Within a few years, Jim Johnsen and Delaney Van Riper may be among the first to benefit from CRISPR-Cas9 gene editing, a breakthrough that has already revolutionized biology research and promises to resurrect gene therapy.

UC San Francisco doctors working closely with UC Berkeley scientists plan to edit their genomes to correct rare genetic mutations and slow or halt progression of their diseases.

If successful, the trials will inaugurate a new era of “genome surgery”—the precision targeting of genetic defects in the genome, using CRISPR-Cas9 customized to individual patients. Such “bespoke” therapies can benefit small groups of individuals or families with particular genetic defects that would never be addressed by large pharmaceutical companies.

Johnsen and his family, including his daughter Greta, are carriers of a rare disorder, Best disease, that afflicts perhaps a thousand people nationwide and leads to early vision loss and eventual blindness, much like the more common macular degeneration.

Van Riper was born with a rare disease called Charcot-Marie-Tooth, which gradually destroys her nerve cells’ ability to relay messages between her brain and muscles, causing her to slowly lose control of her limbs and her muscles to waste.

CRISPR-Cas9, invented at UC Berkeley, could make treating such diseases, if not easy, at least straightforward: with a large enough CRISPR toolbox, doctors can pick and choose the best approach and tailor a therapy to the specific genetic mutation.

“Imagine a world where people go to the doctor, and they get their genome sequenced and learn they have a genetic disorder,” says CRISPR-Cas9 inventor Jennifer Doudna, who pioneered the first CRISPR applications in her UC Berkeley lab in 2012. “And instead of telling them they need to live with that disorder, we have the technology that can actually treat them  –  potentially even cure them.”

Doudna is quoted in an article that highlights the collaboration among scientists in the Innovative Genomics Institute, a joint UCSF/UC Berkeley research initiative that seeks to expand the CRISPR toolbox and make CRISPR-Cas9 gene editing more precise, more effective and safer. Doudna is IGI’s executive director, and is also a Howard Hughes Medical Institute investigator and Berkeley professor of molecular and cell biology and of chemistry.

While Johnsen and Van Riper have yet to be treated, both have donated their cells to Bruce Conklin at UCSF, where they have been coaxed into becoming stem cells that are now being treated with CRISPR-based gene therapy to, ideally, correct their mutations. Once this is successful in the lab, the stem cells will be injected into the eye, in Johnsen’s case, or muscles, in Van Riper’s case, in hopes of alleviating their symptoms.

The researchers acknowledge that Best disease and CMT are simpler targets than many genetic diseases: both are caused by single nucleotide changes in a single gene, making it simpler to fix; and the symptoms occur in tissues that are relatively easy to access. Nevertheless, treatments like this will pave the way for treating more complex genetic diseases.

“Almost universally, the first targets of genome surgery will be incurable diseases, where there is truly no other option,” says Conklin, a senior investigator at the Gladstone Institutes, UCSF professor of medicine and deputy director of IGI. “If we can treat these, it will open the door to a new type of medicine.”

 Explore further: Genome damage from CRISPR/Cas9 gene editing higher than thought

The forthcoming Laser Interferometer Space Antenna (LISA) will be a huge instrument allowing astronomers to study phenomena including black holes colliding and gravitational waves moving through space-time. Researchers from the University of Zurich have now found that LISA could also shed light on the elusive dark matter particle.

The Laser Interferometer Space Antenna (LISA) will enable astrophysicists to observe gravitational waves emitted by black holes as they collide with or capture other black holes. LISA will consist of three spacecraft orbiting the sun in a constant triangle formation. Gravitational waves passing through will distort the sides of the triangle slightly, and these minimal distortions can be detected by laser beams connecting the spacecraft. LISA could therefore add a new sense to scientists’ perception of the universe and enable them to study phenomena invisible in different light spectra.

Scientists from the Center for Theoretical Astrophysics and Cosmology of the University of Zurich, together with colleagues from Greece and Canada, have now found that LISA will not only be able to measure these previously unstudied waves, but could also help to unveil secrets about dark matter.

Dark matter particles are thought to account for approximately 85 percent of the matter in the universe. However, they are still only hypothetical—the name refers to their elusiveness. But calculations show that many galaxies would be torn apart instead of rotating if they weren’t held together by a large amount of dark matter.

That is especially true for dwarf galaxies. While such galaxies are small and faint, they are also the most abundant in the universe. What makes them particularly interesting for astrophysicists is that their structures are dominated by dark matter, making them natural laboratories for studying this elusive form of matter.

