Human brain size gene triggers bigger brain in monkeys


Microscopy image of a section through one brain hemisphere of a 101 day- old ARHGAP11B-transgenic marmoset fetus. Cell nuclei are visualized by DAPI (white). Arrows indicate a sulcus and a gyrus. Credit: Heide et al. / MPI-CBG

The expansion of the human brain during evolution, specifically of the neocortex, is linked to cognitive abilities such as reasoning and language. A certain gene called ARHGAP11B that is only found in humans triggers brain stem cells to form more stem cells, a prerequisite for a bigger brain. Past studies have shown that ARHGAP11B, when expressed in mice and ferrets to unphysiologically high levels, causes an expanded neocortex, but its relevance for primate evolution has been unclear.

Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, together with colleagues at the Central Institute for Experimental Animals (CIEA) in Kawasaki and the Keio University in Tokyo, both located in Japan, now show that this human-specific gene, when expressed to physiological levels, causes an enlarged neocortex in the common marmoset, a New World monkey. This suggests that the ARHGAP11B gene may have caused neocortex expansion during human evolution. The researchers published their findings in the journal Science.

The human neocortex, the evolutionarily youngest part of the cerebral cortex, is about three times bigger than that of the closest human relatives, chimpanzees, and its folding into wrinkles increased during evolution to fit inside the restricted space of the skull. A key question for scientists is how the human neocortex became so big. In a 2015 study, the research group of Wieland Huttner, a founding director of the MPI-CBG, found that under the influence of the human-specific gene ARHGAP11B, mouse embryos produced many more neural progenitor cells and could even undergo folding of their normally unfolded neocortex. The results suggested that the gene ARHGAP11B plays a key role in the evolutionary expansion of the human neocortex.

The rise of the human-specific gene

The human-specific gene ARHGAP11B arose through a partial duplication of the ubiquitous gene ARHGAP11A approximately five million years ago along the evolutionary lineage leading to Neanderthals, Denisovans, and present-day humans, and after this lineage had segregated from that leading to the chimpanzee. In a follow-up study in 2016, the research group of Wieland Huttner uncovered a surprising reason why the ARHGAP11B protein contains a sequence of 47 amino acids that is human-specific, not found in the ARHGAP11A protein, and essential for ARHGAP11B’s ability to increase brain stem cells.

Specifically, a single C-to-G base substitution found in the ARHGAP11B gene leads to the loss of 55 nucleotides from the ARHGAP11B messenger RNA, which causes a shift in the reading frame resulting in the human-specific, functionally critical 47 amino acid sequence. This base substitution probably happened much later than when this gene arose about 5 million years ago, anytime between 1.5 million and 500,000 years ago. Such point mutations are not rare, but in the case of ARHGAP11B its advantages of forming a bigger brain seem to have immediately influenced human evolution.


Wildtype (normal) and ARHGAP11B-transgenic fetal (101 days) marmoset brains. Yellow lines, boundaries of cerebral cortex; white lines, developing cerebellum; arrowheads, folds. Scale bars, 1 mm. Credit: Heide et al. / MPI-CBG

The gene’s effect in monkeys

However, it has been unclear until now if the human-specific gene ARHGAP11B would also cause an enlarged neocortex in non-human primates. To investigate this, the researchers in the group of Wieland Huttner teamed up with Erika Sasaki at the Central Institute for Experimental Animals (CIEA) in Kawasaki and Hideyuki Okano at the Keio University in Tokyo, both located in Japan, who had pioneered the development of a technology to generate transgenic non-human primates. The first author of the study, postdoc Michael Heide, traveled to Japan to work with the colleagues directly on-site.

They generated transgenic common marmosets, a New World monkey, that expressed the human-specific gene ARHGAP11B, which they normally do not have, in the developing neocortex. Japan has similarly high ethical standards and regulations regarding animal research and animal welfare as Germany does. The brains of 101-day-old common marmoset fetuses (50 days before the normal birth date) were obtained in Japan and exported to the MPI-CBG in Dresden for detailed analysis.

Michael Heide explains: “We found indeed that the neocortex of the common marmoset brain was enlarged and the brain surface folded. Its cortical plate was also thicker than normal. Furthermore, we could see increased numbers of basal radial glia progenitors in the outer subventricular zone and increased numbers of upper-layer neurons, the neuron type that increases in primate evolution.” The researchers had now functional evidence that ARHGAP11B causes an expansion of the primate neocortex.

