30 November 2010

New vitamin D guidelines, a disappointment

Over the past decade, there has been tremendous excitement in the world of nutrition centered around the "sunshine vitamin" for its association with reducing risk of influenza, osteoporosis, autoimmune diseases, heart disease, and even some cancers such as prostate and breast cancer. 

However, this morning, the Institute of Medicine, of the National Academy of Sciences released new guidelines for vitamin D (and calcium) that will come as a disappointment to several researchers who consider the report too conservative to deal with a widespread epidemic.

"Vitamin D is the most common medical condition in the world, believe it or not" said Michael Holick, of Boston University Medical Center, to me in a recent interview. Holick, who routinely prescribes 2000-3000 IU per day to his patients, has studied Vitamin D for more than 40 years. In the 1970s he was the first to isolate the major circulating form of Vitamin D in plasma, 25-hydroxyvitamin D, as well as the active form produced in the kidneys. 

In his recently published book, The Vitamin D Solution, Holick cites evidence that: 
  • Half of all children in the US and Europe are Vitamin D deficient at some time, but almost every single one has vitamin D insufficiency.
  • Over the last 10 years there's been 22 percent reduced levels of vitamin D in the US
  • Last year, a study published in Archives of Internal Medicine, showed 70 percent of whites, 90 percent of Hispanics and 97 percent of blacks in the US have insufficient levels.
  • Even near the equator (where you'd think people were getting plenty of sun –think Saudi Arabia, India, Australia, Brazil, Mexico – between 30 to 80 percent of children and adults are deficient or insufficient.
  • Three out of four people in the US are deficient, most are insufficient. Twenty years ago it was only 1 out of 2.
  • New research has linked several common problems of poor health and accelerated aging to one single thing – vitamin D deficiency or insufficiency
Despite these data, the IOM reported that most people in the U.S. and Canada should be able to obtain sufficient amounts from their diet to meet Dietary Recommended Intakes (DRIs), assuming no other vitamin D was synthesized from the sun in the skin.

The IOM raised the DRIs of vitamin D to 600 International Units (IU) for ages 1-70 and to 800 IU for ages 70 and older. Previously the DRIs were 200 IU for ages 1-50, 400 IU for ages 51-70, and 600 IU for ages 70 and older.

The Tolerable Upper Limit was also raised from 2,000 IU to 4,000 IU for adults, which will allow major manufacturers such as the dairy industry and Coca Cola who make Minute Maid orange juice to consider doubling vitamin D in their products.

The IOM committee chair Catharine Ross, of Penn State, said that after reviewing more than 1,000 published studies and listening to testimonies of scientists there still wasn't enough solid evidence for raising vitamin D DRIs or ULs any higher.

In a press conference this morning, she said, "What we were not able to do is take the currently available clinical data including randomized clinical trials and use that information for Dietary Recommended Intakes. The data are not sufficient at present to conclude that intakes should be higher."

When asked about why the Upper Limit was not raised higher, Ross said, "We needed to take a cautious approach because we're looking to reduce risk to the public. There's evidence of harm at the level of 10,000 IU. So we used 4000 IU per day." She said that there was a gap in evidence in between the two numbers.

Other scientists on the committee chimed in:

"There's considerably more evidence, a tremendous amount for vitamin D," said Patsy Brannon, of Cornell, yet not enough to guide decision making on greater intake. She added, "There is research that points to risk. There's also research that shows no risk. We also lack RCTs. We're still needing more research."

Oncologist Steven Clinton, of Ohio State University, said, "As you look across the literature there are inconsistencies." For example, regarding calcium, it's associated with less colon polyps, but increased risk in prostate cancer. He says that in the future as more data become available, there will be more individualized approaches.

"We are still interested in this molecule that affects thousands of genes in the body. But we cannot make this leap at this point," added biochemist Glenville Jones, of Queens University.

The committee had been asked to set new guidelines for DRIs of calcium and vitamin D as well as Upper Limit intakes.

What about supplements?

Despite headlines from the New York Times and several other news outlets, the IOM committee voiced that they did not intend for this kind of position and clarified that they did not specify where the vitamin D amounts should come from--whether it be from the sun, supplements or diet.

Clinton added that, "especially in Canada, we don't want to close the door on those supplements. There's possibility of using supplements." Although, he said he wondered about whether or not the Canadian Cancer Society would change its recommendation from 1,000 IU to 600-800 IU in light of the IOM's new recommendations.

When asked what to make of the new recommendations when it's clear that skin synthesis upon sun exposure yielded amounts of 20000 IU or higher, Brannon responded: "We set our recommendations based on data for total consumption of vitamin D."

She added that the difference between dietary intakes and the skin synthesis is that the body has a natural ability to rid itself of excess made by the sun, "The sun giveth, the sun taketh away."

Apart from Holick, other scientists have voiced their opinions like those representing the Vitamin D Council: Bruce Hollis of Medical University of South Carolina and Robert Heaney of Creighton University.

They have long recommended taking a supplement by as much as 5,000 IU per day to maintain blood levels between 50-80ng/mL year-round.

As Science News reports, Hollis called the IOM report "a big waste of money," although agreed with the panel's decision to double recommendations for children. In addition, Heaney said, “I don’t think this does anything to create confidence in IOM recommendations."

