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Aging, Genetics, Men's Health, Neuroscience, Research, Stanford News, Women's Health

Having a copy of ApoE4 gene variant doubles Alzheimer’s risk for women but not for men

Having a copy of ApoE4 gene variant doubles Alzheimer's risk for women but not for men

brain cactus - smallSince the early 1990s, when Duke University neurologist Allen Roses, MD, first broke the news, it’s been known that a person carrying the gene variant known as ApoE4 is at elevated risk of getting Alzheimer’s disease. To this day ApoE4 is the strongest known single genetic risk factor for Alzheimer’s, a progressive neurological syndrome that robs its victims of their memory and reasoning ability.

But only now is it looking certain that the increased Alzheimer’s risk ApoE4 confers is largely restricted to women. Men’s fates don’t seem to be altered nearly as much by the genetic bad penny that is ApoE4, according to a new Annals of Neurology study led by Mike Greicius, MD, medical director of the Stanford Center for Memory Disorders.

Accessing two huge publicly available national databases, Greicius and his colleagues were able to amass medical records for some 8,000 people and show that initially healthy ApoE4-positive women were twice as likely to contract Alzheimer’s as their ApoE4-negative counterparts, while ApoE4-positive men’s risk for the syndrome was barely higher than that for ApoE-negative men.

What the heck is ApoE4 for, anyway? In my release on the new study, I wrote:

The ApoE gene is a recipe for a protein important for shuttling fatty substances throughout the body. This is particularly important in the central nervous system, as brain function depends on rapid rearrangement of such fatty substances along and among nerve cell membranes. The ApoE gene comes in three varieties — ApoE2, ApoE3 and ApoE4 — depending on inherited variations in the gene’s sequence. As result, the protein that the gene specifies also comes in three versions, whose structures and fatty-substance-shuttling performance differ. Most people carry two copies of the ApoE3 gene variant (one from each parent). But about one in five people carries at least one copy of ApoE4, and a small percentage have two ApoE4 copies. Numerous studies … have confirmed that ApoE4 is a key risk factor for Alzheimer’s disease, with a single copy of ApoE4 increasing that risk twofold or fourfold. Carrying two copies confers 10 times the risk of Alzheimer’s.

Early hints in the medical literature that the ApoE4 variant exerted differential effects on women’s versus men’s brains were largely ignored until now, says Greicius. He says that’s because most of the seminal ApoE4/Alzheimer’s genetics research was conducted as case-control studies: The ApoE4 gene version’s frequency in people with Alzheimer’s was compared to its frequency in people without the disease. (About half of those with Alzheimer’s, but only about 15 percent without it, are positive for ApoE4.)

But that method has limitations, says Greicius: “About 10-15 percent of ‘normal’ 70-year-olds will develop Alzheimer’s if you wait five or ten years.” Their lurking in the “normal” group dilutes the results. Moreover, Greicius says,“these kinds of genetic studies are looking for needles in a haystack, so they require large numbers of subjects – thousands – to achieve statistical significance. If you want to further examine male/female differences, you have to double the sample size.” That’s costly.

And that’s how come the large government- and industry-supported repositories to which Greicius and his team resorted are such a great idea.

Previously: Estradiol – but not Premarin – prevents neurodegeneration in women at heightened dementia risk, Common genetic Alzheimer’s risk factor disrupts healthy older women’s brain function, but not men’s, Hormone therapy halts accelerated biological aging seen in women with Alzheimer’s genetic risk factor and A one-minute mind-reading machine? Brain-scan results distinguish mental states
Photo by Sean Michael Ragan

Cancer, Genetics, Research, Stanford News, Technology

Gene panel screens for dozens of cancer-associated mutations, say Stanford researchers

Gene panel screens for dozens of cancer-associated mutations, say Stanford researchers

Stanford scientists have shown that it’s possible to simultaneously screen for dozens of cancer-associated mutations from a single blood sample using a multiple-gene panel. The research is published today in the Journal of Clinical Oncology (subscription required).

As I describe in my release:

Gene panels allow researchers to learn the sequences of several genes simultaneously from a single blood sample. It stands to reason that screening for mutations in just a few select genes is quicker, easier and cheaper than whole-genome sequencing. The technique usually focuses on fewer than 100 of the approximately 21,000 human genes. But until now, few studies have investigated whether homing in on a pre-determined panel of suspects can actually help people.

