After looking at population size for the roughly 300 hunter-gatherer societies which existed until quite recently, the researchers found that many of these groups were much smaller than might have been expected from the local ecosystem productivity. In regions with short growing seasons, hunter-gatherer groups had smaller populations per square kilometre than groups who depended on abundant plant foods throughout the year.

Need for meat limited population size

“Basically, if people had to live through long dry or cold seasons when plant food was scarce, in order to survive they had to depend on hunting a very limited number of animals,” explains Galbraith, a professor in McGill’s Department of Earth and Planetary Sciences and at the ICTA-UAB (Institut de Ciència i Tecnologia Ambientals of the Autonomous University of Barcelona), and a senior author on the paper published recently in the journal Nature Ecology & Evolution.

“This led to a seasonal bottleneck in the amount of food available, which then set the overall limit on the population size, no matter how much food there was during the plentiful times.”

The team developed a mathematical model that simulates daily human foraging activities (gathering and hunting) and the resultant carbon (energy) flows between vegetation, animals, and hunter-gatherers in a realistic global environment.

“We were struck by the fact that — despite a long list of unknowns — a very strong result emerged from the model equations,” says Galbraith. “Wherever growing seasons were short, hunter gatherers required meat to make up a high percentage of their diets. And — just as in the modern world — it took much more land to produce the same amount of meat as plant-based food.”

The researchers then went back to look at the detailed ethnographic observations and found that, although its significance had not been noticed, this finding was well supported by records of hunter-gatherers including the Ache in the tropical forest, the Hiwi in the savannah, and the Bushmen groups in the Kalahari Desert. Due to similarities between the lifestyles of contemporary hunter gatherers and those of our foraging ancestors, it is likely that strong seasonality limited population sizes throughout our species’ past.

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The study, published Nov. 5 in Science Advances, reported the results of administering arginine, which can be delivered in oral form, prior to standard radiation therapy in 31 patients who had brain metastases. Nearly 78 percent had a complete or partial response in their brain tumors over the follow-up period of up to four years, while only 22 percent of the 32 patients who received a placebo prior to radiotherapy had such a response.

The trial was designed to gauge the effectiveness of arginine as a “radiosensitizer” that enhances the effects of radiation treatment. However, the results, and arginine’s apparent mechanism of action, suggest that the amino acid might be useful more broadly as an anticancer therapy.

“Based on these findings we should continue to investigate arginine in combination with radiotherapy but also in combination with chemotherapy or immunotherapy, and even arginine on its own,” said senior author Dr. Leandro Cerchietti, an associate professor of medicine in the Division of Hematology and Medical Oncology, who participated in designing and implementing the trial at Angel H. Roffo Cancer Institute in Argentina where he was an attending oncologist. The trial was co-led by Dr. Alfredo Navigante at the Roffo Cancer Institute.

Arginine, also called L-arginine, is inexpensive and widely available, generally considered safe, and can get relatively easily from the bloodstream into the brain. The idea of using it to treat cancer arose from observations that tumors often aid their own survival by producing high levels of the related molecule nitric oxide (NO). The latter regulates multiple processes in the body including the flow of blood through blood vessels, and tumors cells often make more NO by upregulating their production of special enzymes called NO synthases, which synthesize NO from arginine.

Reducing NO production is one possible way of exploiting tumors’ dependence on this molecule, but hasn’t worked well, in part because of adverse side effects. The investigators hypothesized that boosting NO production instead — by adding its precursor arginine — might be beneficial, because while tumors can use NO to aid their growth and survival, they must keep its production below certain limits.

“Nitric oxide is a reactive molecule that on its own, or through other reactive molecules derived from it, can stress and damage a cell — so a cell can tolerate only so much of it,” said study lead author Dr. Rossella Marullo, an instructor in medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine.

Overloading a high-NO tumor with much more NO prior to radiation treatment could weaken the tumor’s ability to repair radiation-induced DNA damage, she added — and indeed her preclinical experiments in mice confirmed this effect.

In the clinical trial, patients were treated with high-dose arginine or placebo oral suspensions an hour before radiotherapy for their brain metastases — tumors in the brain that represent the spread from primary tumors elsewhere, such as the lungs.

Six months after their courses of radiotherapy, 82 percent of the arginine group had improvement, or at least no worsening, of their neurological symptoms, compared with 20 percent in the placebo group. Most of the arginine-treated patients who died during the study did so because of their cancers’ spread elsewhere in the body.

Moreover, although metastatic cancer usually has a dire prognosis, there were some arginine-treated patients whose tumors in and outside the brain disappeared, suggesting the possibility of cures.

