A beetle chemical defense gland offers clues about how complex organs evolve

Source: Cell Press
Date: 12/9/2021
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Rove beetles are among the chemists of the insect world, concocting noxious compounds within their bodies that are weaponized to ward off predators, enabling the beetles to survive in leaf litter and soil in ecosystems across the planet. On December 9 in the journal Cell, investigators studying a species of rove beetle report how two distinct cell types have come together to form a specialized gland for making and secreting these defensive cocktails. The work has implications for mapping out the evolution of more sophisticated organs found across the animal kingdom, including in humans.

“These beetles are fantastic models for understanding how new kinds of ecological relationships emerge during evolution through changes at the molecular, cellular, and behavioral levels,” says senior author Joseph Parker (@Pselaphinae) of the California Institute of Technology. “As part of this question, we’re very interested in how rove beetles have pieced together these glandular structures in their abdomens, which are made of different cell types that work together. These structures are the embodiment of a major conundrum: how complex organs evolve that are often composed of many different cell types that appear to seamlessly cooperate with each other. How this cooperativity emerges during evolution is challenging to explain.”

Parker’s lab focuses on rove beetles in part because of their ability to carve out niches for themselves in many different ecosystems, from in the dirt to inside ant colonies. One way they’ve been able to survive in the presence of other insects, such as ants, is through glands in their abdomen that release a defensive chemical compound that triggers pain receptors. The beetles have a supremely flexible body and can smear these chemical cocktails directly onto predators to defend themselves.

The species of rove beetle that was the focus of this research, Dalotia coriaria, has what’s called a tergal gland in its abdomen that releases a cocktail made of two compound types: benzoquinones, which are highly toxic but solids on their own, and solvents, a fatty acid-derived blend of an alkane and three esters. The latter compounds by themselves are benign, but they weaponize the benzoquinones by dissolving them.

Parker’s group investigated the tergal gland and found two cell types that were engaged in a biosynthetic division of labor. “One cell type makes the benzoquinones and the other makes the solvents,” Parker says. “Both are needed to create a functional secretion that confers adaptive value.”

In the study, the investigators used single-cell transcriptomics of the beetles’ abdominal segments to uncover novel enzyme pathways that enable the creation of these substances in each cell type. They then used these findings to dig deeper, exploring how each cell type’s pathway was constructed from components that functioned in other more ancient cell types elsewhere in the beetle. “We were able to discover the biosynthetic pathways in each cell type and could then ask how these pathways were stitched together during evolution,” Parker notes.

Remarkably, one of the cell types — the solvent cells that make the alkane and esters — was found to be a hybrid of cells comprising the beetle’s exoskeleton and two ancient metabolic cell types that make and store lipids and produce pheromones. “The beetle has recruited a major gene expression program from these ancient metabolic cell types and installed it into a patch of cuticle, creating a gland,” Parker says.

Further experiments — including placing the beetles into battle arenas with ants — revealed that when either the solvent or benzoquinone pathway was knocked down, the beetles lost their defensive capabilities. This suggested that under natural selection, both cell types are needed to confer the beetles’ chemical defense system. The investigators also found that the compound made by the tergal gland has antimicrobial properties, further raising the adaptive value of the gland.

The authors think the gland evolved via coevolution between the two cell types. “The solvent cells created a niche for a second cell type to produce the solid benzoquinones, which could dissolve in the alkane and esters. A highly toxic secretion emerged that massively raised the gland’s adaptive value, locking the two cell types into a unit where they cooperate. In essence, a new organ emerged,” Parker says.

“Across the animal tree of life, you see complex multicellular organs that are composed of many different cell types functioning collectively,” Parker concludes. “Think of something like the mammalian eye, which has about 70 different cell types all functioning together to enable our visual system. The scenario we find playing out in the tergal gland — an organ made of only two cell types — you can imagine could go through further rounds as cell types create niches for new ones to be added, eventually generating really elaborate multicellular complexity.”

