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Cancer, Genetics, Research, Science, Stanford News

Using CRISPR to investigate pancreatic cancer

Using CRISPR to investigate pancreatic cancer

dna-154743_1280Writing about pancreatic cancer always gives me a pang. My grandmother died from the disease over 30 years ago, but I still remember the anguish of her diagnosis and the years of chemotherapy and surgery she endured before her death. This disease is much more personal to me than many I cover.

Unfortunately, survival rates haven’t really budged since I was in high school, in part because the disease is often not diagnosed until it’s well established. As geneticist  Monte Winslow, PhD, described to me in an email:

Pancreatic cancer is very common and almost uniformly fatal. Human pancreatic cancers usually have many mutations in many different genes but we know very little about how most of them drive pancreatic cancer initiation, development, and progression. Recreating these cancer-causing mutations in cells of the mouse pancreas can generate tumors that look and behave very similarly to human pancreas cancer.

Unfortunately, traditional methods used to generate mouse models of human cancer are very time-consuming and costly.

Winslow, along with postdoctoral scholar Shin-Heng Chiou, PhD, and graduate student Ian Winters, turned to the latest darling of the biochemistry world — the gene-editing system known as CRISPR — to devise a way to quickly and efficiently turn off genes implicated in the development of pancreatic cancer in laboratory mice. Their work will be featured on the cover of Genes and Development on Monday. As Winslow described:

Our goal was use CRISPR/Cas9 genome editing to make altering a gene of interest in pancreas cancer simple and fast. Shin-Heng and Ian worked together to develop novel tools and bring them together to generate this new system that we hope will dramatically accelerate our understanding of pancreas cancer. The increased basic understanding of how this cancer works may ultimately lead to better therapies for patients.

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Health Policy, In the News, Medicine and Society, Pediatrics, Stanford News

Stanford researchers analyze California’s new vaccine law

Stanford researchers analyze California's new vaccine law

CA vaccine photoWhat do California, West Virginia and Mississippi have in common? Stumped?

Thanks to a recent law signed by California Gov. Jerry Brown, these three states now have strict vaccine policies that require children to be vaccinated before entering school, unless they have a medical exemption. The new requirements eliminate religious and philosophical exemptions.

Stanford’s Michelle Mello, JD, PhD, and David Studdert, LLB, ScD, (along with co-author Wendy Parmet, JD) heralded the change in a New England Journal of Medicine commentary published this week. From a Stanford News release:

“The move represents a stunning victory for public health that affects not only California schoolchildren, but the prospects for strengthening vaccination requirements nationwide,” they wrote.

The new laws come in the wake of a measles outbreak that started at Disneyland last year. It fueled a nationwide debate about the merits of vaccines, and of the large number of children unvaccinated due to parental objections.

The new California law requires all children enrolled in private and public schools and day-care facilities to be vaccinated against measles, whooping cough and several other diseases.

Yet the law is sure to face challenges, particularly from opponents who say it violates their religious rights. In addition, a lack of enforcement may weaken the law’s ability to ensure widespread protection.

Nonetheless, California’s new law is worth celebrating, they say:

“Although California politics may be distinctive, its experience with SB277 teaches us that even strong opposition can be overcome with the right combination of astute public education, political strategy and legislative fortitude,” they wrote. “Fewer vaccination exemptions and vaccine-preventable illnesses would be accomplishments that other states would find difficult to ignore.”

Previously: A discussion of vaccines, “the single most life-saving innovation ever in the history of medicine”, Science Friday-style podcast explains work toward a universal flu vaccine and Side effects of childhood vaccines are extremely rare, new study finds
Image by Niyazz

Cardiovascular Medicine, Chronic Disease, In the News, Research, Stanford News, Transplants

Are donor hearts getting wasted?

Are donor hearts getting wasted?

heart choiceI wrote a press release recently on a study that showed a high percentage of donated hearts were not being used, raising concerns that some were getting wasted when they could be used to save lives. This made me curious about the process of just how a donor heart, which ideally has about a two-hour window before it gets transplanted to a patient with heart failure, gets matched.

The result is a Stanford Medicine magazine story titled “Heart Choices” that describes this process, the tough decisions that family members make when a loved one donates a heart, and the excruciating waiting that patients in need of a new heart go through.

