Thursday, December 18, 2014

Human Foie Gras — A Golden Opportunity

To kick things off, what is foie gras?
It can be explained with a short missive from our friend Wikipedia:
The California foie gras law, California S.B. 1520, is a California State statute that prohibits the “force feed[ing of] a bird for the purpose of enlarging the bird’s liver beyond normal size”…
Former Senator John Burton called foie gras production “an inhumane process that other countries have sensibly banned.”
Given this outrage related to mistreating birds, you might be surprised to learn that human foie gras industries are booming.  Children’s livers are apparently particularly tasty. Not unlike veal, I suppose.
I’m putting $50K of my own money into related investments, but we’ll get back to that in a minute. First, some background…
For most of the 20th century, fatty liver and liver cirrhosis had two primary causes: drinking too much alcohol (e.g. Mickey Mantle) or hepatitis B or C (via IV drug use, unhygienic tattooing, tainted blood transfusions, etc.).
But in the last few decades, even infants are showing up with livers that should belong to hardcore alcoholics.  And the numbers aren’t small.
It’s estimated that one in ten American children now suffer from non-alcoholic fatty liver disease (NAFLD), alongside 40 million affected adults. If you’re an obese Mexican-American boy, the odds are 50-50 (!) that you have NAFLD, thanks to genetic predisposition (PNPLA3gene).
15 years ago, this disease was unheard of.  In 10 years, it’s projected to be the #1 cause of liver transplants. Put another way — In 2001, NAFLD was the reason for 1 out of every 100 liver transplants; by 2010, it was up a ten-fold to 1 in 10; by 2025, assuming nothing stems this tide, there could be five million Americans who need new livers because of it.
Who are driving this trend?
Some point fingers at good folks such as Coca-Cola, juice “cocktail” manufacturers, and the like.  Given that many researchers blame fructose, it’s not a huge stretch. Personally, the whole thing makes me sick.  I’d like to sic the best scientists in the country on them.
Ah, and this is where the good news comes in.
There is a way, albeit an indirect way, to do this. I implore you to read on and bear with me.  This is where it gets exciting.
The NIH alone has spent $155 billion on cancer research since 1972, and cancer survival is up a paltry 3% as a result. The US government spends over $25 billion EACH year on HIV/AIDS. That’s a lot of money.
One might assume fatty liver disease would require similar sums. After all, more American adults have NAFLD than prostate cancer, Alzheimer’s disease, heart disease, or type 2 diabetes.
That’s the disconnect…and the opportunity to be part of history.

Enter the “Manhattan Project of Nutrition”

The Nutrition Science InitiativeNuSI–has been called the “Manhattan Project of nutrition.” They are run like a lean startup, and I’m proud to be a part of their advisory board.
They don’t take industry money, so they have no interests to protect.
They believe the NAFLD epidemic can be curtailed for a total of $50 million, but the whole domino effect starts with just $1 million.  It is a rare day in science when fundamental questions about an epidemic can be answered with such little money (respectively). It’s an incredible Archimedes lever.
For context, NuSI argues that there are dietary triggers of diseases, including obesity, type 2 diabetes, cancer, and fatty liver disease. To determine what the triggers are, NuSI assembles teams of the best scientists in the country (e.g., from Stanford, Harvard, Columbia, NIH, UCSF, UCSD, Emory, etc.) to fund and execute the kind of research nobody else is willing (or able) to perform.
For NAFLD, NuSI’s team of experts have designed three trials to determine the respective roles of too many calories, too many carbohydrates, and too much sugar–the leading three hypotheses–as dietary triggers.
In early 2015, this team will begin the first ever controlled clinical trial to see if removing sugars from the diet can reverse fatty liver disease in children.
40 kids with NAFLD will be split into two groups, with 20 simply observed on their normal diet as controls, and 20 provided with a diet that’s identical to what they usually eat, but completely devoid of added or refined sugars. The scientists’ hypothesis is that the sugar-free diet will at least stop the progression of NAFLD in these kids, and may even reduce the amount of fat in their livers.
If that’s the case, it’ll be the best evidence we have linking sugar to fatty liver disease.

