Infectious Disease

Last week’s C-IDEA global health symposium here at Stanford featured 20 presentations on low-cost ideas for preventing disease in developing nations. As I wrote in an Inside Stanford Medicine article on the event, one of the more clever ideas was “EZPZ,” a method for treating latrine waste with alkalizing lime so that pathogens that might leak into the water supply can be eliminated and the waste can be recycled as crop fertilizer. Developed by a Stanford team from the “Design for Extreme Affordability” course offered at the Hasso Plattner Institute of Design, this solution not only reduces diarrheal diseases, but it also provides Cambodian farming households with about $40 of fertilizer each year.

Another highlight of the conference was the keynote speech delivered by Jeffrey Sachs, PhD, director of The Earth Institute at Columbia University and author of the bestselling book The End of Poverty. Sachs’ call to action for the packed hall of global health innovators was this: The developing world needs you to create smart phone apps that connect people in isolated rural villages to good medical care, clean water and medicine.

Previously: What I did this summer: Stanford medical student helps India nonprofit create community-health maps and A story of how children from Calcutta’s poorest neighborhood became leaders in improving health

Last week at TEDxChange 2013: Positive Disruption, Melinda Gates brought to stage Salim Shekh and Sikha Petra, two of the children featured in the Stanford-produced documentary “The Revolutionary Optimists.” The award-winning film, which was co-directed and co-produced by Maren Grainger-Monsen, MD, and Nicole Newnham, tells the story of a lawyer-turned-social entrepreneur who worked to empower children living in Calcutta’s poorest neighborhood to become leaders in improving health. As described on the film’s website, the youth have “painstakingly track[ed] and collect[ed] data around health issues that impact them – water, sanitation, and infectious diseases” and then made improvements in each of the areas.

The TEDXChange video was recently made available on Facebook (log-in required); scroll to the 1:20 mark to view the movie trailer and to 1:22 to meet Salim and Sikha, who are embarking on a U.S. tour to talk about their work. An amazing figure from the talk: Before the group began promoting polio vaccination, only 35 percent of children in their community were vaccinated. Now 85 percent are.

Previously: Stanford documentary wins award from the Sundance Film Institute, A story of how children from Calcutta’s poorest neighborhood became leaders in improving health and Stanford filmmakers to debut documentary at TEDxChange

You’ve heard of Sputnik, that little tiny antenna-clad chunk of metal heaved into low orbit on October 4, 1957, effectively kicking off the Space Age?

Well, make way for Gutnik. A news release issued by NASA’s Ames Research Center foretells the launch into space of a satellite inhabited by a bunch of nano-mariners who, left to their own devices, would no doubt rather curl up inside a bowel.

Sometime in the next one to three years, according to the release, a so-called “nanosatellite” weighing about 30 pounds and peopled by the intestinal bug E. coli will streak into the sky, with the mission of amassing data on whether the zero-gravity environment that cloaks our planet might increase microbes’ resistance to antibiotics. That’s important, because, as the release states:

Bacterial antibiotic resistance may pose a danger to astronauts in microgravity, where the immune response is weakened. Scientist believe that the results of this experiment could help design effective countermeasures to protect astronauts’ health during long-duration human space missions.

E. coli is probably the most-studied micro-organism in all of science. While most strains are harmless and actually quite friendly (producing vitamin K for us, just to name one of the nice things they do), some of them can cause food poisoning, urinary-tract infections and more.

Gutnik (whose real name is EcAMSat) is the brainchild of Stanford microbiologist A.C. Matin, PhD, the principal investigator for the joint NASA/Stanford University School of Medicine project. Matin’s previous inventions include microbes capable of gobbling up environmental toxins like uranium and chromium, as well as magnetic-field-seeking bacteria that can increase the contrast of magnetic-resonance imaging. So this new satellite caper is just one more in a series of wild but potentially very useful feats of imagination.

The thing that really knocks me out, though, is how all these scientists and engineers will manage to get those billions of little tiny bugs to sit still while the chin straps on their little tiny space helmets are being fastened.

Previously: Space: A new frontier for doctors and patients and Outer-space ultrasound technologies land on Earth
Photo by Per Olof Forsberg

In the last few days, there has been much talk about the baby born with HIV who was reportedly cured of the disease – only the second documented case of an AIDS “cure.” Like a good scientist, Yvonne Maldonado, MD, a pediatric AIDS expert at Stanford, is a bit skeptical and says there are many questions yet to be answered.

