Corgenix Medical Corporation announced it has received U.S. Food and Drug Administration (FDA) emergency use authorization (EUA) of its ReEBOVTM Antigen Rapid Test. The test is to be used for the presumptive detection of Ebola Zaire virus (detected in the West Africa outbreak in 2014) in individuals with signs and symptoms of Ebola virus infection in conjunction and with epidemiological risk factors (including geographic locations with high prevalence of Ebola infection.)

The Corgenix Ebola rapid test is the first rapid diagnostic test (RDT) and the first immunoassay authorized for emergency use by the FDA for the presumptive detection of Ebola virus. The EUA allows the use of the ReEBOVTM Antigen Rapid Test in circumstances when use of a rapid Ebola test is determined to be more appropriate than use of an authorized Ebola nucleic acid (molecular) test, which has been demonstrated to be more sensitive in detecting the Ebola Zaire virus. The authorized ReEBOVTM Antigen Rapid Test is not intended for use for general Ebola virus infection screening, such as airport screening or contact tracing.

Unlike molecular testing, which in West Africa can still take days to return results from central testing laboratories, the Corgenix RDT is a point-of-care test that can be used in any clinical facility adequately equipped, trained and capable of such testing, or in any field laboratory with trained personnel capable of such testing, to diagnose suspected Ebola cases in 15-25 minutes. The U.S. regulatory authorization follows last week’s World Health Organization (WHO) listing for procurement for the Corgenix Ebola RDT, making this test available to the health care community worldwide.

“The FDA and WHO have been working closely with us throughout this process to get this new test in the hands of those battling on the front lines of the Ebola outbreak as quickly as possible,” said Douglass Simpson, Corgenix President and CEO. “Completing this product development in less than a year demonstrates how governmental agencies, regulatory bodies, industry, non-profits and others can work together to find solutions to catastrophic events such as the Ebola virus outbreak. This collaboration has enabled us to quickly deliver this critically important point-of-care test and potential breakthrough in the fight against Ebola in the current outbreak in West Africa.” Corgenix

Scientists at The Scripps Research Institute (TSRI) have identified the long-sought activating molecules for a rare but crucial subset of immune system cells that help rally other white blood cells to fight infection.

In the process, the team also uncovered a previously unsuspected link between the mammalian immune system and the communication systems of simpler organisms such as bacteria.

The findings could lead to novel therapeutic approaches for diseases such as type 1 diabetes that are the result of immune system over-activity, as well as new ways to boost the effectiveness of vaccines, according to study leader Luc Teyton, a professor in TSRI’s Department of Immunology and Microbial Science.

When a virus, bacteria or foreign substance invades the body, specialised cells known as dendritic cells present in the skin and other organs capture the trespassers and convert them into smaller pieces called antigens that they then display on their cell surfaces. White blood cells known as T and B cells recognize the antigens to launch very specific attacks on the invaders.

Dendritic cells also activate a specialized population of T cells known as natural killer T (NKT) cells. Once activated, NKT cells can commandeer the functions of dendritic cells to make them more effective and also recruit and coordinate the responses of T- and B-type cells.

“Because of their dual functions, NKT cells are a bridge between the body’s innate immunity, which is characterised by rapid but less specific responses to pathogens, and adaptive or acquired immunity, which is composed of specialised white blood cells that can remember past invaders,” Teyton said.

Previous studies indicated that NKT cells are activated by molecules known as glycolipids that dendritic cells produce and then display on their outer surfaces. It was widely assumed that the activating molecules were a class of glycolipids known as beta-glycosylceramides, an important component of nervous system cells.

However, this hypothesis had not been thoroughly examined, in part because there is no chemical test currently available to distinguish between two forms of the molecule that have slightly different configurations—beta-glycosylceramide and alpha-glycosylceramide. In addition, when scientists attempt to create either form synthetically for testing, there is always the possibility of small contamination of one by the other.

“When you’re making glycolipids, there is no completely faithful way of controlling the form that you’re making,” Teyton said. ‘You’re favouring the making of one, but you cannot say for sure that you don’t have a small amount of the other form.”

In their new study, Teyton and his colleagues, who included scientists from Brigham Young University, the La Jolla Institute for Allergy & Immunology and the University of Chicago, abandoned the chemical approach altogether. Instead, they combined a series of biochemical and biological assays to create a test that was sensitive enough to distinguish between the two different forms of glycolipids.

“Biological assays are exquisitely sensitive to low amounts of otherwise unmeasurable molecules,” said study first author Lisa Kain, a research technician in Teyton’s lab.

The scientists used custom antibodies to identify and eliminate alpha-glycosylceramides from their test batches. When the team was confident that their test batch contained only beta forms of the glycolipid, they tested it on NKT cells gathered from mice. To their surprise, however, nothing happened. Contrary to the conventional wisdom, the beta-glycosylceramides failed to activate the NKT cells.

“We were very skeptical about the early results,” Teyton said. “We thought we had used the wrong antibody.”

Next, the team combined enzymes designed to digest molecular linkages found only on beta-glycosylceramides with mice NKT cells inside test tubes. Surprisingly, the NKT cells were still being activated.

Finally, when the team used antibodies to disable alpha-glycosylceramides inside live mice, not only did the NKT cells fail to activate, they disappeared altogether from organs such as the thymus, where NKT cells are produced.