The entire IOM report is summed up by registered dietitian Debra Riedesel, who posted on Twitter, as @NutritionistaRD, in response to the debate, "Do you trust the scientists who've researched Vit D for years or 14 IOM scientists who only read the research?"

24 November 2010

Food sharing: Hunter-gatherer "health insurance"

Kim Hill
By pure chance (involving a failed attempt to go hiking and a speeding ticket), I found myself at a talk given by anthropologist Kim Hill, speaking on the "Emergence of Human Uniqueness: Characteristics Underlying Behavioral Modernity."

I previously wrote an article for Scientific American on an Arizona State University workshop that Hill headed up along with Curtis Marean and Lawrence Krauss last February.

Most of Hill's talk was basically the same stuff I wrote about before like that humans are outliers, not unique in any specific way, but contain a combination of non-unique traits that arose through non-unique processes produced a unique outcome -- a "spectacular anomaly."

"If aliens from outerspace came to the Earth," Hill said, then they would be questioning humans instantly because we're so dominant in several ways: technologically, agriculturally, population-wise, etc.

Some would point to the industrial revolution, but Hill argues that hunter-gatherers would have still attracted aliens' attention because they were still the most prosperous species even before agriculture.Humans engage in more ecological niches than all other species combined.

Besides humans, the most successful terrestrial vertebrate is "Canis lupus" (wolves, and that's not counting dog domestication). Both humans and wolves share something in common: cooperative breeding.

So, how do you get this spectacular anomaly?

Hunter-gatherers colonized all the land mass, produced massive megaliths, created complex institutions, and developed languages and cultures.

Hill discusses how he and other scientists came together to discuss what makes humans unique looking at fields of primatology, evolution, hunter-gatherer work, etc.

What makes us uniquely human is a combination of traits that were critical for producing outlier outcomes:

-Cumulative culture

OK, so we know all of this. But now here's the interesting part!

Hill showed data from his work that has to do with the economics of cooperation in humans as compared to chimps. Humans are hypercooperators.

What led to hypercooperation in humans?

Hill discusses that it may be due to:

a) a shift on the feeding niche going from collected foods to extracted foods and predation. This is shown in the paleoanthropolical record from 1) emergence of waist, 2) evidence of cooking, 3) stone tool cut marks.

b) extracted and hunted foods caused by juvenile dependence and long learning period.

Basically, adults need to take care of children for several more years in comparison to chimps. Human kids produce virtually nothing, even as they grow older they produce little versus the adults.

c) high variance in large-package foods promotes food sharing

In other words, Kim says, some adults are hunting and bringing home lots of food, way more than they can eat, or that their nuclear family can eat. This promotes food sharing.

He gives an example of the Ache tribe (hunter-gatherers from Paraguay who he's studied for over 30 years) and how at the end of the day everyone brings their extra food to distribute among the group. Children too are taught to share food from the time they're two years old.

Hill gives data on the percent of food types that are kept versus produced by a nuclear family. Some families give away the majority of food (70 to 90 percent!) they produce (and he joked about comparing that to a tax bracket and socialism).

Food sharing among hunter-gatherers is interesting and complicated, Hill says. The sharing is a type of "health insurance" so that if a man, for example, gets sick or injured taking him out of the production three months, he is covered by the sharing of others. He gives data on "health insurance premiums" given by hunter-gatherers like Ache, Efe, Yora, Tsimane.

Food sharing networks helped us survive and have long lives, Hill said. Because in comparison to chimps, humans have less risk of premature death because if a "chimp falls out of a tree and breaks its arm, it's dead" even though the chimp will heal simply because it will starve to death.

Hill then gave more data on hunter-gatherer habits of women overproducing and then led into cooperative breeding, which is reproducing with the help of others in birth and child rearing.

And, again, wolves are also cooperative breeders, so it's definitely an effective strategy.

"What we now know," says Hill, "is that individuals go through periods of time when they are producing a surplus and other times when families cannot feed all the mouths they have."

To illustrate the point, Hill shows us a picture of a typical hunter-gatherer family that has breeders, helpers, and dependents. He gives data on how these families subsidize food.

"It takes a 'band' to raise a child," is typed up on the slide.

He compares hunter-gatherer systems to an institutionalized social security system. "This is a universal pattern among hunter-gatherer societies," he says. A family without this would not be able to be successful. Kinship like cousins, aunts, and uncles are usually the foundation of human cooperative breeding.

But Hill has been studying how kinship moves to larger social organizations of hunter-gatherer societies.

He showed how chimp communities often are not in contact with each other and often kill each other. But, based on work by Bernard Chapais, pair bonding -- transferring females among groups, for example -- which leads to cooperation between groups.

When a sister is married to a man in another group, a brother will create an alliance with the husband. It leads to sharing food communally.

Hill said people like Paul Davies who are looking for alien species should not be looking for "intelligent life on other planets," but actually be looking for cooperative species -- species that work together to accomplish big tasks.

"Chimps are intelligent and dolphins are intelligent," he said, "but ants are closer to building a spaceship than chimps."

Learn more link: Here's some other crazy neat info from Hill on Amazonian hunter-gatherers widespread belief that they have multiple fathers.

20 November 2010

Chemicals in Store Register Receipts and Fast Food Wrappers

Before the next time you ask a cashier for a receipt, think twice! It might be tainted with bisphenol A, aka BPA.

