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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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Global Health, Infectious Disease, Microbiology, Research, Stanford News

If you gum up a malaria parasite’s protein-chewing machine, it can’t do the things it used to do

If you gum up a malaria parasite's protein-chewing machine, it can't do the things it used to do

chewing gum“Life in the tropics” evokes images of rain forests, palm trees, tamarinds and toucans. It also has a downside. To wit: One-third of the Earth’s population – 2.3 billion people – is at risk for infection with the mosquito-borne parasite that causes malaria.

Thankfully, mortality rates are dropping because of large-scale global intervention efforts. But malaria remains stubbornly prevalent in sub-Saharan Africa and Southeast Asia, where hundreds of millions of people become infected each year and more than 400,000 of them – mostly children younger than 5 – still die from it.

The parasite has the knack of evolving rapidly to develop resistance to each new generation of drugs used to fend it off. Lately, resistance to the current front-line antimalarial drug, artemisinin, is spreading and has now been spotted in a half-dozen Southeast Asian countries.

So it’s encouraging to learn that Stanford drug-development pioneer Matt Bogyo, PhD, and his colleagues have designed a new compound that can effectively kill artemisinin-resistant malaria parasites. Better, exposure to low doses of this substances re-sensitizes them to artemisinin.

By exploiting tiny structural differences between the parasitic and human versions of an intercellular protein-recycling machine called the proteasome, the compound Bogyo’s team has created attacks the malaria parasite while sparing human cells.

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Neuroscience, Research

Successful replacement of eye cells hints at future glaucoma treatment

Successful replacement of eye cells hints at future glaucoma treatment

2553516471_2dbf6fbb2f_oFor the first time, a team has successfully transplanted retinal ganglion cells into living animals. The new cells mimicked existing cells in the eye and responded to light.

The work, which was co-led by Jeffrey Goldberg, MD, PhD, professor and chair of ophthalmology at Stanford, is an effort to improve therapies for retinal and optic nerve diseases including glaucoma, which is the leading cause of irreversible blindness. Glaucoma is caused by a variety of conditions, but it leads to the loss of retinal ganglion cells, nerve cells that transmit information from photoreceptors in the eye to the visual centers in the brain.

“These data provide a hint that replacing these cells and restoring these connections is one step closer to possible,” Goldberg told me.

The team, including first author Praseeda Venugopalan, PhD, a former graduate student in neuroscience at the University of Miami, injected labeled retinal ganglion cells into 152 adult rats. Although the new cells integrated into only about one of six animals, that success rate was surprisingly high, Goldberg said.

Goldberg said they are not sure why their procedure worked when other attempts have failed. They used fully differentiated retinal ganglion cells, rather than undifferentiated stem cells, which could be an important factor, he said.

In this study, the team implanted the cells in healthy eyes, but they’re planning future studies to determine if the procedure is equally successful in eyes already suffering from glaucoma, Goldberg said.

The study appeared recently in Nature Communications. Kenneth Muller, PhD, professor of neuroscience at the University of Miami, is also a senior author.

Previously: Stanford-developed eye implant could work with smartphone to improve glaucoma treatments, What I did this summer: Stanford medical student investigates early detection methods for glaucoma and The retina: One researcher’s window into the brain
Photo by Rachel Collins

HIV/AIDS, Infectious Disease, Research, Science, Stanford News

“Unprecedented” approach for attempting to create an HIV vaccine

"Unprecedented" approach for attempting to create an HIV vaccine

Stanford’s 588732155_c05dda114e_zPeter S. Kim, PhD, was recently elected to the National Academy of Engineering, making him one of only 20 people who are members of all three National Academies (the other two are Medicine and Science). Stephen Quake, PhD, a bioengineer here, is also a member of all three academies.

This honor is particularly fitting for Kim, who joined Stanford in 2014 to be part of the new interdisciplinary institute Stanford ChEM-H, which bridges the schools of medicine, engineering and humanities & sciences for research in human health. Kim had spent a decade as president of Merck Research Laboratories and hopes that in his return to academic research his group will be able to help create a vaccine for HIV.

I talked to Kim recently about why he thinks he’ll succeed where so many have failed in their efforts to develop an HIV vaccine, and the importance of working across disciplines:

How is your approach to creating an HIV vaccine different from ones that haven’t been successful?