The researchers, medical oncologists and geneticists James Ford, MD and Allison Kurian, MD, used a customized 42-gene panel to investigate the presence of cancer-associated mutations in 198 women with a family or personal history of breast or other cancers. The women had been referred to Stanford’s Clinical Cancer Genetics Program between 2002 and 2012 to undergo screening for mutations in their BRCA1 or BRCA2 genes. They found that the panel was  a useful way to quickly screen and identify other cancer-associated mutations in women who did not have a BRCA1/2 mutation. From our release:

Of the 198 women, 57 carried BRCA1/2 mutations. Ford and Kurian found that 14 of the 141 women without a BRCA1/2 mutation had clinically actionable mutations in one of the 42 genes assessed by the panel. (An actionable mutation is a genetic variation correlated strongly enough to an increase in risk that clinicians would recommend a change in routine care — such as increased screening — for carriers.)

Eleven of the 14 women were reachable by telephone, and 10 accepted a follow-up appointment with a genetic counselor and an oncologist to discuss the new findings. The family members of one woman, who had died since giving her blood sample, also accepted counseling. Six participants were advised to schedule annual breast MRIs, and six were advised to have regular screens for gastrointestinal cancers; many patients received more than one new recommendation.

One woman, with a history of both breast and endometrial cancer, learned she had a mutation that causes Lynch syndrome, a condition that increases the risk of many types of cancers. As a result, she had her ovaries removed and underwent a colonoscopy, which identified an early precancerous polyp for removal.

The study shows that gene panels can be a useful tool that can change clinical recommendations for individual patients. It also indicates that patients are willing and eager to receive such information. As Ford explains in the release:

Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information.

Previously: Whole genome sequencing: the known knowns and the unknown unknowns,  Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside and Blood will tell: In Stanford study tiny bits of circulating tumor DNA betray hidden cancers.

Autism, Genetics, Neuroscience, Research, Videos

Building a blueprint of the developing human brain

Building a blueprint of the developing human brain

In an effort to identify and better understand how genes turned on or off before birth influence early brain development, scientists at the Allen Institute for Brain Science have created a comprehensive three-dimensional map that illustrates the activity of some 20,000 genes in 300 brain regions during mid-prenatal development.

A post on the NIH Director’s blog discusses the significance of the project, known as the BrainSpan Atlas of the Developing Human Brain:

While this is just the first installment of what will be an atlas of gene activity covering the entire course of human brain development, this rich trove of data is already transforming the way we think about neurodevelopmental disorders.

To test the powers of the new atlas, researchers decided to use the database to explore the activity of 319 genes, previously linked to autism, during the mid-prenatal period. They discovered that many of these genes were switched on in the developing neocortex—a part of the brain that is responsible for complex behaviors and that is known to be disrupted in children with autism. Specifically, these genes were activated in newly formed excitatory neurons, which are nerve cells that send information from one part of the brain to another. The finding provides more evidence that the first seeds for autism are planted at the time when the cortex is in the midst of forming its six-layered architecture and circuitry.

In the above video, Ed Lein, PhD, an Allen Institute investigator, talks about the atlas and explains how it will allow researchers to examine genes that have been associated with a range of neurodevelopmental disorders and pinpoint when and where that gene is being used.

Previously: NIH announces focus of funding for BRAIN initiative, Brain’s gain: Stanford neuroscientist discusses two major new initiatives and Co-leader of Obama’s BRAIN Initiative to direct Stanford’s interdisciplinary neuroscience institute

Behavioral Science, Genetics, In the News, Research

Can procrastination and impulsivity be inherited?

procrastination_040814Do you always finish items on your to-do list in a timely fashion, or do you wait until the last minute? New research shows that the tendency to defer tasks could be inherited, and that the traits of procrastination and impulsivity could be genetically linked.

In the study (subscription required), researchers at University of Colorado Boulder asked 181 identical-twin pairs and 166 fraternal-twin pairs to complete surveys designed to measure individuals’ propensity to act impulsively or procrastinate, as well as their aptitude to set and maintain goals. Pysch Central reports:

They found that procrastination is indeed heritable, just like impulsivity. Not only that, there seems to be a complete genetic overlap between procrastination and impulsivity — that is, there are no genetic influences that are unique to either trait alone.