A recent study in Environmental Health Perspectives showed that cashiers had highest BPA exposure because of its use in thermal paper for register receipts in a monomer form that is readily absorbed through skin.

BPA is also used as a polymer complex in hard, clear polycarbonate plastic water bottles and as epoxy resins lining aluminum cans.

The study raises concerns about widespread exposure to BPA from a variety of sources, especially for women who are pregnant.

Although the actual BPA amounts in receipts is so little it may not pose enough risk to worry about, it does raise concerns for people—those behind a register, for example—who are in contact with the thermal paper regularly.

The news comes no later than a month after Health Canada officially declared BPA a toxic substance that mimics estrogen, potentially increasing risks of breast cancer and prostate cancer.

Additionally, do you need another reason to avoid junk food? Here’s one: New research shows chemicals used to line fast food wrappers and microwave popcorn bags are contaminating the food and can be observed in the blood stream.

According to research from University of Toronto in the same journal, the greaseproof paper that is frequently used in the packaging of these products contain polyfluoroalkyl phosphate esters (PAPs) that break down into perfluorinated carboxylic acids (PFCAs).

PCFAs are known carcinogens and the scientists suggest that food packaging as well as non-stick and other water- and stain-repellant products like kitchen pans and clothing may be increasing exposure.

Controlling human exposure to these, and other, chemicals has become an active area of research recently as the public gains more understanding about the potential health implications caused by these toxic compounds.


Braun JM, Kalkbrenner AE, Calafat AM, Bernert JT, Ye X, et al. 2010 Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy. Environ Health Perspect doi:10.1289/ehp.1002366

D’eon JC, Mabury SA, 2010 Exploring Indirect Sources of Human Exposure to Perfluoroalkyl Carboxylates (PFCAs): Evaluating Uptake, Elimination and Biotransformation of Polyfluoroalkyl Phosphate Esters (PAPs) in the Rat. Environ Health Perspect doi:10.1289/ehp

How our senses help us decide what we eat

Senses help us select our food.
So, this is a blog post about the importance of sensory criteria for selecting food, which was inspired by a day of cooking up goods for the holidays.

What makes people choose the foods that they do? This question may seem obvious to yourself--after all, you know what you like--but this is a question posed by food industry scientists ask themselves day in and day out.

The science of food selection can get crazy complex when you think of the huge variety of foods that you find at your corner grocery store. Food scientists must continually find new "niches" for products to be placed in the marketplace.

How do they do it? The same question can be asked of musicians who endlessly produce new songs that the radio blares as latest hits, but using the same 12 musical notes. Only, in the case of food, scientists only have five notes, or tastes, the "Five-Taste Stimuli":

-savory (umami - think MSG, mushrooms, tomatoes, broth)

Taste rates high in the evaluation for selection from consumers. As it happens, the sensation is produced when the food comes into contact with cilia (tiny hairs) on gustatory cells, which make up around 10,000 taste buds (depending on age; people lose them as they age).

By itself, taste isn't all that complex, but then food is mixed with other sensory criteria:

-touch (texture, mouthfeel)
-hearing (yes, the sound of food)

Sight has to do with the presentation or appearance of the food. When we first look at food, we are in a sense already "eating it" with our eyes: judging for shape and color, ripeness or rottenness, smoothness or crunchiness, well-cooked or burnt.

Visual signals, mixed up with several other stimuli, instantly tell your brain whether or not you're ready to eat that grilled chicken breast or let it brown a little longer, or whether to eat that banana or wait until it turns from green to yellow (but not to black).

Smell is a wholly vital part of what it is to create food -- and I would argue that any good food scientist is also an expert at using volatile molecules from food to reach our olfactory epithelium. Flavor, in fact, is around 75 percent smell.

In the olfactory epithelium, which is inside the nasal cavity, is where volatile molecules will act on between 10 to 20 million olfactory cells. These cells can pick up between 2,000 to 4,000 different odors. A few experts are so well trained, they can distinguish closer to 10,000 -- an extremely keen sense of smell.

Touch is a sense that we use for picking our foods because it allows us to pick up on texture, astringency, consistency and temperature. Generally, with food, we start our touch evaluations with our fingers and then as the food moves toward our lips, next is the mouthfeel.

Mouthfeel of a food can tell us a lot more: a smooth texture may mean more fat content, which is more desirable to our energy-seeking brains. It also tells us whether that steak is tender or chewy, dry or moist, if the soda pop is bubbly or flat, if the vegetables are crispy or rubbery, if citrus fruits or vinegar is astringent.

Of course, touch inside the mouth also determines a food's temperature and spiciness. Heat and cold are picked up by the taste buds. The sensation of spiciness, like the one caused by capsaicin in hot peppers, is caused by irritating nerves.

A sense of hearing might not seem as important in food selection, but most of us evaluate food all the time with sound without even realizing it. We like to hear the snap of a celery stick, the crackle of potato chips, the pop of popcorn.

The sounds give clues about whether a food is fresh or sufficiently cooked. Think also of the sound a watermelon makes when you tap it to make sure it's fresh, or the sound stir-fry makes when it's sizzling.

