researchers, using the online profiles of 86 million genealogy hobbyists with their permission, assembled more than 5 million family trees. The largest totaled more than 13 million people! By merging each tree from the crowd-sourced and public data, they were able to go back about 11 generations—to the 15th century and the days of Christopher Columbus. Though they may not have caught an accused killer, these large datasets provided some novel insights into our family structures, genes, and longevity.

An Ancient Human Hybrid: Every year, researchers excavate thousands of bone fragments from the remote Denisova Cave in Siberia. One such find would later be called Denisova 11, or “Denny” for short.

Oh, what a fascinating genomic tale Denny’s sliver of bone had to tell. Denny was at least 13 years old and lived in Siberia roughly 90,000 years ago. A few years ago, an international research team found that DNA from the mitochondria in Denny’s cells came from a Neanderthal, an extinct human relative.

In 2018, Denny’s family tree got even more interesting. The team published new data showing that Denny was female and, more importantly, she was a first generation mix of a Neanderthal mother and a father who belonged to another extinct human relative called the Denisovans. The Denisovans, by the way, are the first human relatives characterized almost completely on the basis of genomics. They diverged from Neanderthals about 390,000 years ago. Until about 40,000 years ago, the two occupied the Eurasian continent—Neanderthals to the west, and Denisovans to the east.

Denny’s unique genealogy makes her the first direct descendant ever discovered of two different groups of early humans. While NIH didn’t directly support this research, the sequencing of the Neanderthal genome provided an essential resource.

As exciting as these breakthroughs are, they only scratch the surface of ongoing progress in biomedical research. Every field of science is generating compelling breakthroughs filled with hope and the promise to improve the lives of millions of Americans. So let’s get started with 2019 and finish out this decade with more truly amazing science!

Reference:

[1] “2018 Breakthrough of the Year,” Science, 21 December 2018.

NIH Support: These breakthroughs represent the culmination of years of research involving many investigators and the support of multiple NIH institutes.


Celebrating 2018 Nobel Laureates

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Drs. Francis Collins, Peter WT Pisters, and Jim Allison

It was an honor to attend the Nobel Symposium hosted by the Embassy of Sweden in the U.S. on November 13, 2018. The symposium was held at the House of Sweden in Washington, D.C. to celebrate the 2018 American Nobel Laureates. Four of this year’s six Nobel Laureates were in attendance. Here, I’m standing with Peter WT Pisters (middle), president of the University of Texas M.D. Anderson Cancer Center, Houston; and Jim Allison (right), also with MD Anderson and a co-recipient of the 2018 Nobel Prize in Physiology or Medicine. Dr. Allison played a leading role in developing cancer immunotherapy. Credit: @ppisters


A Tribute to Two Amazing Scientists

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Sulston-Hawking

Caption: Sir John Sulston (left) and Stephen Hawking (right)
Credit: Jane Gitschier, PLoS; Paul Alers, NASA

Over the past couple of weeks, we’ve lost two legendary scientists who made major contributions to our world: Sir John Sulston and Stephen Hawking. Although they worked in very different areas of science—biology and physics—both have left us with an enduring legacy through their brilliant work that unlocked fundamental mysteries of life and the universe.

I had the privilege of working closely with John as part of the international Human Genome Project (HGP), a historic endeavor that successfully produced the first reference sequence of the human genetic blueprint nearly 15 years ago, in April 2003. As founding director of the Sanger Centre (now the Sanger Institute) in Cambridge, England, John oversaw the British contributions to this publicly funded effort. Throughout our many planning meetings and sometimes stormy weekly conference calls about progress of this intense and all-consuming enterprise, John stood out for his keen intellect and high ethical standards.


Regenerative Medicine: The Promise and Peril

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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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