Ethical consideration

Wieland Huttner, who led the study, adds: “We confined our analyses to marmoset fetuses, because we anticipated that the expression of this human-specific gene would affect the neocortex development in the marmoset. In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite—and mandatory from an ethical point of view—to first determine the effects of ARHGAP11B on the development of fetal marmoset neocortex.”

The researchers conclude that these results suggest that the human-specific ARHGAP11B gene may have caused neocortex expansion in the course of human evolution.

More information: “Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset” Science (2020). science.sciencemag.org/cgi/doi … 1126/science.abb2401

https://medicalxpress.com/news/2020-06-human-brain-size-gene-triggers.html

Pig-Monkey Hybrid Engineered in China


This piglet had some cells from a monkey but died within a week of birth
Tang Hai

By Michael Le Page

Pig-primate chimeras have been born live for the first time but died within a week. The two piglets, created by a team in China, looked normal although a small proportion of their cells were derived from cynomolgus monkeys.

“This is the first report of full-term pig-monkey chimeras,” says Tang Hai at the State Key Laboratory of Stem Cell and Reproductive Biology in Beijing.

The ultimate aim of the work is to grow human organs in animals for transplantation. But the results show there is still a long way to go to achieve this, the team says.

Hai and his colleagues genetically modified cynomolgus monkey cells growing in culture so they produced a fluorescent protein called GFP. This enabled the researchers to track the cells and their descendents. They then derived embryonic stem cells from the modified cells and injected them into pig embryos five days after fertilisation.

More than 4000 embryos were implanted in sows. Ten piglets were born as a result, of which two were chimeras. All died within a week. In the chimeric piglets, multiple tissues – including in the heart, liver, spleen, lung and skin – partly consisted of monkey cells, but the proportion was low: between one in 1000 and one in 10,000.

It is unclear why the piglets died, says Hai, but because the non-chimeric pigs died as well, the team suspects it is to do with the IVF process rather than the chimerism. IVF doesn’t work nearly as well in pigs as it does in humans and some other animals.

The team is now trying to create healthy animals with a higher proportion of monkey cells, says Hai. If that is successful, the next step would be to try to create pigs in which one organ is composed almost entirely of primate cells.

Something like this has already been achieved in rodents. In 2010, Hiromitsu Nakauchi, now at Stanford University in California, created mice with rat pancreases by genetically modifying the mice so their own cells couldn’t develop into a pancreas.

Pig-human chimeras

In 2017, Juan Carlos Izpisua Belmonte’s team at the Salk Institute in California created pig-human chimeras, but only around one in 100,000 cells were human and, for ethical reasons, the embryos were only allowed to develop for a month. The concern is that a chimera’s brain could be partly human.

This is why Hai and his team used monkey rather than human cells. But while the proportion of monkey cells in their chimeras is higher than the proportion of human cells in Belmonte’s chimeras, it is still very low.

“Given the extremely low chimeric efficiency and the deaths of all the animals, I actually see this as fairly discouraging,” says stem cell biologist Paul Knoepfler at the University of California, Davis.

He isn’t convinced that it will ever be possible to grow organs suitable for transplantation by creating animal-human chimeras. However, it makes sense to continue researching this approach along with others such as tissue engineering, he says.

According to a July report in the Spanish newspaper El País, Belmonte’s team has now created human-monkey chimeras, in work carried out in China. The results have not yet been published.

While interspecies chimerism doesn’t occur naturally, the bodies of animals including people can consist of a mix of cells. Mothers have cells from their children growing in many of their organs, for instance, a phenomenon called microchimerism.

Journal reference: Protein & Cell, DOI: 10.1007/s13238-019-00676-8

Read more: https://www.newscientist.com/article/2226490-exclusive-two-pigs-engineered-to-have-monkey-cells-born-in-china/#ixzz67RYaU5XS

Monkeys are exquisitely attuned to the same signals signals about sex and social status upon which many successful advertisements rely.

Any ad executive will tell you that sex sells. But why? Do sexy images stimulate our biological urges, somehow motivating us to buy products? Or do marketers merely exploit and perpetuate our cultural obsession with sexual imagery? Do people want the beauty, wealth and power celebrities have, and use the products they endorse in the hope of achieving these same qualities?

These explanations are plausible, but my colleagues and I have a new one, based on decades of work comparing the behavior and neurobiology of decision-making in monkeys and people: Our brains have been fine-tuned by evolution to prioritize social information, and this laser focus on others profoundly shapes our decisions.

