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.