Even as the field of human genomics forged ahead at an astonishing pace, the Y chromosome — one of the sex chromosomes — has long remained overlooked. It has been postulated that the human sex chromosomes once originated from a pair of structurally similar chromosomes, but subsequently one of the sex chromosomes, the ancestral Y chromosome, underwent significant degradation, losing 97%of its former complement of genes over many millions of years. This peculiar evolutionary trajectory has given rise to speculation that the human Y chromosomes might eventually disappear completely, albeit millions of years from now, and we already observe that some biological males do lose them in dividing cells as they age, with unclear health consequences.

In practical terms, the Y chromosome contains a large proportion of repetitive and heterochromatic (highly condensed, gene-poor and not transcribed to messenger RNA) sequences, making it exceptionally difficult to fully sequence. Using sequencing methods that can cover long, continuous sequences, the Telomere-to-Telomere (T2T) consortium has now published the first complete Y chromosome assembly from a single individual of European descent in “The complete sequence of a human Y chromosome” (Rhie et al. Nature). At the same time, a team led by Jackson Laboratory (JAX) Professor and The Robert Alvine Family Endowed Chair Charles Lee, Ph.D., FACMG, has assembled Y chromosomes from 43 unrelated males, with nearly half coming from African lineages in “Assembly of 43 human Y chromosomes reveals extensive complexity and variation” (Hallast et al., Nature). Taken together, these two papers provide intriguing insights into human Y chromosomes, reveal the highly variable nature of Y chromosomes across individuals, and provide an important foundation for future studies on how they may be contributing to certain disorders and diseases.

The need for long reads

Standard short-read genomic sequencing technologies require breaking genomic DNA into short (~250-base-long) fragments. These fragments are then reassembled into the full genome of more than 3 billion base pairs across 46 chromosomes in humans. The method is very accurate and works well for most, but not all, of the genome. Almost all “complete” human genome sequences, including the current reference genome sequence (known as GRCh38), are actually only about 90% complete, because it is difficult to assemble the highly repetitive and other complex sections accurately. GRCh38 falls particularly short for the Y chromosome, as it barely assembles half of that chromosome.

As a result, while the much larger and gene-rich other sex chromosome — the X chromosome — has been extensively studied, the Y chromosome has been often overlooked outside of male-based fertility studies. In a significant step forward for the genomics field, scientists from JAX, including first author and JAX Associate Research Scientist, Pille Hallast, Ph.D., with collaborators from Clemson University, Heinrich Heine University (Germany) and more, have now revealed a full picture of the Y chromosome’s key characteristics and differences between individuals for the first time. Of note is the striking variation in size and structure across the 43 Y chromosomes sequenced that covered 180,000 years of human evolution and range from 45.2 million to 84.9 million base pairs in length.

The inclusion of 43 different individuals representing diverse Y lineages allowed the researchers to redefine inter-chromosomal region boundaries and identify large-scale variations at an unprecedented resolution and clarity. The study also revealed an unexpected degree of structural variation across the Y chromosomes. For example, half of the euchromatin (gene-rich region) of the sequenced chromosomes carries large recurrent inversions — segments that contain the same nucleotide sequences but oriented in the opposite direction — at a rate much higher than anywhere else in the genome. The study further identified regions of the Y chromosome that demonstrate little single nucleotide variation but show high gene copy number variation for specific gene families. Other gene families tended to maintain their copy numbers, however, consistent with their roles in fertility and normal development.

Incredibly important research for overall health

“Having fully resolved Y chromosome sequences from multiple individuals is essential in order for us to begin to understand how this variation can affect function” says Hallast. “The degree of structural variation between individuals came as a big surprise to me, even though the nucleotide sequences within the Y chromosome genes are comparatively conserved. The variable gene copy numbers in certain gene families and extremely high inversion rates are almost certain to hold significant biological and evolutionary roles.”

The Y chromosome’s contributions to male health are poorly understood. Some unexpected indications of its importance to human health have recently come into focus in two new research studies that collectively implicate the Y chromosome in aggressive features of colorectal and bladder cancers in men. Indeed, one of the studies showed that tumors that had lost the Y chromosomes can more effectively evade T cell immunity, are infiltrated with higher numbers of dysfunctional CD8+ T cells, and are more responsive to anti-PD1 treatments compared to similar tumors retaining the Y chromosome.