Evidence from this study and prior research also suggests that arginine can not only directly hobble tumor cells but also boost the activity of antitumor immune cells, Dr. Cerchietti said.

The promising results have prompted the team to start and plan further studies of arginine on its own or in combination with other anticancer treatments.

“In principle any tumor that overexpresses NO-producing enzymes would be vulnerable to arginine treatment — and such tumors are very common,” said Dr. Cerchietti, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. He cautions that further studies are needed and patients should consult their doctor about the use of any supplements outside of a clinical trial. The doses of arginine used in this study are available in formulations that can be only obtained at a medical facility.

Researchers at Indiana University School of Medicine have been investigating how these immune cells in the brain — microglia — relate to a gene mutation recently found in Alzheimer’s disease patients. They published their findings today in Science Advances.

The study, led by Hande Karahan, PhD, postdoctoral fellow in medical and molecular genetics, and Jungsu Kim, PhD, the P. Michael Conneally Professor of Medical and Molecular Genetics, found that deleting the gene — called ABI3 — significantly increased amyloid-beta plaque accumulation in the brain and decreased the amount of microglia around the plaques.

“This study can provide further insight into understanding the key functions of microglia contributing to the disease and help identify new therapeutic targets,” Karahan said. Karahan based her research on a human genetics study of more than 85,000 people — fewer than half were Alzheimer’s patients — that identified the mutation in the ABI3 gene. Researchers concluded this mutation increased the risk of late-onset Alzheimer’s.

“However, there was no investigation into the function of ABI3 gene in the brain or about how this gene affects microglia function,” Karahan said, a fact that led to her research. The team deleted the ABI3 gene from an Alzheimer’s disease mouse model and tested the functions of the gene in microglia in cell cultures. In the mouse model, they saw increased levels of plaques and inflammation in the brain and signs of synaptic dysfunction — characteristics associated with learning and memory deficits of the disease.

Additionally, Karahan said the deletion of the gene impaired the movement of microglia. The immune cells cannot move closer to plaques to try to clear up the proteins. Amyloid plaques are commonly found in the brains of patients with Alzheimer’s; amyloid beta proteins clump together and form plaques, which destroy nerve cell connections.

“Our study provides the first in vivo functional evidence that the loss of ABI3 function may increase the risk of developing Alzheimer’s disease by affecting amyloid beta accumulation and neuroinflammation,” Karahan said.

Over the past few years, Karahan has been building upon her Alzheimer’s disease research. In 2019, Karahan received the Sarah Roush Memorial Fellowship in Alzheimer’s Disease Research, established by the Indiana Alzheimer’s Disease Research Center and funded through a generous donation from James and Nancy Carpenter and a matching contribution from Stark Neurosciences Research Institute, where Karahan conducts her research.

Karahan and Kim received three separate grants supporting this research from the National Institute on Aging, the National Institutes of Health (NIH) branch for Alzheimer’s research, resulting in $7.8 million over the next five years.

“One grant will fund the creation of a mouse model that will allow us to delete the ABI3 gene in any cell types in the body, such as brain microglia and peripheral immune cells,” Kim said. “Once we validate this new model, we will make it available to others in the research community to use this model for their own investigations.”

The other grants will fund additional mouse and cell models for the team to further investigate how the ABI3 gene in microglia affects Alzheimer’s disease pathologies as well as fund state-of-the-art techniques, including brain imaging using the Bruker BioSpec 9.4T PET-MRI scanner, located in the Roberts Translational Imaging Facility at Stark Neurosciences Research Institute.

Each of these projects has an end goal of identifying druggable targets for the treatment of the disease, Karahan and Kim said. The team will collaborate with the IU School of Medicine-Purdue TaRget Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) Center.

These environments include an atom’s nucleus and celestial bodies known as neutron stars, both of which are among the densest objects known to humanity. For comparison, matching the density of a neutron star would require squeezing all the Earth’s mass into a space about the size of Spartan Stadium.

Brown’s theory laid the blueprints for connecting the properties of nuclei to neutron stars, but building that bridge with experiments would be challenging. It would take years and the unique capabilities of the Thomas Jefferson National Accelerator Facility. The facility, also known as Jefferson Lab, is a U.S. Department of Energy Office of Science, or DOE-SC, national laboratory in Virginia. So experimentalists got to work on a decades-long series of studies and Brown largely returned to his other projects.