These multiple lines of evidence strongly indicated that it was the alpha form of the glycolipids that were the triggers for NKT cells. “What we thought was the contaminant turned out to be the activating molecule we were looking for,” Teyton said.

The results were surprising for another reason. Until that moment, scientists did not think mammalian cells were capable of producing alpha forms of the glycolipids. The molecules were thought to exist only in bacteria and other simple organisms, which use them primarily as a means of communicating with one another. The findings thus suggest that the roots of a crucial part of the mammalian immune response are even more ancient than previously thought.

“Nobody expected this,” Teyton said. “It’s like discovering that all languages share a common origin.”

Now that scientists know that alpha-glycosylceramides are made by our own body and activate NKT cells, they might be able to exploit it to create new therapies. For example, Teyton said, researchers could use enzymes to reduce alpha-glycosylceramide levels in order to suppress an overactive immune response, which happens with diseases such as type 1 diabetes. Or they could combine the molecules with antigens to create vaccines that elicit a faster and more efficient immune response.

“This opens up an avenue of new therapeutic approaches that we’ve never even thought about,” Teyton said. The Scripps Research Institute

Chemists at Caltech have developed a new sensitive technique capable of detecting colorectal cancer in tissue samples—a method that could one day be used in clinical settings for the early diagnosis of colorectal cancer.

Colorectal cancer is the third most prevalent cancer worldwide and is estimated to cause about 700,000 deaths every year. Metastasis due to late detection is one of the major causes of mortality from this disease; therefore, a sensitive and early indicator could be a critical tool for physicians and patients.

A paper describing the new detection technique by Caltech graduate student Ariel Furst (PhD ’15) and her adviser, Jacqueline K. Barton, the Arthur and Marian Hanisch Memorial Professor of Chemistry, are the paper’s authors.

‘Currently, the average biopsy size required for a colorectal biopsy is about 300 milligrams,’ says Furst. ‘With our experimental setup, we require only about 500 micrograms of tissue, which could be taken with a syringe biopsy versus a punch biopsy. So it would be much less invasive.’ One microgram is one thousandth of a milligram.

The researchers zeroed in on the activity of a protein called DNMT1 as a possible indicator of a cancerous transformation. DNMT1 is a methyltransferase, an enzyme responsible for DNA methylation—the addition of a methyl group to one of DNA’s bases. This essential and normal process is a genetic editing technique that primarily turns genes off but that has also recently been identified as an early indicator of cancer, especially the development of tumours, if the process goes awry.

When all is working well, DNMT1 maintains the normal methylation pattern set in the embryonic stages, copying that pattern from the parent DNA strand to the daughter strand. But sometimes DNMT1 goes haywire, and methylation goes into overdrive, causing what is called hypermethylation. Hypermethylation can lead to the repression of genes that typically do beneficial things, like suppress the growth of tumours or express proteins that repair damaged DNA, and that, in turn, can lead to cancer.

Building on previous work in Barton’s group, Furst and Barton devised an electrochemical platform to measure the activity of DNMT1 in crude tissue samples—those that contain all of the material from a tissue, not just DNA or RNA, for example. Fundamentally, the design of this platform is based on the concept of DNA-mediated charge transport—the idea that DNA can behave like a wire, allowing electrons to flow through it and that the conductivity of that DNA wire is extremely sensitive to mistakes in the DNA itself.

In the present study, Furst and Barton started with two arrays of gold electrodes—one atop the other—embedded in Teflon blocks and separated by a thin spacer that formed a well for solution. They attached strands of DNA to the lower electrodes, then added the broken-down contents of a tissue sample to the solution well. After allowing time for any DNMT1 in the tissue sample to methylate the DNA, they added a restriction enzyme that severed the DNA if no methylation had occurred—i.e., if DNMT1 was inactive. When they applied a current to the lower electrodes, the samples with DNMT1 activity passed the current clear through to the upper electrodes, where the activity could be measured.

‘No methylation means cutting, which means the signal turns off,’ explains Furst. ‘If the DNMT1 is active, the signal remains on. So we call this a signal-on assay for methylation activity. But beyond on or off, it also allows us to measure the amount of activity.”

Using the new setup, the researchers measured DNMT1 activity in 10 pairs of human tissue samples, each composed of a colorectal tumour sample and an adjacent healthy tissue from the same patient. When they compared the samples within each pair, they consistently found significantly higher DNMT1 activity, hypermethylation, in the tumorous tissue. Notably, they found little correlation between the amount of DNMT1 in the samples and the presence of cancer—the correlation was with activity.

‘The assay provides a reliable and sensitive measure of hypermethylation,’ says Barton, also the chair of the Division of Chemistry and Chemical Engineering.  ‘It looks like hypermethylation is good indicator of tumourigenesis, so this technique could provide a useful route to early detection of cancer when hypermethylation is involved.’ Caltech

Researchers sequenced the genomes of members of 13 families severely affected by autism and compared the sequences to those of healthy controls.
They identified genetic variants that had never before been linked to autism.
One affected gene, CTNND2, plays a critical role in brain development and regulates how many other genes function.
Using a novel approach that homes in on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease. The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.

In recent years, falling costs for genetic testing, together with powerful new means of storing and analysing massive amounts of data, have ushered in the era of the genomewide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism or schizophrenia.

“In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important — if not more so — than how many people are sequenced.”

With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism, but when girls do have the condition, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.

The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in foetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.

While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism. “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.” John Hopkins Medicine