“Research is emerging that shows proper Y chromosome gene function is incredibly important for the overall health of men,” says Lee, senior author on the paper. “Our study enables the inclusion of the full Y chromosome in all future studies when sequencing male genomes to understand health and disease.”

Fresh research from the University of Montana, international partners and NASA-affiliated scientists suggests that parks do indeed enhance bird diversity inside their borders. Large parks also support higher diversity of both birds and mammals in nearby unprotected areas.

The research was published Aug. 23 in Nature.

“We knew that protected areas can reduce logging — you can see that from satellite imagery — but you can’t see the animals in the forest from space,” said the study’s lead author Dr. Jedediah Brodie, the UM Craighead Chair of Conservation. “Our new analysis shows that parks benefit forest wildlife, too.”

Brodie also is a Universiti Malaysia Sarawak (Malaysia) research fellow. He said that some scientists have argued that conservation success inside some parks can come at the expense of neighbouring unprotected habitats — that parks displace extractive impacts like hunting, fishing and logging to other nearby areas.

But on the other hand, marine parks often report biodiversity “spillover,” meaning that species protected within park boundaries produce an abundance of eggs, larvae and adults that then disperse and increase the biodiversity in surrounding habitats.

“So the question is, ‘Do terrestrial land parks displace biodiversity losses or provide biodiversity spillover?'” Brodie said.

The new study recruited scientists from 10 countries to conduct a comprehensive analysis of bird and mammal diversity inside and outside of parks across Southeast Asia, one of the most biodiverse regions on Earth. The scientists compiled a massive database of bird and mammal observations across the region that demonstrated the protective features of national parks.

Brodie said the findings are especially timely for the United Nations, which recently announced ambitious biodiversity conservation targets that include significant expansions of global protected areas. The UN strategy is to conserve 30% of Earth’s lands and waters by 2030, the so-called “30 by 30 goal.”

“Massive expansions to global protected area coverage will be difficult and expensive, but our results show that it’s worth it,” Brodie said.

Indeed, the work provides clear justification to designate protected areas that are as large as possible, as larger parks had significantly stronger influence on mammal diversity in the surrounding landscape. Recent work in the region suggests that some wildlife species are persisting in small parks, but this apparently doesn’t scale up to such areas having landscape-scale “spillover” effects.

The time to move forward with protected area expansion is now, said co-author Professor Mohd-Azlan Jayasilan of the Universiti Malaysia Sarawak.

“If governments responsible for gazetting protected areas think that it is difficult to protect large areas now, it’s simply going to get more difficult with exasperating socio-political setbacks in the future,” Jayasilan said.

“Not all parks are equal,” said co-author Dr. Mairin Deith of the University of British Columbia, Canada. “Larger parks routinely had higher bird diversity. Considering the UN’s goal of increasing protected area to 30% of the world’s surface, these findings support the creation of fewer larger parks compared to many smaller ones, where it is possible to do so.”

At the same time, she said, there might be other invisible social forces researchers couldn’t see from their dataset that may be related to park size, such as differences in funding, enforcement and local buy-in to protections.

Hunting is a key concern for Southeast Asian wildlife conservation and a prime suspect for why diversity has often been assumed to decline outside of parks. Hunters are mobile, so hunting bans within park boundaries may only displace these activities to nearby unprotected areas and undermine their net benefit.

“To be honest, I was surprised that mammal diversity was higher outside large parks,” said co-author Dr. Matthew Luskin of the University of Queensland, Australia. “It’s common to see hunters inside and outside of parks in many countries. I expected that hunters’ selectively removing game animals would reduce diversity. However, it appears parks limit hunting so it does not drive complete extirpations in most cases.”

NASA’s Global Ecosystem Dynamics Investigation operates a near-infrared laser instrument on the International Space Station, providing vertical information on forest structure that the study used in its analysis. Co-author Scott Goetz of Northern Arizona University noted that “while satellite monitoring of forest cover is essential for tracking deforestation, the unique data provided by GEDI allows us to go beyond cover and get at the structural diversity and habitat heterogeneity of forests, which is important for biodiversity.”

Co-author James Ball of the University of Cambridge said, “Integrating NASA’s GEDI data into this analysis allowed us to control for 3D forest structure in a way that simply wasn’t possible a few years ago. This reassures us that the results hold across different forest types.”

