Caption: Adult human fibroblast cells (left) are reprogramed into human induced pluripotent stem cells
(iPS cells). The iPS cells have a characteristic stickiness that lets them to adhere to sorting devices
(right) with different strengths than other cells.
Credit: Ankur Singh and Andres Garcia, Institute for Bioengineering & Bioscience, Georgia Tech

There is much excitement about the potential of stem cells for many applications, including regenerative medicine and treating human diseases. But growing pure cultures of stem cells by reprograming adult cells—like human fibroblasts—into a less differentiated cell type called a human induced Pluripotent Stem cell (iPS cell), is a tricky business. These stem cell cultures are often contaminated with other normal cells that do not have the same coveted therapeutic potential. Manually sorting these stem cells is time consuming and difficult; using chemical approaches can damage the DNA inside. Now, we have a better option: NIH funded researchers from the Georgia Institute of Technology in Atlanta have invented a cell-sorting device that exploits specific characteristics of iPS cells.

iPS cells have a characteristic ‘stickiness’ that allows them to adhere to surfaces inside the sorting chip with different strengths than other cells. This stickiness is due to a signature set of proteins on the surface of these stem cells. Normal cells are coated in other proteins that give their surfaces different adhesive properties.

The researchers say the method is gentle, efficient, rapid, and generates collections of stem cells that are 95–99% pure.

Reference:

Adhesion strength-based, label-free isolation of human pluripotent stem cells. Singh A, Suri S, Lee T, Chilton JM, Cooke MT, Chen W, Fu J, Stice SL, Lu H, McDevitt TC, García AJ. Nat Methods. 2013 May;10(5):438-44.

NIH support: National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke; National Cancer Institute

Caption: Anopheles female blood feeding and Plasmodium falciparum eggs in Anopheles mosquito midguts.
Credit: Image courtesy of Jose Luis Ramirez, Laboratory of Malaria and Vector Research, NIAID, NIH

It turns out that one of the most innovative and effective strategies to fight malaria might involve harnessing a bacterium called Wolbachia. This naturally occurring genus of bacteria infects many species of insects, including mosquitoes. The reason this is important is that Wolbachia-infected mosquitoes become resistant to the parasite Plasmodium falciparum, which causes some 219 million cases of malaria worldwide and more than 660,000 deaths [1]. Wouldn’t it be amazing if Wolbachia-infected mosquitoes blocked the transmission of malaria?

Unfortunately, Wolbachia don’t normally pass from generation to generation in Anopheles, the mosquitoes that spread malaria. But that hurdle has now been overcome.

A team of NIH-funded researchers discovered that when a specific strain of Wolbachia, called wAlbB Wolbachia, was introduced into Anopheles stephensi—the major malaria-transmitting mosquito species in the Middle East and South Asia—it was passed down from generation to generation. In lab experiments, when just 5% of female mosquitoes were infected with wAlbB Wolbachia, researchers saw the bacteria spread to all the mosquitoes after just 8 generations [2].

Wolbachia likely makes the mosquito spew out a cocktail of toxic molecules called reactive oxygen species that kills the malaria parasites as it develops in mosquitoes’ mid-gut and salivary glands. That’s pretty cool—we’re basically using one microorganism to kill another.

This work suggests a potentially powerful public health intervention. Mosquitoes infected with wAlbB Wolbachia could be released in a region where malaria is endemic. These wAlbB Wolbachia mosquitoes would mate with the local mosquitoes. Their progeny would all carry the bacterium and be resistant to the malaria parasite. Eventually, wAlbB Wolbachia mosquitoes would replace the native population. It could be a very effective strategy, particularly for regions like sub-Saharan Africa where malaria claims the most victims.

This approach is promising and has already been tested on a small scale. In an Australian field trial, researchers successfully spread Wolbachia in another mosquito, Aedes aegypti, which transmits a disease called dengue fever. Wolbachia-infected mosquitoes infiltrated the local population and spread the bacteria from one generation to the next. In lab studies, these mosquitoes are resistant to dengue. It’s a clever intervention because the mosquitoes, by spreading Wolbachia, are actually doing all the work of blocking disease transmission.

Resources: 

[1] Malaria Facts. (CDC)

[2] Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection. Bian G, Joshi D, Dong Y, Lu P, Zhou G, Pan X, Xu Y, Dimopoulos G, Xi Z. Science. 2013 May 10;340(6133):748-51.

NIH support: National Institute of Allergy and Infectious Diseases

Caption: Researcher Zhaoxia Sun, at Yale, uses the zebrafish to study Polycystic Kidney Disease, which affects more than 600,000 Americans. Mutations in the zebrafish vhnf1 gene, and its human counterpart, cause cysts in both zebrafish and human kidneys (as shown by the large “bubble” seen in the mutant fish). [3]
Credit: Zhoaxia Sun, Biological & Biomedical Sciences, Yale University

Just last month, an international team of scientists—funded in part by NIH—published the entire genetic code of the zebrafish [1]. This is a vital resource for understanding human health and disease. How does the genetic blueprint of a fish help us or accelerate drug discovery? Well, it turns out that more than 75% of the genes that have been implicated in human diseases have counterparts in the zebrafish. So, if we discover a mutation in a human, we can make the corresponding mutation in the zebrafish gene—and often get a pretty good idea of how the gene works, how the mutation causes havoc, and how it causes disease in humans. We can even use the zebrafish to test potential drug candidates, to see whether they can alter or fix the symptoms before moving on to mice or humans.

A second paper in the same issue of Nature describes how another team has created mutations in 38% of all the zebrafish genes and is now investigating the effects of each mutation [2]. Fishy as it sounds, it’s an amazing system to learn about biology.

References:

[1] The zebrafish reference genome sequence and its relationship to the human genome. Howe K, et al. Nature. 2013 Apr 25;496(7446):498-503. doi: 10.1038/nature12111. Epub 2013 Apr 17.

[2] A systematic genome-wide analysis of zebrafish protein-coding gene function. Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, Sealy I, White RJ, Herd C, Nijman IJ, Fényes F, Mehroke S, Scahill C, Gibbons R, Wali N, Carruthers S, Hall A, Yen J, Cuppen E, Stemple DL. Nature. 2013 Apr 25;496(7446):494-7.

Genomics: Zebrafish earns its stripes. Schier AF. Nature. 2013 Apr 25;496(7446):443-4.

[3] vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Sun Z, Hopkins N.  Genes Dev. 2001 Dec 1;15(23):3217-29.

NIH support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; Office of the Director

Caption: Betatrophin, a natural hormone produced in liver and fat cells, triggers the insulin-producing beta cells in the pancreas to replicate
Credit: Douglas Melton and Peng Yi

Type 2 diabetes (T2D) has arguably reached epidemic levels in this country; between 22 and 24 million people suffer from the disease. But now there’s an exciting new development: scientists at the Harvard Stem Cell Institute have discovered a hormone that might slow or stop the progression of diabetes [1].

T2D is the most common type of diabetes, accounting for about 95% of cases. The hallmark is high blood sugar. It is linked to obesity, which increases the body’s demand for more and more insulin. T2D develops when specific insulin-producing cells in the pancreas, called beta cells, become exhausted and can’t keep up with the increased demand. With insufficient insulin, blood glucose levels rise. Over time, these high levels of glucose can lead to heart disease, stroke, blindness, kidney disease, nerve damage, and even amputations. T2D can be helped by weight loss and exercise, but often oral medication or insulin shots are ultimately needed.

Treating diabetes costs the U.S. a veritable fortune. Last year the bill came to $245 billion [2]—that’s $176 billion in direct medical costs and another $69 billion in lower productivity. We need a game changer. The new discovery just might lead to that, though it won’t happen overnight.

The NIH-funded researchers set out to try to identify a signal that seems to be sent by the liver to the beta cells when the insulin receptor is blocked and blood glucose levels rise.  The researchers found that after the insulin receptor was blocked, one particular liver gene increased its activity rather dramatically. They were able to show that this gene, which turned out to be one of the 20,000 genes that hasn’t attracted much attention so far, coded for a secreted protein. Because it helps beta cells grow, they named it “betatrophin.” This work was done in the mouse, but there’s an almost identical counterpart in the human. When the researchers engineered normal healthy mice to manufacture more of the hormone in their livers, the pancreas responded and made more insulin-producing beta cells.

Betatrophin sends the beta cells into a frenzy causing them to replicate as much as 30 times their normal rate! No other chemical or natural protein has ever caused such a dramatic boost in beta cell proliferation.

It’s not every day that a new and important hormone is discovered! But betatrophin has an important normal role in maintaining normal glucose levels. The amount of betatrophin produced in the liver (and in fat cells) rises naturally whenever the body needs to expand its inventory of beta cells: for example, during pregnancy, when the mother’s body needs to make more beta cells to accommodate the demands of the fetus.

The next step will be to see whether these extra beta cells, produced by administration of betatrophin, can produce enough insulin to halt and possibly reverse the disease in sick diabetic mice. If all goes well, we could be testing betatrophin in humans within two or three years.

Betatrophin could also help treat type 1 diabetes, which develops because the immune system attacks and destroys the insulin-producing beta cells in the pancreas. Currently, the only treatment for type 1 diabetes is insulin shots. But the researchers suspect that betatrophin might work during a critical time called the “honeymoon” period, which is a short window after the onset of disease but before all the patients’ beta cells have been wiped out.

In the future, rather than taking three insulin shots every day to treat their disease, people with T2D might receive a weekly or monthly betatrophin injection to produce more beta cells and keep their blood sugar at a healthy level. That would be a true paradigm shift in the treatment of this disease.

References:

[1] Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation. Yi P, Park JS, Melton DA. Cell. 2013 Apr 24

[2] Economic Costs of Diabetes in the U.S. in 2012. American Diabetes Association. Diabetes Care. 2013 Apr;36(4):1033-46.

Links:

National Diabetes Information Clearinghouse (NDIC): NIDDK

National Diabetes Statistics 2011: NDIC/NIDDK

NIH Clinical Trials

NIH support: The National Institute of Diabetes and Digestive and Kidney Diseases

Caption: Artist rendition of spiny headed worm │The adhesive patch with microneedles that swell
Source: The Karp Lab, Brigham and Women’s Hospital

Inspiration can come from some pretty strange sources. Case in point: a new adhesive Band-Aid inspired by Pomphorhynchus laevis, a spiny-headed worm that lives in the intestines of fish. The parasitic worm pokes its tiny, spiny, cactus shaped head through the intestinal lining and then inflates its head with fluid to stay anchored.

Using the same principle, the team at the Boston-based Brigham and Women’s Hospital created an adhesive patch with needles that swell up when they get wet, interlocking with the tissue. When this sticky patch is applied to anchor skin grafts that have just been placed over an area of injury or burn, it is three times stronger than surgical staples—and it causes less damage to soft tissues. Because it penetrates about one fourth the depth of staples, it should also be less painful to remove.

Hmmm, doesn’t it make you wonder what creepy crawly will inspire the next medical technology? Cockroaches? Spiders?

Source: The Karp Lab

References:

A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue. Yang SY, O’Cearbhaill ED, Sisk GC, Park KM, Cho WK, Villiger M, Bouma BE, Pomahac B, Karp JM. Nat Commun. 2013 Apr 16;4:1702.

Link:

Biomimicry: Inspired by Nature (See what else the Karp lab has developed)

NIH support: National Institute of General Medical Sciences

Source: National Human Genome Research Institute, NIH

We all hope for health care in the genomic era to become as easy and personal as a smartphone app. And perhaps at some point it will be. At some medical centers, electronic health records already include a list of patients’ genetic variations that might trigger harmful drug reactions and send ‘pop-up’ alerts to warn the physician or pharmacist. This is just the tip of the iceberg, but it’s a harbinger of things to come. Our big challenge is to translate all the new discoveries and data from the genome project into a format that physicians and other health care providers can use to improve health.

To bridge that transition from discovery to diagnostics and treatments, the NIH launched the Genetic Testing Registry (GTR) last year. There are hundreds of genetic testing companies, thousands of genetic tests for thousands of diseases, and some diseases have more than 20 names. What a challenge for providers to sort through! GTR is becoming a central repository of all the genetic tests available, and therefore greatly simplifies this search. It’s a vital resource, as providers can’t be expected to know all the diseases and genes or to keep tabs on the growing number of tests.

GTR is a free online tool. Health care providers simply type in a disease or gene, get a list of available genetic tests, and compare and order them. Importantly, the system promotes transparency by encouraging companies to voluntarily share detailed information about the tests, evidence that the tests predict what they claim, and proof that this information improves health in some way for patients and families.

To date, about 285 companies have participated, and NIH has extended invitations to hundreds more. GTR contains information on more than 3,000 tests that encompass about 2,100 diseases—such as Huntington’s, Marfan syndrome, and cystic fibrosis. GTR also includes tests that predict adverse reactions to drugs or the need to adjust doses.

GTR is an expanding resource that also helps health care providers identify relevant clinical trials, access professional practice guidelines, and find support groups for their patients. It also provides links to consumer friendly information about each disease.

Figuring out how to translate all the discoveries about the genome into better health and disease prevention is a major priority. GTR is part of the solution, as noted in a recent article in the Journal of the American Medical Association [2]. As we create new tools like GTR and ClinVar [3]—an online catalog of all known genetic variations and their health consequences—and stitch them together, your health care will be empowered.

References:

[1] Genetic Testing Registry

[2] Accessing genomic medicine: affordability, diffusion, and disparities. Tuckson RV, Newcomer L, De Sa JM. JAMA. 2013 Apr 10;309(14):1469-70.

[3] ClinVar

For more information:

Frequently Asked Questions About Genetic Testing

Genetic Testing

NIH support: National Center for Biotechnology Information, National Library of Medicine; National Human Genome Research Institute

April 25 is a very special day. In 2003, Congress declared April 25^th DNA Day to mark the date that James Watson and Francis Crick published their seminal one-page paper in Nature [1] describing the helical structure of DNA. That was 60 years ago. In that single page, they revealed how organisms elegantly store biological information and pass it from generation to generation; they discovered the molecular basis of evolution; and they effectively launched the era of modern biology.

But that’s not all that’s special about this date. It was ten years ago this month that we celebrated the completion of all of the original goals of the Human Genome Project (HGP), which produced a reference sequence of the 3 billion DNA letters that make up the instruction book for building and maintaining a human being. The $3 billion, 13-year project involved more than 2,000 scientists from six countries. As the scientist tasked with leading that effort, I remain immensely proud of the team. They worked tirelessly and creatively to do something once thought impossible, never worrying about who got the credit, and giving all of the data away immediately so that anyone who had a good idea about how to use it for human benefit could proceed immediately. Biology will never be the same. Medical research will never be the same.

We’ve discovered the 20,500 or so genes, and uncovered many of their regulatory switches, located in vast regions of DNA (once thought of as junk) that are vital for their proper function. We’ve catalogued genetic variations—some 54 million of them so far—that exist in the human species. Some of these variations are linked to disease—like heart disease, cancer, or diabetes—while others reveal specific adaptations that occurred as humans spread around the globe and adapted to different foods and climates. What’s more, we’ve discovered that our genome doesn’t work alone. Our bodies are continually interacting with microbes that are vital to our health, and we’re now decoding their genomes in what is called the microbiome project.

So how cheap is it to read your genome? Today, a scientist can decode it for just $3,000–$5,000 in only a few days; this continues to get cheaper and faster as technologies evolve. We have already done this for thousands of individuals (including my personal hero, South Africa’s Archbishop Desmond Tutu, who just won the Templeton Prize). We have discovered the genetic mutation behind almost 5,000 diseases or conditions. And we’ve harnessed this data to personalize medicine—we’ve matched more than 100 drugs to specific genes and developed genetic tests to help diagnose more than 1,000 diseases [2]. Equally as important, we’re making sure that people can use these genetic tests without fear of discrimination. To this end, Congress passed the Genetic Information Nondiscrimination Act (GINA), a law banning genetic discrimination [3].

