September 14 Research Roundup: Brain in a Dish, Pathway Map for Diabetes, and “Finding Nemo’s” Genome
Published: Sep 14, 2018 By Mark Terry
There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.
Brain in a Dish
Researchers at the University of California, San Diego (UCSD) published their work in the journal Stem Cells and Development describing a fast, cost-effective method to grow human cortical organoids in Petri dishes using primary cells. Because of ethical considerations as well as physiological limitations of animal models, work on the brain can be difficult. However, recently there has been in vitro human organoids, which are three-dimensional, miniaturized, simplified version of an organ developed and grown from pre-programmed stem cells.
“And that includes the brain,” said Alysson R. Muotri, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, and director of the UC San Diego Stem Cell Program, in a statement. “Cerebral organoids can form a variety of brain regions. They exhibit neurons that are functional and capable of electrical excitation. They resemble human cortical development at the gene expression levels.”
However, these are difficult, expensive and time-consuming to develop. Muotri and colleagues described a new, fast and cost-effective method that reprograms individual somatic cells to grow directly into cortical organoids.
Turning Off Cancer Cells’ “Immortality Switch” Using CRISPR
Unlike normal cells, many cancer cells are “immortal,” which is to say, they can seemingly continue dividing forever. Researchers at the University of California, San Francisco (UCSF) studied a portion of a protein called GABP which is essential to cancer cells’ ability to trigger the so-called immortality switch. When the researchers removed the protein segment using CRISPR gene editing techniques, the cancer cells acted like regular sells and halted their uncontrolled division. The research was published in the journal Cancer Cell.
The research was led by Joseph Costello, a UCSF neuro-oncology researcher and graduate students Andrew Mancini and Ana Xavier-Magalhaes. They focused on human glioblastoma cell lines and primary tumor cells both in Petri dishes and in mice. Costello stated, “In theory what we have now is a therapeutic target that is not TERT itself, but a key to the TERT switch that is not essential in normal cells. Now we have to design a therapeutic molecule that would do the same thing.”
To that end, Costello and a former graduate student, Robert Bell, are conducting small molecules screens to find that molecule in partnership with GlaxoSmithKline. They also founded a biotech company, Telo Therapeutics, to do so.
New Insights into How Cancer Cells Spread
The majority of genetic studies of cancers tend to focus on the primary tumors. However, most deaths related to cancer are caused by metastases, which can be more difficult to treat. Researchers at Stanford University, School of Medicine focused on the genetics of metastatic cancer cells, which helped identify specific mutations related to the spread of cancer. The work was published in the journal Science.
“We took samples from multiple untreated metastases of each patient, and we observed a mix of overlapping and differing driver mutations,” said Johannes Reiter, instructor of radiology at Stanford, in a statement. “But through computational analyses, we inferred that the driver mutations that were most likely to contribute to cancer development were shared among all metastases in each patient.”
Driver mutations in genes involved in tumor genesis are usually in genes that control cell division. Part of the research was to determine if the driver gene mutations were the same across all metastases of a patient’s cancer. They discovered anywhere from two to 18 specific driver gene mutations, and that the mutations across all metastases in an individual were often mutated in earlier cancers. The researchers intend to conduct similar work on a larger group of patients to see if the concept of common functional drivers holds up across 20 to 30 cancer types and hundreds of untreated samples.
New Pathway Map for Diabetes
Biochemical pathways in the cells are complicated, and maps of these pathways are constantly being updated. Recently, researchers at the University of Tokyo found that varying levels of insulin activate different cell signaling pathways. The researchers are utilizing a new trans-omics approach to combine genomics, proteomics and metabolomics to map out these pathways. The research was published in the journal iScience.
“Our results look almost like a subway map,” stated Sinya Kuroda, professor at the University of Tokyo. “Each molecule that insulin influences, directly or indirectly, is like a station. But a map is not very useful if you do not know the route. Our method combines database information with new experimental data to show how the different stations, or molecules, connect after receiving the insulin signal.”
Cells not only responded differently to high and low concentrations of insulin, but apparently interpret and respond uniquely to varying concentrations of insulin in order to control specific biological processes. The team is now working to verify the results. “Once we have mapped the large-scale network, we can identify potential drug targets,” Kuroda stated.
European Researchers Create Interactive Model of Human Cell Division
Researchers at the European Molecular Biology Laboratory have created the first interactive map of proteins involved in making cells divide. It allows users to precisely follow the proteins that drive mitosis. The first dynamic protein atlas was published in Nature.
“Until now, individual labs have mostly been looking at single proteins in living cells,” stated Jan Ellenberg, the group leader at EMBL who led the project. “Supported by the follow-up EU project MitoSys we were now able to take a systems approach, and look at the bigger picture by studying the dynamic networks many proteins form in living human cells.”
The model tracks five different proteins during cell division: AURKB, NUP107, CENPA, CEP192 and TUBB4B. Ellenberg stated, “Besides mitosis, the technologies developed here can be used to study proteins that drive other cellular functions, for example cell death, cell migration or metastasis of cancer cells. By looking at the dynamic networks these proteins form, we can identify critical vulnerabilities, points where there’s only one protein responsible to link two tasks together without a back-up.”
Mapping Nemo’s Genome
An international team has mapped Nemo’s genome—the orange clownfish (Amphiprion percula), that is. The researchers, led by the King Abdullah University of Science and Technology and the ARC Centre of Excellence for Coral Reef Studies (Coral CoE), sequenced the genome for the orange clownfish, star of the Disney film, “Finding Nemo.”
Nemo, er, the clownfish, contains 26,597 protein-coding genes and 939 million nucleotides, and is one of the most highly-studied reef fish on Earth. “This species has been central to ground-breaking research in the ecological, environmental and evolutionary aspects of reef fishes,” stated co-author Philip Munday of Coral CoE at James Cook University in Australia. “For example, the clownfish is a model for studying sex change in fishes. It has also helped us understand patterns of larval dispersal in reef fishes and it’s the first fish species for which it was demonstrated that predator behavior could be impaired by ocean acidification.”
The research was published in the journal Molecular Ecology Resources as “Finding Nemo’s Genes: A chromosome-scale reference assembly of the genome of the orange clownfish, Amphiprion percula.”