So, back to how food scientists use all these sensory criteria: With the five-taste stimuli and other sensory signals (as in music with 12 notes, beats and rhythms), food scientists can continue creating thousands of foods that flood our grocery stores annually.

Each and every satisfying food can be appreciated for its particular complexity of visual presentation, flavor aroma, texture and sound -- they are what makes us love to eat.


Brown, A. 2000. Understanding Food: Principles and Preparation. Wadsworth: Belmont, CA.

16 November 2010

What happens on a high omega-6 diet

A while back I wrote a review of Queen of Fats: Why Omega-3s Were Removed from the Western Diet and What We Can Do about Them. Susan Allport's book goes into the history of how omega-3s were discovered and what they'll mean for us in the future.

A controversial topic of the book is how omega-6 (king) and omega-3 (queen) compete for space in eicosanoid pathways. The omega-6s, the king, are the greater competitor and more inflammatory, while the omega-3, the queen, are a lesser competitor and less inflammatory.

She goes on about this relationship between omega-6 and omega-3 and gives examples from nature of how both the oils are found and used -- omega-3s in leaves (leaf fats), omega-6s in seeds (seed fats); omega-3s eaten more often in summer months, omega-6s in winter months by animals. The omega-6s are thought to bring on extra fat for warmth, for storage, for hibernation.

It's all pretty interesting stuff. And again, as I said, a bit controversial.

Now, in a new article, Susan gives a single-person account -- herself -- of results one gets from eating a high omega-6 diet for one month. I mean, we're not talking about a randomized, clinical trial. But nevertheless, her results are particularly interesting:

- reduced RMR
- omega-3 drop in blood (10% to 6%)
- omega-6 rise from 21% to 29%

- brachial artery dilation drop by 22%
- gain of 5 pounds

You can read more about her small experiment here. In the meantime, I'm popping my fish oil pills.

12 November 2010

Resveratrol influences belly fat behavior

Fat can not only be unsightly, but if it’s sitting on your belly, may also contribute to overproduction of signaling hormones called adipokines, which are linked to metabolic changes that can worsen health.

New research from Aarhus University has found that abdominal adipose tissue extracted from overweight adults, and then exposed to resveratrol, exhibited reduced adipokine production. According to these authors, "small interfering molecules such as resveratrol are, in this matter, hypothesized to possess beneficial effects and might improve the metabolic profile in human obesity."

The scientists obtained the abdominal adipose tissue via liposuction from seven women and one man, ages 43-55, who had body mass indexes categorized as overweight. All subjects were Caucasian, healthy and not on any medication that could confound the results.

Because previous studies in rodents have shown that calorie restriction reduces production of adipokines by activating an enzyme called Sirtuin 1, the scientists had hypothesized that resveratrol may act similarly. Resveratrol is well-known as a potent Sirtuin 1 activator.

This most recent in vitro study, published in International Journal of Obesity, suggests that regular dietary intake of resveratrol may guard against the metabolic changes that occur when there is excess fat on the body – as it has with rodents and monkeys.

Resveratrol is a phytoalexin (a plant-produced antimicrobial substance) found in small amounts, most notably, in red wine, as well as in other common foods such as grapes, peanuts, and chocolate. The most concentrated natural source is the Japanese Knotweed (Polyganum cuspidatum).

Resveratrol gained scientific interest after it demonstrated effects similar to calorie restriction in slowing the rate of aging and increasing the lifespan in a number of species including nematode worms, mice, and rhesus monkeys. In addition, resveratrol protects overfed mice from weight gain and lemurs from seasonal weight gain.

Source: Olholm J, Paulsen SK, Cullberg KB, Richelsen B, Pedersen SB. Int J Obes (Lond) 2010;34:1546-53.

09 November 2010

Middle-aged Mice fed BCAAs live longer

Scientists are actively seeking aging-intervention strategies to help people maintain their youth in anticipation of a sharp rise in the elderly population – due to the "baby boomer" generation – and an unprecedented number of elderly in North America and throughout the developed world.

Now, a new study in the October issue of Cell Metabolism reports that middle-aged, male mice given a cocktail of branched-chain amino acids (BCAAs) – leucine, isoleucine, valine – in their drinking water lived an average of 12 percent longer (869 days compared to 774 days) than middle-aged, male mice drinking regular water.

The scientists, from Milan University, found that the BCAA-fed mice exhibited similar changes as those seen with calorie restriction or resveratrol supplementation, showing an increase in longevity-gene SIRT1 activity and an increase in cardiac and skeletal muscle mitochondria levels.

The treated mice also showed improved exercise endurance and motor coordination, and had fewer signs of damage from oxidative stress.

In future studies, the researchers plan on performing similar experiments with female mice.

"This is the first demonstration that an amino acid mixture can increase survival in mice," said lead researcher Enzo Nisoli, referring to prior studies that showed that the cocktail of BCAAs extends lifespan in yeast.

Getting BCAAs in the Diet

Nisoli suggests that older people may find similar anti-aging benefits from including BCAAs in their diets by eating protein or taking supplements high in BCAAs as part of a complete “nutritional approach” for aging gracefully.

Supplements of BCAAs are widely used by athletes, including bodybuilders, because they help to trigger protein synthesis and drive muscle growth, especially when taken within 20 minutes after workouts.

However, one of the most convenient ways to obtain greater amounts of BCAAs in the diet is by drinking one or more servings of a whey protein-based shake daily.

