Writing in the March 16, 2023 issue of Science, a team of scientists, led by senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University of California San Diego School of Medicine, with colleagues and elsewhere, demonstrate that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.

“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” Cleveland said.

Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds upon ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

“In almost all of instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.

“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”

Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides — small bits of DNA or RNA that can bind to specific RNA molecules, blocking their ability to make a protein or changing how their final RNAs are assembled — into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Co-authors include: Michael W. Baughn, Jone López-Erauskin, Melinda S. Beccari, Roy Maimon, Sonia Vazquez-Sanchez, Jonathan W. Artates and Eitan Acks, all at Ludwig Institute for Cancer Research-UC San Diego and UC San Diego; Ze’ev Melamed, Ludwig Institute for Cancer Research-UC San Diego, UC San Diego, and The Hebrew University of Jerusalem; Karen Ling, Paayman Jafar-nejad, Frank Rigo and C. Frank Bennett, all at Ionis Pharmaceuticals; Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil and Cathleen Lutz, all at The Jackson Laboratory; Som Chaturvedi, Mariana Bravo-Hernández, Vanessa Taupin and Stephen Moore, all at UC San Diego; L. Sandra Ndayambaje and Ana R. Agra de Almeida Quadros, Harvard Medical School; Clotilde Lagier-Tourenne, Harvard University and Broad Institute of Harvard University and Massachusetts Institute of Technology.

Yet no one is certain why this disease is suddenly affecting so many young people. In a new paper published in Science, Dana-Farber Cancer Institute researchers outline the complexities of the disease and the research needed to map out a path toward understanding it.

“The rising incidence of young-onset colorectal cancer is extremely concerning, and it is urgent that the scientific community comes together to better understand the underlying causes and biology,” said co-author Kimmie Ng, MD, MPH, associate chief of gastrointestinal oncology and director of the Young-Onset Colorectal Cancer Center at Dana-Farber. The Center provides expert care for patients and conducts the multidisciplinary research required to understand colorectal cancer in young adults and develop new ways to prevent, detect and treat it.

Young-onset Colorectal Cancer: a unique challenge

Young-onset colorectal cancer (CRC), also called early-onset CRC, differs from later-onset CRC in several ways, according to the authors. Young-onset disease is often more aggressive, presents on the left side of the colon rather than the right, and often presents with rectal bleeding and abdominal pain.

At a molecular level, however, studies have shown conflicting results that suggest both similarities and differences in the genetic mutations that drive the diseases. This is likely due to the complexity of the disease, according to the authors, and future research should account for this variability.

More study is also needed to determine if CRC risk factors for young people are similar to those for older adults. Obesity and environmental exposures, for instance, have been associated with young-onset disease, but other factors could also play a role, such as increased antibiotic use or the frequency of Cesarean sections, both of which could influence the microbiome. To begin to understand the risk factors, the authors suggest that investigations should include a combination of genetics, environmental exposures, diet and lifestyle measures, as well as immune system interactions and the microbiome composition.

One clear difference is that young-onset CRC is typically discovered after the disease has advanced. This is due in part to the fact that screening for colorectal cancer starts at age 45 in the U.S., so the disease often goes undetected in younger people.

“It’s important not to dismiss the idea that a young person could have colorectal cancer even though the disease is still more common in older adults,” said co-author Marios Giannakis, MD, PhD, a gastrointestinal oncologist at Dana-Farber.

Responding with multidisciplinary research involving diverse populations

To account for the complexity of young-onset CRC, Ng and Giannakis said that research should be multidisciplinary and include many areas of investigation simultaneously. For instance, genome-wide association studies, which aim to find risk genes for the disease, should also include data about environmental exposures that could also increase risk.

These types of studies could point to new ways to identify young people who are at high risk of young-onset disease and should be screened for CRC. “Risk stratification is going to be very important as we think about screening for young-onset disease,” said Giannakis.

Clinical studies should also include the collection of blood, tissue, and stool samples from patients over time to shed light on the role of immune cells, environmental exposures and the microbiome in disease onset, progression, and treatment response. Ng and Giannakis encourage global collaborations aimed at facilitating the collection of these specimens, such as the Count Me In Colorectal Cancer Project, which directly partners with patients in the U.S. and Canada and makes all data available for research.