My $50,000 Challenge…And How to Get Involved

I’m personally matching up to $50,000 for whatever is raised through this blog post, and every donation–big or small–makes a major difference.
Any donation is also a tax write-off, as NuSI is a non-profit organization (of course, speak with your tax advisor). Perfect for end-of-the-year giving.
NuSI is looking to raise $1 million dollars for the first of these three trials—the one that determines how the rest get done.  The snowball that starts the avalanche. There are few chances in the world to have this type of impact for this type of money.  Could it end up forcing labeling changes, product modifications, obligatory package warnings, policy shifts, and more?  I believe so.
Supporting this campaign very easy, and remember–I’m excited to be putting my own skin in this game.  I sincerely hope you join me.  Every bit counts.
There are three options:
1. Donate by credit or debit card. Visit: Enter your donation amount, indicate “NAFLD — Tim Ferriss” in the message field, and click “Donate.”  Done.
2. Donate by check. Send your check to: NuSI, attention: Lacey Stenson, 6020 Cornerstone Court W. Suite 240, San Diego, CA 92121. Be sure to write “NAFLD – Tim Ferriss” in the memo line.
3. Donate by transferring securities (stocks, etc.). Email [remember the double “r” and double “s”] and they’ll do as much heavy lifting as possible.
Thank you for reading, and thank you for supporting if you’re able.  This is a good fight.
If you’d also like to hear a fascinating chat with Peter Attia, MD, co-founder of NuSI, I interview him here on radical sports experimentation, synthetic ketones, meditation, and more. He’s a competitive ultra-endurance athlete, MD, surgeon, and obsessive self-tracker, so we get along great :)

Friday, July 18, 2014

Fruits and Vegetables Are Trying to Kill You

Antioxidant vitamins don’t stress us like plants do—and don’t have their beneficial effect.

You probably try to exercise regularly and eat right. Perhaps you steer toward “superfoods,” fruits, nuts, and vegetables advertised as “antioxidant,” which combat the nasty effects of oxidation in our bodies. Maybe you take vitamins to protect against “free radicals,” destructive molecules that arise normally as our cells burn fuel for energy, but which may damage DNA and contribute to cancer, dementia, and the gradual meltdown we call aging.
Warding off the diseases of aging is certainly a worthwhile pursuit. But evidence has mounted to suggest that antioxidant vitamin supplements, long assumed to improve health, are ineffectual. Fruits and vegetables are indeed healthful but not necessarily because they shield you from oxidative stress. In fact, they may improve health for quite the opposite reason: They stress you.
That stress comes courtesy of trace amounts of naturally occurring pesticides and anti-grazing compounds. You already know these substances as the hot flavors in spices, the mouth-puckering tannins in wines, or the stink of Brussels sprouts. They are the antibacterials, antifungals, and grazing deterrents of the plant world. In the right amount, these slightly noxious substances, which help plants survive, may leave you stronger.
Eating food from plants that have struggled to survive toughens us up as well.
Parallel studies, meanwhile, have undercut decades-old assumptions about the dangers of free radicals. Rather than killing us, these volatile molecules, in the right amount, may improve our health. Our quest to neutralize them with antioxidant supplements may be doing more harm than good.
The idea that pro-oxidant molecules are always destructive is “oversimplified to the point of probably being wrong,” says Toren Finkel, chief of the center for molecular medicine at the National Heart, Lung, and Blood Institute in Bethesda, Maryland. “Oxidants may be a primordial messenger of stress in our cells, and a little bit of stress, it turns out, may be good for us.”
Although far from settled, a wave of compelling science offers a remarkably holistic picture of health as a byproduct of interactions among people, plants, and the environment. Plants’ own struggle for survival— against pathogens and grazers, heat and drought—is conveyed to us, benefitting our health. This new understanding begins, in part, on a treadmill.