As early as the 1870s, companies like Pearl Tobacco and later, W. Duke & Sons, employed social advertising, showcasing nude or partially exposed women on posters and trading cards. Although the images had no direct link to the products, sales increased. A century and a half later, it seems impossible to escape sexual imagery in advertising. The same is true for celebrities in marketing campaigns—actors, musicians, athletes, even politicians and business leaders. These celebrities often don’t even use the products they advertise, yet the method still seems to work.

Our brains have circuits specialized for identifying, remembering and inferring the mental states of others so we can predict their behavior and make good decisions. In other words, we’re built to deal with people. But we’re not alone in this connection. Many species of monkeys and apes—our closest living relatives—also live in large, complex, dynamic societies. Behavioral studies show that, like us, these primates identify others, track prior encounters, empathize with friends and relatives, and make inferences about individuals’ mental states.

For people and monkeys alike, it’s important to find a good mate, make powerful allies and avoid potential threats. Paying close attention to social cues can improve these choices. In fact, both men and male monkeys are exquisitely sensitive to indications of female fertility. Men rate ovulating women as more attractive, and tip more for lap dances by fertile women. Similarly, male rhesus macaques prefer images of females with artificially reddened faces and hindquarters, coloration that predicts ovulation and sexual receptivity.

Women and female monkeys are also sensitive to clues about male quality, although what we know about that is based on fewer studies. A woman’s preference shifts toward more masculine faces—broader jaw, wider-set but smaller eyes—during ovulation. Female macaques, when ovulating, tend to mate with higher-ranking males and prefer those with reddened faces caused by a testosterone surge. Other studies found that both people and monkeys pay more attention to high-status individuals and are more likely to follow their gaze.

According to economics, we can quantify how much someone values something—coffee, a magazine—by how much he or she will pay for it. In our latest work, we developed an assessment, dubbed the “pay-per-view” test, to measure subconscious value of visual images. In the experiment, monkeys had the option to forego juice or food for a glimpse at a picture of another monkey. People could choose whether to accept a smaller cash reward to peek at a picture of another individual.

Our findings were striking. Male college students paid slightly more money to view an attractive woman than an unattractive one, losing several dollars during the experiment. Female students were much less motivated to see attractive men. Monkeys of both genders valued sex and status, accepting less food or juice to see images of monkey genitalia and faces of high-status males. In contrast, they required extra food or juice to look at faces of low-status males.

Based on these findings, it’s clear that monkeys and humans value information about sex and status so much that it can replace rewards like food, juice and money. Strong parallels between the two suggest shared brain mechanisms at work.

To test this idea, we used fMRI to scan the brains of male students in two circumstances: one, while they viewed female faces of varying attractiveness, the other while money was either deposited or withdrawn from their study stipend. The sight of attractive faces strongly activated a network of brain areas previously implicated in processing rewards—including the orbitofrontal cortex, ventromedial prefrontal cortex, and medial and ventral striatum—and neural activity increased with increasing attractiveness. The same happened with monetary rewards and losses. We believe this network computes economic “utility,” a person’s internal desire for or satisfaction with a good or service, thought to underlie decisions.

To determine the physiological basis of these signals, we measured individual brain cell activity in monkeys. Some fired strongly when male monkeys chose to see female genitalia, a high-status male face, or a large juice reward, but fired less when they chose low-status faces or small juice rewards. Specific brain cells reacted to images of faces and genitals but not juice, indicating the brain’s reward system possesses dedicated hardware for identifying and prioritizing key social information.

Can these discoveries help explain the power of sex and status in advertising? In theory, ads that associate sex or status with specific brands or products activate the brain mechanisms that prioritize social information, and turning on this switch may bias us toward the product.

To test this idea, we exposed male rhesus macaques to logos of household brands like Nike and Pizza Hut paired with a social image (e.g., female genitalia, high-status male face) or the same image with pixels rearranged to make it unrecognizable but retain the same brightness, contrast, and color, salient cues that could draw attention to a stimulus. Monkeys received a sweet treat for touching the screen after the ad, then had the choice between brands paired with a social image or its scrambled version.

Our advertising campaign was remarkably effective. Monkeys developed preferences for brands linked with sex and status. Both males and females preferred logos paired with sexual cues and the faces of high-status monkeys. And the more often male monkeys saw sexual advertisements, the more they preferred the brands. Sound familiar? Even monkeys, it seems, can be persuaded to choose a brand through social advertising.