That is, until 2017. That’s when he said he started thinking about the beautiful precision experiments run by his colleague Kei Minamisono’s group at the National Superconducting Cyclotron Laboratory, or NSCL, and in the near-future at the Facility for Rare Isotope Beams, or FRIB. FRIB is a DOE-SC user facility at MSU that will start scientific user operation in early 2022.

“It’s amazing how new ideas come to you,” said Brown, a professor of physics at FRIB and in MSU’s Department of Physics and Astronomy.

The goal of this new idea was the same as his earlier theory, but it could be tested using what are known as “mirror nuclei” to provide a faster and simpler path to that destination.

In fact, on Oct. 29, the team published a paper in the journal Physical Review Letters based on data from an experiment that took a few days to run. This comes on the heels of new data from the Jefferson Lab experiments that took years to acquire.

“It’s quite incredible,” Brown said. “You can do experiments that take a few years to run and experiments that take a few days and get results that are very similar.”

To be clear, the experiments in Michigan and Virginia are not competing. Rather, Krishna Kumar, a member and past chair of the Jefferson Lab Users Organization, called the experiments “wonderfully complementary.”

“A detailed comparison of these measurements will allow us to test our assumptions and increase the robustness of connecting the physics of the very small — nuclei — to the physics of the very large — neutron stars,” said Kumar, who is also the Gluckstern Professor of Physics at the University of Massachusetts Amherst. “The progress made in both experiment and theory on this broad topic underscores the importance and uniqueness of the capabilities of Jefferson Lab and NSCL, and the future will bring more such examples as new measurements are carried out at FRIB.”

These projects also underscore the importance of theorists and experimentalists working together, especially when tackling fundamental mysteries of the universe. It was this type of collaboration that kicked off the Jefferson Lab’s experiments 20 years ago, and it’s this type of collaboration that will power future discoveries at FRIB.

A mirror to examine the neutron skin

One of the ironies here is that Brown hasn’t spent a lot of his time working on the two theories central to this story. Brown has published more than 800 scientific papers during his career, and the ones that inspired the experiments at NSCL and Jefferson Lab are distinct from his other work.

“I work on many things and these are very isolated papers,” Brown said. Despite that, Brown shared them quickly. “I wrote both papers in a couple months.”

When Brown completed the draft of his 2017 theory, he immediately shared it with Minamisono.

“I remember I was at a conference when I got the email from Alex,” said Minamisono, a senior physicist at FRIB. “I was so excited when I read that paper.”

The excitement came from Minamisono’s knowledge that his team could lead the experiments to test the paper’s ideas and from the theory’s implications for the cosmos.

“This connects to neutron stars and that is so exciting as an experimentalist,” Minamisono said.

Neutron stars are more massive than our sun, yet they’re only about as big as Manhattan Island. Researchers can make accurate measurements for the mass of neutron stars, but getting exact numbers for their diameters is challenging.

A better understanding of the push and pull of forces inside neutron stars would improve these size estimates, which is where nuclear physics comes in.

A neutron star is born when a very large star becomes a supernova and explodes, leaving behind a core that is still more massive than our sun. The gravity of this massive leftover causes it to collapse on itself. As it collapses, the star also begins converting its matter — the stuff that makes it up — into neutrons. Hence, “neutron star.”

There’s a force between the neutrons, known as the strong interaction, that works against gravity and helps puts the brakes on the collapse. This force is also in action in atomic nuclei, which are made up of neutrons and particles known as protons.

“We know gravity, of course. There’s no issue there,” Brown said. “But we’re not so sure about what the strong interaction is for pure neutrons. There’s no laboratory on the Earth that has pure neutrons, so we make inferences from things we see in nuclei that have both protons and neutrons.”

In atomic nuclei, the neutrons stick out a teensy bit, forming a thin, neutron-only layer that extends beyond the protons. This is called the neutron skin. Measuring the neutron skin enables researchers to learn about the strong force and, by extension, neutron stars.

In the Jefferson Lab experiments, researchers sent electrons hurtling at lead and calcium nuclei. Based on how the electrons scatter or deflect from the nuclei, scientists could calculate upper and lower limits for the size of the neutron skin.

For the NSCL experiments, the team needed to measure how much room the protons take up in a specific nickel nucleus. This is called the charge radius. In particular, the team examined the charge radius for nickel-54, a nickel nuclei or isotope with 26 neutrons. (All nickel isotopes have 28 protons, and those with 26 neutrons are called nickel-54 because the two numbers add up to 54.)

What’s special about nickel-54 is that scientists already know the charge radius of its mirror nucleus, iron-54, an iron nucleus with 26 protons and 28 neutrons.

