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Autoimmune Disease, Biomed Bites, Immunology, Research, Videos

Calcium channel plays integral role in immune response

Calcium channel plays integral role in immune response

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative biomedical researchers.

The immune system’s main players — the B cells and T cells, as well as others — are credited for helping the body ward off invaders. And rightly so. But to work their magic, they rely on under-recognized calcium channels, gates in the cell surface that, among other actions, switch the immune cells into “action” mode.

Many unknowns remain about how these cells function, but Richard Lewis, PhD, professor of molecular and cellular physiology, is working to close the gaps in knowledge. He explains in the video above:

We’re mostly interested in two things related to these channels: First, we would like to understand how these channels work. How is it that contact with the antigen-presenting cell turns these cells on to admit calcium into the T cell?

A second area of interest is to understand what happens when the calcium comes into the cell.

Malfunctions in these channels can lead to severe immunodeficiencies or other problems, Lewis says:

We may be able to design better drugs in the future that target these channels to either inhibit them, which would be useful therapy for treating autoimmune disorders like arthritis, multiple sclerosis and lupus, or to potentiate the activity of these channels, which would be a useful way of boosting the immune response in patients with immunosuppressed conditions.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: ‘Pacemaker’ channels in hair stem cells offer clues to tissue regeneration, say Stanford experts, Found: A molecule mediating memory meltdown in aging immune systems and Women and men’s immune system genes operate differently, Stanford study shows

Cancer, Immunology, Research, Stem Cells

How cancer stem cells dodge the immune system

How cancer stem cells dodge the immune system

Hidden cat

Cancer stem cells are tricky beasts. They are often resistant to common treatments and can hide out in the body long after the bulk of tumor cells have been eliminated. Over time, they’re thought to contribute to the recurrence of disease in seemingly successfully treated people.

Stanford head and neck surgeon John Sunwoo, MD, and graduate student Yunqin Lee have been investigating how stem cells in head and neck cancers manage to evade the body’s immune system. Although it’s been known that a type of head and neck cancer cells — CD44+ cells — are particularly resilient to treatment, it’s not been known exactly how they accomplish this feat.

Now, Sunwoo and Lee published today in Clinical Cancer Research a study that sheds some light on the issue. They found that a protein called PD-L1 is expressed at higher levels on the surface membrane of CD44+ cells than on other cancer cells. PD-L1  is believed to play a role in suppressing the immune system during pregnancy and in diseases like hepatitis. It does so by binding to a protein called PD-1 on a subset of immune cells (T cells) and dampening their response to signals calling for growth and activation.

As Sunwoo described to me in an email:

We believe that our work provides very important insight into how cancer stem cells, in general, contribute to tumor cell dormancy and minimally residual disease that may recur years later. Our findings also provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of head and neck cancer following surgical resection.

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Aging, Immunology, Infectious Disease

Found: A molecule mediating memory meltdown in aging immune systems

Found: A molecule mediating memory meltdown in aging immune systems

persistence of memoryEven perfectly healthy older people don’t always remember names as quickly as they did when they were younger. So what. They also don’t walk as fast. Big deal.

A bigger deal: Older immune systems don’t respond as quickly or as well to invasions by pathogens. That’s in large part because they fail to remember previous encounters with pathogens (or their defanged doppelgängers, which we call vaccines). Why do they forget? Stanford immunologist Jorg Goronzy, MD, may have a handle on part of the reason.

In a study published in Cell Reports, Goronzy and his colleagues have shown that immune cells of a particular type are more likely to be marked, in older people, by a surface protein that sparks apoptosis, or cellular suicide. As a result, the immune system’s memory of pathogens or vaccinations of yore gets cloudy, leaving the door open to a repeat attack by intruders that a more adept immune system would have summarily squelched.

A healthy immune system bulks up vigorously in response to pathogens or vaccines. Different types of immune cells that are skilled at recognizing and/or warring with the foreign body start to multiply and morph. Many of these cells effectively become front-line warriors, throwing themselves into battle against the invading pathogen (or its harmless vaccine lookalike). Others are more like archers lobbing darts that can knock off the bad guys while sparing innocent bystanders (the body’s own tissues). Still others, known as CD4 cells, coordinate the whole counterattack, sending chemical signals to other cells, or rubbing up against them at close range to whisper secret instructions.

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Genetics, Immunology, Microbiology, Research, Stanford News

Special delivery: Discovery of viral receptor bodes better gene therapy

Special delivery: Discovery of viral receptor bodes better gene therapy

8565673108_28e017bf50_zGene therapy, whereby a patient’s disorder is treated by inserting a new gene, replacing a defective one, or disabling a harmful one, suffered a setback in 1999, when Jesse Gelsinger, an 18-year-old with a genetic liver disease, died from immense inflammatory complications four days after receiving gene therapy for his condition during a clinical trial. It was quite a while before clinical trials in gene therapy resumed.