Most importantly the article asks the question: Should more “high-risk” donor hearts be used? An estimated 20,000 people across the country are waiting for new hearts, and only a few thousand transplants happen on average per year. My story explains the dilemma:

The general assumption is that there simply are not enough donor hearts available to meet a growing demand. But new research is questioning that assumption. Some researchers and surgeons claim that thousands of donor hearts that could be used are turned away each year. The hearts are considered marginal because they come from older, sicker or riskier donors, but many argue they are safe for transplant, and could be saving lives.

“As patients wait longer, they often get sicker, and we often lose patients,” says Stanford cardiologist Kiran Khush, MD, whose research reports that 65 percent of available heart donations are discarded because of stringent acceptance criteria. Yet the criteria have not been critically evaluated, she says. “Increasing the supply of donor hearts is, of course, a great concern of mine.”

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Global Health, HIV/AIDS, Immunology, Research, Stanford News, Women's Health

HIV study in Kenyan women: Diversity in a single immune-cell type flags likelihood of getting infected

HIV study in Kenyan women: Diversity in a single immune-cell type flags likelihood of getting infected

virally infected cellsWhen it comes to immune cells, “it takes all kinds” isn’t too bad a description of what makes for the best composition of our fighting force for warding off viruses, bacteria and incipient tumors. But in a study just published in Science Translational Medicine, Stanford infectious-disease immunologist Catherine Blish, MD, PhD, and her colleagues have found, unexpectedly, that high diversity in the overall population of one particular type of immune cells strongly correlates with an increased likelihood of subsequent infection by HIV.

The investigators had figured that diversity in so-called natural killer cells, or NK cells, would be a strength, not a detriment. “Our hypothesis was wrong,” Blish (much of whose research focuses on NK cells) told me. In this study,  it was higher, rather than lower, diversity in this immune-cell population that turned out to be associated with increased HIV susceptibility.

NK cells, fierce white blood cells that help fight viruses and tumors, harbor various combinations of receptors on their surface. Some receptors recognize signs of our other cells’ normalcy, while others recognize signs that a cell is stressed — due, say, to viral infection or cancerous mutation. On recognizing their targeted features on other cells’ surfaces, an NK cell’s “normalcy” receptors tend to inhibit it, while its stress-recognizing receptors activate it.

All told, NK cells can have many thousands of different combinations of these receptors on their surfaces, with each combination yielding a slightly different overall activation threshold. At birth, our NK cells are pretty similar to one another. But as they acquire life experience – largely from viral exposure, Blish thinks – they increasingly diverge in the specific combinations of receptors they carry on their surfaces.

From my news release on the study:

In order to assess the impact of NK-cell diversity on adult humans’ viral susceptibility, Blish and her associates turned to blood samples that had been drawn during the Mama Salama Study, a longitudinal study of just over 1,300 healthy … Kenyan women. [T]he researchers carried out a precise analysis of NK cells in the women’s blood and observed a strong positive correlation between the diversity of a woman’s NK cell population and her likelihood of becoming infected with HIV.

This correlation held up despite the women’s being statistically indistinguishable with respect to age, marital status, knowledge of sexual partners’ HIV status, history of trading sex for money or goods, sexually transmitted disease status or reported frequency of recent unprotected sex.

And the NK-diversity-dependent difference in these women’s likelihood of HIV infection was huge. From my release:

Those with the most NK-cell diversity were 10 times as likely as those with the least diversity to become infected. A 10-fold risk increase based solely on NK-cell diversity is far from negligible, said Blish. “By way of comparison, having syphilis increases the risk of contracting HIV two- to four-fold, while circumcised men’s HIV risk is reduced by a factor of 2.5 or 3,” she said.

These surprising findings  could spur the development of blood tests capable of predicting individuals’ susceptibility to viral infection.

Previously: Study: Pregnancy causes surprising changes in how the immune system responds to the flu, Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease and Our aging immune systems are still in business, but increasingly thrown out of balance
Photo by NIAID

Cardiovascular Medicine, Chronic Disease, Imaging, Research, Stanford News, Technology

DNA damage seen after CT scanning, study shows

DNA damage seen after CT scanning, study shows

16288548276_e155ec8843_zUsing new laboratory techniques, Stanford scientists have been able to get a closer look at what happens inside the cells of patients undergoing medical imaging techniques. In a study published today, their research clearly shows that there is cellular damage in heart patients after CT scanning.