In a new study published today in Science Advances, a team of researchers from MBARI, NOAA’s Monterey Bay National Marine Sanctuary, Moss Landing Marine Laboratories, the University of Alaska Fairbanks, the University of New Hampshire, and the Field Museum confirmed that deep-sea octopus migrate to the Octopus Garden to mate and nest. The Octopus Garden is one of a handful of known deep-sea octopus nurseries. At this nursery, warmth from deep-sea thermal springs accelerates the development of octopus eggs. Scientists believe the shorter brooding period increases a hatchling octopus’ odds for survival. The Octopus Garden is the largest known aggregation of octopus on the planet — researchers counted more than 6,000 octopus in a portion of the site and expect there may be 20,000 or more at this nursery.

“Thanks to MBARI’s advanced marine technology and our partnership with other local researchers, we were able to observe the Octopus Garden in tremendous detail, which helped us discover why so many deep-sea octopus gather there. These findings can help us understand and protect other unique deep-sea habitats from climate impacts and other threats,” said MBARI Senior Scientist Jim Barry, lead author of the new study.

The Octopus Garden is located 3,200 meters (10,500 feet, or about two miles) below the ocean’s surface on a small hill near the base of Davidson Seamount, an extinct underwater volcano 130 kilometers (80 miles) southwest of Monterey, California. The site is full of Muusoctopus robustus — a species MBARI researchers nicknamed the pearl octopus because from a distance, nesting individuals look like opalescent pearls on the seafloor.

Over the course of 14 dives with MBARI’s remotely operated vehicle (ROV) Doc Ricketts, the research team learned why such large numbers of pearl octopus are attracted to this location. The presence of adult male and female octopus, developing eggs, and octopus hatchlings indicated that the site is used exclusively for reproduction. The team did not observe any intermediate-sized individuals or any evidence of feeding. Pearl octopus gather at this site solely to mate and nest.

When researchers from NOAA and Nautilus Live first discovered the Octopus Garden, they observed “shimmering” waters. This phenomenon occurs when warm and cool waters mix, suggesting the region had previously unknown thermal springs. Further investigation by MBARI researchers and their collaborators confirmed octopus nests are clustered in crevices bathed by hydrothermal springs where warmer waters flow from the seafloor.

The ambient water temperature at 3,200 meters (10,500 feet) deep is 1.6 degrees Celsius (about 35 degrees Fahrenheit). However, the water temperature within the cracks and crevices at the Octopus Garden reaches nearly 11 degrees Celsius (about 51 degrees Fahrenheit).

Octopuses are ectotherms, or cold-blooded animals. The frigid temperatures of the deep sea slow their metabolism as well as their rate of embryonic development. Most deep-sea octopuses have very long incubation periods compared to their relatives inhabiting warmer shallow seas. Past experiments have measured egg incubation time for a number of octopus species in habitats and locations around the world. Comparing those egg incubation times clearly demonstrates how temperature affects the rate of embryo development — the colder the water, the slower the embryos grow.

At the near-freezing temperatures of the abyss, researchers expected pearl octopus eggs to take five to eight years, if not longer, to hatch. A 4K camera on MBARI’s ROV Doc Ricketts provided a close-up look at nesting mothers. MBARI researchers and their collaborators used the scars and other distinguishing features of individual octopus moms to monitor the development of their broods. Surprisingly, the eggs hatched in less than two years. Warmth from thermal springs increased the metabolism of female octopus and their broods, reducing the time required for incubation.

Researchers believe the shorter brood period in warmer waters greatly reduces the risk that developing octopus embryos will be injured or eaten by predators. Nesting in warmer water boosts the reproductive success of the pearl octopus, better ensuring the offspring’s survival.

“The deep sea is one of the most challenging environments on Earth, yet animals have evolved clever ways to cope with frigid temperatures, perpetual darkness, and extreme pressure. Very long brooding periods increase the likelihood that a mother’s eggs won’t survive. By nesting at hydrothermal springs, octopus moms give their offspring a leg up,” said Barry.

The massive number of octopus in one area attracts both predators and scavengers. Like most other cephalopods, pearl octopus die after they reproduce. Dead octopus at the Octopus Garden provide a feast for scavengers. A rich community of invertebrates lives alongside the nesting females, undoubtedly benefiting from unhatched eggs, vulnerable hatchlings, or adult octopus that have died.