In the mid-20th century, as modern medicine seemed poised to vanquish the infectious diseases of yore, some scientists turned to the degenerative diseases associated with aging. Attention fell on a class of molecules called “reactive oxygen species,” or ROS. These volatile substances could damage DNA. Degenerative diseases, such as cancer and cardiovascular disease, often showed evidence of “oxidative stress,” suggesting that ROS spurred disease.
Oddly, our mitochondria, the energy factories of our cells, emitted ROS naturally. So degenerative disease seemed to stem in part from our own metabolic function: Your mitochondria “burned” fuel, emitted this toxic exhaust, and inadvertently set the limits on your existence. That was the working hypothesis, at any rate.
Experiments on rats and worms showed that reactive oxygen species, such as hydrogen peroxide, tear atoms from other molecules, destroying them in the process. That can be problematic when those molecules are DNA, our cellular instruction manual. We produce native antioxidants, such as the molecule glutathione, to counteract this pro-oxidant threat. They react with ROS, neutralizing the pro-oxidants before they can damage important cellular machinery.
When scientists blocked rodents’ ability to manufacture these protective molecules, lifespan declined. Observational studies, meanwhile, suggested that people who regularly ate vitamin-laden fruits and vegetables were healthier. So were people with higher levels of vitamins E and C in their blood.
Vitamins were strongly antioxidant in test tubes. So the ROS theory of aging and disease rose to prominence. You could slow aging, it followed, by neutralizing free radicals with antioxidant pills. A supplement industry now worth $23 billion yearly in the U.S. took root.
But if those ROS were so harmful, some scientists asked—and the basic design of our (eukaryote) cells was over 1 billion years old—why hadn’t evolution solved the ROS problem? At the same time, scientists began finding that exercise and calorie restriction increased lifespan in animals. Both elevated ROS. According to the ROS model of aging, animals that exercised and fasted should have died younger. But they lived longer.
For Michael Ristow, a researcher of energy and metabolism at the Swiss Federal Institute of Technology in Zurich, the inconsistencies became impossible to overlook. In worms, he found that neutralizing those allegedly toxic ROS reduced lifespan, so he designed a similar experiment in humans.
He had 39 male volunteers exercise regularly over several weeks; half took vitamin supplements before working out. The results, published in 2009, continue to reverberate throughout the field of exercise physiology, and beyond. Volunteers who took large doses of vitamins C and E after training failed to benefit from the workout. Their muscles didn’t become stronger; insulin sensitivity, a measure of metabolic health, didn’t improve; and increases in native antioxidants, such as glutathione, didn’t occur.
Exercise accelerates the burning of fuel by your cells. If you peer into muscles after a jog, you’ll see a relative excess of those supposedly dangerous ROS—exhaust spewed from our cellular furnaces, the mitochondria. If you examine the same muscle some time after a run, however, you’ll find those ROS gone. In their place you’ll see an abundance of native antioxidants. That’s because, post-exercise, the muscle cells respond to the oxidative stress by boosting production of native antioxidants. Those antioxidants, amped up to protect against the oxidant threat of yesterday’s exercise, now also protect against other ambient oxidant dangers.
Contrary to the ROS dogma, Ristow realized, the signal of stress conveyed by the ROS during exercise was essential to this call-and-response between mitochondria and the cells that housed them. To improve health, he figured, perhaps we shouldn’t neutralize ROS so much as increase them in a way that mimicked what happened in exercise. That would boost native antioxidants, improve insulin sensitivity, and increase overall resilience.
Ristow called this idea “mitohormesis.” The term “hormesis” came from toxicology (“mito” was for mitochondrion). It describes the observation that some exposures generally considered toxic can, in minute amounts, paradoxically improve health. For instance, minuscule quantities of X-ray radiation, a known carcinogen, increases the lifespan of various insects.
Hormesis may be most easily grasped when considering exercise. Lift too much weight or run too long, and you’ll likely tear muscle and damage tendons. But lift the right amount and run a few times a week, and your bones and muscles strengthen. The intermittent torque and strain increases bone mineralization and density. Stronger bones may better tolerate future shocks that might otherwise cause fractures.
In his experiment, Ristow saw that vitamin supplements interrupted this sequence of stress followed by fortification, probably because they neutralized the ROS signal before it could be “heard” elsewhere in the cell. By interfering in the adaptive response, vitamins prevented the strengthening that would have otherwise followed the stress of physical exertion. Antioxidant supplementation paradoxically left you weaker.
Vitamins are necessary for health. And supplements can help those who are deficient in vitamins. Insufficient vitamin C, for instance, causes scurvy, which results from defective collagen, a protein in connective tissue. Among other functions, vitamin C aids collagen synthesis.
But the primary role of vitamins in our body, according to Ristow and others, may not be antioxidant. And the antioxidant content of fruits and veggies does not, he thinks, explain their benefits to our health. So what does?

