For years, scientists have been trying to determine what effect a gene linked to the brain chemical serotonin may have on depression in people exposed to stress. But now, analysing information from more than 40,000 people who have been studied over more than a decade, researchers led by a team at Washington University School of Medicine in St. Louis have found no evidence that the gene alters the impact stress has on depression.
New research findings often garner great attention. But when other scientists follow up and fail to replicate the findings? Not so much.
In fact, a recent study published in PLOS One indicates that only about half of scientific discoveries will be replicated and stand the test of time. So perhaps it shouldn’t come as a surprise that new research led by Washington University School of Medicine in St. Louis shows that an influential 2003 study about the interaction of genes, environment and depression may have missed the mark.
Since its publication in Science, that original paper has been cited by other researchers more than 4,000 times, and some 100 other studies have been published about links between a serotonin-related gene, stressful life events and depression risk. It indicated that people with a particular variant of the serotonin transporter gene were not as well-equipped to deal with stressful life events and, when encountering significant stress, were more likely to develop depression.
Such conclusions were widely accepted, mainly because antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) help relieve depression for a significant percentage of clinically depressed individuals, so many researchers thought it logical that differences in a gene affecting serotonin might be linked to depression risk.
But in this new study, the Washington University researchers looked again at data from the many studies that delved into the issue since the original publication in 2003, analysing information from more than 40,000 people, and found that the previously reported connection between the serotonin gene, depression and stress wasn’t evident.
“Our goal was to get everyone who had gathered data about this relationship to come together and take another look, with each research team using the same tools to analyze data the same way,” said the study’s first author, Robert C. Culverhouse, PhD, an assistant professor of medicine and of biostatistics. “We all ran exactly the same statistical analyses, and after combining all the results, we found no evidence that this gene alters the impact stress has on depression.”
Over the years, dozens of research groups had studied DNA and life experiences involving stress and depression in the more than 40,000 people revisited in this study. Some previous research indicated that those with the gene variant were more likely to develop depression when stressed, while others didn’t see a connection. So for almost two decades, scientists have debated the issue, and thousands of hours of research have been conducted. By getting all these groups to work together to reanalyze the data, this study should put the questions to rest, according to the researchers.
“The idea that differences in the serotonin gene could make people more prone to depression when stressed was a very reasonable hypothesis,” said senior investigator Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry at Washington University. “But when all of the groups came together and looked at the data the same way, we came to a consensus. We still know that stress is related to depression, and we know that genetics is related to depression, but we now know that this particular gene is not.”
Culverhouse noted that finally, when it comes to this gene and its connection to stress and depression, the scientific method has done its job.

Washington University School of Medicine
medicine.wustl.edu/news/study-reverses-thinking-genetic-links-stress-depression/

Researchers from the University of Wisconsin School of Medicine and Public Health and Carbone Cancer Center have better defined a pro-growth signalling pathway common to many cancers that, when blocked, kills cancer cells but leaves healthy cells comparatively unharmed.

The study could establish new avenues of therapeutic treatments for many types of solid tumours.

Growth signals typically come in the form of chemical agonists outside of cells that bind to protein receptors on cells. Activated receptors are responsible for transmitting the signal to the inside of the cell, ultimately generating a growth messenger called PIP3.

Two years ago, research out of UW–Madison professor Richard Anderson’s lab found that some of these agonist-stimulated receptors continue to transmit the signal even after they have been pulled into the cell, sequestered in vesicles called endosomes and presumably on their way to being degraded.

“According to dogma in the literature, receptors shouldn’t make PIP3 at these internal sites, but they were,” Anderson says. “We set out to ask, ‘Why is that?’”

In this new study, a postdoctoral fellow in Anderson’s lab, Suyong Choi, showed that the proteins known to be in this signal transmission cascade were all present on endosomes inside the cell, supporting the idea that the key growth message was being signalled from these internal compartments.

However, there was one fact which they could not biologically explain: In a typical signalling cascade, each step amplifies the signal, suggesting there should be more and more of the messenger molecules; but here, levels of PIP3 and other intermediary messengers were too low to be detected in endosomes.

“A scaffold completely solves this issue, because it acts like an assembly line, bringing together all of the proteins and passing one messenger molecule to the next protein in the cascade until the last protein, PI3K, is activated and generates PIP3,” Anderson says. “Suyong Choi found that the scaffolding protein IQGAP1 brings all of these proteins together like a happy family on the endosome. It’s an incredibly efficient mechanism.”

Choi discovered that the IQGAP1 complex pulls together all of the signalling components in the PI3K pathway. Remarkably, this assembly happens in response to nearly all agonists that switch on growth and cell survival signals in cells. Once Choi had established how the proteins in the complex interacted, he was able to block scaffold formation in cells by adding a small, competing fragment of the IQGAP1 protein.

“It worked beautifully to block assembly of IQGAP1 and PI3K complex,” Anderson says. “The really cool thing was, when we treated different cells with these inhibitory fragments, the disruption of IQGAP1 and PI3K complex formation had almost no effect on normal cells but it killed cancer cells very efficiently.”

PI3K is an essential protein, and cells (and whole organisms) die if they do not have any functional PI3K because the protein is involved in multiple signalling pathways. However, it is specifically this pathway, mediated through IQGAP1, that is required for the growth and survival of cancer cells but not normal cells. In fact, mice lacking IQGAP1 develop normally but are resistant to developing solid tumours.