I am a physician; my dream is to see these advances in understanding the genome translated into better methods of prevention, treatment, and cure of disease. And we are seeing that happen in many areas—perhaps most prominently in cancer and in rare genetic diseases, as readers of this blog will have noted. But much work still lies ahead. As we celebrate this special day, let’s resolve to use all means possible to bring the promise of the genomic revolution to those billions of people in the world who are still waiting and hoping for its benefits to reach them.

Infographic from National Human Genome Research Institute, NIH

References:

[1] Watson and Crick’s Landmark paper

[2] American Medical Association: Genetic Testing

[3] The Genetic Information Nondiscrimination Act (GINA)

Learn more with these resources from NIH’s National Human Genome Research Institute:

A Guide To Your Genome

DNA Day 2013: Teaching Tools and Resources

The Genomics Landscape a Decade After the Human Genome Project

Smithsonian NHGRI Genome Exhibition

Videos from HGP Anniversary Symposium (April 25, 2013) will be posted on GenomeTV by May 2

Caption: Transmission electron micrograph of novel coronavirus
Credit: Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH

In Fall 2012 a new coronavirus appeared on the global public health radar. The virus has caused 17 cases of severe respiratory disease in the Middle East and Europe, and 11 of these people died. This new virus attracted immediate attention because of the high fatality rate—and because it was in the same family as the virus that caused the global outbreak of severe acute respiratory syndrome (SARS) in 2003, which sickened more than 8,000 people.

A team here at the virus ecology unit at NIAID got a sample of the virus, called nCoV, from The Netherlands in November. By December they had developed an animal model to study how the virus behaved and caused illness. Now, just a few months later, they report that two antiviral drugs, ribavirin and interferon-alpha 2b, will stop nCoV from replicating in cells grown in the lab.

Clearly more studies are needed to figure out whether the treatment will translate to humans, but it’s an important first step. That’s virus to treatment in about four months—pretty impressive.

References:

Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Sci Rep. 2013 Apr 18;3:1686.

Pneumonia from Human Coronavirus in a Macaque Model. Munster VJ, de Wit E, Feldmann H. N Engl J Med. 2013 Apr 18;368(16):1560-1562. Epub 2013 Apr 3. 

NIH support: National Institute of Allergy and Infectious Diseases

Caption: Children with HGPS
Source: The Progeria Research Foundation

I’d like to tell you about a rare genetic disease that’s very close to my heart: Hutchinson-Gilford progeria syndrome, also called progeria. Though you may not recognize the name, you may well have seen pictures of children with this fatal premature aging disease. By 18-24 months, apparently healthy babies stop growing and begin to lose their hair. They develop wrinkled skin and joint problems and they suffer many other conditions of old age. Though their mental development is entirely normal, they often die of heart disease or stroke by age 12 or 13.

A decade ago, my research lab helped discover the cause of progeria: a mutation in the lamin-A gene [1]. Just a single letter substitution in the genetic code (C to T) creates a toxic version of the protein. The abnormal protein is missing a segment, and is no longer digestible by an enzyme called ZMPSTE24—essentially a molecular scissors. Without that final snip, the lamin-A protein causes molecular havoc.More recently, children who are completely missing the ZMPSTE24 enzyme have been identified, and they have an even more severe form of progeria called “restrictive dermopathy”. Many questions remain but now we are able to get a close up of ZMPSTE24 and understand how, and where, it normally modifies lamin-A.

Caption: A view inside the ZMPSTE24 molecular scissor
Source: Courtesy of Liz Carpenter, University of Oxford.

Using x-ray crystallography, a team based at the UK’s University of Oxford figured out the enzyme’s molecular structure [2, 3]. A cross section of the 3D structure (seen above) reveals a cavernous inner chamber where the authors believe the final snip of lamin-A takes place. It also shows us how mutations in ZMPSTE24, which inhibit lamin-A processing, can also lead to these rare aging disorders.

Knowing ZMPSTE24’s structure will help us better understand its clipping functions. It could also shed light on how this enzyme works in the normal aging processes—as well as in the accelerated aging of progeria. Ultimately, we hope it will also inform drug development for this devastating disease.

References:

[1] Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Nature. 2003 May 15;423(6937):293-8. Epub 2003 Apr 25.

[2] The structural basis of ZMPSTE24-dependent laminopathies. Quigley A, Dong YY, Pike AC, Dong L, Shrestha L, Berridge G, Stansfeld PJ, Sansom MS, Edwards AM, Bountra C, von Delft F, Bullock AN, Burgess-Brown NA, Carpenter EP. Science. 2013 Mar 29;339(6127):1604-7.

[3] Biochemistry. A protease for the ages. Michaelis S, Hrycyna CA. Science. 2013 Mar 9;339(6127):1529-30.

Video Link: Structure of Human ZMPSTE24

Caption: Optogenetic stimulation using laser pulses lights up the prelimbic cortex
Source: Courtesy of Billy Chen and Antonello Bonci

Wow—there is a lot of exciting brain research in progress, and this week is no exception. A team here at NIH, collaborating with scientists at the University of California in San Francisco, delivered harmless pulses of laser light to the brains of cocaine-addicted rats, blocking their desire for the narcotic.

If that sounds a bit way out, I can assure you the approach is based on some very solid evidence suggesting that people—and rats—are more vulnerable to addiction when a region of their brain in the prefrontal cortex isn’t functioning properly. Brain imaging studies show that rat and human addicts have less activity in the region compared with healthy individuals; and chronic cocaine use makes the problem of low activity even worse. The prefrontal cortex is critical for decision-making, impulse control, and behavior; it helps you weigh the negative consequences of drug use.

Addiction is an enormous public health issue. Currently, 1.4 million Americans are addicted to cocaine—and no treatment has been approved by the U.S. Food and Drug Administration, making it one of the National Institute on Drug Abuse’s top research priorities.

So let me first say that nerve cells, or neurons, don’t typically respond to laser beams. The rats in this experiment were engineered to carry light-activated neurons within a part of their prefrontal cortex called the prelimbic cortex. The rats were then fitted with optic fibers to transmit the laser pulses. This technique, called optogenetics, was actually invented by a recipient of the NIH’s Pioneer Award, and it will likely contribute significantly to the BRAIN initiative just announced by President Obama.

The researchers studied rats that were chronically addicted to cocaine. Their need for the drug was so strong that they would ignore electric shocks in order to get a hit. But when those same rats received the laser light pulses, the light activated the prelimbic cortex, causing electrical activity in that brain region to surge. Remarkably, the rat’s fear of the foot shock reappeared, and assisted in deterring cocaine seeking. On the other hand, when the team used a different optogenetics technique to reduce activity in this same brain region, rats that were previously deterred by the foot shocks became chronic cocaine junkies.

Clearly this same approach wouldn’t be used in humans. But it does suggest that boosting activity in the prefrontal cortex using methods like transcranial magnetic stimulation (TMS), which is already used to treat depression, might help. In fact, clinical trials at the NIH are scheduled to begin soon. The researchers plan on using TMS to bump up activity in the prefrontal cortex and see if it decreases addictive behaviors in people.

Links

Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Chen BT, Yau HJ, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, Bonci A. Nature. 2013 Apr 3.

Want to learn more? Check out these two resources from the NIH’s National Institute on Drug Abuse.

http://www.drugabuse.gov/drugs-abuse/cocaine

http://www.drugabuse.gov/publications/drugfacts/cocaine

NIH support: National Institute on Drug Abuse

Using a chemical cocktail, they infuse the brain with a hydrogel that locks in the brain’s form and structure in a type of matrix. Then the fatty layer that coats each nerve cell is stripped away, leaving a transparent brain (check out the transparent mouse brain below). The hydrogel prevents the brain from disintegrating into a puddle once the fat is gone.

Caption: CLARITY transforms a mouse brain at left into a transparent but still intact brain at right. Shown superimposed over a quote from the great Spanish neuroanatomist Ramon y Cajal.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

The new technique, cleverly but mind-bendingly named Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel─or CLARITY─will undoubtedly advance the BRAIN Initiative that President Obama announced just last week at the White House . In fact, Karl Deisseroth, leader of the CLARITY project, was in the East Room that morning, and has been chosen as a member of the NIH BRAIN working group.

Using CLARITY, the authors follow an individual neuron as its snakes through the brain of an autistic individual. They’ve stained the transparent brain in multicolored fluorescent hues to highlight the activity of individual genes, cells, neurotransmitters, and proteins.

Caption: This is the hippocampus, a structure important for learning, memory, and emotion.
Each color represents a different molecular label; this labeling can happen after the brain is
CLARIFied but still fully intact.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

In another extraordinary technical feat, they’ve imaged the transparent mouse brain with a light microscope, revealing a forest of neurons that glow like bioluminescent trees (below).

Caption: A yellow fluorescent protein reveals mostly projection (Thy1) neurons in an entire intact mouse brain.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions.

Video: take a fantastic voyage through a mouse brain

Reference: Structural and molecular interrogation of intact biological systems. Kwanghun Chung, Jenelle Wallace, Sung-Yon Kim, Sandhiya Kalyanasundaram, Aaron S. Andalman,
Thomas J. Davidson, Julie J. Mirzabekov, Kelly A. Zalocusky, Joanna Mattis, Aleksandra K. Denisin, Sally Pak, Hannah Bernstein, Charu Ramakrishnan, Logan Grosenick, Viviana Gradinaru & Karl Deisseroth. Nature.Published online 10 April 2013

For more information: NIH BRAIN Initiative

NIH support: NIH Director’s Transformative Research (TR01) Award (Common Fund; National Institute of Mental Health); National Institute on Drug Abuse; National Institute of General Medical Sciences (Medical Scientist Training Program)

Caption: Alex, then and now, with Dr. Goldbach-Mansky
Credit: Kate Barton and Susan Bettendorf (NIH)

Alex Barton recently turned 17. That’s incredible because Alex was born with a rare, often fatal genetic disease and wasn’t expected to reach his teenage years.

When Alex was born, he looked like he’d been dipped in boiling water: his skin was bright red and blistered. He spent most of his time sleeping. When awake, he screamed in agony from headaches, joint pain, and rashes. After a torturous 14 months, a rheumatologist told his mother that Alex suffered from Neonatal-Onset Multisystem Inflammatory Disease (NOMID). The doctor showed her a brief and scary paragraph in a medical text. Kate Barton, Alex’s mother, admitted that it “knocked her over like a freight train.”

NOMID is the most severe form of an autoinflammatory disease spectrum called Cryopyrin-Associated Periodic Syndromes (CAPS). In 2001, researchers discovered the cause: a genetic mutation in a gene called NLRP3, which makes a protein called cryopyrin. Cryopyrin is part of a sensor in white blood cells that detects bacteria, harmful chemicals, and proteins produced by stressed, damaged, or dying cells. When the sensor detects these danger molecules, it launches an inflammatory response by activating a potent inflammatory protein called interleukin-1β.

In children with NOMID, the mutation yields an overactive sensor that triggers constant release of IL-1β and thus inflammation. This causes fever, rashes, meningitis, joint pain, and unregulated bone growth. If untreated, inflammation in the ear causes hearing loss, and inflammation in the brain can lead to blindness and mental retardation.

When Alex came to the NIH in 2003 at age six to participate in a clinical trial, he was covered in a head to toe rash, had partial hearing loss, vision problems, and couldn’t walk.

Dr. Raphaela Goldbach-Mansky, a rheumatologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, launched a clinical trial together with other NIH specialists to test a drug called anakinra (Kineret^®), which the FDA had approved for rheumatoid arthritis (RA). Anakinra hadn’t been very effective for RA, but Goldbach-Mansky knew its mechanism should allow it to block cells from responding to IL-1β, curbing the inflammation that was destroying Alex’s body.

Just a few hours after Alex got his first injections of anakinra, the rash disappeared. Six days later, Alex was back on his feet and walking out of the NIH Clinical Center, where he recently came back to visit for his 10-year checkup. Goldbach-Mansky says that the results are truly astonishing. Of the estimated 80 or so children with NOMID in the United States, 53 are in her clinical trial on the NIH campus. Many of these patients were in such severe pain that they needed daily pain medication to sleep. After just a couple days of anakinra injections, these children were pain-free [1, 2].

Based on Goldbach-Mansky’s trial data, the FDA approved the use of anakinra for NOMID. You may be surprised to know that anakinra and other related drugs are now also being tested for conditions like gout, type 2 diabetes, and heart disease—diseases that also involve inflammation and that together affect tens of millions of people nationwide. If IL-1β triggers inflammation in these diseases, as it does in NOMID, then anakinra and other IL-1β blockers might prove to be an effective treatment.

So what’s the outlook for Alex? Goldbach-Mansky says that it’s difficult to say whether anakinra will always be effective for treating Alex’s condition. But it has been 10 years so far, and Alex has big plans for the coming year. He’s an excellent student and a fine musician and plans to go to college to study cello or medicine. I say, why not both?

References and links to more information:

[1] Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, Zalewski C, Kim HJ, Bishop R, Hill S, Paul SM, Kicker P, Phillips Z, Dolan JG, Widemann B, Jayaprakash N, Pucino F, Stone DL, Chapelle D, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. Arthritis Rheum. 2012 Jul;64(7):2375-86.

[2] Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O’Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. N Engl J Med. Aug 10;355(6):581-92.

NIH Study Contributes to Approval of Promising Treatment for Genetic Inflammatory Disorder

Anakinra Clinical Trial for NOMID patients

NOMID Alliance

What is NOMID?

Rare Connect

NIH support: National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH Intramural Research Programs (National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute, National Institute on Deafness and Other Communication Disorders; National Eye Institute; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Clinical Center)

Caption: Blood pressure is highest in low-income countries
Source: World Health Organization

On Sunday April 7^th, we mark the 65^th anniversary of the World Health Organization (WHO). Each year, WHO uses the occasion to highlight a particular health issue; this year, they chose high blood pressure—hypertension. It’s a timely choice. Worldwide, at least one in three adults suffers from high blood pressure. That amounts to 68 million adults in the U.S. alone.

Your blood pressure naturally rises and falls a bit during the day, but permanent high blood pressure is a dangerous condition that increases your chance of heart disease, heart attacks, strokes, kidney failure, and even blindness.

Blood pressure is the force of the blood against the walls of your arteries. It’s an indicator of how hard your heart is working. Measured in milligrams of mercury, your blood pressure is recorded in two numbers. The top number, systolic pressure, is measured when blood is being ejected from the heart during a beat; the bottom, diastolic pressure, is the pressure in the arteries in between beats, when the valve above the heart is closed. The table below explains the ranges of normal vs. high blood pressure.

Aside from taking medications, there’s quite a lot you can do to lower your blood pressure: eat less salt, drink responsibly, eat a balanced diet, maintain a healthy weight, don’t smoke, and exercise regularly.

Source: National Heart, Lung, and Blood Institute, NIH

To learn more:

WHO: World Health Day

NHLBI/NIH—Health Topics: High Blood Pressure

CDC: High Blood Pressure

Introducing the President at the BRAIN Initiative event in the East Room of the White House
(Official White House Photo by Chuck Kennedy)

What an exciting day for science and innovation in the United States! I was thrilled to be present at the White House this morning, as President Barack Obama announced a pioneering project to explore the complex workings of the human brain: the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. And I’m proud to report that NIH-supported scientists will be among those at the forefront of this ambitious endeavor.

I’d like to take this opportunity to encourage each of you—whether you’re a researcher, health professional, patient, or young person interested in science—to embrace the
BRAIN Initiative. Not only will this landmark effort continue our nation’s strong tradition of scientific innovation, it will advance NIH’s mission of turning scientific discoveries into better health for all.

For more details on the BRAIN Initiative, check out what DARPA chief Arati Prabhakar and I have to say on WhiteHouse.gov blog.