But what Stanford virologist Jan Carette, PhD, describes as “intense interest” in the field is once again in full bloom. Gene therapies for several inherited genetic disorders have been approved in Europe, and a gene-therapy approach for countering congenital blindness is close to approval in the United States.

That a virologist would be paying such close attention to this topic isn’t odd, as the most well-worked-out method for introducing genetic material to human cells involves the use of a domesticated virus.

If there’s one thing viruses are really good at, it’s infecting cells. Another viral trick is transferring their genes into cellular DNA — it’s part of their modus operandi: hijacking cells’ replicative machinery and diverting it to production of numerous copies of themselves. Scientists have become increasingly adept at taming viruses, tweaking them so they retain their ability to infect cells and insert genes, but no longer contain factors that wreck tissues or taunt the infected victim’s immune system into a rage destructive to virus and victim alike.

Adenovirus-associated virus — ubiquitous in people and not associated with any disease – makes a great workhorse. Properly bioengineered, it can infect all kinds of cells without replicating itself inside of them or triggering much of an immune response, instead obediently depositing medically relevant genes into the infected cells to repair a patient’s defective metabolic, enzymatic, or synthetic pathways.

Figuring out how to tailor this viral servant so it will invade cells more efficiently, or invade some kinds of cells and tissues but not others, would broaden gene therapy’s utility and appeal. In a series of experiments described in a study in Nature, Carette’s group, with collaborators from Oregon Health & Science University and the Netherlands, used a sophisticated method pioneered by Carette to bring that capability a step closer.

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Autoimmune Disease, Immunology, Neuroscience, Research, Stanford News

New perspective: Potential multiple sclerosis drug is actually old (and safe and cheap)

New perspective: Potential multiple sclerosis drug is actually old (and safe and cheap)

new perspectiveAbout 400,000 people in the United States are affected by multiple sclerosis (often referred to by the acronym MS), an autoimmune disorder in which rogue immune cells attack the insulating layer surrounding many nerve cells in the central nervous system.  Some 200 new cases are diagnosed every week in the U.S.

I wrote a while back about a study by Paul Bollyky, MD, PhD, showing that blocking production of a naturally made substance in the body could potentially protect against type 1 diabetes, another autoimmune disorder in which the body’s immune system attacks the pancreas’s insulin-producing cells (the only place where insulin is made). It now appears possible that the same drug Bollyky’s team used to achieve that benefit may also be beneficial in MS.

The substance in question — hyaluronan, a hefty, complex carbohydrate substance — is usually present at trace concentrations in the extracellular matrix that pervades all tissues and, among other things, helps glue those tissues’ constituent cells together. Intriguingly, hyaluronan levels spike markedly at the site of an injury. If you twist your ankle or stub your toe, the swelling you see afterwards is mainly due to hyaluronan, which is prone to soaking up water. That causes fluid buildup, aka swelling,  in the injured region — a cardinal feature of inflammation, along with heat, redness and pain.

In a new study published in Proceedings of the National Academy of Sciences, Bollyky and his colleagues show that hyaluronan also abounds in sites of autoimmune attack in MS patients’ brains after they induced a mousie version of MS in laboratory mice. They confirmed that hyaluronan likewise accumulates near the mice’s MS lesions. And they showed that blocking new hyaluronan synthesis in the mice before symptoms developed prevented many of the mice from succumbing to MS and delayed disease onset and severity in those who did get it, while — importantly — blocking hyaluronan synthesis after symptoms developed alleviated those symptoms.

Perhaps most interesting of all: The drug they used to do that is already on the market for other indications.

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Bioengineering, Immunology, Public Health, Research

Working towards a lifelong, universal flu vaccine

Working towards a lifelong, universal flu vaccine

4919795171_771ae41b50_b_flickr_BlakePatterson_300x247To prepare for holiday socializing, I always roll up my sleeve to get an annual flu shot. I would much rather share food and gifts than a virus with my friends and family. And I don’t want to spend my precious vacation time sick.

However, seasonal flu vaccines are not always effective. There are thousands of strains of influenza virus and each can mutate over the course of the flu season. Seasonal vaccines only protect against a few of the most likely strains. As a result, flu-associated deaths range from 3,000 to 49,000 Americans per flu season, according to the U.S. Centers for Disease Control and Prevention.

Scientists have long sought a lifelong vaccine that would be effective against any variety of influenza, and they are now making significant progress towards this goal.

