Research could lead to clinical laboratory tests in service of precision medicine therapies to reduce a person’s susceptibility to being targeted by blood-sucking insects
Ever wonder why some people attract mosquitoes while others do not? Could biting insects pick their victims by smell? Scientists in California believe the answers to these questions could lead to new precision medicine therapies and clinical laboratory tests.
The research revealed evidence that some blood-sucking insects may identify their prey by homing in on the “scent” of chemicals produced by bacteria located in the skin microbiome of animals and humans.
This is yet another example of research into one area of the human microbiome that might someday lead to a new clinical laboratory test, in this case to determine if a person is more likely to attracts biting insects. If there were such a test, precision medicine therapies could be developed that change an individual’s microbiome to discourage insects from biting that individual.
Then, the clinical laboratory test would have value because it helped diagnose a health condition that is treatable.
Curiosity regarding why mosquitoes seem to gravitate towards some humans over others was the original catalyst for the UCSD Medical School research. “You know when you go to a barbeque and your friend is getting bombarded by mosquitos, but you’re fine? There is some research to support the idea that the difference in mosquito attraction is linked to your skin microbiome—the unique community of bacteria living on your skin,” said Holly Lutz, PhD (above), first author of the UCSD study. “Keeping in mind that some people are more attractive to mosquitoes than others, I wondered what makes insects attracted to some bats but not others.” Lutz’s research could lead to clinical laboratory tests that drive precision medicine therapies to alter human skin microbiomes and make people less attractive to biting insects. (Photo copyright: The Field Museum of Natural History.)
Biting Flies Prefer Specific Bats
“In these caves, I’d see all these different bat species or even taxonomic families roosting side by side. Some of them were loaded with bat flies, while others had none or only a few,” Lutz said in Phys.org. “And these flies are typically very specific to different kinds of bats—you won’t find a fly that normally feeds on horseshoe bats crawling around on a fruit bat. I started wondering why the flies are so particular. Clearly, they can crawl over from one kind of bat to another, but they don’t really seem to be doing that.”
The researchers suspected that the bacteria contained in the skin microbiomes of individual bats could be influencing which bats the flies selected to bite. The bacteria produce a distinctive odor which may make certain bats more attractive to the flies.
The type of fly assessed for the study are related to mosquitoes and most of them are incapable of flight.
“They have incredibly reduced wings in many cases and can’t actually fly,” Lutz explained. “And they have reduced eyesight, so they probably aren’t really operating by vision. So, some other sensory mechanisms must be at play, maybe a sense of smell or an ability to detect chemical cues.”
To test their hypothesis, the research team collected skin and fur samples from the bodies and wings of a variety of bat species located in various caves around Kenya and Uganda. They collected their samples at 14 field sites from August to October in 2016. They then examined the DNA of the bats as well as the microbes residing on the animals’ skin and searched for the presence of flies.
“The flies are exquisitely evolved to stay on their bat,” said Carl Dick, PhD, a professor of biology at Western Kentucky University and one of the study’s authors. “They have special combs, spines, and claws that hold them in place in the fur, and they can run quickly in any direction to evade the biting and scratching of the bats, or the efforts by researchers to capture them,” he told Phys.org.
“You brush the bats’ fur with your forceps, and it’s like you’re chasing the fastest little spider,” Lutz said. “The flies can disappear in a split second. They are fascinatingly creepy.”
Genetic Sequencing DNA of Bat Skin Bacteria
After collecting their specimens, the researchers extracted DNA from the collected bacteria and performed genetic sequencing on the samples. They created libraries of the bacteria contained in each skin sample and used bioinformatics methods to identify the bacteria and compare the samples from bats that had flies versus those that did not.
“How the flies actually locate and find their bats has previously been something of a mystery,” Dick noted. “But because most bat flies live and feed on only one bat species, it’s clear that they somehow find the right host.”
The scientists discovered that different bat families did have their own distinctive skin microbiome, even among samples collected from different locations. They found that differences in the skin microbiomes of certain bats does contribute to whether those bats have parasites. But not all their questions were answered.
“We weren’t able to collect the actual chemicals producing cue—secondary metabolites or volatile organic compounds—during this initial work. Without that information, we can’t definitively say that the bacteria are leading the flies to their hosts,” Lutz said.