BCAA-rich whey protein has been shown consistently in several studies to aid in maintaining muscle as well as speeding up muscle recovery and growth after exercise. Preserving skeletal muscle and strength is a significant factor for maintaining long-term health.

Source: D’Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, Caliaro F, Corsetti G, Bottinelli R, Carruba MO, Valerio A, Nisoli E. Branched-Chain Amino Acid Supplementation Promotes Survival and Supports Cardiac and Skeletal Muscle Mitochondrial Biogenesis in Middle-Aged Mice. Cell Metabolism, 12(4):362-372, October 2010, doi:10.1016/j.cmet.2010.08.016.

08 November 2010

My tour of Yale biotech facilities

I had the good fortune of touring Yale University's biotech facilities today, including the 2007-built Yale Stem Cell Center, with its director as our guide: cell biology professor Haifan Lin, PhD.

Walking through a high-tech stem cell facility with Lin was nothing like I expected. Lin was incredibly personable, and he and his staff took us through their labs and offices with a sense of enjoyment and courtesy if introducing us as friends to their home -- "come on into my lab, here's our million-dollar microscope, there's our genomic analyzer, would you like some tea?"

OK, so Lin didn't actually offer us tea, but he might as well have with his ultra-nice Chinese hospitality. On the tour, there were only three of us, all journalists, so it lended to opportunity of intimate discussion and questions.

Lin generously answered everything we wanted him to and with a genuine excitement about it. He shared that he had an appreciation for what we science writers do, saying, in fact, that he'd thought of joining the ranks so he could spread his own message -- that the science of stem cells is promising us a spectacular future free of certain diseases like neurological diseases and cancer.

The Yale Stem Cell Center is actually a conglomeration of several departments rich in expert faculty in areas of stem cell genetics, translational regulation, transcriptional regulation, stem cell assymetry, clinical transplantation, stem cell programming, cancer stem cells, and stem cell for tissue repair.

They all interact and the way the center is built -- with open labs and offices -- allows for plenty of collaboration. All their objectives are centered around a specific goal. "The key is personalized medicine through stem cells," Lin says.

For example, faculty member Dr. Eugene Redmond showed that Parkinson's Disease could be improved in mice and monkeys by injecting neural stem cells. With more trials underway, stem cell injections will likely become the future of treatment for humans.

Also, faculty members Drs. Christopher Breur and Toshihanau Shinoka have built blood vessels to treat congenital heart disease with stem cells. This is important to help the many "blue babies" born each year. In pigs, they had 100 percent success with treatment. The babies that have received the stem cells grow beautifully.

They actually "create living, growing blood vessels from scratch," which means we could eventually replace temporary treatments of today (that have autoimmune rejection problems) with tissue engineering treatments of tomorrow. In Breur and Shinoka's work, the vessels made were indistinguishable from any other vessels in the body.

Lin will soon be presenting a "big talk" at the next world stem cell meeting and he's hoping that the public will begin to become more thrilled about the possibilities that stem cells will bring to medicine.

Several other examples exist of how stem cells will help solve serious medical puzzles, but each all starts with basic research. This basic research is what Yale Stem Cell Center is all about.

Lin illustrates an example of basic research: he gave us a brief overview of DNA, mRNA, rRNA, and tRNA transcription of proteins, then reminded us that only 1 percent of DNA is involved in transcription. The rest, commonly called "junk DNA," is terra incognita. Lin's lab has been able to show that it's not junk, but produce piRNA, important in regulation of the other "big" genes. They sequenced 60,000 plus piRNA!

New technologies at Yale are allowing these developments to happen. "It is like discovering a new world of genes," Lin says, comparing the development in scope to Columbus discovering America. It will lead to new genetic mechanisms, drugs and therapies.

We toured core labs, Lin's own lab, saw high-powered microscopes, a genomic analyzer that could sequence an entire human genome in a week, and lots and lots of miscellaneous science stuff.

New Paradigms and the Future of Medicine

What is the future of medicine and how will we get there? On Monday morning, as part of New Horizons of Science at Yale, Director of Institutes of Systems Biology Lee Hood discussed the advent of 21st-century medicine: p4 medicine.

What are paradigm changes in biology leading to p4, or proactive medicine? There are several changes needed and all overlap and interconnect, but the main drivers in the process are:

- bringing engineering to biology through high throughput biology
- the human genome project
- cross-disciplinary biology
- systems biology

"What's fascinating is that these four paradigm changes are creating a new foundation in medicine," says Dr. Hood. "And they were each met with skepticism."

What does p4 medicine represent? predictive, preventive, personalized, participatory (p4). In other words, it's the taking of genomics and systems biology to finally unravel the complexity of pathology and seeking out preventive and personalized strategies of healthcare.

When Hood was at Caltech, he realized that he would be working on new bioinformatics technologies. At the time, they had known about DNA, RNA, proteins -- but with technology, he realized, they could transform how to understand biology.

His team created five instruments that changed biology. The instruments were automated (in collecting data), integrated information, and served to produce new ways of understanding biology.

The first instrument he produced was a protein sequencer, two hundred times more sensitive than other instruments. With it, they found the first "cancer gene," a platelet-derived growth factor. It sequenced prions related to Mad Cow Disease. It sequenced the first billion-dollar biotechnology product, epo. Also, it discovered the first blood development factor.