Mark Mattson, Chief of the Laboratory of Neurosciences at the National Institute on Aging, has studied how plant chemicals, or phytochemicals, affect our cells (in test tubes) for years. The assumption in the field has long been that, like vitamins, phytochemicals are directly antioxidant. But Mattson and others think they work indirectly. Much like exercise, he’s found, phytochemicals stress our bodies in a way that leaves us stronger.
Plants, Mattson explains, live a stationary life. They cannot respond to pathogens, parasites, and grazers as we might—by moving. To manage the many threats posed by mobile life, as well as heat, drought, and other environmental stresses, they’ve evolved a remarkable number of defensive chemicals.
Health doesn’t result solely from the instructions your genome contains, but your relationship with the world.
We’re familiar with many components of their arsenal. The nicotine that we so prize in tobacco slows grazing insects. Beans contain lectins, which defend against insects. Garlic’s umami-like flavor comes from allicin, a powerful antifungal. These “antifeedants” have evolved in part to dissuade would-be grazers, like us.
Mattson and his colleagues say these plant “biopesticides” work on us like hormetic stressors. Our bodies recognize them as slightly toxic, and we respond with an ancient detoxification process aimed at breaking them down and flushing them out.
Consider fresh broccoli sprouts. Like other cruciferous vegetables, they contain an antifeedant called sulforaphane. Because sulforaphane is a mild oxidant, we should, according to old ideas about the dangers of oxidants, avoid its consumption. Yet studies have shown that eating vegetables with sulforaphane reduces oxidative stress.
When sulforaphane enters your blood stream, it triggers release in your cells of a protein called Nrf2. This protein, called by some the “master regulator” of aging, then activates over 200 genes. They include genes that produce antioxidants, enzymes to metabolize toxins, proteins to flush out heavy metals, and factors that enhance tumor suppression, among other important health-promoting functions.
In theory, after encountering this humble antifeedant in your dinner, your body ends up better prepared for encounters with toxins, pro-oxidants from both outside and within your body, immune insults, and other challenges that might otherwise cause harm. By “massaging” your genome just so, sulforaphane may increase your resistance to disease.
In a study on Type 2 diabetics, broccoli-sprout powder lowered triglyceride levels. High triglycerides, a lipid, are associated with an increased risk of heart disease and stroke. Lowering abnormally elevated triglycerides may lessen the risk of these disorders. In another intervention, consuming broccoli sprout powder reduced oxidative stress in volunteers’ upper airways, likely by increasing production of native antioxidants. In theory, that might ameliorate asthmatics’ symptoms.
Elevated free radicals and oxidative stress are routinely observed in diseases like cancer and dementia. And in these instances, they probably contribute to degeneration. But they may not be the root cause of disease. According to Mattson, the primary dysfunction may have occurred earlier with, say, a creeping inability to produce native antioxidants when needed, and a lack of cellular conditioning generally.
Mattson calls this the “couch potato” problem. Absent regular hormetic stresses, including exercise and stimulation by plant antifeedants, “cells become complacent,” he says. “Their intrinsic defenses are down-regulated.” Metabolism works less efficiently. Insulin resistance sets in. We become less able to manage pro-oxidant threats. Nothing works as well as it could. And this mounting dysfunction increases the risk for a degenerative disease.
Implicit in the research is a new indictment of the Western diet. Not only do highly refined foods present tremendous caloric excess, they lack these salutary signals from the plant world—“signals that challenge,” Mattson says. Those signals might otherwise condition our cells in a way that prevents disease.
Another variant of the hormetic idea holds that our ability to receive signals from plants isn’t reactive and defensive but, in fact, proactive. We’re not protecting ourselves from biopesticides so much as sensing plants’ stress levels in our food.
Harvard scientist David Sinclair and his colleague Konrad Howitz call this xenohormesis: benefitting from the stress of others. Many phytonutrients trigger the same few cellular responses linked to longevity in eukaryotic organisms, from yeasts to humans. Years of research on Nrf2 in rodents suggest that activating this protein increases expression of hundreds of health-promoting genes, including those involved in detoxification, antioxidant production, control of inflammation, and tumor suppression.
In the dance between animals and plants, there’s true mutualism. “We’re in this together, the plants and us.”
Sinclair studies another class of native proteins, called sirtuins, associated with health. They’re triggered by exercise and also, Sinclair contends, a molecule called resveratrol, found in grape skins and other plants. “It’s too coincidental that time and time again these molecules come out of nature that have the surprising multifactorial benefit of tweaking the body just the right way,” Sinclair says.
They’re not all antifeedants, he argues. Plants churn these substances out when stressed, prompting further adaptations to the particular threat, be it drought, infestation by grazing insects, or excessive ultraviolet radiation from the sun.
For grazers, these stress compounds in plants may convey important information about environmental conditions. So grazers’ ability to “perceive” these signals, Sinclair argues, likely proved advantageous over evolutionary time. It allowed them to prepare for adversity. A grape vine stressed by fungi churns out resveratrol to fight off the infection. You drink wine made from those grapes, “sense” the harsh environmental conditions in the elevated tannins and other stress compounds, gird your own defenses, and, in theory, become more resistant to degenerative disease.
One implication is that modern agriculture, which often prevents plant stress with pesticides and ample watering, produces fruits and vegetables with weak xenohormetic signals. “I buy stressed plants,” Sinclair says. “Organic is a good start. I choose plants with lots of color because they are producing these molecules.” Some argue that xenohormesis may explain, at least in part, why the Mediterranean diet is apparently so healthful. It contains plants such as olives, olive oil, and various nuts that come from hot, dry, stressful environments. Eating food from plants that have struggled to survive toughens us up as well.
Philip Hooper, an endocrinologist at the University of Colorado Anschutz Medical Campus, points out that plant-animal relationships are often symbiotic, and communication goes both ways. One example of direct plant-to-animal, biochemical manipulation comes from the coffee bush. Flowering plants compete with one another for the attention of pollinators, such as bees. Coffee bushes seem to gain advantage in this “marketplace” by using caffeine. The drug excites pollinators’ neurons, etching the memory of the plant’s location more deeply in their brains. Some think that biochemical tweaking increases the probability that the pollinator, which faces a panoply of flower choices, will return to that particular coffee bush.
In the dance between animals and plants, says Hooper, “I think there’s true mutualism. We’re in this together, the plants and us.”