In over 30 years of intense work by many people to try and come up with a vaccine, none has succeeded. That’s in large part because the virus can mutate very quickly. It can change and therefore escape an antibody. The approach that we’re taking is to target a part of HIV that is normally buried but becomes exposed during the infection process. This region is highly conserved – it is 90 percent identical between all HIV strains.

If this region doesn’t mutate often why haven’t other people tried to target it?

It is unprecedented to make a vaccine against a region of a protein that is only exposed briefly. People are skeptical because the vaccine has to be there right at the moment that the virus is infecting the cell.

What gives you confidence the approach will work?

There’s an FDA-approved drug, called Fuzeon, that binds this same region and has been shown to be effective in people. That drug isn’t widely used because it has to be injected, but it validates our idea that targeting this transiently exposed part of the protein can be effective at fighting the virus in humans.

How far along are you?

We’ve shown that we can elicit antibodies in animals that are capable of inhibiting HIV in a lab dish. Thus, we know that our vaccine candidates can generate antibodies against the virus, and that those antibodies recognize and fight the virus. But, we still need to generate a much stronger inhibitory response before we test it in people.

You’re now a member of the three academies that also represent the academic interests of ChEM-H, which brought you to Stanford. Do you think spanning disciplines helps in your work?

The research that we do is greatly enhanced by having the proximity of engineering, medicine and science at Stanford. We study things as basic as the molecular structures of viral proteins. Ultimately, we need to understand how the human immune system creates antibodies against these proteins. This work is greatly facilitated by engineering methods to determine the DNA sequence of single immune cells. In the future, we would also love to see what is occurring at a single molecule level when a virus infects a cell. To do that will require bringing together world class engineering, science and medicine.

Previously: Research investment needed now, say top scientists and Stanford ChEM-H bridges chemistry, engineering and medicine
Image of an HIV particle by AJ Cann

History, Research, Surgery

Ancient surgical technique still used to rebuild noses today

Ancient surgical technique still used to rebuild noses today

When facial surgeon Sam Most, MD, first contacted me about doing a story on one of his favorite procedures called the “forehead flap,” which he uses for major nose reconstructions, he sent along photos of what a patient looks like prior to surgery.

The photos make it clear real fast how unfortunate it is to lose your nose. The nose is the focal point of the face. It’s what people notice first. The numbers of people losing their noses due to skin cancer is on the rise, and many, are left wearing uncomfortable, unflattering prostheses for years.

Enter surgeons like Most, part artist, part scientist — a sculptor of noses. According to Most, it’s the most difficult facial plastic surgery procedure. And key among the many necessary tools needed to succeed is the “forehead flap” — a procedure that originated with cobblers in ancient India. My article tells the story of this fascinating surgery, which was first introduced into Western medicine in 1794:

Most is quick to recount the historical significance of the forehead flap, Most is quick to recount the historical significance of the forehead flap technique, which originated in India probably before the birth of Christ but wasn’t widely known to Western medicine until 1794 with the publication of a letter to the editor in Gentlemen’s Magazine of London. The letter provided the first account in English literature of the procedure.

At the time, India was a colony of the British. A sultan, angry at the occupation, offered bounties for the amputated ears, noses and hands of British sympathizers. The letter describes the nasal reconstruction of an Indian bullock driver who, having been imprisoned by the sultan, had his nose and one of his hands cut off for delivering supplies to British troops. It goes into detail how the driver’s nose was rebuilt 12 months later, after he joined the Bombay Army of the East India Company.

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Research, Science, Sleep, Stanford News

Flashing light at night could help beat jet lag, Stanford study says

Flashing light at night could help beat jet lag, Stanford study says

plane in sunsetThe body will eventually adjust to jet lag, it’s just that it takes time — about an hour a day to be precise. And anyone who has suffered the unpleasant side effects of jet lag – brain fog, body achiness, an overwhelming need for endless pots coffee — might have an interest in speeding the process up.

A new Stanford study suggests that exposing travelers to short bursts of flashing lights the night before a trip while asleep could help speed up the process significantly. In a press release I wrote on the study, which was published today in the Journal of Clinical Investigation, researchers explained how this works at a biological level:

The transfer of light through the eyes to the brain does more than provide sight; it also changes the biological clock. A person’s brain can be tricked into adjusting more quickly to disturbances in sleep cycles by increasing how long he or she is exposed to light prior to traveling to a new time zone.

Light therapy is designed to speed up the brain’s adjustment to time changes. By conducting light therapy at night, the brain’s biological clock gets tricked into adjusting to an awake cycle even when asleep. It’s a kind of “biological hacking” that fools the brain into thinking the day is longer while you get to sleep.