The researchers explained to me in interviews for a press release on the study that this doesn’t link CT scans to cancer. But as Patricia Nguyen, MD, lead author said in the release, it is further indication for caution:

“Whether or not this (cellular damage) causes cancer or any negative effect to the patient is still not clear, but these results should encourage physicians toward adhering to dose reduction strategies.”

Due to an explosion in the use CT scans for heart patients over the past decade, public health concerns have been raised over whether there might be a causal link with cancer. But until now, little has been known about exactly what happens at a cellular level when patients undergo CT scanning, a type of medical imaging which exposes them to low-dose radiation. This study took advantage of new laboratory techniques that made it possible to look inside cells of patients after they underwent CT scanning. As Nguyen explained in my release:

“Because we don’t know much about the effects of low-dose radiation — all we know is about high doses from atomic bomb blast survivors — we just assume it’s directly proportional to the dose. We wanted to see what really happens at the cellular level.”

Researchers examined the blood of 67 patients undergoing cardiac CT angiography using such techniques as whole-genome sequencing and flow cytometery to measure biomarkers of DNA damage. The results:

… showed an increase in DNA damage and cell death, as well as increased expression of genes involved in cell repair and death, the study said. Although most cells damaged by the scan were repaired, a small percentage of the cells died, the study said.

“These findings raise the possibility that radiation exposure from cardiac CT angiography may cause DNA damage that can lead to mutations if damaged cells are not repaired or eliminated properly,” the study said.

Photo by frankieleon

Autism, Behavioral Science, Neuroscience, Pediatrics, Research, Stanford News

A new insight into the brain chemistry of autism

A new insight into the brain chemistry of autism

TrueHugFor several years now, scientists have been testing the hypothesis that one particular hormone, oxytocin, plays a role in autism. It seems logical: After all, this molecule nicknamed the “love hormone” promotes bonding between romantic partners and is one of the main signals involved in childbirth, breastfeeding and helping new mothers form strong bonds with their babies. And social-interaction difficulties are a known characteristic of autism, a developmental disorder that affects one in every 68 kids.

But in the flurry of interest around oxytocin, a related signaling molecule has been largely overlooked. Called vasopressin, it’s structurally very similar to oxytocin. Both are small proteins made of nine amino acids each, and the amino-acid sequence is identical at seven of the nine spots in the two hormones. Vasopressin is best known for its role in regulating blood pressure, but it also has social roles, which have mostly been studied in rodents.

Noting the dearth of autism-vasopressin research, a Stanford team decided to study vasopressin levels and social behavior in children diagnosed with autism and controls who had not been diagnosed with autism. Our press release about their study, which was published today in PLOS ONE, explains:

The research team found a correlation between low levels of vasopressin, a hormone involved in social behavior, and the inability of autistic children to understand that other people’s thoughts and motivations can differ from their own. …

“Autistic children who had the lowest vasopressin levels in their blood also had the greatest social impairment,” said the study’s senior author, Karen Parker, PhD, associate professor of psychiatry and behavioral sciences.

Parker and her colleagues examined “theory of mind,” the ability to deduce that others have a mind of their own – and that they may perceive the world differently than you do. It’s an important underpinning to forming empathetic relationships with other people. In kids with autism, the lower their vasopressin levels, the worse their scores on a test of theory of mind, the study found. Children without autism did not show this link; they all had pretty good theory of mind scores, whether their vasopressin levels were low or high.

It’s worth adding that low vasopressin level did not diagnose whether a child had autism; the hormone’s levels ranged from low to high in both groups of children. So autism is not simply a state of vasopressin deficiency. However, the researchers are interested in whether giving vasopressin might help relieve autism symptoms and are now carrying out a clinical trial to test its effects.

The work also provides an interesting complement to oxytocin findings published by the same team last year. In the oxytocin study, the scientists found that children with autism could have low, medium or high oxytocin levels, just like other children. However, oxytocin levels were linked to social ability in all children, not just those with autism.

Based on the new findings, it’s possible, Parker told me, that vasopressin is uniquely important for children with autism. She’s eager to expand her work in this overlooked corner of brain-chemistry research.