Why not commercialize the instruments? Hood pitched this to the University, but was told, "It's not the role of Academia". So, he went out to sell it himself. There have now been 14 companies founded by Hood Labs.

He discussed the human genome projecg and how, in Spring 1985, his bioinformatics technologies helped shape the feasibility of the challenge in the face of opponents who were "vehemently against" the project -- because it would take a way from "legitimate science" (including the National Institutes of Health).

Why has the genome project transformed biology? It provides complete parts of gene lists, transforms biology by providing access to genomics of species, and increases understanding of evolution, understanding of nutrition, and understanding of medicine.

Another instrument, the DNA sequencer, helped bring forth a cross-disciplinary approach of meeting current medical challenges -- merging chemistry, biology, mathematics, molecular biotechnology. The first cross-disciplinary department, at University of Washington, pioneered the new field of proteomics.

The problem with biology and systems biology is that it's "way too complex," but moving into the 21st century, scientists now have the computational and mathematical tools to turn biology into an informational science. Then, taking a systems approach, p4 medicine can attack vexing challenges of healthcare.

"If you think of yourself as a living creature, there are two types of information" that make you -- digital information about your genome, and environmental imprints -- the genotype and phenotype.

"It's a combination of these two types of information that leads to most diseases," Hood says. We need to think about the relationships between the two sets of information to effectively solve disease.

How you think about systems biology is critical: you need to be able to integrate data types, delineate biological networks, acquire global data, and formulate models for "discovery science."

The agenda: Use biology to drive technology and computation needed to create a cross-disciplinary approach to biology.

The Institutes for Systems Biology has just had its 10th anniversary. Back in 2000 when Hood first started the institute there was a lot of skepticism, but now there are 70 more institutes worldwide.

In short, the impact made by systems biology and a computational and systems approach to disease is grand -- it's the approach of seeing etiology of disease as altered biological networks.

He shows how his technologies compute the dynamics of a brain network in prion disease in mice. They found four networks involved in the disease. There about 300 genes in a mouse, two thirds mapped into the networks.

Going on, Hood explains that blood is a window into health and disease with systems diagnosis to identify key network nodal points for early detection, prevention, treatment. In the future, we should have complete genome sequencing of families, the human proteome project, the second human genome project.

Family genome sequencing has itself demonstrated that scientists can use principles of Mendellian genetics to identify 70 percent of sequencing errors, discover variants, and more rapidly find genetic encoding that leads to disease.

What about the future? "One of the most revolutionary biology fields is single-cell analysis," Hood says. This is along with stem cells and computational, systems, integrative biology.

Concluding, he says, there needs to be a transition in healthcare to p4 medicine, so ISB has set up partnerships for "inventing the future." They will be creating 21st century biomedicine involving systems analysis of biology and medicine, technology development, and preventive strategies.

"P4 medicine is about 1) wellness and 2) demystifying disease," Hood says, noting that the ultimate solution is prevention by using systems biology and bioinformatics technologies.

In the Q&A part after this talk, it was asked "when will we reach the p4 zone?" and Hood replied that there are several examples of companies that are reaching this point (and he names 23andme as a pioneer).

Some day, with Hood's leadership and technologies, our own complex biologies will be hacked, reduced to information, for the development of healthcare strategies built around personalized medicine.

If interested in following p4 medicine as it grows in acceptance, check out ISB's newsroom

Location:Temple St,New Haven,United States

07 November 2010

Why do we make bad decisions? It's evolution, stupid.

In the afternoon session of New Horizons in Science at Yale, psychology professor Laurie Santos delivered a compelling talk on the origins of human irrationality.

Santos studies comparative cognition in primates including humans, chimps, various monkeys, and (my favorite animal) lemurs! There isn't too much about rationality that we don't share with the rest of the primate family.

What makes humans different in irrationality? Well, actually, a lot of us are indeed similarly stupid to most monkeys -- cognitively speaking, because of biases, heuristics, errors in judgment.

It's amazing that we can even become adult humans at all, says Santos. Her research delves into what causes us to be irrational, our "cognitive dissonance."

Cognitive dissonance, it turns out, is shaped by decisions and preferences that lead to our decision making. And, she presented examples of experiments of how they found in adults and children that preferences change dependent on prior decision making.

For example, when children are forced to choose between two stickers (one showing a fish, another animal), they later express avoidance for choices they previously chose against when no additional information is given (Psychological Science, 2007).

Then, the same experiment was performed on monkeys (with M&Ms, not stickers) and found the same -- they prefer to avoid the one they avoided befofe -- when no new information was presented.

She also went through other experiments, in which it was found that we and monkeys consistently make irrational decisions.

A real-world example of irrationality? Our economic choices are often irrational. If we get a $20 parking ticket our emotional responses are often greater than the opposite response produced if we happened to find a $20 bill on the street.

Santos then brought in some audience participation giving us simple choices in which we'd have to make some kind of risk analysis. If we have a coffee mug for sale, we often have a higher perceived value of it versus if we were buying it.

Basically, the feeling you get from potential loss aversion is often stronger than the feeling you get from potential gain.

In a primate trading method experiment, Santos describes how her team gave monkeys tokens to buy "products" and she shows a video of the monkeys making choices depending on the products given.