While xenohormesis is a compelling idea, it remains unproven. Barry Halliwell, a biochemist at the National University of Singapore, and an expert on antioxidants, has seen the dietary fads, from vitamins to fiber, come and go. He says the hormetic and xenohormetic ideas are plausible, but not certain. Various studies suggest that people who consume a lot of fruits and vegetables have healthier lifestyles generally. Those people probably go easy on the junk food, which alone may improve health.
Even within the hormetic idea, Halliwell sees the attempts to bore down on the individual chemicals as problematic. “That’s worked very well in pharmacology, but it hasn’t worked at all well in nutrition,” he says. He doesn’t think any single phytonutrient will explain the apparent health-promoting benefits of fruits and veggies. “Variety seems to be good,” he says. That critique speaks to a larger problem: It’s often unclear how lab research on simple organisms or cell cultures will translate, if at all, into recommendations or therapies for genetically complex, free-living humans.
What works in genetically uniform organisms, or cells, living in highly controlled environments, does not necessarily work in people. Human studies on resveratrol in particular have yielded contradictory results. Proper dosage may be one problem, and interaction between the isolates used and particular gene variants in test subjects another. Interventions usually test one molecule, but fresh fruits and vegetables present numerous compounds at once. We may benefit most from these simultaneous exposures.
The science on the intestinal microbiota promises to further complicate the picture; our native microbes ferment phytonutrients, perhaps supplying some of the benefit of their consumption. All of which highlights the truism that Nature is hard to get in a pill.
These caveats aside, research into xenohormesis reminds us that we are not at the complete mercy of our genetic inheritance. Genes matter, but health depends in large part on having the right genes expressed at the right time—and in the right amount. If our genome is a piano, and our genes are the keys, health is the song we play on the piano. The science on hormesis, the stresses that may keep us strong, provides hints about what kind of song we should play. Keep the body conditioned with regular exercise. Keep your cells’ stress-response pathways intermittently engaged with minimally processed, plant-based food.
These recommendations end up sounding rather grandmotherly—if your grandmother was a spartan, no-nonsense peasant who lived off the land. But the underlying thrust contradicts assumptions about the need to protect oneself from hardship. Certain kinds of difficulty, it turns out, may be required for health. That’s because health doesn’t result solely from the instructions your genome contains, but from your relationship with the wider world. Resilience isn’t completely inherent to your body; it’s cultivated by outside stimuli. And some of those stimuli just happen to be mildly noxious, slightly stressful chemicals in plants.