“It brings a lot of promise and hope but there are lots of details to be looked at before the next step can move forward,” said Maldonado, chief of pediatric infectious disease at Stanford and Lucile Packard Children’s Hospital. She has been doing research on mother-to-child HIV transmission for many years, working with a group of women in Zimbabwe.

According to news reports, the Mississippi mother came to the hospital in labor, and tests showed she was HIV-positive. Because the mother had never been treated for HIV, doctors knew the chance was high that she would transmit the virus to her baby. So within 30 hours of the baby’s birth, they took the unusual step of treating the infant aggressively, with a full cocktail of antiretroviral drugs. The child continued treatment for 18 months, then stopped. And when the mother brought the two-year-old back for a checkup, tests showed – remarkably – that the baby was virus-free.

One pressing question, Maldonado says, is whether the baby was truly infected. Babies can acquire HIV from their mothers in several ways – either in utero, during labor and delivery or as a result of breastfeeding.

Did this child become infected in utero with the virus, which was ultimately eliminated by the antiretrovirals? Or did the child simply carry some circulating virus from the mother in its blood – and the drugs stopped the virus from establishing itself in the baby?

“Those are two different things,” Maldonado told me. In the first case, “That would be a functional cure. The other would be preventing early post-partum infection,” a form of prevention, rather than cure.

She said there have been anecdotal reports of babies who have been able to clear the virus from their bodies. “You can find virus in infants that then disappears because they haven’t become infected,” she said.

If, on the other hand, this is truly a functional cure, then that has many implications for treatment of infants down the road. “If in fact that was the case, maybe that means instead of giving light therapy to prevent infection, all these babies (of HIV-positive mothers) should be getting heavy-duty therapy right from the start.”

Maldonado notes that pediatrics has routinely led the way in HIV prevention and treatment, as unlike adults, one can often identify when a baby became infected – and then quickly move to intervene. She said it’s unfortunate the latest case, reported at a scientific meeting, occurred during the weekend of the budget sequester.

“Our capacity to study this will be limited,” she said. “NIH will be flat-funded, and yet here’s an opportunity to look at these paradigm-shifting concepts. But these things need resources. It may be a serendipitous finding, but it will be just that if you don’t do more science-based inquiries.”

Previously: International AIDS Conference Day Three: Daring to talk about a cure and Experts discuss German patient who appears cured of HIV

A University of California, Los Angeles study published online this week in Science offers clues about how various bacteria masquerade as viruses and, as a result, trick the immune system into using the wrong defense strategy. As explained in a university release, the bacteria manipulates the body into using a protein called interferon-beta to fend off its attack, but such an approach dose more harm than good:

Not only is interferon-beta ineffective against bacteria, but it can also block the action of interferon-gamma, to the advantage of bacteria. Further, if a real virus were to infect the body, triggering interferon-beta, it would divert the attention of the immune response, preventing an attack on the bacterial invader. The researchers say this may explain why the flu can lead to a more serious bacteria-based infection like pneumonia.

In the study, researchers used leprosy as a model to understand how bacteria can fool the immune system. Senor author Robert Modlin, MD, said the team opted to study leprosy because it “is an outstanding model for studying immune mechanisms in host defense since it presents as a clinical spectrum that correlates with the level and type of immune response of the pathogen.”

The above image shows leprosy bacteria marked in red and with the interferon-beta highlighted in green.

Photo by UCLA

Biological aging, as opposed to the chronological kind we celebrate or curse annually, is what makes us describe some people as “ageless” and others as “old beyond their years.” We are collections of cells, and what happens in the cell doesn’t stay in the cell. It generates large-scale effects on our overall appearance, health and longevity.

A new study in JAMA indicates that otherwise healthy adults carrying a cellular signature of biological aging may be more vulnerable to infection and, once infected, more likely to exhibit symptoms. The experimenters first drew blood from 152 Pittsburgh residents, none of them over 55 years old, and dosed them with nose drops containing a common cold virus. Monitoring these volunteers for five days, the researchers took note of who sniffled and sneezed and who didn’t, and saw a correlation between study subjects’ susceptibility to the virus and a measure of biological aging called telomere shortening.

Telomeres, which cap the ends of each chromosome in every cell of all living creatures from fungi right on up to humans, are kind of like those plastic caps ringing each end of a shoelace. They stabilize chromosomes, keeping them from unraveling. (They prevent other damage, too.)