 To determine whether continuous or flashing lights would provide the fastest method of sleep cycle adjustment, researchers had 39 study participants sleep in a lab, exposing some to continuous light for an hour, and others to flashing light for an hour. They found that the flashing light —which most could sleep through just fine— elicited about a two-hour delay in the onset of sleepiness, while those exposed to continuous light, the delay was only 36 minutes.

Jamie Zeitzer, PhD, the senior author of the study, described how flashing-light therapy could be used to adapt to traveling from California to the East Coast: “If you are flying to New York tomorrow, tonight you use the light therapy. If you normally wake up at 8 a.m., you set the flashing light to go off at 5 a.m. When you get to New York, your biological system is already in the process of shifting to East Coast time.”

“This could be a new way of adjusting much more quickly to time changes than other methods in use today,” he told me.

Previously: Cheating jet lag: Stanford researchers develop methods to treat sleep disturbances, Why sleeping in on the weekends may not be beneficial to your health, How sleep acts as a cleaning system for the brain, Study shows altered circadian rhythms in the brains of depressed people, Jet-lag drug is a no go and Jet-lagged hamsters flunk IQ test
Photo by Eric Prado

Behavioral Science, Cardiovascular Medicine, Neuroscience, Research, Stanford News

Scientists zero in on brain’s sigh-control center

Scientists zero in on brain's sigh-control center

sighWhy do we sigh?

(Sigh…) How should I know? Don’t I already have enough on my mind?

As we all well know, sighing is a long, deep involuntary inhalation accompanying sensations of yearning, sadness, relief, boredom, exhaustion, or (see above) exasperation. Fewer of us know (at least I didn’t, but now I do!) that the typical person also sighs spontaneously about every five minutes or so.

If you’re a mouse, you do it much more often – as much as 40 times per hour. (Nobody said it would be easy, little mousie.)

Those spontaneously sighs (and all the other ones), it’s thought, may be helping to keep our half-billion or so alveoli – the tiny sacs through which our lungs exchange oxygen and carbon dioxide with the atmosphere that surrounds us – pumped up and operating efficiently.

That could be, at least in part, why we sigh. But Mark Krasnow, MD, PhD, Stanford biochemist and molecular biologist and Howard Hughes Medical Institute Investigator, has figured out how.

In a series of experiments described in a Nature study, Krasnow’s team, along with colleagues at Stanford and UCLA, painstakingly employed genetic, pharmacological and surgical techniques to map out a precise set of nerve circuits in the brain that are essential to the act of sighing. They showed that a sigh results when inhalation-initiating nerve impulses generated rhythmically within these circuits double up: One impulse effectively laps another and rides piggyback on top of it, producing a deeper, drawn-out inhalation.

The experiments were performed in mice. But the brain circuits involved are sufficiently ancient that our common ancestors no doubt had them, too – and therefore we (probably) do, too, or at least very similar ones.

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Big data, Genetics, Precision health, Research

Individuals’ medical histories predicted by non-coding DNA in Stanford study

Individuals' medical histories predicted by non-coding DNA in Stanford study

image.img.320.highAs whole-genome sequencing gains ground, researchers and clinicians are struggling with how best to interpret the results to improve patient care. After all, three billion base pairs are a lot to sift through, even with powerful computers. Now genomicist Gill Bejerano, PhD, and research associate Harendra Guturu, PhD, have published in PLoS Computational Biology the results of a study showing that computer algorithms and tools previously developed in the Bejerano lab (including one I’ve previously written about here called GREAT) can help researchers home in on important regulatory regions and predict which are likely to contribute to disease.

When they tried their technique on five people who agreed to publicly share their genome sequences and medical histories, they found it to be surprisingly prescient. From our release:

Using this approach to study the genomes of the five individuals, Guturu, Bejerano and their colleagues found that one of the individuals who had a family history of sudden cardiac death had a surprising accumulation of variants associated with “abnormal cardiac output”; another with hypertension had variants likely to affect genes involved in circulating sodium levels; and another with narcolepsy had variants affecting parasympathetic nervous system development. In all five cases, GREAT reported results that jibed with what was known about that individual’s self-reported medical history, and that were rarely seen in the more than 1,000 other genomes used as controls.