Moises Velasquez-Manoff is a science writer and author of An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. He lives in California.

Saturday, July 12, 2014

Why wiping out HIV “reservoirs” is so hard

Virus sometimes inserts near genes that make cells divide faster.

HIV (green false color) buds off an immune cell (red).
HIV, the virus that causes AIDS, does its damage by decimating immune cells. But it also lies dormant in some cells, creating a reservoir that can restart an active infection long after the active virus has been cleared by treatments. This is apparently what happened to a child from Mississippi who was thought to have been cured of infection following antiviral treatments.
Researchers may now have found one of the reasons that it's so hard to clear out these reservoirs of infected cells. As part of the infection process, HIV normally inserts a copy of itself into a cell's chromosomes. By chance, some of these insertions cause the cell to grow faster, ensuring that more copies of the virus are around to cause trouble.
The researchers, who are all based in Seattle, took a pretty simple approach to discover this: they sampled cells from HIV patients who were receiving long-term antiviral treatment, looking for the sites of HIV insertion. In these patients, viral replication was suppressed by the drugs, often for periods of over a decade. Therefore, any viruses researchers found were from those cells that had quiescent viruses inserted into their genome.
In total, the team identified over 500 individual viral insertion sites. They then figured out whether the virus was inserted in or near a gene and, if so, what that gene does. In many cases, the nearby genes were involved in controlling cell growth. Of the 20,000 or so human genes, only a bit over five percent have been associated with cancer. But over 12 percent of the genes that had HIV insertions in or near them had been implicated in cancer, and an even higher number had been found to control cell growth and proliferation.
In one patient, 31 percent of the infected cells had HIV insertions near a gene that stops cell division if DNA damage is detected. Another had seven distinct HIV insertions in a gene that acts as a tumor suppressor in immune cells (a second had two additional insertions in the same gene). In total, at least 12 genes had HIV insertions in at least two of the three patients; several of these genes have also been associated with controlling growth.

Why growth genes?

It might be tempting to speculate that HIV selectively targets those genes that are involved in growth, but the authors suggest that an evolutionary process is at play. HIV inserts at random, and some of those insertions happen to be near genes. When that's the case, the presence of the virus can alter the gene's activity, either by disrupting it or by causing it to become more active. In some cases, this will be harmful and the cell will die or grow poorly; in others, it will have little effect.
But in a few cases, the virus' insertion will affect nearby genes in a way that can cause the cell to grow faster. Either the insertion will inactivate a gene that slows down growth or it will up-regulate a gene that promotes growth. Over the course of a decade, even if the boost in growth is very small, this will cause the virus-infected cell to outgrow other infected cells, as well as uninfected cells. In short, through random chance and selection, a few insertions will ensure that there are plenty of cells with silent HIV insertions, waiting to re-establish an active infection should the chance appear.
The authors suggest that their results may be an underestimate of how often cell growth genes are involved. To begin with, some of the sites of HIV insertion may not be very close to genes yet will still be able to alter their activity. In addition, some of the genes that the authors have identified are known to affect cell growth but aren't listed that way in the major databases, so they don't show up in the list of genes associated with cancer.
The results highlight an unfortunate fact of HIV: while learning how to control the virus was hard, learning how to eradicate it is going to be really hard. Scientists have lots of ideas about how to go about this, but until one of them makes some substantial progress, any talk of an actual "cure" is premature.
Science, 2014. DOI: 10.1126/science.1256304  (About DOIs).