Caption: Snapshot of changes that occur (black) when surfactant molecules are stressed by carbon nanoparticles. For the less spectacular “before” image, click the ”Continue reading” link.
Source: Prajnaparamita Dhar, Department of Chemical Engineering, University of Kansas, Lawrence

These eye-catching spirals may resemble a trendy print from Diane von Furstenberg’s Spring Collection, but they’re actually a close-up of lung surfactant—a lipid-protein film that coats the inside of the air sacs in the lungs, making it easier to breathe. Made using fluorescence microscopy techniques, this image shows what happens to the surfactant (black) when it interacts with carbon nanoparticles.

Scientists found that carbon nanoparticles rearrange the surfactant molecules from kidney bean shaped clusters into solid spirals. Since carbon nanoparticles may be effective drug delivery vehicles, it’s important to know how these molecules alter the surfactant—and whether these changes are harmful.

The verdict is still out on whether disrupting the surfactant triggers breathing problems, but we can still be mesmerized by the image.

Caption: Lung surfactant before the addition of carbon nanoparticles
Source: Prajnaparamita Dhar

Reference:

Lipid-protein interactions alter line tensions and domain size distributions in lung surfactant monolayers. Dhar P, Eck E, Israelachvili JN, Lee DW, Min Y, Ramachandran A, Waring AJ, Zasadzinski JA. Biophys J. 2012 Jan 4;102(1):56-65.

As highlighted in Biomedical Beat, a monthly digest of research news from the National Institute of General Medical Sciences, NIH.

NIH support: the National Heart, Lung, and Blood Institute; the National Institute of Environmental Health Sciences; and the National Institute of General Medical Sciences

Caption: Brown fat cells (stained brown with antibodies against the brown fat-specific protein Ucp1) nestled in amongst white fat cells.
Credit: Patrick Seale, University of Pennsylvania School of Medicine

Fat has been villainized; but all fat was not created equal. Our two main types of fat—brown and white—play different roles. Now, two teams of NIH-funded researchers have enriched our understanding of adipose tissue. The first team discovered the genetic switch that triggers the development of brown fat [1], and the second figured out how the body can recruit white fat and transform it into brown [2].

Why would we want to change white fat into brown? White fat stores energy as large fat droplets, while brown fat has much smaller droplets and is specialized to burn them, yielding heat. Brown fat cells are packed with energy generating powerhouses called mitochondria that contain iron—which gives them their brown color. Infants are born with rich stores of brown fat (about 5% of total body mass) on the upper spine and shoulders to keep them warm. It used to be thought that brown fat disappeared by adulthood—but it turns out we harbor small reserves in our shoulders and neck.

In mice, brown fat does something remarkable: it burns more calories when mice are overfed, protecting them from obesity. (Don’t you wish eating a plate of fries did that for you?) Furthermore, mice genetically predisposed to have with extra brown fat are actually leaner and healthier. In humans, there is evidence that more brown fat is associated with a lower body weight. So, how might we increase our brown fat production?

The team led by the University of Pennsylvania figured out the switch for creating a brown fat cell—a protein called early B cell factor-2 (Ebf2). Comparing the active genes in brown and white fat cells, they discovered Ebf2 is present in larger quantities in brown fat. This protein seems to mark which genes will later be turned on to transform certain types of precursor cells into brown fat. When the team engineered mice lacking this protein, the animals had white fat cells on their upper back and spine rather than the typical brown. When the team expressed high levels of Ebf2 in white fat, these cells turned brown and consumed more oxygen—a sign they were producing more heat.

The second team, led by Harvard’s Joslin Diabetes Center, noted that mice have two types of brown fat: constitutive brown fat, which they have from birth, and “recruitable” brown fat, scattered throughout the muscles and white fat. When researchers engineered mice lacking a protein called Type 1A BMP-receptor (BMPR1A)—which is needed for the correct development of brown fat—the mice were born with just a tiny bit of constitutive brown fat on their back.

You would think that these mice would be terribly cold. Surprisingly, they kept a normal body temperature. How did they manage this feat?

The lack of brown fat apparently sends a signal via the brain to the recruitable fat cells, telling them to make the switch and transform into brown fat. The mice stayed warm, and the recruited brown fat even protected them from obesity.

In humans, too much abdominal white fat promotes heart disease, diabetes, and many other metabolic diseases. It would be potentially therapeutic if we could transform some of our white fat into brown. Determining which genes control the development of white and brown fat may be the first step toward developing game changing treatments for diabetes and obesity.

References:

[1] EBF2 determines and maintains brown adipocyte identity. Rajakumari S, Wu J, Ishibashi J, Lim HW, Giang AH, Won KJ, Reed RR, Seale P. Cell Metab. 2013 Mar 12

[2] Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH. Nature. 2013 Mar 13

NIH support: the National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institute of General Medical Sciences

Courtesy of Indiana University

The scientists at the IU School of Medicine-Bloomington nicknamed their new microscope the “OMG” for good reason—the images it produces are showstoppers. The DeltaVision OMX imaging system (its official title) is a $1.2 million dollar microscope that can peek inside a cell and image fluorescent proteins in unprecedented detail.

Jane Stout, a researcher in the NIH-funded lab, used the OMG to create this spectacular image that won her first place in the high- and super-resolution microscopy category of the 2012 GE Healthcare Life Sciences Cell Imaging Competition.

What you’re looking at is a cell in the midst of dividing into two identical copies—a process called mitosis. Here, the chromosomes (in blue) are aligned at the cell’s equator. Microtubules (red) from opposite poles of the cell attach to the chromosomes using the kinetochores (green) and pull them to opposite ends of the cell, which then splits in half. But sometimes cells do not divide properly—a common problem in cancer. Understanding the mechanics of cell division could help us correct this process when it goes wrong.

Jane Stout’s prize: her mitosis image will light up a billboard in Times Square in New York City in April. That is a wonderful celebration of science!

NIH support: the National Institute of General Medical Sciences

Credit: Brendan Lee and Zhechao Ruan, Department of Molecular and Human Genetics,
Baylor College of Medicine, Houston, TX

Our joints are pretty amazing marvels of engineering, but they don’t last forever. As we age, or if we suffer certain injuries, the smooth, slippery white cartilage covering the ends of our bones begins to fray and degrade. This causes osteoarthritis (OA), or ‘wear-and-tear’ arthritis. As the cartilage thins and disappears, the bones can even grow spurs that grate against each other, causing swelling and pain. It’s a major cause of disability, and there’s currently no cure—other than joint replacement, which is a pretty big deal and isn’t available for all joints. About 27 million Americans already have osteoarthritis; about 1 in 2 will suffer from some form of the disease over their lifetime. Those are lousy odds.

So I was excited when I read about an NIH-funded study [1] describing a protein that prevents age-related and injury-induced OA—in mice. The researchers, based at the Baylor College of Medicine and the Howard Hughes Medical Institute, focused on a protein called lubricin.

Children with a rare genetic form of OA have a mutation in the proteoglycan 4 (PRG4) gene, which then produces less lubricin. Lubricin, as the name suggests, lubricates joints and the cartilage—and is produced by the same cells that build cartilage.

The researchers figured that if too little lubricin was associated with arthritis in these kids, perhaps a bit extra of it would slow down or prevent the disease. So they genetically engineered mice to cause them to produce abnormally large amounts of lubricin throughout development and adulthood. Then, using a powerful new imaging technique called phase contrast-micro-CT, they found that the cartilage and skeleton in these high-lubricin mice appeared exceptionally healthy, and they were protected against age-related OA.

Moreover, the engineered mice also seemed to respond to injury better. When the researchers studied mice with an anterior cruciate ligament (ACL) tear—a common, and sometimes career ending, knee injury in athletes—the normal mice showed signs of injury-triggered OA: the quantity of cartilage covering the bone had shrunk and the animals moved less well. The mice with extra lubricin, on the other hand, seemed resistant to OA and were almost indistinguishable from normal, uninjured mice.

And lubricin did more than grease the joints. Comparing the activity of all the genes in the normal mice with those in the genetically engineered mice, they found that lubricin activated a set of genes that protected the cartilage-producing chondrocytes.

To test whether these findings could be translated into a treatment for diseased joints, the researchers used gene therapy: a technique for carrying a healthy gene into a cell or whole organism that’s missing, or has a bad copy, of that gene. In this case, they studied normal mice with an ACL tear.  Then they used a virus (engineered so that it can’t cause disease) to carry PRG4 into the cartilage-producing cells and into the cells lining the joint. The transfected cells then cranked out lubricin for at least a year and protected the animals from OA after the cruciate ligament tear.

The next step will be to test the gene therapy in horses—which also suffer from osteoarthritis—and if successful, in humans.

References:

[1] Proteoglycan 4 expression protects against the development of osteoarthritis. Ruan MZ, Erez A, Guse K, Dawson B, Bertin T, Chen Y, Jiang MM, Yustein J, Gannon F, Lee BH. Sci Transl Med. 2013 Mar 13;5(176):176ra34.

Osteoarthritis, PubMed Health, National Library of Medicine, NIH

Osteoarthritis and You, CDC Feature

NIH support: The Eunice Kennedy Shriver National Institute of Child Health and Human Development

This video shows a molecular view of the reactions that take place inside the pyruvate dehydrogenase complex, a protein machine found in the cell’s powerhouse, the mitochondria. 3D imaging of this machine by high-resolution electron microscopy reveals how the different components essential for the reaction are organized. Watch the flexible arms move inside the protein machine as pyruvate (an essential compound made from glucose) gets converted into acetyl-CoA (a precursor to the cell’s energy supply).

Credit: Jacqueline Milne and Sriram Subramaniam, Laboratory of Cell Biology, National Cancer Institute; Donald Bliss, National Library of Medicine; NIH

References:

Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: a multifunctional catalytic machine. Milne JL, Shi D, Rosenthal PB, Sunshine JS, Domingo GJ, Wu X, Brooks BR, Perham RN, Henderson R, Subramaniam S. EMBO J. 2002 Nov 1;21(21):5587-98.

Molecular structure of a 9-MDa icosahedral pyruvate dehydrogenase subcomplex containing the E2 and E3 enzymes using cryoelectron microscopy. Milne JL, Wu X, Borgnia MJ, Lengyel JS, Brooks BR, Shi D, Perham RN, Subramaniam S. J Biol Chem. 2006 Feb 17;281(7):4364-70.

Extended polypeptide linkers establish the spatial architecture of a pyruvate dehydrogenase multienzyme complex. Lengyel JS, Stott KM, Wu X, Brooks BR, Balbo A, Schuck P, Perham RN, Subramaniam S, Milne JL. Structure. 2008 Jan;16(1):93-103

I’m blogging today to tell you about a new NIH funded report [1] describing a possible cause of Parkinson’s disease: a clog in the protein disposal system.

You probably already know something about Parkinson’s disease. Many of us know individuals who have been stricken, and actor Michael J. Fox, who suffers from it, has done a great job talking about and spreading awareness of it. Parkinson’s is a progressive neurodegenerative condition in which the dopamine-producing cells in the brain region called the substantia nigra begin to sicken and die. These cells are critical for controlling movement; their death causes shaking, difficulty moving, and the characteristic slow gait. Patients can have trouble swallowing, chewing, and speaking. As the disease progresses, cognitive and behavioral problems take hold—depression, personality shifts, sleep disturbances.

The disease affects 1 in 100 people over the age of 60, but it can strike earlier, too—as it did for Michael J. Fox. Recent detailed studies of the brain in Parkinson’s disease have shown that the dying nerve cells are filled with toxic blobs of a protein called alpha-synuclein, which is an important component of nerve cell health. But what causes this protein to form clumps? That’s what this new study may be revealing.

While most forms of Parkinson’s are sporadic, there are rare familial types in which a misspelled gene raises the likelihood of developing the disease. Rare families have misspellings in alpha-synuclein itself, causing the protein to be stickier and more likely to form aggregates.  But the most common cause of the familial form of Parkinson’s disease can be traced to misspellings in the LRRK2 (pronounced “lark-2”) gene—which then produces an abnormal LRRK2 protein. The authors of this new study, led by a team at the Albert Einstein College of Medicine in New York, found that healthy versions of the LRRK2 protein are rapidly degraded in a disposal compartment in the cell called a lysosome—but the mutant forms are not. How might mutations in LRRK2 eventually cause the alpha-synuclein protein to accumulate?

Cells need to get rid of their used up byproducts. When they don’t, the “trash”—old and damaged proteins—builds up and becomes toxic, just like your house would be if you never took out the trash. In one disposal method, a “chaperone” protein targets the unwanted or damaged protein and escorts it to the lysosome, where it is digested by enzymes, broken down, and the building blocks are recycled. But when the LRRK2 protein is mutated, it apparently gums up the entire system.  Lots of proteins targeted for disposal (including LRRK2 itself) are blocked from proper processing.  The most serious consequence is that alpha-synuclein is prevented from entering the lysosome and being recycled—causing it to build up as toxic aggregates in the cells.

An exciting aspect of this research is that investigators in other fields have identified certain compounds that might be capable of re-booting the chaperone-mediated garbage disposal system, potentially facilitating the breakdown of the toxic alpha-synuclein bundles. Though it will require many more steps to test that idea, this is an intriguing new approach to tackling this crippling disease.

References:
[1] Interplay of LRRK2 with chaperone-mediated autophagy. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM. Nat Neurosci. 2013 Mar 3.

For more information:

Parkinson’s disease, A.D.A.M. Medical Encyclopedia, National Library of Medicine, NIH

Parkinson’s Disease Information Page

Parkinson’s Disease Research Overview (recommended for scientists)

Michael J. Fox Foundation for Parkinson’s Research

NIH support: the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke

Human astrocytes in a mouse brain
Source: Steven Goldman, M.D., Ph.D., University of Rochester Medical Center

What happens when you implant human glia—a type of brain cell that protects and nurtures neurons—into the brains of newborn mice? Well, it turns out these glia mature into multi-talented astrocyte cells that provide nutrients, repair injuries, and modulate signals just like they do in a human brain. They even assume the same complex star shape!

We know the cells in question are indeed human astrocytes because they produce a group of specific proteins, which are tagged with a combination of dyes that together appear yellow in this image. In contrast, the mouse cells are blue.

This all looks very pretty, but you might wonder what impact these human astrocytes have on mouse cognition. Researchers found mice that received the implants were better able to learn and remember than those that didn’t. In short, the human cells seem to have made the mice smarter.

Interestingly, human astrocytes are larger, more complex, and more diverse than their counterparts in other species. So, perhaps these cells may hold some of the keys to our own unique cognitive abilities.

Reference:

Forebrain Engraftment
by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice. Xiaoning Han, Michael Chen, Fushun Wang, Martha Windrem, Su Wang, Steven Shanz, Qiwu Xu, Nancy Ann Oberheim, Lane Bekar,  Sarah Betstadt,  Alcino J. Silva, Takahiro Takano, Steven A. Goldman, and Maiken Nedergaard. Cell Stem Cell 12, 342–353, March 7, 2013.

NIH support: the National Institute of Mental Health; and the National Institute of Neurological Disorders and Stroke

NIH grantees receiving the Breakthrough Prize in the Life Sciences
(in order as listed below)

The brand new $3 million Breakthrough Prize in the Life Sciences [1] delivered a very nice reward and well deserved recognition to eleven exceptionally creative scientists who have devoted their careers to biology and medicine. And, with five awards to be given each year, I hope this inspires other life scientists to embark on innovative and high-risk endeavors.

For this inaugural round, I’m proud to say that nine of the eleven winners were NIH grant recipients—some for more than three decades. Now, you may not have heard of most of these scientists. Quite frankly, that’s a shame. These folks have discovered fundamental principles of biology—everything from cancer causing genes to techniques for creating stem cells. These discoveries have boosted our understanding of health and disease, and led to the development of many drugs and therapies.

