Posted tagged ‘genetics’

The skinny on how chickens grow feathers and, perhaps, on how humans grow hair

July 24, 2017

How do skin cells make regularly spaced hairs in mammals and feathers in birds? Scientists had two opposing theories, but new research at the University of California, Berkeley surprisingly links them.

The first theory contends that the timing of specific gene activation dictates a cell’s destiny and predetermines tissue structure — for example, in the skin, gene activation determines whether a skin cell becomes a sweat gland cell or hair cell, or remains a skin cell. The second theory asserts that a cell’s fate is determined instead by interacting with other cells and the material that it grows on.

Now, Berkeley researchers have found that the creation of feather follicles (like hair follicles) is initiated by cells exerting mechanical tension on each other, which then triggers the necessary changes in gene expression to create the follicles. Their results were recently reported in Science.  

“The cells of the skin in the embryo are pulling on each other and eventually pull one another into little piles that each go on to become a follicle,” said first author Amy Shyer, PhD, a post-doctoral fellow in molecular and cell biology at the University of California, Berkeley, in a recent news release. “What is really key is that there isn’t a particular genetic program that sets up this pattern. All of these cells are initially the same and they have the same genetic program, but their mechanical behavior produces a difference in the piled-up cells that flips a switch, forming a pattern of follicles in the skin.”

The research team grew skin taken from week-old chicken eggs on different materials with varying stiffness. They found that the stiffness of the substrate material was critical to forming feather follicles — material that was too stiff or too soft yielded only one follicle, whereas material with intermediate stiffness resulted in an orderly array of follicles.

“The fundamental tension between cells wanting to cluster together and their boundary resisting them is what allows you to create a spaced array of patterns,” said co-author Alan Rodgues, PhD, a biology consultant and former visiting scholar at Berkeley.

The researchers also showed that when the cells cluster together, this activated genes in those cells to generate a follicle and eventually a feather.

Although the study used chicken skin, the researchers suggest that they have discovered a basic mechanism, which may be used in the future to help grow artificial skin grafts that look like normal human skin with hair follicles and sweat pores.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Clinical guidance on genetic testing: A Q&A

April 18, 2017

 

Earlier this month, an FDA ruling gave 23andMe permission to market its personal genetic tests for 10 diseases, including Parkinson’s and late-onset Alzheimer’s.

But with the increase in genetic testing at home and in clinical settings comes challenges. What do physicians do with all of these data? And how do they evaluate the validity and clinical utility of genetic tests?

To tackle these questions and others, the National Academy of Medicine formed a committee to provide guidance. I recently spoke with one of the committee members, Sean David, MD, DPhil, an associate professor of medicine at Stanford, about the committee’s new recommendations and report.

What inspired you to participate in the NAM Committee on the Evidence for Genetic Testing?

“The National Academy of Medicine consensus reports have high impact on national health policy and practices, so I jumped at the chance. In our work at Stanford, we struggle with advising patients on which genetic tests to recommend, which ones to order when requested by a patient and how to interpret results from the many direct-to-consumer genetic tests. We need guidance and a framework for making these decisions. The NAM committee addressed this challenge.

Years ago, I had a patient bring in a whole stack of direct-consumer whole genome sequencing results that showed her genetic risks for different illnesses. She asked me to interpret it for her, but there was far too much for me to consume during our brief office visit. And it was unclear what criteria to use when evaluating these tests. There’s been a rapid increase in the development of genetic tests with thousands of commercially available tests, but limited evidence regarding their validity for diagnosing disease and improving patient outcomes.”

What was the committee’s mission?

“Our charge was to examine the relevant medical and scientific literature to determine the evidence base for different types of genetic tests, as well as recommend a framework for decision-making regarding the use of genetic tests in clinical care.

This is the first consensus report on this topic. Although it was designed for the Military Health System, it should still be applicable to both military and civilian populations and may set benchmarks for private insurance companies. The report also encourages different agencies to cooperate and create a clinical data repository of evidence-based genetic testing decisions, which will be available to everyone. I think someone needs to do this to set the standard. Once that’s been done, at least we’ll have something we can all use as a benchmark.”

How can this decision-making framework help guide clinical practice?