Previously: Stanford research clarifies biology of oxytocin in autism, “Love hormone” may mediate wider range of relationships than previously thought and Volunteers sought for autism drug study
Artwork by Dimka

Genetics, Research, Stanford News

Genetic study supports single migratory origin for aboriginal Americans

Genetic study supports single migratory origin for aboriginal Americans

In a long list of hypotheses going back decades, researchers have tried to explain the peopling of North and South America as a series of separate waves of immigration by ancient people from Siberia. For decades, in fact, researchers have been arguing about how many distinct peoples walked over the massive, 600,000-square-mile land bridge that once connected Siberia and Alaska and, also, how many thousands of years ago each of those migrations occurred.

In the last few years, some researchers have begun to suspect that a single group of Siberians may have walked onto that land bridge and became marooned there for several thousand years before traveling the rest of the way into the Americas. But others have been holding out for a two-wave hypothesis, with a first wave of Asians from as far away as India and a later wave of people from farther north.

Today, in Science, an international team of geneticists, evolutionary biologists, and statisticians concluded that all Native Americans descended from a single immigration event out of Siberia. The team looked at the DNA from 110 modern Native Americans and 23 who died 200 to 6,000 years ago and compared their genomes to those of more than 3,000 individuals from around the world.

One of the lead authors is María Ávila-Arcos, PhD, a postdoctoral researcher in the lab of Stanford professor of genetics Carlos Bustamante, PhD. Ávila-Arcos led many of the statistical analyses for the paper, including comparison of whole human genomes from diverse Native American populations—both modern and ancient. Bustamante is also a co-author, along with Stanford professor of structural biology and of microbiology and immunology, Peter Parham, PhD, five other Stanford researchers, and dozens of researchers from around the world.

“For a long time,” Bustamante told me, “we’ve sought to understand the genetic history of the first people to populate the Americas and how they relate to modern day populations. This project brought together a large interdisciplinary team and amassed the largest data set to date on this problem. We found strong evidence for a single major wave and subsequent divergence of the founding population.”

The new genetic analysis suggests that the first immigrants to America left Siberia no more than 23,000 years ago, and then lived in isolation on the grassy plains of the Beringia land bridge for no more than 8,000 years. Those plains disappeared beneath rising seas 10,000 years ago.

Once in the Americas, ancient Native Americans split into two major lineages about 13,000 years ago. One lineage populated both North and South America and one stayed in North America.

Previously: Kennewick Man’s origins revealed by genetic studyUsing genetics to answer fundamental questions in biology, medicine and anthropology and Melting pot or mosaic? International collaboration studies genomic diversity in Mexico
Video by National Climatic Data Center/NOAA via DarthMaximolonus

Imaging, Immunology, Mental Health, Neuroscience, Research, Stanford News

Are iron, and the scavenger cells that eat it, critical links to Alzheimer’s?

Are iron, and the scavenger cells that eat it, critical links to Alzheimer's?

iron linkIf you’ve been riding the Alzheimer’s-research roller-coaster, brace yourself for a new twist on that wrenching disease of old age.

In a study published in Neurobiology of Aging, Stanford radiologists Mike Zeineh, MD, PhD,  and Brian Rutt, PhD, and their colleagues used a ultra-powerful magnetic-resonance-imaging (MRI) system to closely scrutinize postmortem tissue from the brains of people with and without Alzheimer’s disease. In four out of five of the Alzheimer’s brains they looked at, but in none of the five non-Alzheimer’s brains, they found what appear to be iron-containing microglia – specialized scavenger cells in the brain that can sometimes become inflammatory – in a particular part of the hippocampus, a key brain structure that’s absolutely crucial to memory formation as well as spatial orientation and navigation.

Zeineh and Rutt told me they don’t know how the iron gets into brain tissue, or why it accumulates where it does. But iron, which in certain chemical forms can be highly reactive and inflammation-inducing, is ubiquitous throughout the body. Every red blood cell that courses through our microvasculature is filled with it. So one possibility – not yet demonstrated – is that iron deposits in the hippocampus could result from micro-injury to small cerebral blood vessels there.