So these individuals really should be household names—and more of that kind of recognition would be a good thing to inspire youth to explore careers in science. In the United States, virtually everyone can list names of multiple movie stars and athletes, but two-thirds of Americans can’t name a single living scientist [2].

The six-pack who launched the Breakthrough Prize—Google co-founder Sergey Brin and his wife 23&Me co-founder Anne Wojcicki; Facebook CEO Mark Zuckerberg and his wife Pricilla Chan; Apple chairman Art Levinson; and Russian venture capitalist Yuri Milner—want to signal to society that science is exciting, inspiring, and respected. They want the public to appreciate those who have done so much to advance medicine.

So here’s a very brief review of what these NIH-funded researchers have done:

Cornelia I. Bargmann (Rockefeller University) used a 1 millimeter long transparent worm with just 302 neurons to explore how genes and the environment converge to trigger behavior.

David Botstein (Princeton University) developed novel methods for pinpointing disease genes by following the inheritance pattern of specific disease-linked DNA markers. He’s now trying to model all the gene activity in a single cell when it is exposed to various stimuli—like a certain nutrient.

Lewis C. Cantley (Weill Cornell Medical College) discovered that many cancers arise when the phosphoinositide 3-kinase (PI3K) pathway is disrupted. He continues to explore the role of the PI3K enzyme in breast, ovarian, and endometrial cancer, and also in diabetes.

Titia de Lange (Rockefeller University) was recognized for her work on telomeres, the protective sequences at the ends of our chromosomes. She continues to explore how loss of these structures lead to cancer and aging.

Eric S. Lander (Broad Institute of Harvard and the Massachusetts Institute of Technology) was a leader in mapping the mouse and human genomes (and many others) and he has developed many of the tools to identify disease genes in cancer and other conditions.

Charles L. Sawyers (Memorial Sloan Kettering Cancer Center) has focused on signaling pathways that drive the growth and proliferation of cancer cells—including how they become drug resistant. In particular, he focuses on developing treatments for chronic myelogenous leukemia (CML), brain, and prostate cancers.

Bert Vogelstein (Johns Hopkins University) discovered a gene that suppresses tumor formation but is inactivated in colon cancer (as well as most cancers). He’s developed models of cancer initiation and progression. These findings are being used to develop diagnostic tests for colon cancer risk.

Robert A. Weinberg (Whitehead Institute) discovered the first ‘oncogene,’ which is a gene that has ‘gone rogue’ after a mutation and then drives tumor growth. Today he continues his study of cancers and how they metastasize.

Shinya Yamanaka (Kyoto University and the Gladstone Institutes in San Francisco) won a Nobel Prize last year for figuring out how to reprogram adult skin cells and transform them into “induced pluripotent stem (iPS) cells,” which behave like embryonic stem cells.

Congratulations to all of the winners!

References:

[1] Breakthrough Prize in Life Sciences: http://www.breakthroughprizeinlifesciences.org

[2] Research!Amercia National Poll 2010

Photo from liner notes of the Folkways CD

Today is International Rare Disease Day. In honor of the occasion, I’d like to pay tribute to a few real-life heroes whose struggles have forever changed the landscape of rare disease research.

Folk singer Woody Guthrie is best known for his song, “This Land Is Your Land.” Written more than 70 years ago, “This Land” has taken its place among our nation’s great anthems, setting forth a vision of inclusiveness that has inspired generations of Americans to “sing along.” But the last couple of verses are often omitted. Here’s a version of one of them:

As I was walkin’—I saw a sign there
And that sign said—no trespassin’
But on the other side … it didn’t say nothin’!
Now that side was made for you and me!

These verses brought into the foreground those whom society had marginalized. “This Land” reminded us of their existence, challenged us to live up to our ideals—and include all people in our best vision of ourselves.

Woody performing one version of “This Land”:

Even as he was singing about inclusiveness, Woody Guthrie was starting a long battle against a disease that increasingly cast him outside mainstream society: Huntington’s disease. In most cases—and as was indeed the case for Woody—symptoms of Huntington’s disease do not appear until adulthood. Gradually, this rare, inherited neurological disorder seizes control of its sufferer’s body, mind—and even voice. In 1965, 13 years after he was diagnosed, Woody fell mute. He had long since lost his ability to play guitar. Two years later, he died at the age of 55.

Fortunately for Woody and for all of us, his second wife, Marjorie, was by his side as he struggled with his failing health. Marjorie Guthrie responded to her husband’s death by founding what is now the Huntington’s Disease Society of America. Over the years, Marjorie raised our country’s awareness, not just of Huntington’s, but of all kinds of rare diseases. She made her case in Washington, DC—and right here in Bethesda, where she encouraged NIH to expand its efforts to understand rare diseases. Her foundation worked with NIH to support such research. And she was involved in the movement that eventually led to the passage of the Orphan Drug Act in 1983—the year she died. In its 30 year history, the Orphan Drug Act has greatly encouraged the development of drugs for rare diseases. While we have a long way to go—there are an estimated 7000 rare diseases, and there are drugs available for approximately 300 of those—there remains great cause for hope. The founding of the Therapeutics for Rare and Neglected Diseases (TRND) program at NIH, now located in the new National Center for Advancing Translational Sciences, is just one of many steps that seek to build a bridge from a veritable deluge of recent discoveries about the causes of rare diseases to new and effective treatments.

At the same time Marjorie Guthrie was setting up her society, Dr. Milton Wexler was establishing the Hereditary Disease Foundation (HDF) in response to his wife’s struggles with Huntington’s disease. Soon his daughter Nancy joined her father’s campaign. A clinical psychologist by training, Nancy Wexler learned genetics from the ground up. She was part of the group that, in 1983, successfully discovered the general location of the Huntington’s gene, on the short arm of chromosome 4. The HDF helped support that research. So did NIH.

Nancy then pulled together a research team—including my own research lab at the University of Michigan—to search for the causative gene. Nancy’s leadership led to an unprecedented collaborative model, where research groups that would normally have competed with each other agreed to work together. With the support of NIH and HDF, discovery of the HD gene was published in March, 1993, just about exactly 20 years ago. That gene discovery has directed new research aimed at developing treatments for Huntington’s: a quest that continues to this day, with growing confidence that it will ultimately succeed.

Shortly after being diagnosed with Huntington’s, Woody Guthrie wrote a poem, entitled “No Help Known” [1]:

Huntington’s Chorea
Means there’s no help known
In the science of medicine
For me …
All look at me and say
By your words or by your looks
Or maybe by your whispers
There’s just not no hope.…

Today, I contend that, precisely because of the efforts of folks like Woody, Marjorie, and Nancy, there is help, and there is hope. The landscape of many rare diseases is no longer uncharted. These heroes, and so many others, have helped make this a land for you and me.

For more information, please visit:

The NIH Genetic and Rare Disease Information Center

National Center for Advancing Translational Sciences, Office of Rare Diseases Research

Reference:

[1] Tracing Woody Guthrie and Huntington’s disease. Arévalo J, Wojcieszek J, Conneally PM. Semin Neurol. 2001 Jun;21(2):209-23.

“This Land is Your Land” by Woody Guthrie from Folkways: The Original Vision, Smithsonian Folkways Recordings SFW40000, provided courtesy of Smithsonian Folkways Recordings. Copyright 2005.

With special thanks to Smithsonian Folkways

Researchers have discovered one genetic recipe for this family’s thick dark hair.
Source: National Cancer Institute, NIH; Bill Branson, photographer.

It’s intriguing to find the roots of physical traits: skin color, height, and those weird tufts of hair on Uncle Mike’s ears. We’re all curious to know why we look the way we do. But new technologies are allowing us to discover the precise genetic roots of human traits that vary across the world. Variations in our DNA have helped us resist diseases and adapt to different climates and foods, enabling us to colonize just about every environment on the planet.

Recent studies have pinpointed variations responsible for lighter skin in Northern climates (such as SLC24A5 [1]) and the ability to tolerate milk sugar (lactose) in adulthood [2]. But a new NIH-funded study of a gene variant that arose in China adds a fascinating wrinkle—the use of a mouse model to help understand a potential human advantage [3]. (Regular readers will note that last week in this space I wrote about how mouse models could sometimes be misleading—this week the mouse is a champion!)

The lead author of this new report, Pardis Sabeti, is a geneticist at the Broad Institute in Cambridge, MA, and also happens to be a fine musician (check out thousanddays.com). I had fun in a musical jam with Pardis a couple of years ago. But more importantly for today’s blog, Dr. Sabeti is a NIH Director’s New Innovator Awardee and has been mining through the growing database of genome sequences from people all over the world, searching for key genetic mutations in recent human evolution (the last 100,000 years) that show evidence of positive selection.

This search led Sabeti and her international team to the Ectodysplasin A Receptor (EDAR), an ancient gene that seems to be involved in development of teeth and hair. Africans and Europeans carry the same version of EDAR, but a variant called V370A (that means the amino acid valine is replaced by alanine at position 370 in the protein) is present almost exclusively in East Asian and Native American populations—suggesting some sort of turning point in human evolution. According to Sabeti’s reconstructions, this variant arose in Central China about 30,000 years ago and spread rapidly though the East Asian population, suggesting that it conferred an environmentally advantageous or sexually selected trait.

So what exactly does this V370A variation in the EDAR gene do? With so much additional variation in the human population, the effect of this one variant would be hard to nail down. So instead, the researchers created mice that either carried the normal spelling or the East Asian V370A variant.  (Otherwise the mice were all effectively identical twins, because they were derived from an inbred strain.)

When the researchers examined the V370A mice, they found thicker hair and a higher density of sweat glands in the skin. They then tested people of Han Chinese descent and found that they did indeed have thicker hair (which had been noticed previously) and also they had significantly more sweat glands—a real surprise!

So what’s the selective advantage of V370A? Well, China was a pretty warm place 30,000 years ago, so more sweat glands might have helped cool the body. But alternatively, a preference for certain physical traits, including lush thick dark hair, might have influenced mate choice.

The EDAR gene is just one of about 400 genetic regions being studied by Dr. Sabeti’s group that seem to be important in recent human evolution. Which traits do they control? What stories can they tell us about human history? And how have they shaped our evolution?

 References:

[1] SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O’donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC. Science. 2005 Dec 16;310(5755):1782-6.

[2] Identification of a variant associated with adult-type hypolactasia. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I. Nat Genet. 2002 Feb;30(2):233-7. Epub 2002 Jan 14.

[3] Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant. Kamberov YG, Wang S, Tan J, Gerbault P, Wark A, Tan L, Yang Y, Li S, Tang K, Chen H, Powell A, Itan Y, Fuller D, Lohmueller J, Mao J, Schachar A, Paymer M, Hostetter E, Byrne E, Burnett M, McMahon AP, Thomas MG, Lieberman DE, Jin L, Tabin CJ, Morgan BA, Sabeti PC. Cell. 2013 Feb 14;152(4):691-702.

NIH support: the National Institute of General Medical Sciences; the National Human Genome Research Institute; and the National Center for Advancing Translational Sciences

Source: Medline Plus

The brain shrinks as we age—it’s normal. But in Alzheimer’s disease, neurons die-off in the billions, causing the brain to shrink more rapidly. Initially the disease wipes out neurons in brain structures that create and store memories. The disease then destroys regions responsible for language and behavior. As the rest of the brain breaks down, Alzheimer’s patients lose touch with the world and the people around them.

The NIH is testing therapies to treat, delay, and ultimately prevent Alzheimer’s disease.

For more information:

• NIH Alzheimer’s Disease Education and Referral (ADEAR) Center Website
• Alzheimer’s Disease Fact Sheet: National Institute on Aging, NIH

Will a chip challenge the mouse?
Source: Wyss Institute and Bill Branson, NIH

The humble laboratory mouse has taught us a phenomenal amount about embryonic development, disease, and evolution. And, for decades, the pharmaceutical industry has relied on these critters to test the safety and efficacy of new drug candidates. If it works in mice, so we thought, it should work in humans. But when it comes to molecules designed to target a sepsis-like condition, 150 drugs that successfully treated this condition in mice later failed in human clinical trials—a heartbreaking loss of decades of research and billions of dollars. A new NIH-funded study [1] reveals why.

Sepsis is a life-threatening systemic infection. It can be caused by a variety of pathogens, including bacteria, viruses, and fungi. Serious consequences occur when tissues damaged by infection produce proteins sometimes called “alarmins” that send the immune system into overdrive. Traumatic injuries involving extreme blood loss or burns can set off the same dangerous response. To probe the molecular response to all of these triggers, the authors took periodic blood samples from 167 trauma (car crashes, falls) patients; from 244 patients with burns over at least 20% of their body; and from four healthy volunteers who had been injected with a low-dose bacterial toxin. Then they studied the activity of the genes in the white blood cells. Comparing the results, they found that of the 5,500 or so genes that responded to traumatic injury, 91% also played a role in burn response and recovery. And about 45% of these same genes were involved in recovery from the bacterial toxin exposure.

Mice, however, apparently use distinct sets of genes to tackle trauma, burns, and bacterial toxins—when the authors compared the activity of the human sepsis-trauma-burn genes with that of the equivalent mouse genes, there was very little overlap. No wonder drugs designed for the mice failed in humans: they were, in fact, treating different conditions!

But that doesn’t mean studying mice is useless. There’s still much the mouse might teach us. Mice, as the authors note, are more resilient to infection and mount a much more regulated immune response to pathogens than humans. While it takes relatively few bacteria in the bloodstream to make humans critically ill, it takes a million-fold more bacteria to sicken a mouse. Perhaps this is because mice nose around in some filthy places and can’t afford to overreact to every microbe? If we knew how these rodents limit the drama of their immune response, it might be useful for us humans.

But this study’s implications may well go beyond mice and sepsis. It suggests that we should not assume a mouse’s drug response will always accurately predict a human’s. It would be wise to monitor the activity of the genes and pathways of interest in humans and mice, to see whether a drug works the same way in the two species.

The new study provides more reason to develop better and more sophisticated models of human disease. More than 30% of all drugs successfully tested in animals later prove toxic in human trials. The NIH plans to commit $70 million over the next five years to develop “tissue chips”—miniature 3-D organs made with living human cells—to help predict drug safety and efficacy [2]. Though this is high-risk research, these chips may ultimately provide better models of human disease and biology than the use of animals.

References:

[1] Genomic responses in mouse models poorly mimic human inflammatory diseases. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG; the Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Proc Natl Acad Sci U S A. 2013 Feb 11.

[2] Tissue Chip for Drug Screening

NIH support: the National Institute of General Medical Sciences; and the National Human Genome Research Institute

A vaccine patch and a view of the “needles” using scanning electron microscopy.
Credit: Peter DeMuth/Wellcome Trust

This might be a new way to get a shot. Funded in part by the NIH, this vaccine patch [1] is coated in a thin film that literally melts into the skin when the patch is applied. The film contains DNA, rather than protein, which is absorbed by the skin cells and triggers an immune reaction. It seems to be effective in animal models. DNA vaccines are attractive because they may not require refrigeration like typical protein vaccines and can be stably stored for weeks. And, though this patch looks spiky, the length of the needles can be adjusted so that they don’t reach the skin layers that contain nerves. Thus: no ouch.

[1] Polymer multilayer tattooing for enhanced DNA vaccination. Demuth PC, Min Y, Huang B, Kramer JA, Miller AD, Barouch DH, Hammond PT, Irvine DJ. Nat Mater. 2013 Jan 27.

 NIH support: the National Institute of Allergy and Infectious Diseases

Source: National Cancer Institute Visuals Online, NIH

There are numerous tests to gauge the health of your heart. But no such widely accepted test exists for the many parts of the immune system. How can we tell if the immune system is strong or weak? Or quantify how badly it’s malfunctioning when we suffer from asthma, allergies, or arthritis?

A team led by scientists at Stanford University has taken the first steps toward creating such a test—by taking “snapshots” of the immune system.