I recently spoke with Ian Wilson, PhD, a leading structural and computational biologist at the Scripps Research Institute, about his team’s universal flu vaccine research. He told me:

Our research has identified a good target for such a vaccine on a protein called hemagglutinin (HA) that is present on the surface of all influenza viruses. The HA protein has two major components: the head portion, which mutates and varies from strain to strain, and the stem, which is similar across most flu strains. We know that the HA stem is the virus’s most vulnerable spot, and provokes the greatest breadth of immune response. So a synthetic version of the stem was designed, called a mini-HA that mimicked the HA stem.

A key part of Wilson’s flu research took place at the Stanford Synchrotron Radiation Lightsource at SLAC National Accelerator Laboratory, where the scientists used a technique called x-ray crystallography to look at the atomic structure of the mini-HA at each stage of its development. I wrote a recent news article about their efforts.

Though this is important research, more work needs to be done. “We still need to perform human trials and also want to develop a vaccine that protects against all types of influenza that cause human pandemics,” Wilson said.

Jennifer Huber, PhD, is a science writer with extensive technical communications experience as an academic research scientist, freelance science journalist, and writing instructor.

Previously: Working to create a universal flu vaccineScience Friday-style podcast explains work toward a universal flu vaccine and Experts and 8-year-olds agree: It’s worth getting a flu shot
Photo by Blake Patterson

Cancer, Immunology, Research, Science, Stanford News, Stem Cells, Transplants

One (blood stem) cell to rule them all? Perhaps not, say Stanford researchers

One (blood stem) cell to rule them all? Perhaps not, say Stanford researchers

4294019174_3f269b3f38_oThe blood stem cell, or hematopoietic stem cell, is a cell that’s believed to give rise to all the components of the blood and immune system. Nestled in our bone marrow, it springs into action as necessary and is a key component of bone marrow transplantation procedures (more accurately called hematopoietic stem cell transplantation) conducted to save patients with blood diseases or whose immune systems have been wiped out by large doses of chemotherapy or radiation.

But new research published today in Stem Cell Reports by research associate Eliver Ghosn, PhD, and colleagues in the laboratory of geneticist Leonore Herzenberg suggests that, at least in laboratory mice, this stem cell may not be as omnipotent as previously thought. In particular, it seems unable to give rise to an important subpopulation of B cells, a type of immune cell. As Ghosn explained to me in an email:

Briefly, our findings challenge the idea that a single blood, or hematopoietic, stem cell (HSC) can fully regenerate all components of the immune system. We’ve shown that transplantation with highly purified HSCs fails to fully regenerate the B lymphocyte compartment, which is needed to protect against infections such as influenza, pneumonia and other infectious diseases, and also to respond to vaccinations.

Further studies conducted by the researchers suggest that these B cells may arise from an alternative fetal progenitor cell distinct from the HSC — perhaps as an evolutionary effort to separate what’s known as innate immunity from adaptive immunity. They urge further research into the clinical outcomes of the transplantation of purified HSC in humans. As Ghosn said:

From a clinical standpoint, these findings raise the key question of whether human HSC transplantation, widely used in human regenerative therapies to restore immunity in immune-compromised patients, is sufficient to regenerate human tissue B cells that help protect transplanted patients from subsequent infectious diseases. This is specially relevant today considering that the field is moving toward using highly purified human HSCs in clinical settings. 
More research is needed to confirm the findings in humans, however. If you’re interested in learning more about this, Ghosn expanded upon the idea earlier this month with a review in the Annals of the New York Academy of Sciences.

Genetics, Immunology, Microbiology, Research, Science, Stanford News

Stanley Falkow awarded National Medal of Science, White House announces today

Stanley Falkow awarded National Medal of Science, White House announces today

Falkow picExciting news today: Stanley Falkow, PhD, has been awarded the 2015 National Medal of Science. The honor was announced today by the White House. Falkow is being recognized for his pioneering work in studying how bacteria can cause human disease and how antibiotic resistance is transmitted.

Dean Lloyd Minor, MD, commented in our release:

Dr. Falkow is deeply deserving of this award. He has made invaluable contributions to the field of microbiology and the effect of bacteria on human health. We at Stanford Medicine are extremely proud and honored that he has been recognized by his peers in this way.

Falkow, 81, is an emeritus professor of microbiology and immunology and a member of the Stanford Cancer Institute. The award will be presented in a ceremony at the White House in January 2016.

Falkow is well known for his work on extrachromosomal elements called plasmids and their role in antibiotic resistance and pathogenicity in humans and animals. As a graduate student in the 1960s, he discovered that bacteria gained their resistance to antibiotics by sharing their genes much more promiscuously then had been thought possible. When Falkow arrived at Stanford in 1981, he set aside his study of plasmids to concentrate on how organisms as diverse as cholera, plague and whooping cough cause disease in humans. Along the way he’s mentored countless students and spoken out about the growing threat of antibiotic resistance due to the routine use of antibiotic in animal feed.