As surprising as the iron-laden, inflamed microglia Zeineh, Rutt and their associates saw in Alzheimer’s but not normal brains was what they didn’t see. Surprisingly, in the brain region of interest there was no consistent overlap of either iron or microglia with the notorious amyloid plaques that have been long held by many neuroscientists and pharmaceutical companies to be the main cause of the disorder. These plaques are extracellular aggregations of a small protein called beta-amyloid that are prominent in Alheimer’s patients’ brains, as well as in mouse models of the disease.

Because they weren’t able to visualize small, soluble beta-amyloid clusters (now believed to to be the truly toxic form of the protein), Rutt and Zeineh don’t rule out a major role for beta-amyloid in the early developmental stages of pathology in Alzheimer’s.

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Big data, Cancer, Genetics, Immunology, Research, Science, Stanford News

Linking cancer gene expression with survival rates, Stanford researchers bring “big data” into the clinic

Linking cancer gene expression with survival rates, Stanford researchers bring "big data" into the clinic

Magic 8 ball“What’s my prognosis?” is a question that’s likely on the mind, and lips, of nearly every person newly diagnosed with any form of cancer. But, with a few exceptions, there’s still not a good way for clinicians to answer. Every tumor is highly individual, and it’s difficult to identify anything more than general trends with regard to the type and stage of the tumor.

Now, hematologist and oncologist Ash Alizadeh, MD, PhD; radiologist Sylvia Plevritis, PhD; postdoctoral scholar Aaron Newman, PhD; and senior research scientist Andrew Gentles, PhD, have created a database that links the gene-expression patterns of individual cancers of 39 types with the survival data of the more than 18,000 patients from whom they were isolated. The researchers hope that the resource, which they’ve termed PRECOG, for “prediction of cancer outcomes from genomic profiles” will provide a better understanding of why some cancer patients do well, and some do poorly. Their research was published today in Nature Medicine.

As I describe in our release:

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. By doing so, it may be possible to learn what has gone wrong in the cancer cells, and give ideas as to how best to block the cells’ destructive growth. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

Instead, the researchers pulled back and sought patterns that might become clear only when many types of cancers, and thousands of patients were lumped together for study:

Gentles and Alizadeh first collected publicly available data on gene expression patterns of many types of cancers. They then painstakingly matched the gene expression profiles with clinical information about the patients, including their age, disease status and how long they survived after diagnosis. Together with Newman, they combined the studies into a final database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” said Alizadeh. “Then we could ask what we could learn more broadly.”

The researchers found that they were able to identify key molecular pathways that could stratify survival across many cancer types:

In particular, [they] found that high expression of a gene called FOXM1, which is involved in cell growth, was associated with a poor prognosis across multiple cancers, while the expression of the KLRB1 gene, which modulates the body’s immune response to cancer, seemed to confer a protective effect.

Alizadeh and Plevritis are both members of the Stanford Cancer Institute.

Previously: What is big data?Identifying relapse in lymphoma patients with circulating tumor DNA,  Smoking gun or hit-and-run? How oncogenes make good cells go bad and Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study
Photo by CRASH:candy

Global Health, Health Policy, Stanford News

Stanford India Health Policy Initiative fellows are in Mumbai – come follow along

Stanford India Health Policy Initiative fellows are in Mumbai - come follow along

India Health Policy students

Today, I’m on my way to India to join the 2015 Stanford India Health Policy Initiative fellows. These fellows are part of a program that designs and conducts collaborative student projects focused on generating new, on-the-ground insight into the factors that distinguish health-delivery success and failure. This summer, the four fellows are Mark Walsh, a rising senior who is majoring in economics; Pooja Makhijani, a second-year medical student; and Lina Vadlamani and Hadley Reid, both rising seniors who are majoring in human biology.

The students are spending seven weeks investigating the pharmaceutical networks in urban Mumbai in an effort to understand how informal providers interface with these networks and whether it impacts how providers practice, prescribe and dispense medication. The fellows are traveling house to house to investigate community preferences for medications.

We’ll be updating this Storify page with stories on their time there, and we’ll be tweeting from @StanfordHP (and using the hashtag#StanfordHealthIndia) over the next few weeks. I hope you’ll follow along.

Beth Duff-Brown is communications manager for the Center for Health Policy and Center for Primary and Outcomes Research (CHP/PCOR).

Photo, of Walsh, Makhijani and Vadlamani, courtesy of CHP/PCOR

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