Bejerano and Guturu focused on a subset of regulatory regions that control gene expression. As I explained:

The researchers focused their analyses on a relatively small proportion of each person’s genome — the sequences of regulatory regions that have been faithfully conserved among many species over millions of years of evolution. Proteins called transcription factors bind to regulatory regions to control when, where and how genes are expressed. Some regulatory regions have evolved to generate species-specific differences — for example, mutating in a way that changes the expression of a gene involved in foot anatomy in humans — while other regions have stayed mostly the same for millennia. […]

All of us have some natural variation in our genome, accumulated through botched DNA replication, chemical mutation and simple errors that arise when each cell tries to successfully copy 3 billion nucleotides prior to each cell division. When these errors occur in our sperm or egg cells, they are passed to our children and perhaps grandchildren. These variations, called polymorphisms, are usually, but not always, harmless.

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Biomed Bites, Genetics, Research, Videos

RNA editing: Many mysteries remain

RNA editing: Many mysteries remain

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

DNA, RNA, protein, end of story, right? Well, no. Sometimes, RNA is edited after it is created. These new revised copies can perform different functions or contribute to the development of disease.

But for decades, no one had a great way to examine post-transcriptional changes to RNA, much less understand what role they play in cellular processes. Thanks to advances in technology, that is changing.

In the video above, Jin Billy Li, PhD, assistant professor of genetics, explains how his lab is working to unravel RNA’s remaining secrets. “In the future, we hope to associate this interesting phenomenon with human neurological conditions such as autism, epilepsy, depression and ALS,” he says.

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

Previously: Tissue-specific gene expression focus of Stanford research, grant, “Housekeeping” RNAs have important, and unsuspected, role in cancer prevention, study shows and Make it or break it — or both: New research reveals RNA’s dual role

Applied Biotechnology, Ask Stanford Med, Clinical Trials, Research, Stanford News

SPARKing a global movement

SPARKing a global movement

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Many academic researchers are tenacious, spending years in the lab studying the processes that lead to human diseases in hopes of developing treatments. But they often underestimate how difficult it is to translate their successful discovery into a drug that will be used in the clinic.

That’s why Daria Mochly-Rosen, PhD, founded SPARK, a hands-on training program that helps scientists move their discoveries from bench to bedside. SPARK depends on a unique partnership between university and industry experts and executives to provide the necessary education and mentorship to researchers in academia.

In recent years, Stanford’s program has sparked identical programs throughout the world; at TEDMED 2015, Mochly-Rosen described this globalization. I recently spoke with her about the SPARK Global program, which she co-directs with Kevin Grimes, MD, MBA.

How has SPARK inspired similar programs throughout the world?

We’ve found our solution for translational research to be particularly powerful. Of the 73 completed projects at Stanford, 60 percent entered clinical trials and/or were licensed by a company. That’s a very high accumulative success rate. So I think it has showed other groups that we have a formula that really works – a true partnership with academia and industry. It’s the combination of industry people coming every week to advise us and share lessons learned and our out-of-the-box, risk-taking academic ideas that makes SPARK so successful.

We feel that what we’ve learned is applicable to others. Kevin and I also feel very strongly that universities need to take responsibility to make sure inventions are benefitting patients. So we’re trying to do our part.

How do you and Dr. Grimes help develop the global programs?

When a university asks about our program, we invite them to come visit us for a couple of days so they can talk to SPARKees (SPARK participants), meet SPARK advisors and watch our weekly meeting. Sometimes they also ask Kevin and I to come to their country to help set up a big event or assist in other ways. If they begin a translational research program at their institution, we offer for them to be affiliated with SPARK Global. Everyone is invited.

There are now SPARK programs throughout the world, including the United States, Taiwan, Japan, Singapore, South Korea, Australia, Germany and Brazil. We are also working with other countries, including Norway, Israel, Netherlands, Poland and Finland, to help them start a program.

Do researchers in other countries face the same challenges as those in the U.S. when developing new drugs?

There are many common challenges. And there are also some advantages and challenges that are different in other places. So it’s a mix, both within and outside the U.S.

There are several key components to the success of translation research. It’s important to have a good idea. It’s even more important to have good advisors from industry to help develop the idea. And it’s very important that the people involved are open-minded and not inhibited by hierarchical structures. In some places, there is a big problem with hierarchy – particularly in parts of Europe and East Asia. In some cultures, it’s also difficult to get experts to volunteer and academics can’t afford to pay multiple advisors. Also, some universities don’t have a good office of technology to help with patent licensing, which can be a major challenge.

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