Next Steps
“So, next steps will be to sample bats in a way that we can actually tie these compounds to the bacteria. In science, there is always a next step,” she added.
This research illustrates that there may be a reason why certain animals and humans tend to be more attractive to insects than others. It is also possible that an individual’s skin microbiome may explain why some people are more prone to mosquito and other types of insect bites.
More research and clinical studies on this topic are needed, but it could possibly lead to a clinical laboratory test to determine if an individual’s skin microbiome could contribute to his or her potential to being bitten by insects. Such a test would be quite beneficial, as insects can carry a variety of diseases that are harmful to humans.
Perhaps a precision medicine therapy could be developed to alter a person’s microbiome to make them invisible to blood-sucking insects. That would be a boon to regions of the world were diseases like malaria are spread by insect bites.
Radboud University researchers fear oncology, molecular biology, pharmacology, and other cell-centric medical research efforts are at risk due to verification that at least 30,000 studies published in 33,000 scientific journals included data derived from misidentified or contaminated cell lines
Many research findings that underpin the science behind various diagnostic technologies used regularly by clinical laboratories and anatomic pathology groups may not be valid. This is because a large number of published studies may have used misidentified or contaminated cell lines.
Biomedical scientists have known for a long time that many research papers exist containing reports on the wrong cells due to cell line misidentification. And yet, few studies have measured the true scope of the problem. Until now. Researchers at Radboud University in the Netherlands have determined that this problem may have influenced the findings of thousands of published research studies and upon which many other research studies were conducted.
Because clinical laboratories and anatomic pathology groups use assays and diagnostic tests that are developed as a result of these research studies, identifying how many published papers have inaccurate findings that cannot be duplicated would affect how and when it is appropriate for physicians to order certain medical laboratory tests and rely on the results.
Additionally, cancer research is based on cell line studies as well. Thus, it may prove necessary to restudy existing published findings and revise them as appropriate. In turn, these new findings might change how and when some cancer tests are ordered and the results interpreted.
“We considered a reference to this original article as a good proxy for the usage of a cell line,” the researchers noted in their study published in the journal PLOS ONE. “Since typically the original papers are focused on reporting the establishment of the cell line only.”
They focused on misidentified cell lines that were caused by HeLa cells, also known as “immortalized cells.” HeLa cells have been used in scientific research for decades. They were the first mass-producible cells that could be used in vitro, making them highly desirable for biomedical research.
However, the process of creating immortalized cells involves mutation, during which contamination can be introduced by other cells. Immortalized cells can be identified as one type of cell when in fact they are actually another type of cell.
Research scientists have been aware of this problem for about as long as immortalized cells have been in use. They attempt to take it into account when completing their analyses, though not always successfully.
The Radboud researchers found 32,655 records of primary literature based on contaminated cell lines. They then cross-referenced the ICLAC Register of Misidentified Cell Lines with a range of databases to determine if articles were available for each of the 451 cell lines listed on Table One of the ICLAC Register.
With this information, they further researched published articles in the Web of Science database using cell line identifiers. They noted both primary literature and any citation report entries for each cell line.
The researchers noted in their published study, “As we only searched for cell lines known to be misidentified, this constitutes a conservative estimate of the scale of contamination in the primary literature. Moreover, to avoid false positives, we excluded several cell lines, such as the ones with non-unique identifiers or the cell lines for which verified stock is still in circulation.”
Their estimate for secondary contaminated literature based off primary articles is larger still. “In total, we can conservatively estimate the citations to the primary contaminated primary literature at over 500,000, excluding self-citations,” the authors noted in their PLOS ONE article. “Thereby leaving traces in a substantial share of the biomedical literature.” They concluded, “… the amount of research potentially building on false grounds remains worrisome.”
Impact of Contaminated Cell Lines on Research, Clinical Laboratory Communities
Many of the assays and diagnostic tests performed by clinical laboratories and pathology groups were developed using cell line research. Should further scrutiny into the ability to duplicate and verify study findings fail to produce positive outcomes, it might call into question the validity and appropriate use of these tests.
For the research community, these findings represent yet another call to promote accountability and define standards for verifying authenticity of cell lines to further strengthen research findings.