Given the nearly identical specializations of brain reward circuits to prioritize social information in monkeys and people, is it any wonder that sex and status sell?

https://blogs.scientificamerican.com/observations/what-monkeys-can-teach-us-about-advertising/

Meet Zhong Zhong and Hua Hua, the First Monkey Clones Produced by Method that Made Dolly

The first primate clones made by somatic cell nuclear transfer are two genetically-identical long-tailed macaques born recently at the Institute of Neuroscience of Chinese Academy of Sciences in Shanghai. Researchers named the newborns Zhong Zhong and Hua Hua—born six and eight weeks ago, respectively—after the Chinese adjective “Zhōnghuá,” which means Chinese nation or people. The technical milestone, presented January 24 in the journal Cell, makes it a realistic possibility for labs to conduct research with customizable populations of genetically uniform monkeys.

“There are a lot of questions about primate biology that can be studied by having this additional model,” says senior author SUN Qiang, Director of the Nonhuman Primate Research Facility at the Chinese Academy of Sciences Institute of Neuroscience. “You can produce cloned monkeys with the same genetic background except the gene you manipulated. This will generate real models not just for genetically based brain diseases, but also cancer, immune or metabolic disorders, and allow us to test the efficacy of the drugs for these conditions before clinical use.”

Zhong Zhong and Hua Hua are not the first primate clones—the title goes to Tetra, a rhesus monkey made in 1999 by a simpler method called embryo splitting (Science, v. 287, no. 5451, pp. 317-319). This approach is how twins are made, but can only generate up to 4 offspring at a time. Zhong Zhong and Hua Hua are the product of somatic cell nuclear transfer (SCNT), the technique used to create Dolly the sheep over 20 years ago, in which researchers remove the nucleus from an egg cell and replace it with another nucleus from differentiated body cells. This reconstructed egg then develops into a clone of whatever donated the replacement nucleus.

Differentiated monkey cell nuclei, compared to other mammals such as mice or dogs, have proven resistant to SCNT. SUN and his colleagues overcame this challenge primarily by introducing epigenetic modulators after the nuclear transfer that switch on or off the genes that are inhibiting the embryo development. The researchers found their success rate increased by transferring nuclei taken from fetal differentiated cells, such as fibroblasts, a cell type in the connective tissue. Zhong Zhong and Hua Hua are clones of the same macaque fetal fibroblasts. Cells from adult donor cells were also used, but those babies only lived for a few hours after birth.

“We tried several different methods but only one worked,” says SUN. “There was much failure before we found a way to successfully clone a monkey.”

The first author LIU Zhen, a postdoctoral fellow, spent three years practicing and optimizing the SCNT procedure. Including quickly and precisely removing of the nuclear materials from the egg cell and various methods of promoting the fusion of the nucleus-donor cell and enucleated egg. With additional help of epigenetic modulators that help re-activate the suppressed genes in the differentiated nucleus, he was able to achieve much higher rates of normal embryo development and pregnancy in the surrogate female monkeys.

“The SCNT procedure is rather delicate, so the faster you do it the less damage to the egg you have, and Dr. LIU has a green thumb for doing this,” says Muming Poo, a co-author on the study, who directs the Institute of Neuroscience of CAS Center for Excellence in Brain Science and Intelligence Technology and helps to supervise the project. “It takes a lot of practice, not everybody can do the enucleation and cell fusion process quickly and precisely, and it is likely that the optimization of transfer procedure greatly helped us to achieve this success.”

The researchers plan to continue improving the technique, which will also benefit from future work in other labs, and monitoring Zhong Zhong and Hua Hua for their physical and intellectual development. The babies are currently bottle fed and are growing normally compared to monkeys their age. The group is also expecting more macaque clones to be born over the coming months.

The lab is following strict international guidelines for animal research set by the US National Institutes of Health, but encourage the scientific community to discuss what should or should not be acceptable practices when it comes to cloning of non-human primates. “We are very aware that future research using non-human primates anywhere in the world depends on scientists following very strict ethical standards,” Poo says.

This work was supported by grants from Chinese Academy of Sciences, the CAS Key Technology Talent Program, the Shanghai Municipal Government Bureau of Science and Technology, the National Postdoctoral Program for Innovative Talents and the China Postdoctoral Science Foundation.

http://english.cas.cn/head/201801/t20180123_189488.shtml

Self-Medicating Monkeys Gobble Painkilling Bark

By Jason G. Goldman

When a monkey has the sniffles or a headache, it doesn’t have the luxury of popping a few painkillers from the medicine cabinet. So how does it deal with the common colds and coughs of the wildlife world?