Before we talk about what they did, let me review how the immune system protects us against disease. The innate immune system is like a standing army that defends us against invading microbes. But the innate system has no memory. It doesn’t recognize the invaders more quickly if they return. This is the job of the adaptive immune system—B and T cells. These cells not only remember invaders; they’re able to adapt their weapons—antibodies and T-cell receptors—to make them more effective. Think of them as the Special Forces.

When a vaccine enters the body, it introduces a specific but benign preview of the potential invader—say, flu virus—to allow our Special Forces to begin honing their weapons in advance of any attack. If the full-fledged invader later arrives, your body deploys those pre-made antibodies and, most times, defeats it before it makes you sick.

But as we age, we’re increasingly at risk for flu. Why? A census of our antibodies might offer clues. And this is where the Stanford-led team comes in [1].

With support from NIH, these researchers recruited 17 volunteers, aged eight to 100 years, gave each a seasonal influenza vaccine and took blood samples—once before the vaccine, and twice after.

Using high throughput sequencing technology, the team characterized every single antibody, from each volunteer, at each of the three time points—that’s 5 million antibodies! They noted the types of antibodies present (there are five possible types) and the specific number of each type. They then compared individual antibodies of the same type with each other. Such information allows you to figure out whether two antibodies share the same lineage—like a family tree.

When the researchers crunched the numbers, they found that the 70–100 year old volunteers had a significantly less diverse collection of antibodies than the younger volunteers. That is, as people aged, their immune system had a more limited repertoire of antibodies to offer.

Does this circumstance affect how the elderly react to the flu vaccine? Does it hinder their ability to fight infection?  It’s certainly possible. Perhaps this smaller, or less diverse, collection of antibodies could explain why the vaccine is somewhat less effective in elderly individuals. We’ll need more research to figure it out. Having snapshots of our immune system will help us find answers.

This kind of antibody snapshot, only made possible in the last couple of years because of advances in genomics, could also be used to diagnose immune disorders—especially if diseases have an antibody “fingerprint.” It might also provide a robust tool for measuring whether individuals were benefiting from specific treatments, and even provide a personal risk assessment for flu and other conditions: another element of personalized medicine.

But while all this exciting research is going on, it’s still wise for you to get an annual flu shot!

Want to know more?

Where can you get a flu shot?

Understanding Flu

Stephen Quake’s Lab Page

References:

[1] Lineage structure of the human antibody repertoire in response to influenza vaccination. Jiang N, He J, Weinstein JA, Penland L, Sasaki S, He XS, Dekker CL, Zheng NY, Huang M, Sullivan M, Wilson PC, Greenberg HB, Davis MM, Fisher DS, Quake SR. Sci Transl Med. 2013 Feb 6;5(171):171

 NIH support: the National Institute of Allergy and Infectious Diseases

Map of clinical trials in the U.S. as of Feb. 7, 2013
Source: ClinicalTrials.gov

NIH conducts clinical research studies for many diseases and conditions, including cancer, Alzheimer’s disease, allergy and infectious diseases, and neurological disorders. What’s more, this work is being carried out in every state of the nation, as you can see from this interactive map showing clinical studies supported by NIH and others.

Before you start exploring this map, let’s take a moment to review the basics. A clinical study involves research using human volunteers that is intended to add to medical knowledge. One common type of clinical study, called a clinical research trial, looks at the safety and effectiveness of new ways to prevent, detect, or treat diseases. Treatments might be new drugs or new combinations of drugs, new surgical procedures or devices, or new ways to use existing treatments.

If you’re interested in taking part in a clinical study, a terrific place to start is ClinicalTrials.gov, which is a service of NIH. This searchable database lists more than 139,000 federally and privately funded clinical studies in the United States, as well as around the world. For each study, the database provides information on the purpose of the research, who may participate, where the study is being conducted, and who to call or e-mail for more details. To help you in your quest, we’ve pulled together some handy search tips, along with some real-life stories from both volunteers and researchers.

Finally, please keep in mind that ClinicalTrials.gov is just a starting point. Any information that you find there should be used conjunction with advice from your doctor or another health care professional.

A child suffering from kwashiorkor.
Source: CDC/Phil

Here’s a surprising result from a new NIH-funded study: a poor diet isn’t the only cause of severe malnutrition. It seems that a ‘bad’ assortment of microbes in the intestine can conspire with a nutrient poor diet to promote and perpetuate malnutrition [1].

Most of us don’t spend time thinking about it, but healthy humans harbor about 100 trillion bacteria in our intestines and trillions more in our nose, mouth, skin, and urogenital tracts. And though your initial reaction might be “yuck,” the presence of these microbes is generally a good thing. We’ve evolved with this bacterial community because they provide services—from food digestion to bolstering the immune response—and we give them food and shelter. We call these bacterial sidekicks our ‘microbiome,’ and the latest research, much of it NIH-funded, reveals that these life passengers are critical for good health. You read that right—we need bacteria. The trouble starts when the wrong ones take up residence in our body, or the bacterial demographics shift. Then diseases from eczema and obesity to asthma and heart disease may result. Indeed, we’ve learned that microbes even modulate our sex hormones and influence the risk of autoimmune diseases like type 1 diabetes. [2]

Now, thanks to this new research, we have fresh insight into the connection between microbes and malnutrition.  The study is based on 317 pairs of young twins living in Malawi, where an acute form of malnutrition called kwashiorkor is common. While the name might not be familiar, you’ve seen pictures of children with this disease. They are the heartbreaking poster children for starvation and malnutrition–fragile, skeletal forms with large distended bellies.

These children suffer from swelling, liver damage, and skin ulcers, and their muscle and fat waste away. In the Malawi study of twins, all had a rather poor diet, but some developed kwashiorkor and some did not.

By analyzing fecal samples, the researchers discovered the gut microbiome of the healthy kids versus those with kwashiorkor differed dramatically. To see whether nutritional therapy could change the microbiome, they fed both the sick and healthy twin a therapeutic peanut-based diet and took fecal samples before, during, and after. They found that the community of bacteria in the sick twin shifted toward that of well-nourished children. But the change was temporary. When the children returned to a Malawian diet, the cohort of gut-dwelling microbes stopped normalizing—and often reverted to those present in the earlier malnourished state. Was the diet or the microbes to blame?

To answer that question, the researchers took microbiomes from malnourished children with kwashiorkor, and microbiomes from healthy children, and transplanted them into the guts of sterile mice (specially bred to be previously free of bacteria). When these mice were fed a nutrient poor, Malawian-based diet, only mice with the kwashiorkor microbiome lost weight. When these mice ate the therapeutic diet they gained weight but then lost it again after switching back to a Malawian diet.

So it seems that children carrying the “bad” kwashiorkor gut microbes can’t make the most efficient use of the Malawian diet and end up with malnutrition. But for children with a healthy batch of microbes, even a Malawian diet may provide enough nutrition. Though more research is necessary, experts suspect that combating malnutrition and undernutrition will require more than just extra calories. We may need to spike therapeutic foods with good bacteria to create healthy microbiomes in malnourished kids.

Want to know more?

Human Microbiome Project: http://commonfund.nih.gov/hmp/

NIH Human Microbiome Project Data Analysis and Coordination Center: http://www.hmpdacc.org

References:

[1] Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor. Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, Kau AL, Rich SS, Concannon P, Mychaleckyj JC, Liu J, Houpt E, Li JV, Holmes E, Nicholson J, Knights D, Ursell LK, Knight R, Gordon JI. Science. 2013 Jan 30.

[Perspective on 1] Undernutrition—Looking Within for Answers. David A. Relman. Science. 1 February 2013: 530-532.

[2] Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS. Science. 2013 Jan 17.

For more information:
The Heart Truth: http://www.nhlbi.nih.gov/educational/hearttruth/
Women and Heart Disease: http://www.nhlbi.nih.gov/health/health-topics/topics/hdw/

Click on the image to view full sized.
Source: National Heart, Lung, and Blood Institute, NIH

Image created using a nuclear label of a flat-mount preparation of the hyaloid vessels from the eye.
Source: Richard Lang, Cincinnati Children’s Hospital Medical Center, OH

This image may conjure up thoughts of bioluminescent jellyfish, but it actually shows a network of developing blood vessels in the eye of a three day old mouse. A study in Nature last week determined that light regulates the pattern of mouse blood vessels as they develop. Observing the intermediate states of eye development is important because abnormal blood vessel development is a major cause of blindness in premature infants.

Funded by National Eye Institute, NIH.

Source: Smokefree.gov

Smoking harms just about every body part—from heart and lungs to bladder and blood vessels. What’s new is that smoking is more of a health hazard than we thought. Two new, NIH-funded reports make the persuasive, and alarming, case—on average, smoking takes an entire decade off of your life! But smokers take note: there are tremendous benefits from quitting, regardless of your age.

In the first report [1], the authors examined data from about 220,000 adult smokers who were followed for roughly 7 years. They showed that people who currently smoke are about three times more likely to die prematurely compared to “never-smokers.” Adults who quit smoking at ages 30, 40, and 50 gained 10, 9, and 6 years of life, respectively, compared with those who continued to light up.

The second study [2] measured 50-year trends in smoking in over 2.2 million men and women. One group the authors studied was the first generation of women to follow what had been primarily a male smoking pattern: starting seriously in adolescence and continuing into middle and older ages. Their relative risks of death from lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular conditions were virtually identical with those of men, confirming the prediction that if women smoke like men they will die like men.

Another surprise was that the rate of COPD among male and female smokers is climbing. COPD is a progressive lung disease, including chronic bronchitis and emphysema, which makes it difficult to breathe; smoking is the leading cause. The authors suggest that changes in cigarettes promoting deeper inhalation may be contributing to this trend by exposing more lung tissue to cancer-causing chemicals and irritants.

Both papers show that if you quit early—before age 40—you can avoid most smoking-related health risks. That’s not to say you shouldn’t quit earlier; quit by 30 and you can gain back that entire lost decade.

In the US, about 45 million adults (18 years and older) smoke—that’s just over 19% of the population. Smoking kills 443,000 annually [3]. Smoking rates are the highest in the Midwest and South. While rates have declined over the last 50 years, they remain much higher in less educated and lower income groups, and in regions where there are fewer anti-smoking laws. Of great concern is that despite these frightening statistics, smoking rates have stopped declining in recent years.

Cigarette smoking costs the US $193 billion annually in lost productivity and health care [4]. How can we discourage people from smoking? At the World Economic Forum in Davos, which I just attended, several successful approaches were discussed—high cigarette prices, taxes, smoking bans, and anti-smoking campaigns. Physicians should educate all of their patients about the dangers of smoking, and provide resources to help smokers to quit. But let’s not blame the victims—smoking is an addiction, and it’s not easy to stop cold turkey.  Support groups and counseling should be readily available.

The evidence is overwhelming. The burden—to smokers, their loved ones, and our society—is even greater than we knew. We must redouble our efforts to end our addiction to smoking.

Source: Smokefree.gov

Want help quitting?  Here are some resources that can help:

NHBLI Strategies To Quit:
http://www.nhlbi.nih.gov/health/health-topics/topics/smo/strategies.html

Quit Smoking Help:
These resources can help you set up a plan for quitting smoking:
1–800–QUIT–NOW and http://smokefree.gov

SmokefreeTXT is a mobile service designed for young adults across the United States. It provides 24/7 encouragement, advice, and tips to help smokers stop smoking for good.

References:

[1] 21st-century hazards of smoking and benefits of cessation in the United States. Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, McAfee T, Peto R. N Engl J Med. 2013 Jan 24;368(4):341-50.

[2] 50-year trends in smoking-related mortality in the United States. Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, Hartge P, Gapstur SM. N Engl J Med. 2013 Jan 24;368(4):351-64.

[3] Adult Cigarette Smoking in the United States: Current Estimate

[4] Smoking and Tobacco Use, CDC Factsheet

Credit: Frank DeLeo, National Institute of Allergy and Infectious Diseases, NIH

At first glance, this image looks like something pulled from the files of NASA, not NIH. But, no, you are not looking at alien orbs on the rocky surface of some distant planet! This is a colorized scanning electron micrograph of a white blood cell eating an antibiotic resistant strain of Staphylococcus aureus bacteria, commonly known as MRSA.

MRSA stands for methicillin-resistant Staphylococcus aureus, and it’s one nasty bug. You’ve probably heard about the dangers of MRSA infections, but what’s the easiest way to prevent one? Just like with the flu, you should wash your hands – frequently! Personal hygiene is key. And while MRSA infections are more common in people with weakened immune systems, other folks, such as athletes who share towels, are also vulnerable. To learn more about MRSA and how to protect yourself and your loved ones from this increasingly common health risk, go to http://www.nlm.nih.gov/medlineplus/ency/article/007261.htm.

COOL TOOL. See how the TALE protein (rainbow colored) recognizes the target DNA site and wraps around the double helix. When this TALE protein is fused to a nuclease (the scissors), creating a TALEN, the hybrid protein will clip the DNA at the target site. Credit: Jeffry D. Sander, Massachusetts General Hospital

If I made a spelling mistake in this blog, and you were my copy editor, you’d want to fix it quickly. You’d delete the wrong letter and insert the correct one. Well, DNA is a language too, with just four letters in its alphabet; and disease can occur with just one letter out of place if it’s in a vulnerable position (think sickle cell anemia or the premature aging disease, progeria). Wouldn’t it be great for tomorrow’s physicians to be able to do what the copy editor does? That is, if they could fix a genetic mutation quickly and efficiently, without messing up the rest of the text?

We hear the phrases “genetically modified” and “genetically engineered” everyday, which may lead you to think it’s simple to edit DNA surgically. But it’s not! So, whenever researchers create a new tool for precisely modifying DNA the way a copy editor does, it’s a big deal. Today, I’d like to give a shout out to a new generation of tools we’ll call copy-editing nucleases. These new tools, all of which were developed with the help of NIH funding, are making it faster, easier, and cheaper to edit DNA, and they’re revealing tantalizing new possibilities for treating human diseases.

To give you an idea of how challenging it is to edit DNA, consider this: the human genome has about 3 billion pairs of the chemical letters A, C, G, and T (adenine, cytosine, guanine, and thymine). Now, imagine how much work it would take to search a book with 3 billion letters for a single appearance of the word “CAT,” and then cut out a “C” and paste in a “T” to make the word “TAT.”

To meet this challenge, you would need an enzyme that is both capable of precise recognition of a specific DNA sequence and outfitted with scissors and paste to modify it. The simplest version is just to include the scissors, interrupting the targeted gene. Researchers [1] have developed editing tools called zinc finger nucleases (ZFNs), which are proteins specifically designed to grab onto a sequence of DNA and cut it.

Why would you do this? Well, you might want to find out what happens if you delete a gene from an organism’s genome. Or you might want to snip out one version of a gene and then, using another trick, replace it with a different segment to compare how different versions affect disease risk. For example, a team at The Whitehead Institute in Cambridge, MA, has used ZFNs to produce stem cells that carry one of two different genetic mutations known to increase the risk of early onset Parkinson’s disease [2].

Ultimately, you might want to replace a disease-causing mutation with a “healthy” snippet of DNA. In 2011, a team from Massachusetts General Hospital in Boston and Stanford University in Palo Alto, CA did just that. They used a specially engineered ZFN to correct the mutation that causes sickle cell anemia in induced pluripotent stem (iPS) cells derived from a patient with the disease [3].

This strategy could, someday, be used to generate genetically corrected, patient derived cells that could be transplanted without fear of rejection or the use of immunosuppressive drugs.

However, we still need better tools. ZFNs are tricky to engineer and can be quite expensive if purchased from a commercial source—about $6,000 each. The high cost and difficulty of working with ZFNs drove the discovery and development of new editing tools called transcription activator-like effector nucleases (TALENs) in 2009 [4] [5] and, most recently, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas nuclease systems. Despite their horribly complicated names, this next generation of seek-and-slice nucleases [6] is simpler to design and much cheaper to make, e.g., $150 for a pair of TALENs.