That finding suggests that, genetically speaking, procrastination is an evolutionary byproduct of impulsivity — one that likely manifests itself more in the modern world than in the world of our ancestors.

In addition, the link between procrastination and impulsivity also overlapped genetically with the ability to manage goals. This finding supports the idea that delaying, making rash decisions, and failing to achieve goals all stem from a shared genetic foundation.

Researchers hope that better understanding the underpinnings of procrastination will be useful in determining how these two traits relate to higher cognitive abilities.

Previously: Ask Stanford Med: Answers to your questions about willpower and tools to reach our goals, The science of willpower and How your perceptions about willpower can affect behavior, goal achievement
Photo by EvelynGiggles

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

5507073256_36387f3df9_zBlood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there’s another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don’t) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

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Aging, Genetics, Stanford News, Videos

Unlocking the secrets to human longevity

Unlocking the secrets to human longevity

Does the key to extending life lie within our genetic code? In this Stanford+Connects micro lecture, Stuart Kim, PhD, a professor of developmental biology and genetics, explains why he believes the answer is yes.

In his lab at Stanford, Kim and colleagues study functional genomics and aging and the search for genes that can either speed up or slow down aging, in particular with respect to the kidney. During this talk, he shares some of his lab’s advances in developmental biology in doubling the lifespan of a nematode, which is the world’s fastest-aging animal.

Previously: Male roundworms shorten females’ lifespan with soluble compounds, say Stanford researchers, Key to naked mole rat longevity may be related to their body’s ability to make proteins accurately, Longevity gene tied to nerve stem cell regeneration, say Stanford researchers and California’s oldest person helping geneticists uncover key to aging

Genetics, In the News, Research, Science, Stanford News, Technology

Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness

Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness

edited paperAs a writer, I think a lot about editing. Will this sentence work here? Maybe I should change this word. Argh – a typo! But I’m not alone. Biologists also appreciate the power of editing, particularly when it comes to modifying genes in cells or organisms.

Recently a powerful new technology has emerged (called CRISPR) that allows researchers to make small, precise and permanent changes in the DNA of animal and human cells. It builds on the concept of genome editing that is key to generating cells, cell lines or even whole animals such as laboratory mice, containing specific genetic changes for study. With CRISPR, however, researchers can generate in days or weeks experimental models that usually take months or years. As a result, they can quickly assess the effect of a particular gene by deleting it entirely, or experiment with repeated, tiny changes to its DNA sequence.

According to a recent New York Times article, scientists roundly agree that CRISPR is revolutionary. At least three companies have been launched in the mere 18 months since the first results were reported by researchers at the University of California, Berkeley and Umea University in Sweden, and more than 100 research papers based on the technique have been published. But, although it’s highly specific, it’s (sadly) not perfect. According to the New York Times piece:

Quick is not always accurate, however. While Crispr is generally precise, it can have off-target effects, cutting DNA at places where the sequence is similar but not identical to that of the guide RNA.

Obviously it’s important to know when (and how frequently) this happens. Unfortunately, that’s been difficult to assess.

Enter researchers in the laboratory of pediatric cancer biologist Matthew Porteus, MD, PhD. Porteus’s lab is interested in (among other things) learning how to a particular type of genome editing called homologous recombination to treat diseases like sickle cell anemia, thalassemia, hemophilia and HIV. They’ve devised a way to monitor the efficiency of genome editing by CRISPR (as well as other more-traditional genome editing technologies) that could be widely helpful to researchers worldwide. Their technique was published today in Cell Reports. As postdoctoral researcher Ayal Hendel, PhD, told me:

We have developed a novel method for quantifying individual genome editing outcomes at any site of interest using single-molecule real-time (also known as SMRT) DNA sequencing. This approach works regardless of the editing technique used, and in any type of cell from any species.

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Events, Genetics, Stanford News, Technology

Euan Ashley discusses harnessing big data to drive innovation for a healthier world

Euan Ashley discusses harnessing big data to drive innovation for a healthier world

Euan_AshleyElectronic patient records, clinical trials, DNA sequencing, and medical imaging and disease registries are a sampling of the sources contributing to the exponential growth of public databases housing biomedical information. Researchers hope mining this vast reservoir of data will accelerate the process of understanding disease while driving down the costs of developing new therapies.