“The decision framework can be used by physicians to determine which genetic tests are really ready for prime time in the clinic. For example, we know that if people are tested based on their family history and found to be at high risk for hereditary breast or ovarian cancer, they can have interventions that will improve their survival and outcomes. By using the decision framework, a physician can come up with a quick triage decision that it’s a ‘yes’ test for someone with several family members with breast and/or ovarian cancer, and one that really all providers should know about.

Other genetic tests like tests for Alzheimer’s aren’t as clear. For instance, there could be a genetic test for a particular rare form of early onset Alzheimer’s associated with a particular mutation. If someone has that mutation, he may have a very high risk of early onset Alzheimer’s disease. Do we screen people for that? It will depend on the clinical testing scenario. If someone has family members who developed Alzheimer’s in their 40s, then it might be a good diagnostic test. Whereas, there might be another genetic test for associated risk of dementia where the causal relationship with Alzheimer’s may not be established. That’s an issue of clinical validity. So we might not offer that test routinely — to avoid giving patients information that might be misleading and might even cause some harm.

In addition, ethical, legal and social implications of genetic testing are important. For many patients — including parents of children with undiagnosed rare diseases — genetic testing may help end a diagnostic odyssey. Oftentimes geneticists will order whole genome testing without testing for something specific. There may be thousands or even millions of different genetic markers that are tested with the hope that they’ll find something that leads to a diagnosis. Evidence of clinical utility may be lacking in scenarios like these, but taking into account the value of tests to patients and their families is important — the context matters. There needs to be a certain amount of clinical judgment, and the committee isn’t saying anything against this.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Genomic screening may help predict breast cancer survival

March 21, 2017

Photo by 3dman_eu

Breast cancer patients are often faced with a difficult decision at the end of their primary treatment: Should they get systemic adjuvant therapy, such as the anti-estrogen drug tamoxifen? Such therapies lower the risk that the cancer will come back, but they also carry the risk of potentially serious side effects.

What would be helpful is for physicians to have a way to predict which patients have the best prognosis and might not need adjuvant therapy. Now, researchers from the Lawrence Berkeley National Laboratory may have a solution, according to a study recently published in Oncotarget.

The research team analyzed clinical patient data and large genomic datasets of normal and tumor breast tissues — identifying 381 genes associated with the relapse-free survival of breast cancer patients. With further analysis, they were able to develop a scoring system based on a 12-gene signature that predicts breast cancer survival. Patients with a low score were more likely to live longer.

Senior author Antoine Snijders, PhD, a research scientist at Berkeley Lab, explained in a recent news release:

“Distinguishing patients with good prognosis could potentially spare them the toxic side effects associated with adjuvant therapy. Determining prognosis involves a range of other clinical factors, including tumor size and grade, the degree to which the cancer has spread, and the age and race of the patient. Our scoring system was predictive of survival independent of these other variables.”

The study showed that their 12-gene signature was effective at predicting patient survival for two specific subtypes of breast cancer — luminal-A and HER2 — but it wasn’t effective for other subtypes.

In addition, the researchers identified seven genes as potential tumor suppressors that could be targeted when developing new breast cancer therapies. They hope that their work will help doctors and patients make more informed treatment decisions, as well as help others develop better breast cancer drugs.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Head injuries alter genes linked to serious brain disorders, new study shows

March 13, 2017

Photo by geralt

Traumatic brain injuries, like those caused by concussions, are common. But suffering even a mild brain injury boosts the likelihood of developing neurological and psychiatric disorders, such as Alzheimer’s disease and posttraumatic stress disorder, years later. Exactly how and why that happens remains a mystery.

“Very little is known about how people with brain trauma — like football players and soldiers — develop neurological disorders later in life,” said Fernando Gomez-Pinilla, PhD, a University of California, Los Angeles professor of neurosurgery and of integrative biology and physiology, in a recent news release.

Now, Gomez-Pinilla and his colleagues have discovered that a brain injury harms “master” genes that control other genes throughout the body. This triggers the alteration of hundreds of genes, which are linked to disorders like Alzheimer’s disease, Parkinson’s disease, PTSD, attention deficit hyperactivity disorder and depression. Their study was recently published in EBioMedicine.

In the study, the researchers trained 20 rats to navigate through a maze. They then injected a fluid into the brain of half the rats to simulate a concussion-like brain injury. When all the rats were retested in the maze, the rats with a brain injury took about 25 percent longer than the controls to solve the maze — indicating a change in basic cognitive function.