As Falkow, who learned of the award on Dec. 19 in an email from John Holdren, PhD, the president’s chief science advisor, said in our announcement:

It was a total surprise. I always say, ‘In science, it’s not ‘I,’ it’s ‘we.’ And it’s so true. There are hundreds of students and colleagues around the world with whom I’d like to share this honor.

I had the honor of writing about Falkow’s work in 2008, when he was awarded the Lasker-Koshland Award for Special Achievement in Medical Science. I thoroughly enjoyed my conversation with him and I’m so happy for today’s announcement.

Previously: National Medal of Science winner Lucy Shapiro: “It’s the most exciting thing in the world to be a scientist”Stanford’s Lucy Shapiro receives National Medal of Science and FDA changes regulation for antibiotic use in animals
Photo by Krista Conger

Genetics, Immunology, Infectious Disease, Precision health, Research, Stanford News

Precision health: A blood test that signals need for antibiotics

Precision health: A blood test that signals need for antibiotics

antibioticsGo to your doctor with a sinus infection and the first thing she’ll likely ask you is how long you’ve been sick. If it’s been less than two weeks, chances are she’ll say you probably have a viral infection and won’t prescribe an antibiotic. If you say it’s been three or four weeks, she’ll probably give you a prescription, assuming viral infections typically resolve in two weeks. But this rule of thumb is more educated guess than science.

In a nice example of precision health, a new blood test being developed at Stanford could indicate whether you have a bacterial infection or a viral infection and tell you and your doctor whether an antibiotic would help.

So if you have a bacterial infection that an antibiotic could cure, you won’t have to wait days or weeks to get treatment. And if you don’t need a prescription, you won’t damage your body’s microbiome with a round of antibiotics you don’t need.

The test, developed by Purvesh Khatri, PhD, assistant professor of medicine, and a team of six other researchers at Stanford, is based on changes in the way human immune cells express their genes.

It seems almost like science fiction, but Khatri’s team has found that cells don’t just respond differently to bacterial infections and viral infections; they also respond differently to different kinds of viral infections, so it’s possible to tell whether someone has a cold versus the flu as much as 24 hours before they even show symptoms.

The same test could have other uses, including quickly showing whether a vaccine is working and, someday, telling if someone is infected with Ebola or other deadly and contagious viruses.

You can read more details in our press release and even more in the paper (subscription required), which was published online today in the journal Immunity.

Previously: Study means an early, accurate, life-saving sepsis diagnosis could be coming soon
Photo by Sheep purple

Immunology, Microbiology, Research, Stanford News

Microbiome explorations stoke researcher’s passion

Microbiome explorations stoke researcher's passion

Dr. Ami Bhatt, MD., PhD, Department of Medicine and Department of Genetics at her lab at Stanford University , on Thursday, September 24, 2015.

Start talking with physician-scientist Ami Bhatt, MD, PhD, about the microbiome — the vast community of bacteria, fungi, and life that live on the body — and she’ll discuss the potential of these dynamic microscopic ecosystems with such contagious enthusiasm and clarity that you’ll find yourself nodding alongside her, agreeing with her every point.

Bhatt is intensely curious, a trait she’s had since childhood, and deeply committed to the idea of using science to help others. These dual instincts initially led her to medicine, where she found her calling as a physician-scientist.

I feel like I am one of those lucky few who get to do exactly what they want to do.

Today Bhatt runs her own laboratory at Stanford, where she studies how shifts in the microbiome affect human disease and patient outcomes.

“The fundamental thesis that drives our research,” Bhatt explained in a recently published piece on the Department of Medicine website, “is that patient outcomes are manipulated or modified by the alterations in their microbiota, and that we can discover these microbes using sequence-based technologies.”

Another of Bhatt’s initiatives aims to unravel a particularly interesting—and timely—question: What molecular changes occur during a fecal microbiota transfer? To answer this, Bhatt and her colleagues have developed a computational pipeline that will provide a time-based characterization of what actually happens during a transfer.

While her research goals are ambitious and varied, the source of Bhatt’s passion remains the same. “I’m still committed to the idea of being able to help people using science,” she said. “I feel like I am one of those lucky few who get to do exactly what they want to do.”

Previously: At TEDMED 2015: How microbiome studies could improve the future of humanity, Investigating the human microbiome: “We’re only just beginning and there is so much more to explore” and Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease
Photo by Norbert von der Groeben

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