Davidson Seamount and its Octopus Garden are protected as part of Monterey Bay National Marine Sanctuary. Previous MBARI expeditions to Davidson Seamount in 2002 and 2006 revealed the stunning community of life on its rocky slopes. MBARI’s images and video of beautiful deep-sea corals, vibrant sponges, and curious fishes engaged and inspired audiences worldwide. Ocean champions spoke up to protect this unique, and still untouched, ocean wilderness. In 2008, resource managers expanded the Monterey Bay National Marine Sanctuary to include Davidson Seamount.

“Essential biological hotspots like this deep-sea nursery need to be protected,” said Barry. “Climate change, fishing, and mining threaten the deep sea. Protecting the unique environments where deep-sea animals gather to feed or reproduce is critical, and MBARI’s research is providing the information that resource managers need for decision-making.”

This work is funded as part of the David and Lucile Packard Foundation’s long-term support of MBARI’s ocean research and technology.

Background

For more than two decades, researchers from MBARI and NOAA have collaborated to study Davidson Seamount. Since the first expedition to the seamount in 2002, NOAA has leveraged MBARI expertise in marine geology and benthic biology and ecology to develop a comprehensive research program that aims to understand the unique community of life on and around Davidson Seamount. Now, Davidson Seamount is considered one of the best-studied and well-protected seamounts in the world.

In October 2018, a team of researchers from NOAA, the Ocean Exploration Trust, and collaborators made an expedition to Davidson Seamount aboard the E/V Nautilus. At the suggestion of MBARI geologists and NOAA researchers, the Nautilus Live team decided to expand their exploration from the top of the seamount to its surrounding foothills. The researchers discovered thousands of octopus aggregated around a rocky ridge adjacent to the towering seamount.

Most of the octopus were oriented upside down, inverting their arms and folding them around their bodies. This posture was an indication of pearl octopus (Muusoctopus robustus) mothers protecting, or brooding, their eggs. The pearl octopus is a pale purple species about the size of a grapefruit that occurs in the northeastern Pacific Ocean from Oregon to Baja California. MBARI has observed this species at depths of 2,300 to 3,600 meters (7,500 to 11,800 feet).

MBARI researchers and their collaborators deployed a suite of advanced scientific instruments developed by MBARI engineers to better understand the Octopus Garden.

“The expertise of the MBARI team — the engineers, pilots of our submersible vehicles, and crew of our research vessels — was integral to studying this hotspot of life two miles below the surface. We leveraged decades of experience in deep-sea exploration to develop and deploy instruments to study the Octopus Garden without disturbing the nesting mothers,” said Barry.

MBARI’s ROV Doc Ricketts recorded high-definition and 4K video of the brooding pearl octopus and their neighbors. MBARI’s skilled submersible pilots maneuvered the ROV close to brooding pearl octopus to deploy instruments to measure the environmental conditions within their nests, including temperature and oxygen levels, and to film mothers and their eggs up close in ultra-high definition resolution. A stereoscopic camera allowed MBARI engineers to visualize sites within the Octopus Garden in 3D. The team also launched one of MBARI’s autonomous underwater vehicles to map the Octopus Garden at meter-scale resolution.

MBARI engineers outfitted the ROV Doc Ricketts with an innovative, custom-built sensor suite, the Low-Altitude Survey System (LASS), to see the Octopus Garden in even greater detail.

The LASS gathered detailed bathymetry information to help researchers characterize the seafloor habitat at centimeter-scale resolution. The LASS also took high-resolution photographs of the Octopus Garden. Researchers assembled these photographs into a photomosaic to count the number of nests within this deep-sea nursery. They documented 5,718 octopus within a 2.5-hectare (6.2-acre) area at the center of the Octopus Garden. The team estimated the total population of the 333-hectare (823-acre) hillock could easily exceed 20,000 individuals.

A time-lapse camera collected long-term observations of the octopus’ behavior and changes in the community over a period of more than six months, allowing researchers to keep watch on the octopus nursery between research expeditions. The camera recorded an image every 20 minutes and amassed a trove of more than 12,200 images from March 2022 to August 2022. These photographs revealed various activities and behaviors of octopus, their predators, and local scavengers.