But telomeres aren’t so stable themselves. Rounds of cell division, bouts of stress, and episodes of inflammation cause them to shrink. If a telomere reaches a point where a chromosome’s integrity is challenged, the result could be cancer or some other malfunction in the cell housing the challenged chromosome.

Evolution has engineered protective mechanisms into cells so that if their telomeres get too short they die or, at least, lose their ability to divide any more. But this evolutionary emergency brake has its downside: It contributes to the slow but steady deterioration that manifests visibly in our aging skin and, less visibly, in all the other bodily organs.

In this case, the researchers were specifically interested in those bloodborne cells that comprise the immune system. But it’s widely believed that the state of telomeres in blood cells (the cells examined in the study) reflects their state in other tissues as well.

Just a week ago, a study in PLOS ONE led by Stanford psychopharmacologist Natalie Rasgon, MD, PhD, compared the telomeres in blood cells taken from high-functioning, well-educated, apparently fully healthy middle-aged women with a well-known genetic risk factor for late-onset Alzheimer’s disease (a good 15 percent of us are carriers) to those of otherwise matched non-carriers. The first group’s telomeres shortened by as much in two years as the second group’s did in ten, perhaps shedding some light on how this risk factor, called ApoE4, promotes cognitive decline. The good news was that the accelerated telomere shortening seen in ApoE4 carriers wasn’t observed if they’d been on estrogen-based hormone therapy at the onset of menopause and stayed on it for the study’s two-year duration.

While it might be nice to think longer telomeres are all it takes to ensure longevity, even the lengthiest telomeres are no match for a speeding truck. So be sure to look both ways before you cross the street.

Previously: Hormone therapy halts accelerated aging seen in women with Alzheimer’s genetic risk factor, Hormone therapy soon after menopause onset may reduce Alzheimer’s risk and Common genetic Alzheimer’s risk factor disrupts healthy older women’s brain function, but not men’s
Photo by ultrakickgirl

Anyone who has ever eaten a rancid food-truck taco has a gut-level feeling for what it’s like to have the human immune system launch a full-scale attack along 30 feet of intestinal tract. Now you can watch this fascinating process at a microscopic level, pain free, thanks to a new animation posted by Nature: Immunology.

Watching it makes me appreciate the amazing complexity of the human immune system. It also serves as a graphic reminder of how much easier it is to understand these processes when you can see them in action.

Readers interested in irritable bowel syndrome might want to skip to minute 4:00, where the animation shows what happens when pathogens sneak past the gut’s protective mucosal barrier. Spoiler alert: Watch out for the “voracious phagocyte” and the “NETosis explosion.”

Previously: The dawn of a new era in microbiology, Study shows intestinal microbes may fall into three distinct categories and A social networking service for digestive health?

An article in today’s New York Times highlights just-published work by Massachusetts General Hospital researchers and Stanford genomics expert Ron Davis, PhD, in which the scientists presented “stunning evidence that the mouse model has been totally misleading for at least three major killers - sepsis, burns and trauma.” As a result, according to the Times article, “years and billions of dollars have been wasted following false leads.”

The newspaper story is referring to a Proceedings of the National Academy of Sciences study that writer Gina Kolata says may help explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed.

This work goes back several years, with Davis and his associates finding patterns of gene activity that seemed to predict which sepsis victims will live and which will die. The researchers tried to publish their results in several journals but were initially rebuffed because they hadn’t tested their findings in mice to see if the same things happened, according to the article:

“They were so used to doing mouse studies that they thought that was how you validate things,” [Davis] said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?” The group decided to look, expecting to find some similarities…

But when the investigators looked, there were none at all. In fact, some genes that were “turned on” by sepsis in mice were “turned off” in humans. Further, in humans, similar genes were activated by sepsis, trauma and burns - three conditions in which the immune system overreacts and inflicts more damage to the body than the bacteria, knock to the head or house fire, respectively, that originally caused the problem. But in mice, these three different types of stimuli trigger three quite different gene-activation patterns.

So, a drug that might work in a human could have the opposite effect in a mouse. And vice versa.

The man/mouse mismatch, intriguingly, shows up in other places, too. For instance, a recent study led by Stanford immunologist Mark Davis, PhD, suggests that experimental mice - who spend their entire lives in artificial, ultra-germ-free environments - may be a poor model for adult humans’ more battle-hardened immune systems, which have acquired quite a bit of savoir faire.