Next, the team investigated how the brain injuries altered the rats’ genes. They analyzed RNA samples from the rats’ white blood cells and hippocampi, the part of the brain that plays a central role in memory processes. In the injured rats, they found almost 300 genes had been altered in the hippocampus and over 1200 genes in the white blood cells.

More than 100 of these altered genes have counterparts in humans that are linked to neurological and psychiatric disorders. The researchers concluded that concussive brain injury reprograms key genes and this reprogramming could make neurological and psychiatric disorders more likely.

In addition, almost two dozen of the altered genes occurred in both the hippocampus and white blood cells. The researchers hope this genetic signature can be used to develop a gene-based blood test that determines whether a brain injury has occurred and whether future neurological disorders are likely.

They also hope their identification of master genes can give scientists new targets to develop better pharmaceuticals for brain disorders. However, more research is needed to fully understand the role of these master genes. Gomez-Pinilla said he now plans to study the phenomenon in people who have suffered a traumatic brain injury.

This is a reposing of my Scope blog story, courtesy of Stanford School of Medicine.

Feeling fatigued? Your genes may be partially responsible, a new study says

March 7, 2017

Photo by geralt

How often, in the last two weeks, have you felt tired or lacked energy?

Daily? Never? For me, and I’m guessing for many of you, the answer is somewhere in between.

Researchers posed that question to tens of thousands of study participants to investigate whether tiredness has a genetic basis. They found that genes play a small but significant role in overall fatigue.

The multi-institutional team of researchers analyzed genetic data from the UK Biobank for 108,976 individuals who reported whether they had felt tired in the last two weeks. The participants selected four possible answers, ranging from “not at all” to “nearly every day”; most answered either “not at all” or “several days.”

The researchers found that genetic factors account for about 8 percent of the participants’ differences in self-reported tiredness, according to a paper recently published in Molecular Psychiatry. This implies that tiredness is largely due to other factors, such as not getting enough sleep.

Some inherent factors such as personality traits or poor health can contribute, however. By averaging tiredness across a large sample and performing a genomic-wide association study, the researchers identified genetic links between tiredness and inherent factors — using the UK Biobank’s data on the participants’ physical health, mental health, personality and cognitive functioning.

They found that an individual’s genetic predisposition to some physical and mental illnesses — not just the presence of these illnesses — was associated with feeling tired. For instance, people who were genetically prone to Type 2 diabetes were also prone to tiredness, even if they did not have diabetes.

The authors summarized that tiredness is a “partly heritable, heterogeneous and complex phenomenon,” which requires further research to fully understand. However, they indicate that most people’s differences in tiredness can be attributed to external factors such as the lack of sleep.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Genetic counselor offers insights on testing for inherited heart conditions

December 27, 2016
Illustration by waldryano

Illustration by waldryano

Genetic tests are now available for many conditions — everything from Alzheimer’s to familial hypercholesterolemia. But genetic testing isn’t necessarily the best option for everyone, and some of the tests aren’t highly accurate yet.

However, clinicians agree that genetic testing is important for people with hereditary heart conditions in their families. That’s why Stanford created the Stanford Center for Inherited Cardiovascular Disease, which specializes in caring for patients and their families with genetic disorders of the heart and blood vessels. Genetic counseling is a key part of the center, so I spoke with Colleen Caleshu, MSc, their lead genetic counselor to learn more.

What inspired you to become a genetic counselor?

“When I was in college, I was very interested in the science and molecular basis of disease. I was considering a PhD in genetics, but I was also drawn to peer counseling and psychology courses. When I looked at genetic counseling programs, they required an unusual combination of science and humanities such as psychology, ethics, genetics and biochemistry. Before going to graduate school, I spent a year with a research team that focuses on the psychological impact of familial breast cancer risk — that experience solidified that genetic counseling was what I wanted to do. For me, it comes down to a combination of loving the science and being intellectually challenged by a field that is moving really quickly, while also really being able to help people.”

What cardiovascular diseases does genetic testing identify?

“Genetic testing isn’t yet useful for all diseases or for all people. For cardiology, we recommend genetic testing when a patient is diagnosed with an inherited disease. The two most common inherited cardiac diseases are familial hypercholesterolemia and hypertrophic cardiomyopathy. We also care for patients with several other inherited heart muscle, arrhythmia and aorta diseases. If you put all of these genetic cardiac diseases together, greater than one in a 100 people have one in their genes.”