Both male and female pearl octopus migrate to the Octopus Garden. Females search for a warm nesting spot to deposit a clutch of approximately 60 elongate, sausage-shaped eggs. When brooding, mothers cover their eggs with their body and protect them from predators that creep too close. She lives off food reserves from her own tissues while tending to her developing eggs.

The transformation from egg to hatchling is not easy. In addition to going through development successfully, embryos must avoid injury, predation, infection, and other external sources of mortality. Maternal care protects them from most external risks, but a shorter brooding period generally allows more eggs to survive.

As is typical of cephalopods, male and female pearl octopus die after reproducing — the Octopus Garden will be their final resting spot. Most females live until their eggs have hatched. Sometimes, however, a mother octopus runs out of energy and dies before her eggs complete their development, exposing the developing eggs to greater risk.

The time-lapse camera revealed that nesting mothers push aside the carcasses of dead octopus. Food is scarce in the deep sea and nothing goes to waste. Larger scavengers like rattail fishes (family Macrouridae), cusk eels (family Ophidiidae), whelks, and sea anemones feast on octopus remains. Near Davidson Seamount, life on the deep seafloor depends on the rain of organic matter from above. Researchers estimated the turnover of male octopus and nesting females to calculate how much nutrition this massive aggregation provides. Biomass from dying octopus represents a substantial carbon subsidy to the local seafloor community, providing 72 percent more food than is available outside the Octopus Garden.

Many questions still remain about the Octopus Garden, including where pearl octopus go after hatching, how this octopus species became adapted to breeding in thermal springs, how adult octopus find the thermal springs, what advantage individuals breeding in these hydrothermal springs have over those that breed elsewhere, and how common hydrothermal springs are in the deep sea.

The deep sea is not immune to threats like fishing, pollution, and climate change. By documenting deep-sea biodiversity and identifying hotspots of life on the ocean floor, scientists are gathering important information that resource managers can use to guide protections for this unique environment and its inhabitants.

“Technological advances in our ability to study the ocean have helped us discover and document incredible biodiversity across an array of deep-sea environments. As the imprint of human activities reaches deeper into ocean ecosystems, we need to protect not only the octopus nurseries found off California and Costa Rica, but also the many other biological treasures that remain undiscovered,” emphasized Barry.

Deep-sea octopus nurseries: A new field of exploration

Researchers have documented four deep-sea octopus nurseries to date — two off the coast of Central California and two off the coast of Costa Rica — and are continuing to study these sites to learn more about octopus behavior.

December 2013: Discovery of first octopus nursery at Dorado Outcrop (Costa Rica) Researchers from the University of Akron, the Field Museum, and the University of Alaska Fairbanks observed an aggregation of more than 100 octopus at the Dorado Outcrop, a hydrothermal spring located approximately 160 kilometers (100 miles) off the Pacific coast of Costa Rica at a depth of 3,000 meters (9,800 feet). The team identified the octopus as a potentially undescribed species of Muusoctopus. Nearly all of the individuals were in a brooding position, however, none of the eggs that researchers observed were viable.

April 2018: Researchers publish findings from the Dorado Outcrop (Costa Rica) The team of researchers from the University of Akron, the Field Museum, and the University of Alaska Fairbanks published their observations of deep-sea octopus brooding unviable eggs at the Dorado Outcrop in Deep Sea Research Part I.

October 2018: Discovery of second octopus nursery at the Octopus Garden (Davidson Seamount, United States) During a Nautilus Live expedition with the E/V Nautilus, researchers from NOAA’s Monterey Bay National Marine Sanctuary, the Ocean Exploration Trust, and collaborators observed a large aggregation of brooding octopus on a hillock approximately 12 kilometers (7.5 miles) southeast of Davidson Seamount at a depth of 3,200 meters (10,500 feet). Researchers identified the octopus as Muusoctopus robustus. A second visit by researchers from NOAA and the Woods Hole Oceanographic Institution (WHOI) in March 2019 confirmed the presence of warm hydrothermal springs at this site. The expedition team also confirmed that the octopus were brooding viable eggs and observed baby octopus hatching from the eggs.