University of Georgia ecologist Ria R. Ghai and her colleagues observed a troop of more than 100 red colobus monkeys in Uganda’s Kibale National Park for four years to figure out whether the rain forest provides a Tylenol equivalent.

Monkeys infected with a whipworm parasite were found to spend more time resting and less time moving, grooming and having sex. The infected monkeys also ate twice as much tree bark as their healthy counterparts even though they kept the same feeding schedules. The findings were published in September in the journal Proceedings of the Royal Society B.

The fibrous snack could help literally sweep the intestinal intruder out of the simians’ gastrointestinal tracts, but Ghai suspects a more convincing reason. Seven of the nine species of trees and shrubs preferred by sick monkeys have known pharmacological properties, such as antisepsis and analgesia. Thus, the monkeys could have been self-medicating, although she cannot rule out other possibilities. The sick individuals were, however, using the very same plants that local people use to treat illnesses, including infection by whipworm parasites. And that “just doesn’t seem like a coincidence,” Ghai says.

University of Helsinki researchers recently announced the first evidence of self-medication in ants. When the biologists exposed hundreds of Formica fusca ants to a dangerous fungus, many of the infected insects chose to consume a 4 to 6 percent hydrogen peroxide solution made available for the experiment. Healthy ants avoided the household chemical, which can quash infections in small doses but is otherwise deadly. The sick ants that partook were less likely to succumb to the grips of the fungus. In the wild, they could perhaps acquire the compound by eating plants that release it to fight aphid infestations.

http://www.scientificamerican.com/article/self-medicating-monkeys-gobble-painkilling-bark/

Head transplant has been successfully done on a monkey, neurosurgeon Sergio Canavero claims

by Andrew Griffin

The scientist who claims to be about to carry out the first human head transplant says that he has successfully done the procedure on a monkey.

Maverick neurosurgeon Sergio Canavero has tested the procedure in experiments on monkeys and human cadavers, he told New Scientist.

Dr Canavero says that the success shows that his plan to transplant a human’s head onto a donor body is in place. He says that the procedure will be ready before the end of 2017 and could eventually become a way of treating complete paralysis.

“I would say we have plenty of data to go on,” Canavero told New Scientist. “It’s important that people stop thinking this is impossible. This is absolutely possible and we’re working towards it.”

The team behind the work has published videos and images showing a monkey with a transplanted head, as well as mice that are able to move their legs after having their spinal cords severed and then stuck back together.

Fusing the spinal cord of a person is going to be key to successfully transplanting a human head onto a donor body. The scientists claim that they have been able to do so by cleanly cutting the cord and using polyethylene glycol (PEG), which can be used to preserve cell membranes and helps the connection recover.

The monkey head transplant was carried out at Harbin Medical University in China, according to Dr Canavero. The monkey survived the procedure “without any neurological injury of whatever kind,” the surgeon said, but that it was killed 20 hours after the procedure for ethical reasons.

It isn’t the first time that a successful transplant has been carried out on a monkey. Head transplant pioneer Robert J White successfully carried out the procedure in 1970, on a monkey that initially responded well but died after nine days when the body rejected the head.

https://en.wikipedia.org/wiki/Robert_J._White

The newly-revealed success is likely to be an attempt to help generate funds for the ultimate aim of giving a head transplant to Valery Spriridonov, the Russian patient who has been chosen to be the first to undergo the procedure. Dr Canavero has said that he will need a huge amount of money to fund the team of surgeons and scientists involved, and that he intends to ask Mark Zuckerberg to help fund it.

While the scientists behind the procedure have published the pictures and the videos, they haven’t yet made any of their work available for critique from fellow scientists. That has led some to criticise the claims, arguing that it is instead “science through PR”, and an attempt to drum up publicity and distract people from “good science”.

Peers have criticised the maverick scientist for making the claims without allowing them to be reviewed or checked out. But Dr Canavero claims that he will be publishing details from the study in journals in the coming months.

http://www.independent.co.uk/news/science/head-transplant-has-been-successfully-done-on-a-monkey-maverick-neurosurgeon-sergio-canavero-claims-a6822361.html

Thanks to Kebmodee for bringing this to the It’s Interesting community.