The CRISPR/Cas system is a little different, because rather than using a protein to find the desired DNA sequence, it uses RNA to guide the slicing enzyme to the target [7]. This takes advantage of the natural pairing of RNA and DNA sequences, using the matching properties that Watson and Crick figured out almost 60 years ago. RNA also happens to be cheaper to manufacture than a protein.

Just this month in the journal Science [8], another team of researchers reported success in using two of these CRISPR/Cas RNAs to edit multiple sites simultaneously in a group of human cells—an impressive achievement that’s been dubbed “multiplex editing.”

Still, a lot more research remains to be done before we can think about moving these copy-editing strategies out of the lab and into the clinic. One big unknown is whether these new tools have “off-target” effects. This issue is critical because while fixing a target gene, you don’t want to damage another gene important for health or development. And the genome is like a very big encyclopedia, so even a small risk of hitting the wrong word could be a problem.

What’s clear today is that these new DNA-editing tools are transformative technologies that are serving to accelerate biological science around the world. They’re enabling researchers to gain a better understanding of exactly how a gene, mutation, or simple variation, affects cell function and health. And, while the ability to manipulate the genome of any organism represents a leap forward in scientific knowledge, I expect that ultimately we will develop the ability to edit our own genome in safe, responsible ways that relieve human suffering and improve human health.

REFERENCES:

[1] Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Kim YG, Cha J, Chandrasegaran S. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):115660.

[2] Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Soldner F, Laganière J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK, Vu BJ, Meng X, Urnov FD, Rebar EJ, Gregory PD, Zhang HS, Jaenisch R. Cell. 2011 Jul 22;146(2):318-31.

[3] In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Sebastiano V, Maeder ML, Angstman JF, Haddad B, Khayter C, Yeo DT, Goodwin MJ, Hawkins JS, Ramirez CL, Batista LF, Artandi SE, Wernig M, Joung JK. Stem Cells. 2011 Nov;29(11):1717-26.

[4] A simple cipher governs DNA recognition by TAL effectors. Moscou MJ, Bogdanove AJ. Science. 2009 Dec 11;326(5959):1501.

[5] Breaking the code of DNA binding specificity of TAL-type III effectors. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U. Science. 2009 Dec 11;326(5959):1509-12.

[6] FLASH assembly of TALENs for high-throughput genome editing. Reyon D, Tsai SQ, Khayter C, Foden JA, Sander JD, Joung JK. Nat Biotechnol. 2012 May;30(5):460-5. 

[7] RNA-Guided Human Genome Engineering via Cas9. Mali P, Yang L, Esvelt KM, Aach J, Guell M, Dicarlo JE, Norville JE, Church GM. Science. 2013 Jan 3.

[8] Multiplex Genome Engineering Using CRISPR/Cas Systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Jan 3.

Credit: White House

Stuttering is a speech disorder that’s affected some very famous people, including King George VI, actress Marilyn Monroe, and, believe it or not, even Vice President Joe Biden.

About 5% of children stutter, but many like the Vice President outgrow the disorder.

About 1% of adults stutter. That’s about 3 million people in the United States and 60 million worldwide.

Until recently, the cause of most stuttering was a mystery. However, researchers at the NIH’s National Institute on Deafness and Other Communication Disorders have identified several genes involved in inherited forms of stuttering and are busy looking for additional clues that may open new avenues for treatment. Find out more about what science is doing to help.

Credit: Vira V. Artym, National Institute of Dental and Craniofacial Research, NIH

We humans have long wondered how, exactly, we develop from embryos into adults. This photo of an embryonic smooth muscle cell hints at the tremendous complexity of this fundamental biological mystery. And for those of you who might be wondering just what smooth muscles are, they’re the involuntary muscles found in places like the walls of our blood vessels, the digestive tract, the bladder, and the respiratory system.

This exquisite photo was produced using laser scanning confocal microscopy — a precise imaging method that includes the dimension of depth for scientific analysis. Here, green is used to label thin filaments of the protein actin, which is a key component of the cell’s cytoskeleton, and blue indicates another protein, called vinculin, which is enriched in locations involved in cell-cell adhesion.

Slowly but surely, using all the technology and tools available to us, we are unraveling the mysteries of biology — and turning our discoveries into health.

X-ray image of the hands of a patient with rheumatoid arthritis. Note that the joints at the base of the fingers are eroded — and some, like the index finger on both hands, are actually dislocated.
Copyright (2012) American College of Rheumatology.

About 1.5 million [1] people in the US suffer from rheumatoid arthritis (RA). It is a chronic illness in which the immune system, which protects us from viral and bacterial invaders, turns on our own body and viciously attacks the membranes that line our joints. The consequences can be excruciating: pain, swelling, stiffness, and decreased mobility.  Over time, the joints can become permanently contorted, as in this X-ray image.

There are several RA medications on the market, but I want to tell you about a new one called tofacitinib, a pill which the FDA approved late last year [2]. The drug works by targeting a protein called Janus kinase 3, which was discovered by John O’Shea and colleagues here at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 20 years ago [3]. As I mentioned in a previous post it takes a really long time to go from a basic discovery to a drug—in most cases nearly 15 years. This drug has been even longer in the making! Shortly after discovering Janus kinase 3 in 1993, NIAMS researchers also revealed its role in inflammation, leading to a public-private collaboration with Pfizer that has now culminated in the approval of tofacitinib.

These Janus kinases (we call them JAKs) are critical messengers in the cell. They receive signals from immune proteins and growth hormones, among others, and convey that message to another group of proteins called STATs (signal transducers and activators), which then alter the activity of particular genes. This JAK-STAT messenger system is absolutely essential for regulating cell growth and development, metabolism, blood cell formation, immune system function, and many other activities critical for normal health and development.

Mutations in a particular JAK or STAT can make these proteins too active, or not active enough, disrupting the messenger system and causing diseases ranging from cancer to dwarfism to autoimmune conditions, including rheumatoid arthritis. Other mutations in the JAKs and STATs make some people more vulnerable to viruses and bacteria, or block the development of their white blood cells.

Tofacitinib is particularly noteworthy because it is the first FDA approved drug for treatment of an autoimmune disease that works by inhibiting a JAK protein.

There’s a terrific review article on the role of JAKs and STATs in the January 10^th issue of the New England Journal of Medicine [4] that describes the four JAK proteins, and the seven STAT proteins, and their roles in health and disease. For example, a mutation in JAK3 that makes the protein less active causes an immune deficiency condition similar to that suffered by the Bubble Boy, David Vetter, 30 years ago. On the other side of the coin, mutations in other JAKs that make these proteins hyperactive can trigger T-cell and B-cell acute leukemia or types of lymphomas. Hindering the activity of STAT1 leaves a person vulnerable to bacteria and viruses. You get the idea. Each of these proteins has a specific job, so if you are developing a drug you want to target only the misbehaving protein—you don’t want to disrupt the functions of all members of that protein family as well.

Tofacitinib inhibits three of the four JAKs, ratcheting down the overactive immune response that drives RA. It changes the way the immune system works, potentially raising the risk of some cancers. However, the most common side effects have been upper respiratory infections, headaches, and diarrhea.

Ultimately researchers will likely discover drugs that specifically target each one of these JAK and STAT proteins, so that we can minimize drug side effects and treat the broad array of diseases that occur when the JAK-STAT pathway is disrupted. But for now, having the first magic bullet to target this pathway in autoimmune disease and help the legions of people with RA is a great step forward.

REFERENCES:

[1] Rheumatoid Arthritis. (CDC Factsheet)

[2] FDA approves Xeljanz for rheumatoid arthritis. (FDA News Release, Nov. 6, 2012)

[3] Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O’Shea JJ. Nature. 1994 Jul 14;370(6485):151-3.

[4] JAKs and STATs in immunity, immunodeficiency, and cancer. O’Shea JJ, Holland SM, Staudt LM. N Engl J Med. 2013 Jan 10;368(2):161-70.

Source: National Eye Institute, NIH

This graph provides a frightening look at a problem that could threaten the vision of more than 6 million Americans by 2050: glaucoma. Glaucoma is a group of diseases that damage the eye’s optic nerve — a bundle of 1 million-plus nerve fibers connecting the light-sensitive retina to the brain — and that can lead to vision loss and blindness.

NIH research is trying to change this picture by developing better strategies for treatment and prevention. But you can also help. How? By getting your eyes checked regularly.

Source: National Eye Institute, NIH

With early detection and treatment, serious vision loss can often be prevented. Anyone can develop glaucoma, but some folks are at higher risk:

• African Americans over age 40
• Everyone over age 60, especially Mexican Americans
• People with a family history of glaucoma

Glaucoma often has no symptoms until a lot of damage has already been done.  So the best way to prevent a bad outcome from glaucoma is by undergoing a simple eye exam that can be done by an ophthalmologist or an optometrist — at least once every 2 years for people in high-risk groups.

Source: National Eye Institute, NIH

Courtesy of Dr. Ole Isacson, McLean Hospital and Harvard Medical School.

Certainly – as you can see here – stem cells are spectacularly beautiful. But they also hold spectacular promise for medicine.  That’s why I immediately expressed my enthusiasm for Monday’s Supreme Court ruling that effectively enables NIH to continue conducting and funding responsible, scientifically worthy stem cell research.

There are many kinds of stem cells. This is a picture of induced pluripotent stem cells – or, iPS cells. Investigators have recently begun using iPS cells to model several neurological diseases – including Parkinson’s. The cells here have been treated with growth factors that coax them into becoming the dopamine producing (dopaminergic) neurons lost in Parkinson’s. The colorized markers indicate the presence of three proteins found within dopaminergic neurons: (1) the enzyme needed to produce dopamine (tyrosine hydroxylase, in blue), (2) a structural protein specific to neurons (Type III beta-tubulin, in green), and (3) a gene regulatory protein needed in dopaminergic neurons (FOXA2, in red). The color-mixing in some cells indicates that all three proteins are present – confirming that these cells are on their way to becoming dopaminergic neurons.

Today’s image is more than just a pretty picture. It’s a window into the ways that disease affects the body – and possibly the ways we might counter those affects. The NIH/NINDS web site has more information about how iPS cells are being used to study Parkinson’s and other neurological disorders.

Colorized scanning electron micrograph of Mycobacterium tuberculosis. Source: Clifton E. Barry III, Ph.D., NIAID, NIH.

Tuberculosis is an ancient scourge that has evolved in lockstep with humans for more than ten millennia. It infected residents of ancient Egypt; remnants of Mycobacterium tuberculosis, the deadly bacterium that ravages the lungs and other organs of its victims, have been found in Egyptian mummies dating back 3,000 years. It is considered one of the world’s deadliest diseases.

I’ve had my own experience with TB. As a medical resident in the intensive care unit in North Carolina in 1977, I was exposed to the bacterium during emergency care of a young migrant worker who arrived at our hospital in extremis from internal bleeding. Only after the hemorrhaging was stopped did we discover his advanced tuberculosis. But I’m happy to say we treated him successfully with a battery of drugs, and he walked out of the hospital. My own TB skin test tested positive a few months later, and so I had to take a year’s worth of therapy with isoniazid to wipe out those little microbial invaders. That was all it took.

For the most part, TB cases have been reduced to a trickle in the Western world—thanks to antibiotics—and relegated to the history books with descriptions of ‘consumption’ in nineteen-century England and tales of jail-like sanatoria where those consumptives were quarantined and often died.

But it may surprise you to learn that this highly infectious, often lethal disease is once again a growing menace in the developing world. In 2011 there were about 9 million new TB cases and 1.4 million deaths, according to the World Health Organization [1]. That same year in the US, 10,528 people were diagnosed with TB. Treatments can prove effective, but they are long, expensive, and difficult to enforce: a cure requires that patients adhere to a strict six-month regimen of several different antibiotics. When patients stop taking the medications, or use them improperly, the bacteria become resistant to the drugs, making them more difficult to kill. This is exactly what is happening across the globe, from Brazil, Russia, and South Africa to India and China, [2] where many people cannot or will not comply with the treatment regimen. These resistant strains are thriving and spreading widely, particularly in people with HIV and others with suppressed immunity. About one third of the TB deaths now occur in individuals with HIV [1]. I saw this scourge in all of its frightening dimensions when I recently visited South Africa.

Worldwide, public health experts are now detecting rising numbers of TB strains that are resistant to our most powerful anti-TB drugs. And with international travel and commerce, these highly contagious strains present a threat to the entire world. Last year, an estimated 630,000 people were infected with multi-drug resistant TB (MDR-TB), with 98 of those cases here in the US. The WHO estimates the global caseload of MDR-TB could mushroom to about 2 million within three years.

But today I’ve got some potentially excellent news. The FDA just approved [3] a new drug to fight these treacherous MDR-TB strains. Sirturo (bedaquiline) is the first innovative TB drug in over 40 years. The drug, which was developed by scientists at Janssen (the pharmaceutical arm of Johnson and Johnson), uses a novel killing mechanism to defeat the bacterium. It enters the Mycobacterium tuberculosis cell and blocks its ability to produce energy, essentially starving the cell from inside out. What’s even more impressive is that it doesn’t harm human cells.

The FDA approval of Sirturo was fast-tracked because it is a “drug of last resort.” It carries some significant risks, and still requires further testing and larger trials that will reveal its promise and perils. The NIH is collaborating with Janssen to see how best to use Sirturo in combination with AIDS drugs in places like South Africa to curb the rise of MDR-TB in this vulnerable population.

Although total TB cases continue to decline in the US [4], it’s critical that we continue to develop and test new approaches to kill these resistant strains. Sirturo’s approval was the culmination of Janssen’s decade long program that brought together the NIH, FDA, The Bill and Melinda Gates Foundation, The TB Alliance, and the Critical Path to TB Drug Regimens (CPTR) Initiative. Without all of these players it wouldn’t have happened. This is a very promising first step, but we will need many more novel anti-TB drugs in the future.

——————

REFS:

[1] WHO: How many TB cases and deaths are there?
http://www.who.int/gho/tb/epidemic/cases_deaths/en/

[2] WHO: Multidrug-resistant tuberculosis 2012 Update
http://www.who.int/tb/publications/MDRFactSheet2012.pdf

[3] FDA press release
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm

[4] Reported Tuberculosis in the United States, 2011
http://www.cdc.gov/tb/statistics/reports/2011/executivecommentary.htm

Can you believe the average length of time from target discovery to approval of a new drug currently averages about 14 years? That is WAY too long. Even more shocking is that the failure rate exceeds 95 percent, and the cost per successful drug surpasses $2 billion, after adjusting for all of the failures. The National Center for Advancing Translational Sciences was specifically established one year ago to apply innovative scientific approaches to the bottlenecks in the pipeline. An example of game-changing innovation is the NCATS collaboration with the Defense Advanced Research Projects Agency (DARPA) to develop a biochip for testing drug safety. Devices like this and other tissue chips may someday reduce the amount of animal and human clinical trials necessary to determine if a drug works. That could be a huge step toward making drug development faster and cheaper—which is better for all of us.

Credit: Dylan T. Burnette, NICHD, NIH

This stunning picture of a human bone cancer cell won artistic accolades: 3rd place in the Nikon Small World Competition. DNA, the blueprint of life, is actually blue in this photo. The yellow squiggles are little powerhouses called mitochondria that generate ATP ‘fuel’ for the cell. The purple wisps are filaments of actin, which help the cell move, keep its shape, and traffic chemicals from one part of the cell to another.

Happy New Year everyone.

Credit: Bijal Trivedi

Have trouble sleeping? If so, you’re not alone. At least 40 million Americans suffer from chronic, long-term sleep disorders, and another 20 million have occasional problems. Many more (including me) just don’t seem to find enough hours in the day and night to get adequate sleep.