Saturday, April 26, 2014

Scientists at Johns Hopkins Come Closer to Eliminating Heart Disease

A world without heart disease seems impossible. But researchers at Johns Hopkins just got one step closer.
Scientists at Johns Hopkins University may be one step closer to eradicating debilitating heart diseases in humans, particularly those caused by excessive buildup of cholesterol.
A new study published in the journalCirculation shows that a synthesized drug reduces, and may even eradicate, the effects of high-fat and high-cholesterol diets. And though the drug is prosperous for the heart and brain most specifically, the entire body may benefit from this development.  
“It’s the entire cardiovascular system that’s affected,” Ekaterina Pesheva, a representative for Johns Hopkins, told The Daily Beast. “The reason we’re worried about the heart and the brain is because those are the centers that end up being the most debilitating to human life when affected by fatty buildups.”
The study shows that the new drug under examination, known now as D-PDMP, changes the way fat metabolism works, and eliminates the risk of heart attack and heart disease. The drug halts the development of atherosclerosis, a word referring to the hardening of the arteries. Atherosclerosis is based on a buildup of fat and cholesterol in blood vessels, and happens to be the main cause of heart attacks in humans. Most notably, atherosclerosis is the No. 1 cause of death in humans (perhaps a little-known fact in a world rampant with famine, war, and crime).
Atherosclerotic heart disease is the most common type of heart disease, which develops when fat builds inside the blood vessels over time, rendering them stiff, narrowed, and hardened. This, in turn, reduces blood flow to the heart and brain.
Other kinds of heart disease include structural heart disease—people born with malformations of their heart, which is rare, and heart failure (mostly a result of poorly functioning heart muscle, which can be due to a number of causes, including atherosclerosis. It can also be caused by other conditions such as viral infections of the heart) will also benefit from this development.
Perhaps the most remarkable aspect of these new developments is that the compound used to control the atherosclerosis is a widely available, man-made compound.
Dr. Subroto Chatterjee, Ph.D, a cardio-metabolic expert at Johns Hopkins Medicine, spearheaded the research and development of this project. “Atherosclerotic, in most colloquial terms, means clogged vessels, or vessels thickened by buildup of fat inside the vessel,” Chatterjee told The Daily Beast. “And this research was quite challenging,” he said, “but we feel like we got quite lucky with the development here.”
Chatterjee and his team found that D-PDMP almost totally eliminated the buildup of cholesterol in vital regions of the body. Perhaps the most remarkable aspect of these new developments is that the compound used to control the atherosclerosis is a widely available, man-made compound.
The researchers tested the drug in mice and rabbits, Chatterjee told The Daily Beast. The mice were known to already have heart problems and the rabbits were known to have healthy hearts. That complicates the study, if only because the control group of the species isn’t specific to one cardiovascular system. Researchers fed both species a high-fat and high-cholesterol diet.
“Indeed, this diet nearly guarantees arteriosclerosis in these transgenic/mutant mice as they fail to handle LDL [low-density liver] cholesterol,” Chatterjee said. “In these animals on this diet, the risk of this disease is nearly 100%. There is one chance in four that your child may have blood cholesterol that is too high. Healthy individuals have a one in two chance of abnormally elevated blood cholesterol,” he said. “More than 70 million Americans have high cholesterol, according to the CDC.”
Cholesterol control is a contentious field in medical research, because the side effects of drugs used to treat the issue can be dangerous. The Daily Beast spoke with John McEvoy, a cardiology fellow in preventive cardiology physician, at Johns Hopkins, who was not involved with this particular study.
“It’s always very important when a new mechanism for treating high cholesterol and heart disease comes about,” McEvoy said. “This pathway and new treatment are very exciting in that regard. However, the next step for these researchers will be making sure there are no side effects of the drug that are harmful to humans.”
Chatterjee said that the actual development of the drug is about five years away. He put its science in simple terms 
“Imagine you have clogged up plumbing due to debris,” Chatterjee said. “Similar clogging in our blood vessels occurs due to fat and cholesterol building up over time. Our drug, we hope, will prevent [or] delay the rise in cholesterol and fat and thus prevent thickening/hardening of the blood vessel. This is like the use of Drano to clean up our plumbing at home.”

Tuesday, March 11, 2014

Unique individual with lupus and HIV demonstrates desired immune response to HIV

Duke Medicine
One person’s unique ability to fight HIV has provided key insights into an immune response that researchers now hope to trigger with a vaccine, according to new findings. The person had a rare combination of both lupus and HIV. Lupus, specifically systemic lupus erythematosus, or SLE, is a disease in which the immune system attacks the body's cells and tissue.