Black holes and dark matter are connected

In a new study reported in Astrophysical Journal Letters, UZH Ph.D. student Tomas Ramfal conducted high-resolution computer simulations of the birth of dwarf galaxies, yielding surprising results. Calculating the interplay of dark matter, stars and the central black holes of these galaxies, the team of scientists from Zurich discovered a strong link between the merger rates of these black holes and the amount of dark matter at the center of dwarf galaxies. Measuring gravitational waves emitted by merging black holes can thus provide hints about the properties of the hypothetical dark matter particle.

The newly found connection between black holes and dark matter can now be described in a mathematical and exact way for the first time. Lucio Mayer, the group leader, says, “Dark matter is the distinguishing quality of dwarf galaxies. We had therefore long suspected that this should also have a clear effect on cosmological properties.”

The connection comes at an opportune moment, as preparations for the final design of LISA are under way. Preliminary results of the researchers’ simulations were met with excitement at meetings of the LISA consortium. The physics community sees the new use of gravitational wave observations as a promising new prospect for one the biggest future European space missions, which is expected to launch in about 15 years and could link cosmology and particle physics—the incredibly big and the unimaginably small.

 Explore further: Is dark matter made of primordial black holes?

More information: Tomas Tamfal et al, Formation of LISA Black Hole Binaries in Merging Dwarf Galaxies: The Imprint of Dark Matter, The Astrophysical Journal (2018). DOI: 10.3847/2041-8213/aada4b

Antennas have come a long way from the rabbit ears on your old TV. But the antenna that Northeastern doctoral student Hwaider Lin has been working on since 2015 is about 100 times smaller than the one currently in your smartphone.

Lin said the antenna he is developing could eventually be used in a chip implanted in a patient’s brain to help treat disorders such as depression or severe migraines. Currently, researchers use electromagnetic currents created outside a patient’s head to stimulate neurons in the brain to help treat these medical conditions. But this method is imprecise. With a smaller antenna, researchers may be able to create an implant in the brain that would more precisely target specific neurons.

Lin’s antenna recently won first prize in design a contest run by the publishers of NASA Tech Briefs magazine. More than 800 applicants from 60 different countries submitted their technology to the “Create the Future Design Contest,” which judges feats of innovative engineering in seven different categories. Lin topped the category for Electronics/Sensors/Internet of Things.

“I’m kind of surprised I got the first prize,” Lin said. “But I think [the antenna] is worth it.”

Conventional antennas send signals by bouncing electrons back and forth along a metal cable. This creates waves of electromagnetic radiation that can be picked up by other antennas tuned to the right frequency. Changing the size of the antenna changes the frequency. There’s a limit to how small these antennas can be before they stop being effective.

The antenna Lin has been working on starts with a different kind of wave: an acoustic one. Acoustic waves are slow-moving physical vibrations. Because of their slower speed, they can match the frequency of an electromagnetic wave, but will have a wavelength that is thousands of times smaller. This means the antenna can be smaller too.

Lin’s antenna is able to translate those acoustic waves into faster-moving electromagnetic ones with the same frequency. This is because the material vibrating in Lin’s antenna is magnetic.

“We actually do materials science first,” said Lin, who works in Northeastern’s Advanced Materials and Microsystems Lab. “Our material is the most important thing for this antenna.”

This work was first published in August 2017 in Nature Communications. Since then, Lin and his advisor, Northeastern professor Nian Sun, have been refining it to be used in different applications.

“So far, the best choice is biomedical applications,” Lin said. “They need a really small antenna that can receive power and transmit information back to the computer outside.”

The team recently started working with a group at Harvard Medical School to find ways to use this technology in medical implants. Together, they have the potential to design new devices to sense what is going on in the brain, stimulate different areas, and communicate important information back to researchers.

But first, Lin will be flying to a reception in New York to receive his prize from NASA Tech Briefs: a high-end computer that can handle the complicated simulations his work requires.

“This event is very special,” Lin said. “They see the potential of this technology.”

 Explore further: New membrane-based antenna much smaller than conventional ones

More information: Tianxiang Nan et al. Acoustically actuated ultra-compact NEMS magnetoelectric antennas, Nature Communications (2017). DOI: 10.1038/s41467-017-00343-8

Researchers at Stanford University have reworked CRISPR-Cas9 gene-editing technology to manipulate the genome in three-dimensional space, allowing them to ferry genetic snippets to different locations in a cell’s nucleus.

The new technique, dubbed CRISPR-genome organization or simply CRISPR-GO, uses a modified CRISPR protein to reorganize the genome in three dimensions. If CRISPR is like molecular scissors, then CRISPR-GO is like molecular tweezers, grabbing specific bits of the genome and plunking them down in new locations of the nucleus. But it’s more than just physical relocation: Displacing genetic elements can change how they function.