What is a typical genetic counseling appointment like?

“The clinic appointment is about an hour long. It involves establishing a relationship with the patient and their family to understand: Who are they? What are they experiencing? What are their values? What do they most need help with right now? Then we often shift to the medical side of things with a comprehensive four-generation family history. This involves a lot of detective work with the patient and afterwards — calling family members and searching medical records, death certificates and autopsy reports. The rest of the visit is a mixture of medical and genetics education, as well as psychological counseling. All medical conditions can have a psychological impact, but the genetic nature of these diseases mean they can strike healthy people at an unusually early age compared to most heart diseases. And they have reproductive and family planning implications.

Our genetic counselors also function within a broader, multidisciplinary team, including a cardiologist who gives his assessment, diagnosis and management recommendations. And all of this is based on a separate, hour-long intake appointment with a nurse that happens prior to the clinic appointment. “

How can genetic counseling help?

“Genetic counseling definitely benefits both the patient and the patient’s family — by helping them cope better with the familial heart condition and by helping healthy family members get the necessary medical workup and tests.

For example, a patient came to us a few years ago after being diagnosed with hypertrophic cardiomyopathy. Several generations of his family had the disease, and two of his siblings died suddenly from it a few years apart. He was really wrestling with whether or not to get an implanted defibrillator. He came to our center to get everything we offer.

We had several visits with him and his family members. At one point we had more than 10 family members in the room — the patient, siblings, nieces and nephews — grappling with a lot of pain and grief. We provided grief counseling and we addressed what it meant medically and psychologically for each family member. Using genetic testing, we were able to identify a disease-causing genetic variant in the original patient and his family. By proactively checking the heart of other family members, we were also able to diagnose people who didn’t know they had the disease — including members who went on to get implanted defibrillators to protect them from sudden death. Genetic counseling can absolutely save lives.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Genomic analysis allows researchers to identify three subtypes of prostate cancer

October 7, 2016
Photograph by Raul654

Photograph by Raul654

Many men with prostate cancer have slow-growing tumors that don’t require aggressive treatments such as surgery or radiation therapy, whereas others have rapidly-growing prostate tumors that are life threatening. Distinguishing between these patients with indolent versus aggressive disease is a major challenge, but researchers have just made a significant step towards identifying genetic risk factors for prostate cancer prognosis.

A multi-institutional research team has identified three distinct molecular subtypes of prostate cancer, which are correlated with survival rates and may guide future treatment planning. Their study results were presented at the annual meeting of the American Society of Radiation Oncology by Daniel Spratt, MD, an assistant professor in radiation oncology at the University of Michigan Heath System.

Spratt explained in a recent American Society of Radiation Oncology press release:

“Tumors that appear similar under a microscope can behave very differently, from a clinical standpoint. One promise of genomic analyses is to elucidate subtypes of cancer based on the genetics of the tumor rather than merely how they look or what size they are.”

The research team analyzed the RNA expression patterns of 4,236 primary prostate cancer samples taken from nine independent groups of men, who had their prostate surgically removed to treat primary prostate cancer. The investigators’ statistical clustering analysis identified three distinct patient groups based on 100 key genes, which they named the Prostate Cancer 100. These study results were then validated using samples from over 2100 patients.

The subtypes were found to be correlated with androgen receptor activity, ERG oncogene expression and other factors known to promote prostate tumor growth. They were also correlated with how long patients survived without metastasis. The distant metastasis-free survival rates varied among the three subgroups — 73.6 percent for group A, 64.4 percent for group B and 57.1 percent for group C — showing that subtype A patients had the most favorable prognosis.

Furthermore, the study found that subtype B and C patients responded significantly better to postoperative radiation therapy, which was used after the prostate was surgically removed in order to kill any remaining cancer cells. This is important because radiation therapy has many potential side effects, including impotence and incontinence.

Spratt summarized in the press release:

“We believe that these subtypes reflect truly distinctive underlying biology and that this work represents a significant advance in our understanding of prostate cancer biology. Moreover, our findings identify numerous genes and enriched biologically active pathways in prostate cancer that have been underappreciated to date but may be potential targets to improve cure rates in this disease by developing new targeted therapies.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.


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