“Pharmaceutical companies have developed PI3K inhibitors, but many of these have failed, likely because they’re hitting all PI3Ks and the different pathways,” Anderson said. “If you can specifically disrupt this agonist-activated PI3K pathway, the one that has a specific role in cancer, then you can effectively treat

University of Wisconsin School of Medicine and Public Health www.med.wisc.edu/news-events/cancer-signaling-pathway-could-lead-to-new-cancer-therapies/49720

A person carrying variants of two particular genes could be almost three times more likely to develop multiple sclerosis, according to the latest findings from scientists at The University of Texas Medical Branch at Galveston and Duke University Medical Center.
One of these variants is in IL7R, a gene previously associated with MS, and the other in DDX39B, a gene not previously connected to the disease.
The discovery could open the way to the development of more accurate tests to identify those at greatest risk of MS, and possibly other autoimmune disorders, the researchers said.
A disease in which the body’s own immune system attacks nerve cells in the spinal cord and brain, MS is a major cause of neurological disease in younger adults, from 20 to 50 years of age, and disproportionally affects women. While treatable, there is no cure for MS, which can lead to problems with vision, muscle control, balance, basic body functions, among other symptoms, and could lead to disability.
Available treatments have adverse side effects as they focus on slowing the progression of the disease through suppression of the immune system.
Thanks to the collaboration between scientists at UTMB, Duke, University of California, Berkeley, and Case Western Reserve University, researchers found that when two particular DNA variants in the DDX39B and IL7R genes are present in a person’s genetic code, their interaction can lead to an over production of a protein, sIL7R. That protein’s interactions with the body’s immune system plays an important, but not completely understood, role in MS.
“Our study identifies an interaction with a known MS risk gene to unlock a new MS candidate gene, and in doing so, open up a novel mechanism that is associated with the risk of multiple sclerosis and other autoimmune diseases,” said Simon Gregory, director of Genomics and Epigenetics at the Duke Molecular Physiology Institute at Duke University Medical Center and co-lead author of the paper in Cell.
This new information has potentially important applications.
“We can use this information at hand to craft tests that could allow earlier and more accurate diagnoses of multiple sclerosis, and uncover new avenues to expand the therapeutic toolkit to fight MS, and perhaps other autoimmune disorders,” said Gaddiel Galarza-Muñoz, first author on the study and postdoctoral fellow at UTMB.
It can sometimes take years before an MS patient is properly diagnosed allowing the diseases to progress and resulting in further damage to the nervous system before treatment begins.
With more accurate measures of risk, health care providers would be able to screen individuals with family histories of MS or with other suspicious symptoms. It could lead those with certain genotypes to be more vigilant.

University of Texas Medical Branch
www.utmb.edu/newsroom/article11473.aspx

Scientists at the Francis Crick Institute and UCL have found that unstable chromosomes within lung tumours increase the risk of cancer returning after surgery, and have used this new knowledge to determine the risk of relapse up to a year before the cancer returns. These are the first findings from the Cancer Research UK-funded TRACERx lung cancer study.
TRACERx is the first study to look at the evolution of cancer in real time and immense detail. Researchers followed patients all the way from diagnosis through to either disease relapse or cure after surgery, tracking and analysing how their cancer developed.
Professor Charles Swanton, the study’s lead researcher based at the Crick, said: "The TRACERx study is Cancer Research UK’s single biggest investment in lung cancer, and for the first time we’ve revealed new insights into how tumours evolve and evade treatment, a leading cause of cancer death.
"We believe that this invaluable data generated during TRACERx will be seized upon by research teams across the world, helping us to answer more questions about lung cancer biology. We’ve only scraped the surface in terms of what is possible by looking at tumour evolution in such detail."
In one study scientists analysed tumours from 100 non-small cell lung cancer (NSCLC) patients. They found that unstable chromosomes are the driving force behind genetic diversity within tumours.
They also showed that patients with a high proportion of unstable chromosomes in their tumour were more than four times more likely to have their cancer return, or die from their disease, within two years.
This is because genetically diverse tumours are more likely to evolve, spread and become drug resistant, making a patient’s cancer much harder to treat.
Dr Mariam Jamal-Hanjani, lead author based at the UCL Cancer Institute, said: "Determining the relationship between diversity within tumours and patient survival is one of the primary goals of TRACERx, so to find evidence for this so early on in the study is really encouraging.
"We’ve also identified what causes lung cancer to advance, providing us with insight into the biological processes that shape the evolution of the disease."
Armed with this discovery, researchers conducted a second study, published today in Nature, to investigate whether this genetic diversity could be tracked clinically.
Using blood samples from 96 of the 100 patients, they demonstrated that the patchwork of genetic faults present in non-small cell lung cancer, could be monitored using bits of DNA in the blood that have broken off from a tumour (circulating tumour DNA).
They then analysed blood taken from 24 patients after surgery for NSCLC, and accurately identified more than 90 per cent of those destined to relapse – up to a year before clinical imaging could confirm the disease’s return.
This finding opens up numerous opportunities for new drug trials in lung cancer to try to prevent relapse.
Monitoring benefit from chemotherapy after surgery is not currently possible as there are often no clinical signs of disease.
With this in mind, the team also compared circulating tumour DNA levels immediately before and after chemotherapy was given to patients following surgery. When levels of tumour DNA in the blood were not reduced following chemotherapy, the disease returned, suggesting that at least part of the tumour had become resistant to treatment.
The results provide a new means to monitor treatment after surgery, and point to an avenue for new treatments to target parts of the tumour that are resistant to existing approaches.

Francis Crick Institute
www.crick.ac.uk/news/science-news/2017/04/26/tracking-unstable-chromosomes-helps-predict-lung-cancers-return/