The research sheds new light on how the genome’s spatial organization in the nucleus governs the function of the cell overall.

“The question of why spatial organization in a cell matters is an important one, and it’s also not one that scientists agree on,” said Stanley Qi, Ph.D., assistant professor of bioengineering and of chemical and systems biology. “CRISPR-GO could provide an opportunity to answer that question by enabling us to target, move and relocate very specific stretches of DNA, and see how their new placements in the nucleus change how they function.”

Most mammalian cells contain a nucleus that houses more than 6 feet of DNA, if stretched out in a line. This genetic material determines the fate of the cells and, if out of place or damaged, can lead to disease. Previous studies have shown that DNA tends to clump in certain areas in the nucleus. How that placement affects the DNA’s function, however, is still unclear.

In the proof-of-principle study, Qi investigated three distinct subregions of the nucleus using CRISPR-GO, testing an overarching hypothesis: Do genes and other genetic elements behave differently in different zones of the nucleus?

So far, their data show that specific compartments and some free-floating bodies of proteins in the nucleus can sway the function of repositioned DNA. Depending on where the genetic materials are located, some nuclear regions repress gene expression and some accelerate telomere growth, and subsequently cell division. One protein body may even hold the power to suppress tumor formation.

A study detailing this research will be published online Oct. 11 in Cell. Qi is the senior author. Postdoctoral scholar Haifeng Wang, Ph.D., is the lead author.

Bridging the gap

Demystifying the physical details of the genome has proved to be a tedious task, but there are some existing technologies that allow scientists to peer into cells and see how their guts are physically organized. What’s been missing is a way to tamper with this organization. CRISPR-GO is the first to offer researchers a means to do so.

By decommissioning the “cutting” mechanism of CRISPR-Cas9, the editing tool becomes more of a delivery system, which Qi used to deliver small stretches of DNA via a programmable guide RNA to a new location in the nucleus.

There are three essential parts of CRISPR-GO. First, there’s what Qi calls the “address” of the genetic target that you want to relocate—a stretch of DNA that’s targeted with a complementary strand of binding RNA. Then, you need the destination’s address—the specific portion of DNA in a nuclear compartment to which you want to move the chromatin. Finally, there’s the “bridge,” which, in this case, is a catalyst that sparks the congealing of the target DNA to its new home in the nucleus.

“Kids often like to build little railroads to help trains get from one station to another,” said Qi. “It’s not so different from what we’re doing here.”

Different room, different function

Qi describes the functionalities of the nuclear compartments like the spaces of a house. In every room of your home, you do different things—in the kitchen, you cook; in the bedroom, you sleep. In the nucleus of a cell, the same concept applies. There are multiple compartments in the nucleus that all have specific roles in upholding cell functionality overall. Qi and his lab investigated three distinct areas of the nucleus, testing whether they could somehow shift the function of chromatin depending on where they moved it.

By using CRISPR-GO, the researchers observed that genes relocated to a part of the nucleus called the Cajal body, an amorphic and somewhat mysterious blob of proteins and RNA, stopped expressing proteins.

“We were super-excited to see this; it’s the first time that researchers have evidence to show the Cajal body can have a direct gene-regulation effect, in this case repressing gene expression,” Qi said. “It suggests that the Cajal body has some unexpected role in controlling transcription.” That could be big, as transcription is an important process that synthesizes the “code” for protein production.

When Qi used CRISPR-GO to move the DNA of telomeres—the molecular caps of chromosomes that are associated with longevity—from the middle to the edge of the nucleus, the telomeres stopped growing, halting the cell cycle and reducing cell viability. The opposite, however, happened when telomeres were moved closer to the Cajal body: They grew and, in doing so, increased cell viability.

The third application used CRISPR-GO to form a promyelocytic leukemia body. This glob of proteins is known to suppress pro-tumor genes. By positioning it next to cancer-causing genes in the nucleus, Qi plans to test if it can help curb tumor formation.

“Another unique advantage of CRISPR-GO is that we can track the interactions between chromatin DNA and nuclear compartments in real time under a microscope,” Wang said.

While the evidence shown by CRISPR-GO is exciting, the research is still in a pilot stage, and there’s more work to be done before the findings can be confirmed, Qi said.

“We’re very excited about the potential here and, while we’ve answered a couple questions, we’ve opened up about 20 more,” Qi said.

It will be even more important to decipher why these location-based effects take place in specific nuclear compartments, and what the underlying cause is, he said. One day, Qi hopes, this line of research will come to bear on human health.

 Explore further: Researchers show that nucleosomes can inhibit CRISPR-Cas9 cleavage efficiency