Do monkeys have a concept of ownership? She showed that the "endowment effect" does exist in monkeys. If given cereal or fruit (which they treat with equal preference) to trade for the opposite, they will prefer what they were originally given. However, if the monkeys are given the choice of trading their goods for a "good deal" like fruit roll-ups, then they'll capitalize the opportunity.

The capuchins evaluate choices relative to reference points, they exhibit loss aversion, endowment effect, and switch preferences depending on how risk is presented (avoiding loss aversion).

"What we're starting to discover..." Santos says, "a lot of these irrationalities are shared broadly across the primate order suggesting that they originated in a common ancestor."

So, what are the next steps? "We like to think of our species as special," so if we find the kinds of things that show a unique bias, then we can understand more about what makes humans unique.

Also, how does advertising work? They're designing experiments where they show advertisements to the monkeys like an alpha male drinking Coke versus Pepsi, with the thought suggested, "Be alpha male, drink Coke!"

In short, Santos proposes, we can learn a lot about ourselves by researching not just how smart we are, but how "dumb we are" too. After all, we are apt to purposely lose with intent of punishing others, an example of emotional human irrationality.

There may even be cases of uniquely human irrationalities.

Location:Chapel St,New Haven,United States

What microbes in our soil (not dirt!) mean to us

Most people have no idea just how large the role of microbes play as a part in our world, in our soil, in our bodies. That was the introduction we received on the subject from Yale professor Jo Handelsman at New Horizons in Science (as part of #sciwri10).

As a molecular, cellular and developmental biologist, Handelsman takes issue with any scientist or science writer who dares refer to the world's largest organ as simply "dirt" (a mistake I've already made and won't make again).

In human health, microbes do a lot more than we thought, says Handelsman. There are interesting associations of feelings like anger and different composition of human gut microbiota. Microbes or microbial products or microbial interactions with host tissues are also shown in animals to be linked to diseases including obesity, diabetes, etc. (apart from genetics and diet).

We are "microbial organisms"! says Handelsman, noting that our bodies contain 10 times more microbes than cells. Similarly, the Earth is largely a microbial organism as the microbes affect climate, provide most of the nitrogen on the planet, and make up the soil that produces our food.

How much do microbes play in climate? A lot. The microbes in the ocean are what fix much of the carbon creating oxygen, but "the plants get most of the credit."

Bacteria are also what stabilizes the soil, by living and forming the crust on the surface of sand -- preventing erosion and providing planetary health.

So, in reality, microbes are good! They are not simply pathogens and toxic, as many people believe, says Handelsman.

Soil itself is mostly microbial with 10 billion bacteria per gram. Soil supports 95 percent of our food. And soil bacteria are our primary source for antibiotic drugs.

Antibiotics, in particular, present a reason why we must study soil. There are few antibiotics in the pharmaceutical industry pipeline, there's bacterial resistance to most antibiotics in use, and overuse and abuse is worsening the problem.

"Now we're facing a health crisis that is unprecedented," says Handelsman. "But worse than that is that industry has abandoned the study of antibiotics (with the exception of Merck and Pfizer)."

This is scary considering the growth and density of the human population, which could lead to a major catastrophe that Handelsman says "we are not prepared for."

She then shows a graph to illustrate an example of how resistant bacterial strains can spread rapidly, which cannot be treated -- an area of "enormous concern" of which she studies.

Why does antibiotic resistance exist? It's well established that excessive use, especially in livestock, creates the development of resistance. The antibiiotics used on animals leaks into the environment, into the soil, into the water.

About a decade ago, Handelsman and her team developed microbial observatories to study the soil. They asked questions about whether or not antibiotic resistance genes move from soil to humans, where are the origins, and is there contact between soil and wounds (such as in Iraq, Afghanistan).

Her team has three sites for microbial observation: West Madison, Alaska, and Epplegarden. The sites are strategically located to collect data on how antibiotics overuse could lead to antibiotic resistance.

Coming back now to soil bacteria, she notes that most bacteria that we know of can't be cultured. They are dramatically different than bacteria we can culture. So, how to identify and study?

The team developed "metagenomics" ("bypassing the culturing step") and going to genomic analysis. They also analyze the activities expressed by clones carrying fragments of genomic DNA extracted from the organism assemblage.

In other words, they take a sample of soil, place it in a vessel, extract DNA, clean uop the DNA (because it's "dirty"!), and then replicate by introducing DNA fragments into E. coli.

For example, they take E. coli resistant to kanamycin (an aminoglycoside), penicillin resistance, then isolate genes that are responsible for the resistance. They found three kanamycin-resistant genes in orchard soil, which produced fusions of proteins that conferred the resistance.

Handelsman also described what they found when they looked at Alaskan soil bacteria with beta-lactam (amoxicillin, penicillin) resistance. The bacteria harbored a gene producing bifunctional enzyme, beta-lactamase.

"Interestingly, the resistance genes were relatively poorly related to other known resistance genes," Handelsman says. So, the data reveal that bacteria don't have specific "drug-resistant determinant."

Antibiotic use in livestock, agriculture, "pig operations, in particular," is an environment ripe for drug-resistant strains of microbes. An example is flurophenicol.