Lack of sleep has been linked to a variety of health conditions, including diabetes, cardiovascular disease, obesity, and depression. Sleep deprivation can also affect alertness and reflexes. And that can be lethal—tired drivers cause an estimated 100,000 motor vehicle accidents and 1,500 vehicle-related deaths each year.

So, how much sleep do you really need? While there’s a lot of individual variation based on age, health status, and genetic factors, average daily sleep needs are:

And a special note for expectant parents: women often need several extra hours of sleep during the first three months of pregnancy.

If you’d like to test your sleep I.Q., check out this online quiz.

And visit the National Center on Sleep Disorders Research to learn more about sleep, and what NIH research is doing to better understand its effects on health and behavior.

Artificial Liver
Source: NIBIB, NIH

Growth of blood vessels (red) enables implanted human ectopic artificial livers (HEALs) to grow and function in the mouse. This miniature human liver was removed from a HEAL-humanized mouse. Mice implanted with these organs are particularly useful for monitoring drug metabolism, drug-drug interactions, and predicting how certain drugs can damage and destroy the human liver.

Here’s a quick taste of just what makes these grantees so noteworthy. Guttman, an assistant professor at Caltech, is studying a new type of gene that regulates embryonic development. Gregory Sonnenburg, an immunologist at University of Pennsylvania, studies the role of beneficial bacteria in the gut and why the immune system sometimes turns against these friends. Daniela Witten, assistant professor at the University of Washington, is creating machine learning programs that massage vast amounts of data into useful and actionable knowledge—one example is personalized cancer therapy. Adam de la Zerda, assistant professor at Stanford, is using nanotechnology to understand cancer and age-related macular degeneration.

Another exceptional advocate for medical research tops the Forbes’ list of 30 under 30. Josh Sommer, a young man who was diagnosed with a rare cancer called chordoma when he was 18, is someone I have had the pleasure of encouraging and mentoring. Josh now runs the Chordoma Foundation that has raised $2.5 million and supports research in 11 labs.

All of these young scientists are amazing, and I look forward to seeing all the wonderful innovative work they do.

With a healthy dose of tongue in cheek, I’m happy to announce that the AARP just chose me as one of the “50 over 50” influential leaders—so I guess there’s also hope at the other end of the spectrum.

Happy holidays, everyone!

Cover of Science, November 30, 2012.

This looks like the type of Lego kit I would get my grandkids for Christmas, or a new version of Tetris. It is, in fact, much cooler. These are ‘DNA bricks’—short strands of DNA that plug into each other like a peg in a hole. I’m excited to tell you that the scientists at the Wyss Institute in Boston, MA, who developed this technology were recipients of the NIH Director’s New Innovator Award, which encourages out of the box thinking specifically for young researchers. So what can you do with these bricks? Build microscopic 3-D structures. In some cases, if the recipe of DNA bricks is just right the set of bricks can self-assemble. In fact the scientists have already created 100 different self-assembling structures (like the ones pictured above on the cover of the November 30^th issue of Science). These structures could be used for designing intricate labyrinths for everything from biomedicine to nanotechnology. Very, very exciting stuff.

Check out these quick flicks to see the range of structures up close; the second one looks like a collection of rainbow worms attacking each other.

Building 3D Structures with DNA Bricks

DNA Bricks – Molecular Animation

The implanted wires stimulate the fornix, one of the first regions destroyed by Alzheimer’s. Credit: Functional Neuromodulation

Alzheimer’s is the most common form of dementia, robbing those it affects of their memory, their ability to learn and think, and their personality. It worsens over time. People forget recent events, and gradually lose the ability to manage their daily lives and care for themselves. It currently affects an estimated 5.1 million Americans; this number is expected to rise to somewhere between 11 and 16 million by 2050 unless treatments can be found in the meantime.

There’s no cure for Alzheimer’s disease (AD), but biomedical researchers are testing new drugs and biochemical approaches, treatments that could stem and possibly reverse the course of the disease. They are also exploring how conditions like obesity and diabetes—which are at epidemic levels in the U.S. and worldwide—play a role. I want to tell you about a new NIH-funded experimental approach that was tried for the first time in the U.S. in November.

Neurosurgeons at Johns Hopkins Hospital, in Baltimore, MD, implanted a ‘pacemaker’ in the brain of a patient with mild AD. You are probably familiar with the concept of a pacemaker that stabilizes heart rhythms. The implanted device sends electrical pulses to the heart muscle, resetting a normal heartbeat. In some ways, this pacemaker for AD is similar. It, too, sends electrical pulses, but targets a region of the brain called the fornix—a bundle of 1.2 million axons that normally serves as a superhighway for learning, emotion, and forming memories. The fornix is one of the first regions to be destroyed by Alzheimer’s.

To implant the pacemaker, surgeons drill two small holes in the skull and implant two ultrathin wires into the fornix on both sides of the brain. The wires are then connected to a matchbox-size control device that is inserted beneath the collarbone. After surgery, the device is completely invisible. The wires deliver 130 pulses every second. These pulses, also called deep brain stimulation, deliver just four to eight volts of electricity, so tiny a charge that the patients are completely unaware of them. The hypothesis is that these pulses will kick start and drive the ailing neurons, making them function more effectively.

The current trial is taking place at five locations—four in the U.S. and one in Canada—and will include 40 patients. Half of these will have the ‘pacemaker’ or stimulators activated two weeks after surgery while the others will have the device turned on after one year.

The current trial (called the ADvance Study) was inspired by an experiment done in Canada about five years ago in which stimulating the hypothalamus and fornix caused a surprising improvement in memory [1]. This was followed in 2010 by a small Canadian trial of six patients with mild AD. When the researchers looked at the brains of these patients, they saw increased glucose metabolism in the temporal and parietal lobes of the brain over a 13-month period—a sign of healthy functioning neurons [2]. Typically, in Alzheimer’s patients, glucose metabolism in the brain decreases as the disease progresses—so the bump in metabolism is promising.

Like any surgical procedure, there is the risk of infection, and the surgery can cause minor bleeding in the brain. But the risks are small, and while mechanically stimulating the brain to improve cognitive function is new for Alzheimer’s disease, similar hardware and surgery have been used to treat 80,000 patients with Parkinson’s disease—another progressive neurodegenerative condition. Brain stimulation is also used for depression.

This is not a cure, but if successful it might delay the steady advance of memory loss that otherwise characterizes Alzheimer’s disease. This new trial is an NIH-industry collaboration and is just one of many exciting areas of research being pursued by NIH. To learn more about the broad range of Alzheimer’s research studies currently underway, take a look at:

The National Institute on Aging’s news highlights: http://www.nia.nih.gov/alzheimers/news

Click here to learn more about this particular clinical trial: http://www.advancestudy4ad.com

To find Alzheimer’s Clinical Trials near you: http://www.nia.nih.gov/alzheimers/clinical-trials

Alzheimer’s Disease Research Centers: http://www.nia.nih.gov/alzheimers/alzheimers-disease-research-centers

REFERENCES:

[1] Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Hamani C et al. Ann Neurol. 2008 Jan;63(1):119-23.

[2] A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Laxton AW et al. Ann Neurol. 2010 Oct;68(4):521-34.

X-Ray diffraction image created from a crystal of Bacteriophage HK97.
Source: John Johnson, The Scripps Research Institute

This year marks the 100^th anniversary of X-ray diffraction technology. Developed in 1912, this important tool enables researchers to figure out the 3-D structure of a molecule by beaming X-rays, often through its crystallized form. More than 85% of the protein structures we know today have been determined via this method.

For more information about x-ray diffraction, I recommend Structural Biology Fact Sheet and The Structures of Life: X-ray Crystallography.

Here you see the X-ray diffraction image that James Watson and Francis Crick used to decipher the double helix structure of DNA in 1953.

And now for a trivia question! As some of you may know, one of my hobbies is playing the guitar—a guitar that happens to have a DNA double helix inlaid on its fretboard. All special guitars should have a name.  B.B. King has Lucille. Eric Clapton had Blackie. After which famous scientist, responsible for the image used by Watson and Crick, is my guitar named?

A: ɹosɐlıup Ⅎɹɐuʞlıu

These chemists begin with an organic chemical “scaffold” (generally made up of carbon, hydrogen, oxygen, nitrogen, and a few other atoms) and then tinker; they often create hundreds of incrementally different versions of the same structure, adding a side chain of additional atoms here or there, to improve the potency or selectivity of the drug. It is painstaking, costly research.

That’s why the new “toolkit” developed by NIH-supported researchers at The Scripps Research Institute in La Jolla, CA, and featured in the November 28^th issue of Nature, is such a big hit [1]. The researchers have created a collection of 10 new recipes that can be used to modify “heterocycles”—flat, ring shaped molecules made of carbon and nitrogen that are the building blocks for many drugs. The presence of nitrogen traditionally makes these heterocycles very uncooperative—they are difficult to dissolve and frequently deactivate the reagents or catalysts with which they are supposed to react. Until now adding a branch to one of these molecules could take days or even weeks, at the cost of thousands of dollars per gram (just for comparison, a gram of gold is currently worth about $55).

The Scripps researchers have exploited the hidden romantic tendencies of heterocyclic molecules—their love and attraction for radicals (highly reactive compounds). They have created a toolkit of “zinc salts” that morph into superhero radical molecules under the right conditions and react with the heterocycle, slyly attaching the desired chemical group to these rings as the two mingle. These zinc salts are particularly handy for attaching fluorine atoms, which can help a drug absorb into the bloodstream and remain in circulation longer. The practical implication is that a patient might need less of a drug or need to take it less frequently.

The toolkit has been very successful in multiple applications, and medicinal chemists at several pharmaceutical companies, including the world’s biggest, Pfizer, are already using these salts in their quest to speed up drug development. That’s vital because developing a drug from scratch takes on average about 14 years.

A spinoff from this basic research is that chemists from all fields who work with heterocycles will benefit from this cheap and easy short cut, which can now be performed in any lab.

Another advantage of these new tools is that they can complete their mission under many conditions – even in chemically complicated, or what scientists might call “dirty,” surroundings. To demonstrate this point, the Scripps team turned to oolong tea, which is a complex brew of hundreds of chemicals. They filled a paper cup with oolong tea and then, instead of stirring in a teaspoon of sugar, they added one of the new zinc salts. To their delight, the zinc-based salt formed a radical and zeroed in on the caffeine molecules in the tea, altering their structure. The tool kit is simple, practical, and cheap—just the right cup of tea for drug design!

Easy Recipe for Drug Design (Warning: professional drivers only. Don’t try this at home!)
1) Ingredients: zinc-based salt, a simple peroxide called TBHP, and oolong tea
2) Add zinc salt to tea
3) Squirt in the TBHP which transforms salt into a radical
4) Stir
5) Voila! Modified caffeine molecules, indicated by pale blob on far right.

[1] Practical and innate carbon–hydrogen functionalization of heterocycles. Fujiwara Y et al. Nature (2012) November 28.

Credit: NCBI

You don’t need to be a researcher to enjoy keeping up with the latest discoveries in biomedical research, and now there’s a great new tool to help you.

In case you didn’t know, PubMed Central is a free archive of biomedical and life science journal literature at the NIH’s National Library of Medicine. PubMed Central provides electronic access to that journal collection—more than 2.6 million scientific articles and counting. And, anyone can use it. In fact, PubMed Central is a hot site—700,000 individuals visit it everyday to take advantage of this great knowledge base.

But until today reading the E-version of these articles has been a bit of a drag. Poring over scientific articles on a laptop, tablet, or even your phone involved patiently scrolling up and down the columns, keeping your place, and being able flip back and forth to find tables, figures, and references.

Now, the folks at the National Center for Biotechnology Information (NCBI) at the National Library of Medicine have created the “PubReader”—a reader friendly presentation style—that will magically fit a journal article to any screen, laptop, or tablet, and enable you to flip through a paper the way you would a novel on an E-reader. No special app is needed. And, it works on most browsers. As of today about 1.3 million articles, or about half the entire collection, will be readable in the new PubReader style.

PubReader bookmarks your place in the paper and there’s another neat feature: a bar at the bottom of the page that contains thumbnails of all the tables and figures in the paper. So you can keep your place in the discussion while just touching the thumbnail to review a figure anywhere in the paper.

It is also invaluable tool for medicine and public health initiatives that rely on mobile devices like phones, tablets, or laptops; here PubReader presents articles in a way they can be read easily in the field.

I think this is a great tool that will make biomedical science more accessible to everyone. Could this quench our need to print out hard copies of scientific articles?  Could entire forests of trees be saved? I’m counting on PubReader to allow me to stay on top of the latest discoveries—whether I’m on the train, on the tarmac, or just waiting in line for a latte.

So check it out: http://www.ncbi.nlm.nih.gov/pmc/about/pubreader/

Office of Behavioral and Social Sciences Research, NIH

This week, I was excited to join some of the world’s top experts on technology and health at the 2012 mHealth Summit. It’s a booming field, with a recent Pew survey finding 11% of cell phone users and 19% of smart phone users now have at least one health app on their mobile devices.

Among the hot topics at this year’s Summit was the need for rigorous research to determine which of these apps actually serve to improve health—and which don’t! To learn more, check out this video featuring NIH-supported researcher Charlene Quinn.

Dr. Quinn’s work focuses on mHealth approaches aimed at managing diabetes, but her message is relevant to all of us who’d like to use our smart phones, iPads, and other mobile devices to improve our health.

Flu season is upon us! Check out this NIH video to see how these pandemics emerge and spread new flu viruses around the globe.

The force of the water blew metal doors open and destroyed years worth of experiments.
Credit: Lori Donaghy

From what we saw during our visit, I can tell you the damage is truly appalling. The violent surge of water from the East River at 31^st Street topped all predictions and came with great swiftness, bursting through concrete walls and blowing open iron doors.  The lab animal facility was quickly submerged, and thousands of valuable mice and rats were lost. Central facilities for electrical power and heating in an older building were severely damaged; this will take many months to repair since the flood also exposed vast amounts of asbestos.

We met with NYU leadership in a chilly conference room to learn of their 24/7 efforts to respond to this unprecedented disaster. Then, we toured some of the labs that are unusable because the infrastructure has been essentially obliterated. Dr. Rockey and I also met with faculty, staff, and postdocs in a town meeting and expressed our solidarity with this beleaguered community. We promised to use all available tools from NIH to help: altering submission deadlines for grant applications, allowing researchers to negotiate new specific aims, and extending training periods for trainees whose research projects have been seriously affected. Soon, NIH will issue an opportunity for NYU researchers who have lost precious equipment or supplies to apply for additional funding through Administrative Supplements.

My hat is off to NYU Langone’s Chief Scientific Officer Dr. Dafna Bar-Sagi and her colleagues for leading the recovery effort. They are engaged in a heroic endeavor that will extend over many months, possibly years, as they construct a new animal facility. While the road ahead is long, there is no doubt from what we saw on Friday that the scientists at NYU are determined and resilient.  All of us should do whatever we can to help this vital part of our nation’s biomedical research community during these terribly difficult circumstances.

Source: National Institute on Drug Abuse, NIH

First-term finals are nearly upon us and sadly a disturbing percentage of high school seniors are abusing stimulants Adderall (dextroamphetamine) and Ritalin (methylphenidate), which are prescribed for Attention Deficit Hyperactivity Disorder (ADHD). These drugs increase alertness, attention, and energy the same way cocaine does—by boosting the amount of the neurotransmitter dopamine.

Even though these drugs are legal, they’re quite dangerous if not used properly. Taking high doses can cause irregular heartbeat, heart failure, or seizures. High doses of these stimulants can lead to hostility or feelings of paranoia. So, rather than popping pills, it’s a lot safer—and smarter—to boost your grades the old-school way: by studying.