Walking fish suggests locomotion control evolved much earlier than thought

Source: Cell Press
Date: 02/08/2018
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Cartoons that illustrate evolution depict early vertebrates generating primordial limbs as they move onto land for the first time. But new findings indicate that some of these first ambulatory creatures may have stayed under water, spawning descendants that today exhibit walking behavior on the ocean floor. The results appear February 8 in the journal Cell.

“It has generally been thought that the ability to walk is something that evolved as vertebrates transitioned from sea to land,” says senior author Jeremy Dasen (@JeremyDasen), a developmental neurobiologist in the Department of Neuroscience and Physiology at the New York University School of Medicine. “We were surprised to learn that certain species of fish also can walk. In addition, they use a neural and genetic developmental program that is almost identical to the one used by higher vertebrates, including humans.”

The researchers focused on the neural development of a type of fish called the little skate (Leucoraja erinacea). Related to sharks and rays, these cartilaginous fish are considered to be among the most primitive vertebrates, having changed little from their ancestors that lived hundreds of millions of years ago.

Little skates have two sets of fins: large pectoral fins, which they use for swimming, and smaller pelvic fins, which they use for walking along the ocean floor. Previous research had shown that these fish use alternating, left-right motions when they walk, similar to the motions used by animals that walk on land, making them a valuable model to study.

The investigators used a technology called RNA sequencing (RNA-seq) to assess the repertoire of genes that are expressed in the skate’s motor neurons. They found that many of these genes are conserved between skates and mammals. In addition, they discovered that the neuronal subtypes that are essential for controlling the muscles that regulate the bending and straightening of limbs are present in the motor neurons of the skate. “These findings suggest [that] the genetic program that determines the ability of the nerves in the spinal cord to articulate muscles actually originated millions of years earlier than we have assumed they appeared,” Dasen says. “This fin-based movement and walking movements use the same developmental program.”

The discovery went beyond the nerves that control muscles. The researchers also looked at a higher level of circuitry–the interneurons, which connect to motor neurons and tell them to activate the muscles. Interneurons assemble into circuits called central pattern generators (CPGs). CPGs determine the sequence in which different muscles are activated, thereby controlling locomotion. “We found that the interneurons, nearly a dozen types, are also highly conserved between skates and land mammals,” Dasen says.

Dasen’s team plans to use the little skates to study how motor neurons connect with other types of neurons and how they are regulated. “It’s hard to study the circuitry that controls walking in higher organisms like mice and chicks because there are so many more muscles and types of neurons that facilitate that behavior,” he says. “We think this species will serve as a useful model system to continue to work out the nerves that control walking and how they develop.”

Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People

Source: Memorial Sloan Kettering - On Cancer
Date: 11/07/2019
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Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they don’t work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

“Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs,” says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. “It’s important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.”

Looking to Evolution and Population Diversity for Answers

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

“The classic battle between pathogens and the human immune system plays out in the HLA genes,” Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the body’s ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chan’s co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chan’s lab and graduate student Federica Pierini from Dr. Lenz’s lab were the co-first authors.

Recognizing Tumors as Foreign

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasn’t seen before.

“For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign,” Dr. Chan says. “High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.”

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. “These are the yin and yang of T cell–based immune checkpoint treatment,” Dr. Chan says. “High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.”

Finding New Ways to Measure Genetic Diversity

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. “But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out what’s going on,” he says. “It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation that’s seen in the role of TMB in immunotherapy trials.”

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chan’s team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

This research was funded by National Institutes of Health grants (R35 CA232097, RO1 CA205426, and P30 CA008748), the PaineWebber Chair in Cancer Genetics at MSK, and a German Research Foundation grant.

Dr. Chan has filed for a patent related to HED. Additionally, he is an inventor on a patent application filed by MSK relating to the use of TMB in cancer immunotherapy. MSK and the inventors may receive a share of revenue from license agreements relating to these patent applications. Dr. Chan is also a co-founder of Gritstone Oncology and holds equity. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as an adviser for Bristol-Myers Squibb, Illumina, Eisai, and An2H.