But the challenge of harnessing big data to transform scientific research and improve human health is one that is so complex that it can’t be solved alone by a single person, institution or company; collaboration among government, academia and industry is imperative. To foster such partnerships, Stanford and Oxford University are sponsoring the Big Data in Biomedicine conference from May 21-23.

The conference is part of a big data initiative launched by Stanford and Oxford to solve large-number problems at a global scale to improve health worldwide. Euan Ashley, MD, who directs the effort at Stanford, has been involved in several major projects over the past few years to link an individual’s genome sequence to possible increases in disease risk. In the following Q&A, he shares insights about the upcoming conference program, provides an update on the initiative, and discusses how big data can drive innovation for a healthier world.

A collaborative effort between Oxford and Stanford aims to accelerate discovery from large-number data sets to provide new insight into disease and to apply targeted therapies on an unprecedented scale. In what ways are the universities currently working together to achieve this goal?

The Global Institute for Human Health Initiative is a very exciting new venture between these two universities. Catalyzed by the Li Ka Shing Foundation, the initiative draws on the complementary strengths of each institution. Stanford excels in innovation, technology and data management and analysis. Oxford has global reach through its School of Public Health. So it makes sense to work together.

One of our primary goals will be to build “bridges” between the largest databanks of health information in the world. These individual large-scale efforts are remarkable in their own way, but each one has by definition to focus primarily on its own data. This means that limited bandwidth is available to develop mechanisms of secure sharing and analysis. That bandwidth and expertise are things we hope to provide through the initiative. The seed grants awarded through our program in Data Science for Human Health are another way we have started to collaborate. Each one has an Oxford-Stanford collaboration at its heart.

Tell us more about those seed grants. How many have you awarded, and for what kinds of projects?

We received 60 applications and were able to award 12 grants totaling $807,171.48. Among the projects receiving funding were new methods for analyzing accelerometer data in smartphones, approaches to imaging data, and ideas for large scale data analysis, point of care testing for infectious disease and mobile application development. It was an amazing group of applications and I wish we could have funded more projects. At the conference, there will be a brief satellite meeting for the recipients to interact.

Let’s talk more about the upcoming conference. What else can attendees expect from it?

We have an exciting program with a number of high-profile speakers. I’m particularly pleased this year with the broad representation of presenters across sectors. There will be speakers across government, industry and academia, including representatives from the National Institutes of Health, Google, Intel, Mount Sinai and Duke.

We’ve also expanded our international reach, and one of the keynote speeches will be delivered by Ewan Birney, director of the European Bioinformatics Institute. Additionally, this year’s program includes two new topic areas: computing and architecture, which will be chaired by Hector Garcia Molina, PhD, and infectious disease genomics, a particular strength at Oxford. Another addition is the Big Data Corporate Showcase, where companies ranging from industry giants to start-ups will share their achievements and innovations related to big data. So, lots to look forward to!

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Genetics, Ophthalmology, Pediatrics, Research, Stanford News

Crying without tears unlocks the mystery of a new genetic disease

Crying without tears unlocks the mystery of a new genetic disease

LittlePackardGirlSometimes one tiny clue holds the key to a baffling medical mystery. That was the case for a San Francisco Bay Area child whose family and doctors struggled for the first three years of her life to pinpoint the cause of her developmental delays and neurologic, muscle, eye and liver problems. The essential clue? Grace Wilsey doesn’t make tears when she cries.

Grace’s combination of symptoms didn’t fit any known condition. Her team of caregivers at Lucile Packard Children’s Hospital Stanford, led by pediatric geneticist Gregory Enns, MB, ChB, strongly suspected that she had an as-yet-undiscovered genetic disease. Several genetics experts at Stanford helped sequence her genome, then came up with a list of eight mutated genes that might be responsible for her symptoms. They ranked the genes in order of likelihood that each was involved and began working down the list to try to pinpoint the culprit.