Ng and Giannakis also call for more effort in ensuring diverse populations are included in studies of young-onset CRC. Studies show underrepresented minorities are disproportionally burdened by young-onset CRC and non-Hispanic Black patients have a higher mortality rate when compared to non-Hispanic whites.

“Although each of these steps require commitment and perseverance,” said the authors, “it is the growing numbers of young patients bravely battling this disease that will be the compass that keeps us on the path towards better understanding, preventing, and treating young-onset colorectal cancer.”

Venus, although similar to Earth in size and mass, differs markedly in that it does not have plate tectonics. The boundaries of Earth’s moving surface plates are the primary locations of volcanic activity.

New research by University of Alaska Fairbanks Geophysical Institute research professor Robert Herrick revealed a nearly 1-square-mile volcanic vent that changed in shape and grew over eight months in 1991. Changes on such a scale on Earth are associated with volcanic activity, whether through an eruption at the vent or movement of magma beneath the vent that causes the vent walls to collapse and the vent to expand.

The research was published today in the journal Science.

Herrick studied images taken in the early 1990s during the first two imaging cycles of NASA’s Magellan space probe. Until recently, comparing digital images to find new lava flows took too much time, the paper notes. As a result, few scientists have searched Magellan data for feature formation.

“It is really only in the last decade or so that the Magellan data has been available at full resolution, mosaicked and easily manipulable by an investigator with a typical personal workstation,” Herrick said.

The new research focused on an area containing two of Venus’ largest volcanoes, Ozza and Maat Mons.

“Ozza and Maat Mons are comparable in volume to Earth’s largest volcanoes but have lower slopes and thus are more spread out,” Herrick said.

Maat Mons contains the expanded vent that indicates volcanic activity.

Herrick compared a Magellan image from mid-February 1991 with a mid-October 1991 image and noticed a change to a vent on the north side of a domed shield volcano that is part of the Maat Mons volcano.

The vent had grown from a circular formation of just under 1 square mile to an irregular shape of about 1.5 square miles.

The later image indicates that the vent’s walls became shorter, perhaps only a few hundred feet high, and that the vent was nearly filled to its rim. The researchers speculate that a lava lake formed in the vent during the eight months between the images, though whether the contents were liquid or cooled and solidified isn’t known.

The researchers offer one caveat: a nonvolcanic, earthquake-triggered collapse of the vent’s walls might have caused the expansion. They note, however, that vent collapses of this scale on Earth’s volcanoes have always been accompanied by nearby volcanic eruptions; magma withdraws from beneath the vent because it is going somewhere else.

The surface of Venus is geologically young, especially compared to all the other rocky bodies except Earth and Jupiter’s moon Io, Herrick said.

“However, the estimates of how often eruptions might occur on Venus have been speculative, ranging from several large eruptions per year to one such eruption every several or even tens of years,” he said.

Herrick contrasts the lack of information about Venusian volcanism with what is known about Jupiter’s moon Io and about Mars.

“Io is so active that multiple ongoing eruptions have been imaged every time we’ve observed it,” he said.

On a geological time scale, relatively young lava flows indicate Mars remains volcanically active, Herrick said.

“However, nothing has occurred in the 45 years that we have been observing Mars, and most scientists would say that you’d probably need to watch the surface for a few million years to have a reasonable chance of seeing a new lava flow,” he said.

Herrick’s research adds Venus to the small pool of volcanically active bodies in our solar system.

“We can now say that Venus is presently volcanically active in the sense that there are at least a few eruptions per year,” he said. “We can expect that the upcoming Venus missions will observe new volcanic flows that have occurred since the Magellan mission ended three decades ago, and we should see some activity occurring while the two upcoming orbital missions are collecting images.”

Co-author Scott Hensley of NASA’s Jet Propulsion Laboratory performed the modeling for the research.

Landslides are projected to be a growing concern as climate change produces more extreme rainfall events that can destabilize slopes and trigger these events. Research presented in the session will include investigations of landslide hazards in Puerto Rico, Vermont, Pennsylvania, Michigan, Tennessee, West Virginia, and southern and central Appalachia.