The Radboud researchers ranked the number of contaminated articles they discovered by research area. Top affected areas include:
Oncology
Molecular Biology
Pharmacology
Cell Biology
Immunology
The distribution of contaminated primary literature over the research areas as defined by Web of Science. Only the 25 most affected research areas are included. (Graphic copyright: PLOS ONE.)
Addressing the Problem of Cell Line Contamination and Misidentification
Adapting the ever-growing body of published medical literature to reflect the known misidentifications, as well as the possibility of invalid results, will be a major undertaking. Ultimately, resolving this problem could require changes to practices and procedures currently used by research facilities and medical laboratories.
While the cost to authenticate cell lines adds to the bottom line of research projects, the money spent on research that becomes invalidated by misidentified cell lines is far greater.
In a 2015 Retraction Watch article, Leonard P. Freeman, PhD, President, Global Biological Standards Institute, notes, “An NIH RePORT search identified 9,000 active projects using cell lines, totaling $3.7 billion. Required use of authentication techniques would affect over $900 million in research dollars annually.”
Additionally, failure to adapt authentication as a part of standard operations brings other consequences. “A 2004 survey reported that just one-third of laboratories authenticate their cell lines,” Freeman noted. “10 years later, a Sigma-Aldrich survey found that only 37% of respondents ‘validate the purity and identity before first use’ of cell lines. Understanding the existing barriers that prevent implementation of universal cell authentication is central to changing this sad state of affairs.”
Mixed Recommendations for Fixing Inaccurate Published Studies
Of course, none of this will change the vast body of archived literature that might contain errors due to misidentification. Recommendations for addressing this aspect of the problem vary. The Radboud study authors suggest posting notes on any previously published articles stating that misidentified cell lines were used.
However, in a STAT article, Ivan Oransky, MD, and Adam Marcus, Managing Editor, Gastroenterology and Endoscopy News, co-founders of Retraction Watch, recommend more severe measures. “When we polled readers of Retraction Watch last December about the issue, 55% said journals should correct papers known to describe contaminated or misidentified cell lines, and more than 40% said retraction was the right choice.”
Thanks to the Radboud study, as cell lines continue to power the innovations of modern biomedical research, concerns will surely increase surrounding cell-line authentication and research findings. For pathology groups and medical laboratories, staying abreast of these developments will work to ensure data validity and reduce reputation and liability concerns.
Researchers sought to improve the tedious laboratory task of pipetting. Their app-based solution increases productivity, improves safety, and doesn’t rely on expensive robots.
Even something as mundane as pipetting is getting a high-tech makeover and clinical laboratory scientists around the world are likely to benefit from an innovation that incorporates an iPad into the pipetting process.
As pathologists and clinical laboratory workers know, many busy laboratories rely on robotic pipetting to avoid risky manual processes. And while technically able to perform higher volumes of tests, robotic pipetting is extremely expensive and requires technical support personnel that many labs cannot afford. This is why Whitehead’s iPad application, which makes the process more productive and accurate, is a positive development. It’s also important to note that iPipet protects technologists’ jobs (as opposed to robots), and iPipet may be easier to learn and less expensive for labs to adopt, as well. (more…)
This investigation of the fruit fly’s transcriptome—the complete collection of the genome’s RNA—unearthed thousands of new genes, transcripts, and proteins
Scientists have teased another level of information out of the genome. This time, the new insights were developed from studies of the fruit fly’s transcriptome. This knowledge will give pathologists another channel of information that may be useful in developing assays to support more precise diagnosis and therapeutic decisions.
The findings were published in a recent issue of Nature. The study focused on the transcriptome—a complete collection of the genome’s RNA—of the common fruit fly−Drosophila melangogaster.(more…)
Researchers at Penn State identified 160,000 ‘transcription initiation machines’ throughout the human genome
DNA “dark matter” may have something in common with comedian Rodney Dangerfield, who liked to say, “I don’t get no respect!” As many pathologists know, for years the human exome that has been the focus of most research. This is the 1% of the human genome that contains the genes that produce proteins and do other useful functions.
Meanwhile, the remaining 99% of the human genome—sometimes called “junk DNA” and generally known as dark matter—got relatively little attention from researchers. But that is changing. At Pennsylvania State University, a research team has discovered that coding and noncoding RNA, or genomic dark matter, originates at the same types of locations along the human genome. (more…)