At the bottom of the list was a gene called NGLY1, which normally codes for N-glycanase 1, a housekeeping enzyme that helps cells break down and recycle mis-folded proteins. Part way through the investigation of the list of eight suspect genes, Grace’s parents, Matt and Kristen Wilsey, contacted a team at Baylor College of Medicine that had also previously performed whole genome sequencing on Grace and consulted on Grace’s case. A postdoctoral associate there, Matthew Bainbridge, PhD, reran Grace’s raw sequence data against the latest algorithms. NGLY1 jumped to the top of the candidate list of what was causing Grace’s underlying condition. As a next step, Dr. Bainbridge searched the scientific literature and found something so new that the Stanford researchers hadn’t yet run across it: a report of one child with suspected NGLY1 deficiency. From our press release about the discovery:

Bainbridge read in the medical literature of another child, studied at Duke University, whose caregivers there suspected his unusual symptoms were tied to an NGLY1 gene defect. But without a second patient for comparison, they weren’t sure.

As part of his detective work, Bainbridge emailed Kristen Wilsey to ask if Grace produced tears when she cried. Wilsey replied that although Grace’s eyes were moist, she never really made tears. Bainbridge wrote back, “I think I have it.”

“My heart jumped out of my chest,” Wilsey said. The first patient identified with NGLY1 deficiency, it turned out, also did not make tears, and the same characteristic has since been observed in seven of the eight children with NGLY1 gene defects whom the researchers have identified.

The scientific implications of the diagnosis are profound: Researchers can start looking for treatments or a cure. So far, the way that malfunctioning N-glycanase 1 causes the children’s symptoms is not understood, so unraveling the connection is a large area of focus for scientists.

They can also look for variants of the disease, Enns told me. “We are likely detecting the most severe form of NGLY1 deficiency – ascertainment bias – and it is quite possible that more mild forms of the disease exist,” he said. The first eight children found with NGLY1 deficiency are described in a new scientific paper publishing today in Genetics in Medicine; Enns and Bainbridge are both primary authors. Of the children, six have the same mutation in their NGLY1 gene and (probably not coincidentally) also share a very severe manifestation of the disease. Two children, including Grace, have different NGLY1 mutations and also have less severe disease, a finding that hints that other children with as-yet-unexplained developmental delays may also have less-severe variants of NGLY1 deficiency.

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Genetics, Podcasts, Stanford News

Whole genome sequencing: The known knowns and the unknown unknowns

Whole genome sequencing: The known knowns and the unknown unknowns

A few years ago, when I spoke with Euan Ashley, MD, associate professor of medicine and of genetics, about the promise of genomics for diagnosing and treating diseases he agreed that the field was in the wild, wild west. Now, in my latest 1:2:1 podcast with him, I asked how would he describe this moment in time, when so much has changed so quickly in whole genome sequencing (WGS). First, he said, the costs of sequencing the genome have plummeted. “At the point we spoke we were just coming off the $20,000 genome,” he told me. “Which seems remarkable, because we’d just been at… $200,000, and before that at the $2 million genome. In looking around in science… in medicine, I have not seen a technology that has changed that much.”

Euan AshleyAshley recently published a paper that my colleague, Krista Conger, has written about; in it, Ashley and his fellow researchers, Michael Snyder, PhD, professor and chair of genetics, and Thomas Quertermous, MD, professor of medicine, analyzed the whole genomes of 12 healthy people and took note of the degree of sequencing accuracy necessary to make clinical decisions in individuals, the time it took to manually analyze each person’s results and the projected costs of recommended follow-up. Quite clearly, Ashley says, the study shows “there are still some challenges, not that these are non-solvable problems.”

Ashley often cites an infamous quote that Donald Rumsfeld, former Secretary of Defense, said when he was asked about the lack of evidence of Iraqi weapons of mass destruction, as he thinks the questions that Rumsfeld raised about WMDs are analogous to the field of genetics today. Ashley told me:

There are really a number of things that we really know that we know, because they’re genetic variants we’ve seen many times. Also, there are a number of known unknowns… which are genes that we know are a problem but maybe variants we haven’t seen before, so they look pretty suspicious… There [are] the complete unknowns, the unknown unknowns… Many genes about which we really do not know very much at this point in time.

Who would have thought Rumsfeld was laying out the future of WGS and not just WMD’s?

Previously: Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside, Coming soon: A genome test that costs less than a new pair of shoes, Stanford researchers work to translate genetic discoveries into widespread personalized medicine, New recommendations for genetic disclosure released, Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine and You say you want a revolution
Photo of Euan Ashley by Mark Tuschman

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