“One nucleus has 28 protons and 26 neutrons. For the other, it’s flipped,” said Skyy Pineda, a lead author on the new research paper and a graduate student researcher on Minamisono’s team. By subtracting the charge radii, the researchers effectively remove the protons and are left with that thin neutron layer.

“If you take the difference of the charge radii of the two nuclei, the result is the neutron skin,” Pineda said.

To measure the charge radius of nickel-54, the team turned to its Beam Cooler and Laser Spectroscopy facility, abbreviated BECOLA. Using BECOLA, experimentalists overlap a beam of nickel-54 isotopes with a beam of laser light. Based on how the light interacts with the isotope beam, the Spartans can measure the nickel’s charge radius, Pineda said.

Using Brown’s earlier theory, Jefferson Lab scientists needed on the order of a sextillion electrons for a measurement, or a trillion billion particles. Using the new theory, researchers instead need thousands, maybe millions of nuclei. That means that measurements that once required years can be replaced with experiments that take days.

A future of discovery built on a history of teamwork

This new research feels like the passing of a baton in a couple ways. For one, the Jefferson Lab experiments are entering their final phase, while FRIB stands poised to continue the exploration.

FRIB itself represents another leg of the relay. BECOLA started running at NSCL and will continue operating at FRIB.

Each leg builds on the last and on the collective work the runners have put in together.

Again, that formula is nothing new. It’s what enabled a theorist at NSCL to inspire and inform experiments at a world-class lab in Virginia. What stands out about NSCL and FRIB, however, is that the user facilities are connected to a university, letting veterans and the next generation of leaders interact and share ideas that much sooner.

“MSU is unique in having had NSCL and now FRIB. In most cases, labs like these aren’t integrated into a university campus,” said Kristian Koenig, a postdoctoral researcher on Minamisono’s team and a co-lead author on the new paper. “It gives everyone here a great opportunity.”

Joining the MSU team on the Physical Review Letters publication were researchers from Florida State University along with the Technical University of Darmstadt and the GSI Helmholtz Center for Heavy Ion Research in Germany.

This work is supported in part by the National Science Foundation Grant No. PHY-14-30152, PHY-15-65546, PHY-18-11855, PHY-21-10365 and PHY-21-11185, the DOE-SC under Award No. DE-FG02-92ER40750, and German Research Foundation Project ID 279384907 SFB 1245.

NSCL is a national user facility funded by the National Science Foundation, supporting the mission of the Nuclear Physics program in the NSF Physics Division.

Michigan State University (MSU) operates the Facility for Rare Isotope Beams (FRIB) as a user facility for the U.S. Department of Energy Office of Science (DOE-SC), supporting the mission of the DOE-SC Office of Nuclear Physics. FRIB is funded by DOE-SC, MSU, and the State of Michigan, with user facility operation supported by the DOE-SC Office of Nuclear Physics.

Thomas Jefferson National Accelerator Facility (Jefferson Lab) is a U.S. Department of Energy Office of Science (DOE-SC) national laboratory. Jefferson Science Associates, LLC, manages and operates Jefferson Lab for the DOE-SC.

“This research extends our information about glatiramer acetate’s potential use in Alzheimer’s disease,” said M. Kerry O’Banion, M.D., Ph.D., professor of Neuroscience and senior author of the study. “This isn’t a cure, but it could be a step in the right direction for a treatment to slow the symptoms of this debilitating disease.”

Using a mouse model, researchers found changes in microglia — part of the brain’s immune system — and improvements in cognitive behavior when glatiramer acetate was used. These changes were associated with less amyloid plaques and modifications to tau pathology — a protein found in neurodegenerative diseases — in the brain, indicating that molecular hallmarks of Alzheimer’s disease had been impacted. Previous studies have found that glatiramer acetate can alter brain pathology in Alzheimer’s disease mouse models, but the exact mechanisms that are impacted in the brain are still unknown.

“Overall, these findings provide further evidence that therapies that modify the immune system could be effective in the treatment of Alzheimer’s disease,” said Dawling Dionisio-Santos, Ph.D., a first-year resident in Neurology and graduate of the Medical Scientist Training Program and co-first author on the paper. “It adds evidence to support trials that test the use of glatiramer acetate in patients at risk for developing Alzheimer’s.”

Co-authors on this paper include Berke Karaahmet, Elizabeth K. Belcher, Ph.D., Laura D. Owlett, Ph.D., Lee A. Trojanczyk, and John A. Olschowka, Ph.D. The research was funded by the National Institute on Aging.

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