April 2019: First MBARI expedition to Octopus Garden (Davidson Seamount, United States) MBARI researchers made their first visit to the Octopus Garden as part of the 2019 Seafloor Ecology expedition. Along with collaborators, they visited the site 14 times with the R/V Western Flyer between April 2019 and August 2022. Additionally, MBARI researchers visited the Octopus Garden with the R/V Rachel Carson in February 2022 to launch a mapping autonomous underwater vehicle and create meter-scale maps of the site.

October 2019: Discovery of third octopus nursery at Octocone (Davidson Seamount, United States) During a Nautilus Live expedition with the E/V Nautilus, researchers from NOAA, the Ocean Exploration Trust, and collaborators observed a second aggregation of brooding octopus on a volcanic cone to the east of Davidson Seamount. This site is approximately 17 kilometers (10.5 miles) northeast of the Octopus Garden. Researchers identified the octopus as Muusoctopus robustus. The octopus were confirmed to be brooding viable eggs.

June 2023: Discovery of fourth octopus nursery (Costa Rica) During a Schmidt Ocean Institute expedition with the R/V Falkor (too), researchers from the Bigelow Laboratory for Ocean Sciences and the University of Costa Rica observed a previously unknown octopus nursery near an unexplored and still-unnamed seamount off the Pacific coast of Costa Rica. Upon returning to the nearby Dorado Outcrop, the team also observed octopus brooding viable eggs, confirming this location is indeed an active octopus nursery. Both Costa Rican nurseries host a potentially undescribed species of Muusoctopus.

August 2023: MBARI researchers publish findings from the Octopus Garden (Davidson Seamount, United States) MBARI researchers and their collaborators from NOAA, Moss Landing Marine Laboratories, the University of Alaska Fairbanks, the University of New Hampshire, and the Field Museum published their research on brooding pearl octopus in Science Advances, confirming that deep-sea octopus migrate to the Octopus Garden to mate and nest.

However, Joel Rubenstein, M.D., M.S., a research scientist at the Lieutenant Colonel Charles S. Kettles Veterans Affairs Center for Clinical Management Research and professor of internal medicine at Michigan Medicine, says that preventative measures can be a saving grace.

“Screening can identify pre-cancerous changes in patients, Barrett’s esophagus, which is sometimes diagnosed in individuals who have long-term gastroesophageal reflux disease, or GERD,” he said.

“When early detection occurs, patients can take additional steps to help prevent cancer.”

While current guidelines already consider screening in high-risk patients, Rubenstein notes that many providers are still unfamiliar with this recommendation.

“Many individuals who develop these types of cancer never had screening to begin with,” he said.

“But a new automated tool embedded in the electronic health record holds the potential to bridge the gap between provider awareness and patients who are at an increased risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma.”

Rubenstein and a team of researchers used a type of artificial intelligence to examine data regarding EAC and GCA rates in over 10 million U.S. veterans.

Their findings were published in Gastroenterology.

Rubenstein and his team developed and tested the Kettles Esophageal and Cardia Adenocarcinoma predictioN tool, called K-ECAN for short.

“K-ECAN uses basic information already readily available in the EHR, like patient demographics, weight, previous diagnoses and routine laboratory results, to determine an individual’s risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma,” said Rubenstein.

“We developed a prior tool, M-BERET, over a decade ago for identifying patients with Barrett’s esophagus. However, that tool requires measuring patients’ hip and waist circumferences, which is not something that routinely occurs. In addition, providers must remember to use the corresponding website to calculate their patient’s risk when using this tool.”

To alleviate this burden, Rubenstein said that they “envisioned harnessing the large amount of data already present in the EHR, as well as presenting their patients’ risk to their providers at opportune times,” such as when an individual is due for a colorectal screening or refilling an acid reducing prescription medication.

According to Rubenstein, K-ECAN is more accurate than published guidelines or previously validated prediction tools and can “accurately predict cancer at least three years prior to a diagnosis.”

“Symptoms of GERD, like heartburn, are an important risk factor for esophageal adenocarcinoma,” he said.

“But most people with GERD symptoms will never develop esophageal adenocarcinoma and gastric cardia adenocarcinoma. In addition, roughly half of the patients with this form of cancer never experienced prior GERD symptoms at all. This makes K-ECAN particularly useful because it can identify people who are at elevated risk, regardless of whether they have GERD symptoms or not.”

Akbar Waljee, M.D., M.Sc., professor in the Departments of Learning Health Sciences and Internal Medicine and senior author on the study, adds that this research wouldn’t be possible without a collaborative effort.