Puerto Rico

After Hurricane Maria in 2017, researchers documented more than 70,000 landslides on the island of Puerto Rico. Geologist Stephen Hughes at the University of Puerto Rico Mayagüez saw a gap in the monitoring and forecasting of landslides on the island, and to fill that gap he started a research and outreach program: Storm-induced Landslide Impact Dynamics on Environment and Society in Puerto Rico (SLIDES-PR). Through partnership with the U.S. Geological Survey, SLIDES-PR has developed a landslide susceptibility map for the island and installed 14 real-time monitoring stations on landslide-prone slopes.

“These are shallow, relatively small landslides, but extremely widespread. It doesn’t matter that it’s a small landslide if it comes through your house,” says Hughes.

The monitoring stations measure soil moisture, pore pressure, and groundwater level, collecting data every five minutes and sending it back to the university every hour. The monitoring network has already saved lives. During Hurricane Fiona in 2022, Hughes was able to use real-time monitoring to warn the town of Naguabo that the soil moisture had crossed the threshold for imminent slope failure, prompting evacuation before a debris flow buried a home.

In addition to monitoring and forecasting, the SLIDES-PR program has developed guides for residents to understand the warning signs for landslides, what human activities can promote them, and ways to prepare and cope after they happen. At the conference, Anishka Ruiz-Perea will share the science and risk communication work done by SLIDES-PR , and Kiara Cunillera-Cote will present on the development of forecasting thresholds using the data from monitoring stations.

Vermont

In 2019, a hillside in Vermont’s Mt. Mansfield State Forest failed and generated a 12.5-acre landslide with a volume equivalent to 80 Olympic-sized swimming pools. The material formed a dam in Cotton Brook, which eventually carried the influx of sediment to the nearby Waterbury Reservoir.

Smuggler’s Notch, one of the most popular tourist destinations in the state, is a 1,000-foot high mountain gap that has seen major rock slides over several decades, sometimes dropping boulders the size of school buses onto the road below.

“We are convinced, just like many others, that as climate change gets more extreme, we will generate more landslides and more sediment systems,” explains Jonathan Kim of the Vermont Geological Survey, who will present on the many approaches taken to assess, monitor and mitigate landslide hazards in Vermont.

The Vermont Geological Survey has been collaborating with the University of Vermont (Burlington) and Norwich University (Northfield, Vermont) to establish comprehensive tools for monitoring and understanding the risk of landslides in the state. These investigations led to a Federal Emergency Management Agency (FEMA) buyout of a parcel containing a large landslide that posed a threat of additional slope failures in 1999. Rainfall and flooding during Hurricane Irene in 2011 led to slope instability throughout the state, prompting the development of statewide landslide protocols and the formation of a statewide landslide database that can be contributed to by landslide experts and residents.

Pennsylvania

The greater Pittsburgh region experienced record rainfall in February-April of 2018 that triggered more than 200 landslides. Built on clay-rich sedimentary rocks and with steep topography from downcutting by river erosion, southwestern Pennsylvania is one of the more landslide-prone regions in the country. The landslides are small and typically not deadly, affecting residences, roads, streams, and other infrastructure. As a result of the 2018 landslides, one natural gas pipeline ruptured, and the resulting explosion destroyed a house and several other buildings.

“It’s very clear that this was a climatically anomalous circumstance. We had a hugely anomalous amount of rain in February when Pittsburgh would normally be getting snow and the ground would be frozen. The ground wasn’t frozen, and almost all of the precipitation fell as rain. We had shallow soil slides as well as deeper-seated slides that require bigger changes in hydraulic conditions,” explains Helen Delano of the Pennsylvania Geological Survey, who will present about the record landslide year at the conference.

While the scope of damage from the landslides was extensive, an application for FEMA support was denied because the several months of increased landslides were not deemed a single event. When considered as separate events, they did not meet the threshold of damages required to declare a federal disaster. Delano says the record-breaking year has increased awareness at the state level of the need to prepare for landslides. Clean-up from the landslides of 2018 remains ongoing.