And in another study a few months back, Stanford drug-development expert Gary Peltz, MD, PhD, developed mice with humanized livers, explicitly to address another disparity that can easily result in costly failures of new drugs in clinical trials: Mice’s livers, being different from ours, often metabolize new experimental drugs quite differently from the way ours would.

Previously: Professor Ronald Davis wins 2011 genetics prize from the Gruber Foundation, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Fortune teller: Mice with “humanized” livers predict HCV drug candidate’s behavior in humans
Photo by gliuoo

Probably no human whose age consists of two digits hasn’t at one time or another experienced a case of deja vu, the uncanny sense of having been through this (whatever “this” may be) before.

Well, it turns out that (as the scary narrator of a kitchy sci-fi TV series I inhaled with both nostrils as a kid might say about UFOs and the like), “We’re not alone…” Our own immune systems, among whose chief functions is to fight off invading pathogens, also entertain “memories” of infectous microbes they’ve never, ever encountered. And that’s a lucky thing.

A human has only 20,000 or so genes, so it’s tough to imagine just how our immune systems are able to recognize potentially billions of differently shaped microbial body parts (or “epitopes” in immune-speak). Stanford immunologist Mark Davis, PhD, tore the cover off of immunology in the early 1980s by solving that riddle.

Now, in a just published study in Immunity, Davis and his team have used an advanced technique developed in his lab in the 1990s to show that a surprising percentage of adult humans’ workhorse immune cells targeting one or another microbial epitope are poised to pounce on the particular epitope they target (and the bug it rode in with) despite having never come across it before. This hypervigilant configuration, called the ”memory” state, was previously supposed to be limited to immune cells that have previously had a run-in with the epitope of interest.

Davis think’s he’s got the dirt on what’s behind the phenomenon: Dirt. He reasons that the kind of immune cells in question have more flexibility than has been thought, so each of them can “cross-react” to a small set of similarly but not identically shaped ”lookalike” epitopes it’s never experienced. Our daily exposures to ubiquitous, mostly harmless micro-organisms that dwell in dirt, on doorknobs, and in our diets gradually produces an aggregate immune “memory” of not only these microbes’ body parts, but those of other bugs as well - including some nasty ones like HIV (the virus that causes AIDS), herpesvirus, and more.

Because cells in the “memory” configuration can react much, much faster to an infectious pathogen than “naive” cells targeting the exact same pathogen, this eerie foreknowledge can spell the difference between life and death.

But this immune memory still depends on having been exposed to something. In the study, the immune cells in blood from newborns’ umbilical cords showed no “memory” of anything at all.

As I wrote in my release on the new findings:

[This discovery] could explain why young children are so much more vulnerable to infectious diseases than adults. Moreover, the findings suggest a possible reason why vaccination against a single pathogen, measles, appears to have reduced overall mortality among African children more than can be attributed to the drop in measles deaths alone.

“It may even provide an evolutionary clue about why kids eat dirt,” Davis told me.

Previously: Immunology escapes from the mouse trap, Age-related drop in immune responsiveness may be reversible and Common genetic Alzheimer’s risk factor disrupts healthy older women’s brain function, but not men’s
Photo by Damian Gadal

I was around eight years old when I got chicken pox, and I remember there was a lot of scratching and calamine lotion involved. These days, you don’t really hear about kids catching chicken pox, thanks to a vaccine approved by the FDA in 1995.

Had a chicken pox vaccine been available to me as a child, would I now be immune to developing shingles, a disease caused by the same virus? An article in today’s San Francisco Chronicle describes how experts, including Ann Arvin, MD, who led research that helped explain immune responses to varicella zoster (the virus that causes chicken pox), are uncertain of the answer. But:

In the meantime, [Arvin] offers advice to adults over 50 who fear shingles’ wrath: Get the shingles vaccine. Zostavax, which is also created from a weakened form of varicella, boosts adults’ ability to fight the existing virus if it reactivates. The FDA approved the vaccine for people 50 and over in 2011, after a study of 22,000 people showed that people who had the vaccine were 70 percent less likely to get shingles within a year than people who received a placebo…

Previously: CDC: More U.S. adults need to get recommended vaccinations, “Herd immunity” causes dramatic drop in infant chicken pox and Vaccination could eliminate chicken pox-related deaths in the U.S.