One person's unique ability to fight HIV has provided key insights into an immune response that researchers now hope to trigger with a vaccine, according to findings reported by a team that includes Duke Medicine scientists.
The person had a rare combination of both lupus and HIV. Lupus, specifically systemic lupus erythematosus, or SLE, is a disease in which the immune system attacks the body's cells and tissue.
In an analysis published March 10, 2014, in the Journal of Clinical Investigation, the Duke-led research team detailed how the individual's immune system made a desired type of neutralizing antibodies that is considered essential to an effective vaccine response.
"Over the years we have searched for and now have found one person with SLE who was also chronically infected with HIV to determine if this person could make broad neutralizing antibodies," said Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute and senior author of the study. "We found that the patient did indeed make these important antibodies, and by determining how this immune response occurred, we have enhanced our understanding of the process involved."
Haynes said a huge barrier to creating an effective HIV vaccine has been the difficulty in eliciting the broad neutralizing antibody response. These antibodies arise in a few people infected with HIV, but it takes at least two years.
In 2005, Haynes found that some broad neutralizing antibodies to HIV cross-reacted with the body's tissues in a process termed autoreactivity. Autoreactive antibodies are kept in check by the body's immune tolerance controls, which sense antibodies that react with the body and prevent them from being made.
Haynes's hypothesis has been that these autoreactive broad neutralizing antibodies are not routinely made because the immune system targets them as harmful and keeps them in check. In essence, the virus has found a unique escape mechanism from neutralizing antibodies by adapting itself to look like the body's tissues.
In an autoimmune disease such as lupus, the immune tolerance controls are defective, so the broad neutralizing antibodies should be produced, the Duke team reasoned.
Haynes and colleagues, including lead author Mattia Bonsignori, M.D., assistant professor of medicine at Duke, identified an individual with both lupus and HIV and found that, after several years, the person made the desired broad neutralizing antibodies.
Remarkably, the broad neutralizing antibody found in the lupus individual was autoreactive, and reacted with similar molecules in the body called double stranded DNA, or dsDNA, that are made in individuals with lupus who do not have HIV.
"The cross-reactivity of the broad neutralizing antibody with dsDNA was very surprising and provided support for the hypothesis that broad neutralizing antibodies are similar to the autoantibodies that arise in lupus patients who are not infected with HIV," Bonsignori said.
The findings in no way suggest that individuals with lupus are immune to HIV, and they, like all individuals, should protect themselves from contracting the virus. Rather, it suggests that when individuals with lupus do become infected with HIV, they can eventually make broad neutralizing antibodies, although unfortunately too late to help them fight off the infection.
"Our study of this person with SLE and HIV has been critically instrumental in our understanding of the unusual biology of the remarkable host control of antibody responses to the conserved broad neutralizing sites of the HIV envelope," Bonsignori said. "We are hopeful that these insights in lupus will aid in our implementation of strategies for designing experimental vaccines capable of overcoming the host tolerance control of broad neutralizing antibodies."
In addition to Haynes and Bonsignori, study authors from Duke include Kevin Wiehe, Guang Yang, Daniel M. Kozink, Florence Perrin, Abby J. Cooper, Kwan-Ki Hwang, Xi Chen, Mengfei Liu, Robert J. Parks, Joshua Eudailey, Minyue Wang, Megan Clowse, Lisa G. Criscione-Schreiber, M. Anthony Moody, Feng Gao, Garnett Kelsoe, Laurent Verkoczy, Georgia D. Tomaras, Hua-Xin Liao, and David C. Montefiori. Other authors include Sabastian K. Grimm and Margaret E. Ackerman from Dartmouth College; Rebecca Lynch, Krisha McKee and John R. Mascola from the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases; and Scott D. Boyd of Stanford University.
The National Institute of Allergy and Infectious Diseases funded the study (AI067854 and AI100645).

Story Source:
The above story is based on materials provided by Duke Medicine. Note: Materials may be edited for content and length.

Journal Reference:
  1. Mattia Bonsignori, Kevin Wiehe, Sebastian K. Grimm, Rebecca Lynch, Guang Yang, Daniel M. Kozink, Florence Perrin, Abby J. Cooper, Kwan-Ki Hwang, Xi Chen, Mengfei Liu, Krisha McKee, Robert J. Parks, Joshua Eudailey, Minyue Wang, Megan Clowse, Lisa G. Criscione-Schreiber, M. Anthony Moody, Margaret E. Ackerman, Scott D. Boyd, Feng Gao, Garnett Kelsoe, Laurent Verkoczy, Georgia D. Tomaras, Hua-Xin Liao, Thomas B. Kepler, David C. Montefiori, John R. Mascola, Barton F. Haynes. An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI73441

Cite This Page:
Duke Medicine. "Unique individual with lupus and HIV demonstrates desired immune response to HIV." ScienceDaily. ScienceDaily, 10 March 2014. <>.