In apple orchards, sprayed with streptomycin, there was concern about strep resistance. But they found that there was little resistance since, perhaps, the strep didn't penetrate the soil. Also, the strep-resistance genes in humans were not the same.

Takeaways? Bacteria are wonderful, should be revered. Most aren't culturable, metagenomics provides us access to unculturable bacteria. Through metagenomics we've also discovered novel resistant genes, raising question about resistance origins, such as agricultural practices that raise more questions. In short, soil is super and needs more study.

In the Q&A session, Handelsman also commented on the unwillingness of the meat industry to understand, or do anything about, the evidence showing the problems with antibiotic resistance related to agricultural practices. Their defense, "the data are inconclusive."

If you found the idea of metagenomics as neat as I did, then you might also find Jo Handelsman's 2004 paper on the subject interesting, which is published in Microbiology and Molecular Biology Reviews.

Location:Chapel St,New Haven,United States

On the Hunt for Neuropsychiatric Disorder Genes

Next speaker up at New Horizons in Science is co-director of Yale's Neurogenetics Program Matthew State, a child psychiatrist who describes himself as a gene hunter.

The genes he seeks out are those that may be linked to child neuropsychiatric disorders including autism, Tourette, and obsessive-compulsive disorders.

What he and other researchers use as a tool is high-throughput, high-resolution genomic analysis, which is so fast that in the near future we may know quite a bit more about many of the chromosomal rearrangements linked to several genetics disorders.

However, he says, "we still have not been able to find a single common variation" in gene sequence that explains any of the child psychiatric disorders. But, he expresses a certain excitement about the future of genomics analysis because of fast technologies.

What he predicts is that rare gene variations, or rare combinations of gene variations, will finally explain the etiology of the child psychiatric disorders. Soon, we'll know enough to put the science on par with other more-understood diseases like cancer.

He shares findings from his lab, published in Nature last month, of a defective gene involved in the expression of histamine, which is linked to neuropsychiatric disorders.

Histamine acts as a neuromodulator that opposes dopamine activity, so the discovery may lead to a number of compounds already in clinical trials related to histamine as options for potential treatments.

Dr. State also shared information about the pathways that are involved or may be involved in autistic spectrum disorders.

The point, really, that he's pushing in this talk is that "next-generation sequencing helps us map pedigrees that we couldn't map before." In fact, he adds, "new sequencing technology is transforming" the entire way we look at the future of medicine.

Many genes lead to a phenotype and one gene that goes wrong can lead to large implications in a phenotype. The complexity of genetic disorders, unfortunately, is staggering.

So far the study of genetics has not produced much in terms of real-world treatments and benefits because of complexity, Dr. State says. He has high hopes for what cheaper, faster methods will bring in the future.

Location:Church St,New Haven,United States

Deep-brain stimulation for depression

On Sunday morning at New Horizons in Science at Yale -- after some coffee for brain stimulation -- we were treated to our first science talk of the day: on deep-brain stimulation as a treatment for severe depression.

Emory University professor of psychiatry and neurology Helen Mayberg, MD, showed us several brain scans she uses to study moods and neural networks. She can tell from these neural images whether you're glad, mad or sad.

Then, she targets areas of the brain with what she describes as an "implantation of a very, small wire... with electrodes on the end." The electrodes are guided to wherever she wants it in the brain and an IPG is implanted in the chest.

Dr. Mayberg worried about the safety of acute stimulation of areas of the brain. What happens if you stimulate the hypothalamus and it causes a drop in blood pressure? But she couldn't rely on surgeons as "gatekeepers," so she performed intra-operative safety testing.

During the testing, patients self-reported spontaneous feelings such as "intense calm" or resolution of pain and dread -- interoceptive release. These reports happened patient after patient, says Dr. Mayberg, so she knew something was going on. The feelings were followed by interest, energy -- exteroceptive awareness.

Dr. Mayberg's first study was published in 2005, then she expanded and published again in 2008 (in Biol Psych). The studies showed deep-brain stimulation was effective in treatment-resistant depression. "The [patients] not only got better, they stayed better," she says.

She then gave us some preliminary results of an Emory study of active treatment for six months with a two-year follow-up on bipolar and unipolar patients. The results so far look very, very promising. "This is an anti-depressant treatment, not a mood stabilizer," says Dr. Mayberg. "No one remains in pre-treatment state, everyone is on road to recovery."

She says now we know not just where to stimulate in the brain, but what fibers must be impacted for the treatment -- a treatment that can take patients with "gnawing pain" or feelings of "being in a room with 10 screaming children" to a place of a finding serious relief.

So, what's next? Dr. Mayberg says the treatment needs to go through a series of placebo-controlled trials to establish safety and to confirm initial results.

Even more exciting, however, is that with neural images it may be possible to soon predict and even prevent depression. "This is teaching us an amazing amount about depression," Dr. Mayberg says. The more we learn, the greater the understanding of what goes wrong in neural networks that leads to development of severe depressive disorders.

She's careful to point out that a stimulator is not the only thing you need to come out of a depressive state and it's not a device that will ever guarantee that people can forever say goodbye to "bad days."

But along with continual therapy over time, from a patient's perspective, the treatment can mean the difference between feeling like you are at the bottom of the Grand Canyon without any chance of hiking out and the feeling that you have when you have a pathway toward the top.