“This publication, which leveraged invaluable data from millions of U.S. veterans, was made possible through the dedicated efforts of numerous staff members at our VA Health Services Research & Development Center of Innovation, as well as through collaborative partnerships between the VA Center for Clinical Management Research, Michigan Medicine, the University of Michigan Department of Statistics, and members of U-M’s Institute for Healthcare Policy & Innovation and E-Health & Artificial Intelligence, or e-HAIL. This exemplifies the power of team science, data and machine learning to improve cancer prevention.”

Incorporating this artificial intelligence tool into the EHR could alert providers with an automated notification regarding which patients are at an increased risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma.

And Rubenstein says that this can significantly decrease the burden of these cancers.

“Our devoted team was able to use sophisticated machine learning tools to develop this unique tool, and we are very excited that this could potentially lead to increased screening and a decrease in preventable deaths. We look forward to conducting additional work validating K-ECAN for use outside of the VA.”

But many researchers believe that the neurodegenerative disorder may get started far away from the brain — in the gut — and years before the first neurological signs appear.

New findings by Columbia researchers David Sulzer, PhD, and Dritan Agalliu, PhD, and two of their graduate students are adding to evidence backing this hypothesis — and showing that what triggers initial gastrointestinal changes in Parkinson’s could be a misdirected immune attack.

“If this is the beginning of Parkinson’s in many people, we could potentially identify who has the disease before it ever reaches the brain and hopefully stop it in its tracks,” Sulzer says. The new findings were published Aug. 18 in Neuron.

Autoimmunity and the gut

The gut-first theory of Parkinson’s, originally proposed 20 years ago, started to intrigue Sulzer after his own research pointed toward the role of an autoimmune response in Parkinson’s.

In Parkinson’s, a protein called alpha-synuclein becomes misfolded, accumulates inside neurons, and slowly poisons the cells. Sulzer’s lab in collaboration with immunologists at the La Jolla Institute of Immunology has shown that small portions of the misfolded alpha-synuclein also can appear on the outside of neurons, which makes the neurons vulnerable to attack from the immune system. The immune attack could be doing more acute damage to the neurons than the internal deposits of alpha synuclein.

“The blood of Parkinson’s patients often contains immune cells that are primed to attack the neurons,” Sulzer says, “but it’s not clear where or when they are primed.”

The gut was an intriguing possibility because it contains the same neurons and because most Parkinson’s patients experience constipation years before brain symptoms emerge and the disease is diagnosed. To pursue this hypothesis, Sulzer teamed up with Agalliu, a neuroimmunologist with expertise in mouse models of another neurological disorder (multiple sclerosis) that has autoimmune features.

Immune response to alpha synuclein leads to gut symptoms

To find out if an immune reaction to alpha-synuclein can kick-start the disease and where, Francesca Garretti and Connor Monahan, grad students directed by Agalliu and Sulzer, first created a mouse capable of displaying pieces of misfolded alpha-synuclein on cell surfaces (natural mice do not have this ability). They then injected the mice with alpha-synuclein and monitored what happened in the brain and the gut.

The researchers did not see any signs resembling Parkinson’s disease in the brain, but they did see that an immune attack on neurons in the gut produced constipation and other gastrointestinal effects resembling those seen in most Parkinson’s patients years before they are diagnosed with the disease.

“This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s and is strong support that Parkinson’s is in part an autoimmune disease,” Sulzer says.

The findings also raise the possibility that early detection — and then interruption — of an immune response in the gut could prevent a later attack on the brain’s neurons and stop Parkinson’s in its tracks.

Wanted: A mouse with Parkinson’s disease

Right now, though, it’s not clear how big a role the immune system plays in the Parkinson’s brain. The answer to that question may become clearer if the researchers find out why the brains of their mice did not develop any signs of Parkinson’s.

The team hypothesizes that the immune cells in their mouse model may not be reaching the brain because the animals are young and age has not yet weakened the blood-brain barrier sufficiently to let immune cells squeeze through. Opening the barrier or accelerating the aging process may lead to mice that develop gastrointestinal and brain symptoms.

“Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the human disease process, which doesn’t exist right now,” Sulzer says. “That will be critical in answering questions about the disease that we can’t explore in people and eventually developing better therapies.”