Woman cooking. India. Photo Credit: Curt Carnemark / World Bank

Nearly 3 billion people in the developing world—almost half the global population—cook food and heat their homes with traditional indoor cookstoves or open fires.

Toxic emissions from these indoor cooking fires cause low birth weights among babies; pneumonia in young children; and heart and lung problems in adults. All told, more than 2 million people die prematurely every year as a result of poorly ventilated indoor cooking fires, such as this one in India.

At the NIH, our research efforts focus on reducing the impact of existing cookstoves, while evaluating new, cleaner technologies to improve human health.

Lung-on-a-chip. Source: Wyss Institute at Harvard University

Tissue engineering is turning into a very powerful tool to learn about biology. We haven’t quite figured out how to grow full sized replacement organs, but we’re able to cultivate miniature versions on a chip. These organs-on-a-chip are poised to revolutionize and fast-track drug discovery and development.

Already a new lung-on-a-chip, developed by NIH-funded investigators at the Wyss Institute in Boston, MA, is a game changer. This nifty little thumb-sized device offers a new way to model human diseases, and a cheaper and faster way to screen potential drugs.

Currently, molecules that are promising drug candidates are tested in test tubes or Petri dishes, then in animals, and then, if they’re successful, in a series of human clinical trials. It’s a long, costly process that, on average, takes about 14 years from discovery to clinic with a price tag of up to $2 billion.

To further complicate matters, what works in mice or monkeys isn’t always an accurate indicator of what will work in humans. In fact, only about 10% [1] of drugs that work in animal trials are ultimately successful in humans. That’s what makes this new paper [2] just published in Science Translational Medicine so exciting. The researchers are creating representations of living human organs outside living humans, which may eventually better our understanding of disease processes and also reduce our dependence on animals for testing.

The new lung-on-a-chip is designed like a sandwich to mimic the interface between the lung’s bubble-like air sacs (called alveoli) and tiny blood vessels (called capillaries). At the center of the chip is a flexible, porous membrane. One side of the membrane contains a layer of lung cells that make up the alveoli; the other side has a layer of human cells that line capillaries. A channel above the lung cells allows air to flow over the cells just as it would in the alveoli, and a second channel below the capillary cells carries a blood-like liquid. When intermittent suction is applied to the chip, the cells flex and stretch rhythmically just as they do in our lungs when we breathe.

The researchers’ goal is not just to create a good mock-up of the lung, but also to model disease processes. In the latest study, the disease was pulmonary edema, a serious health condition in which fluid from the blood vessels leaks into the air sacs making it difficult, if not impossible, to breathe. Heart failure and an immune protein called interleukin-2 (IL-2), which is also used as a cancer drug, can trigger this condition.

The researchers pumped IL-2 through the blood channel on the chip at a concentration similar to that used in cancer patients. Over the next four days, they saw liquid leak through the capillary cells, cross the porous membrane and completely flood the air channel—the chip version of pulmonary edema. When the cells in the chip were examined, clots of blood proteins were found caked on top of the lung cells. When the chip was flexed to simulate breathing, the leakiness increased three-fold, making the situation worse. This is something that would have been very hard to appreciate in an animal model – you can’t ask the animal to stop breathing!

The researchers then tested a potential new drug, GSK2193874, which could be given to cancer patients to prevent the pulmonary edema induced by IL-2. They saw that the drug completely prevented leakage in the lung chip, just as it had done in rat and dog trials. Amazing!

This same team of researchers has also created kidney, bone marrow, and gut chips. And there’s more in the pipeline. We at the NIH, in collaboration with the Defense Advanced Research Projects Agency (DARPA) and the Food and Drug Administration (FDA), have launched a 5-year, $140 million program funding the development of additional types of tissue chips, including liver and heart. These chips not only hold promise for testing whether a drug works, but if it is potentially toxic and at what concentrations.

Just think, if we can eventually link all these organ chips together in a functional way we may even be able to produce “You-on-a-Chip.” The remarkable new science of induced pluripotent stem cells (which are derived from adult cells) could make it possible to convert your skin cells or blood cells into multiple different cell types. If we loaded these onto a biochip outfitted with appropriate readouts, it could rapidly test what drugs just might work best for you!

[1] Bioengineering. Lung-on-a-chip breathes new life into drug discovery.
Service RF.
Science. 2012 Nov 9;338(6108):731

[2] A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice. Huh D, et al. Sci Transl Med. 2012 Nov 7;4(159):159ra147.

Photo Credit: Jennifer Peters, Ph.D., and Michael Taylor, Ph.D. at the Cell and Tissue Imaging Center at St. Jude Children’s Research Hospital.

This may look like a tangle of holiday lights, but it’s actually a peek inside  the developing brain of a live zebrafish. NIH-supported researchers created this award-winning picture by labeling the brain’s endothelial cells with fluorescent proteins and then using a confocal microscope to snap 3-D images as the cells assembled into the blood-brain barrier. So why are these guys taking photos of fish brains? They want to gain a better understanding of how the blood-brain barrier develops. And that’s  important because a major hurdle in the treatment of many brain disorders is figuring out better ways to move drugs and other therapies from the bloodstream and into the brain.

Today, as many of you may already know, low-dose aspirin can play a key role preventing heart attacks and strokes; it’s often prescribed as a daily therapy for people who’ve suffered a heart attack or are at high risk of one. But it doesn’t stop there. Scientists are now exploring whether this pharmaceutical multitasker can also suppress cancer.

In recent trials, researchers have been testing aspirin for people with colon or colorectal cancer, the third most deadly cancer in the United States. However, they weren’t sure who would benefit. Recently, NIH-supported researchers based in Boston showed that taking aspirin boosted survival among patients diagnosed with colon cancer. But here’s the 21^st century catch: the aspirin only had an impact in the 15-20% of patients whose tumors carried a mutation in the PIK3CA gene. (Note: This is not a mutation we inherit from our parents, it is a harmful mutation that arises spontaneously in tumors during the course of cancer development.)

This study [1], published in the New England Journal of Medicine, included 964 patients who had been diagnosed with colon cancer and had had their tumor DNAs analyzed. The researchers also knew which individuals were taking aspirin. Five years after their cancer diagnosis, 97% of patients with PIK3CA mutations who were taking aspirin were still alive, compared to 74% of similar patients who didn’t take the drug.

Strikingly, the aspirin provided no benefit for colon cancer patients whose tumors had normal copies of the PIK3CA gene. Why is this? The researchers hypothesize that the mutated PIK3CA gene acts like an oncogene, fueling cancer growth by putting cells into overdrive and making them relatively immune to cell death. The aspirin, they believe, somehow blocks this effect, making it easier to kill off the cancer cells.

If these results are replicated, doctors might use the presence of the PIK3CA mutation in colon cancer tissue as a screening tool or biomarker to identify patients who would benefit from aspirin in addition to surgery or other therapies. Some might argue it would be easier just to recommend aspirin to everyone with colon cancer, but that might be risky because aspirin does increase the risk of bleeding.

Personalizing or choosing drug regimens to match each person’s unique genetic makeup is called pharmacogenomics. This field is absolutely booming, and it’s becoming obvious that our current “one-size-fits-all” model of using aspirin and many other drugs will soon give way to personalized, or what many are now calling “precision,” medicine. So, for colon cancer and a wide variety of other conditions, I fully expect the variations hidden in your genes will someday help your health-care provider choose the medicines that work best for you, and at the dose that is right for you. And that’s something that even King Tut with all his treasures couldn’t buy!

Ref:
[1] Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. Liao X, et al. N Engl J Med. 2012 Oct 25;367(17):1596-606.

• Type 2 diabetes wreaks havoc on the body by raising the levels of glucose in the blood, increasing the risk of blindness, heart disease, kidney failure, nerve damage, and even Alzheimer’s disease.
• Pre-diabetes is a condition in which blood glucose levels are higher than normal, but not high enough to be called diabetes. 79 million U.S. adults age 20 and older have pre-diabetes.
• NIH studies have shown that losing just 6–7% of body weight and increasing physical activity can prevent or delay pre-diabetes from progressing to diabetes. 85% of people with diabetes are overweight.

I want to share new research from three recent papers in the New England Journal of Medicine (NEJM) because, together, they provide some of the most compelling evidence of the role of sugary drinks in childhood obesity, which affects nearly one-fifth of young people between the ages of 6 and 19.

In the first study [1], researchers randomly assigned 641 normal-weight school children between the ages of 4 and 12 to one of two groups. The first group received an 8 oz sugary drink each day; the second received the artificially sweetened version. After 18 months, it was clear that the kids consuming the sugary drink had gained about 2.25 pounds more weight, compared with the kids drinking the zero calorie drinks. They also packed on more fat.

The second study [2] focused on 224 overweight and obese adolescents, who consumed up to two sugary drinks every day, yielded a similar result. Here, the intervention group received a delivery of bottled water and diet drinks to discourage sugary beverages in the home, which is where most of these products are consumed. The control group simply continued on the same path. After one year, teenagers in the sugar-free intervention group gained less weight. This was particularly true with Hispanic teenagers.

The third study [3] was a little different but provides an interesting example of how your genes interact with the environment—in this case, the drinks you imbibe. Here, the researchers used obesity risk variants in 32 genes to calculate an “obesity risk score” for the approximately 200,000 people in their study. The research team showed that if two people consume one or more sugar-loaded drinks each day, the one with the higher genetic risk score is more likely to put on the pounds. This is a sobering example of the old saying that “genetics loads the gun, but environment pulls the trigger.”

It may soon be possible to calculate your own obesity risk based on the genes you carry, enabling you to consider adjusting your diet accordingly. This personalized approach is just one feature of a rapidly evolving science called nutrigenomics. Yes, this is another one of those “omics” fields, there are lots of them popping up!

The NEJM findings support New York City’s courageous but controversial move to ban supersized drinks, and the American Medical Association’s proposal to impose a “soda tax” to discourage consumption. Tough strategies have worked for tobacco, and many would argue that similar steps are needed for sugary soda, because for some groups in the U.S. these beverages account for 15% of their daily calories. Adolescent boys, for example, down about 357 calories worth of these drinks each day, and sugar-sweetened beverages are the largest source of calories for children between 2 and 18 years old. Plus there’s evidence that drinking these beverages doesn’t suppress the appetite, so these may truly be just extra, empty calories.

It’s no secret that obesity has reached epic and epidemic proportions in the US; two thirds of adults and one third of children are obese or overweight. (See: A VIEW OF THE U.S. OBESITY EPIDEMIC). And, the consequences go well beyond appearance. Obesity raises the risk of type 2 diabetes, heart disease, fatty liver disease, and some cancers—the list goes on.  If we don’t come to grips with this growing epidemic, this may be the first time in U.S. history where children will have a shorter life expectancy than their parents.

Americans spend more than $60 billion on weight loss schemes and products each year. These recent papers suggest that one strategy that might help us all is to cut out these sugary drinks (and, sadly, most fruit juices aren’t much better)—these beverages don’t curb your appetite and only add calories. This decision just might be the easiest, not to mention cheapest, part of any plan to achieve and maintain a healthy weight.

[1] A trial of sugar-free or sugar-sweetened beverages and body weight in children.
de Ruyter JC, et al. N Engl J Med. 2012 Oct 11;367(15):1397-406.

[2] A randomized trial of sugar-sweetened beverages and adolescent body weight.
Ebbeling CB, et al. N Engl J Med. 2012 Oct 11;367(15):1407-16.

[3] Sugar-sweetened beverages and genetic risk of obesity.
Qi Q, et al. N Engl J Med. 2012 Oct 11;367(15):1387-96.

One condition for which NIH researchers are working to reduce disparities is asthma, the most common chronic condition that keeps kids home from school.

Compared to white children, Puerto Rican youngsters are 2.4 times more likely to suffer from asthma, African Americans, 1.6 times; and American Indians/Alaska Natives, 1.3 times.

Source: National Heart, Lung, and Blood Institute, NIH

These snapshots reveal a very disturbing trend: the rise in obesity in the US from 1985 to 2010. Today one third of adults in the US are obese, another third are overweight.

Because obesity has risen to epidemic levels—causing devastating and costly health problems, reducing life expectancy, and provoking stigma and discrimination—the NIH has established the NIH Obesity Research Task Force to accelerate progress in obesity research. For example, why are some individuals more susceptible to obesity? Can knowledge of biology and behavior be leveraged to develop better intervention strategies? What strategies work? For whom? Can these approaches be scaled up?

The connectome refers to the exquisitely interconnected network of neurons (nerve cells) in your brain. Like the genome, the microbiome, and other exciting “ome” fields, the effort to map the connectome and decipher the electrical signals that zap through it to generate your thoughts, feelings, and behaviors has become possible through development of powerful new tools and technologies.

For some time, neuroscientists have been able to infer loosely the main functions of certain brain regions by studying patients with head injuries, brain tumors, and neurological diseases—or by measuring levels of oxygen or glucose consumption in healthy people’s brains during particular activities. But all along it’s been rather clear that these inferences were overly simplistic.  Now, new advances in computer science, math, and imaging and data visualization are empowering us to study the human brain as an entire organ, and at a level of detail not previously imagined possible in a living person.

Some have likened this new ability to the difference between listening to the string section (evaluating an isolated part of the brain) versus listening to an entire orchestra (the whole organ). If you listen only to the string or percussion section, you’ll gain a pretty good understanding of how that particular group of instruments sounds. However, that experience would not compare to the experience of listening to the whole orchestra and chorus perform Beethoven’s Symphony No. 9, the Ode to Joy.

Today, I’d like to tell you about an NIH-supported effort that’s aimed at revealing the “symphony” that’s happening at the speed of thought within our brains every second of every day. This effort, called the Human Connectome Project, has set out to map the brain’s neural connections in their entirety. Given that a typical human brain contains 100 billion neurons, each with about 10,000 connections, this sounds like an impossible task. But it’s been done already, albeit for a much simpler creature: a roundworm called C. elegans. It took researchers a little more than decade to produce a “circuit diagram” of the C. elegans’ nervous system, which contains roughly 300 neurons that make a total of about 7,000 connections.

Clearly, mapping the human brain is vastly more complicated. To meet this challenge, the Connectome Project has enlisted a diverse entourage—biologists, physicians, computer scientists and physicists—at many different institutions all across the nation. Some are scanning the brains of 1,200 healthy adults to generate a high-resolution map of the brain, while others are layering on genetic and behavioral data to build a more complete picture of the brain’s neural architecture.

With a detailed connectome map of a normal human brain, I believe we will gain a better understanding of the roots of human neurological disorders, including schizophrenia, autism spectrum disorders, and other baffling conditions that may arise from abnormal “wiring” during brain development. This knowledge should yield new and better ways to detect, treat, and, ultimately, prevent the brain disorders that currently disrupt and devastate so many lives.

The connectome will also give us a new tool to explore how genes influence the brain’s connections—and how behavioral and environmental factors act to sculpt those connections, affecting everything from our ability to solve crossword puzzles to our risk for addiction.

While the Connectome Project is very much a work in progress, I’m pleased to tell you that it’s already yielding some exciting results. A recent study by connectome researchers, published in the journal Science, revealed that the brain’s neurons are not the haphazard tangle that some had thought, but are arranged in a tidy grid that resembles a city street map. Pretty cool work, and I’m betting there’ll be even more impressive findings in the near future. So, stay tuned—this is one of the most exciting areas of rapid progress in biomedical research.

To show you a few of the many ways in which researchers are now working to save, extend, and improve lives, I’d like to share this video from the recent “Celebration of Science” forum at NIH. Not only will you hear from a leader in Congress, you’ll see how research is touching the lives of some ordinary people: an HIV-positive woman with dreams of having children, a young man using his brain waves to control a robotic arm, and teenage twins up against a mysterious disease. Take a look—we even have a celebrity cameo from a Seinfeld star!

My own research background has involved hunting for disease genes and leading the effort to sequence the human genome. So naturally this blog may gravitate a bit towards genomics and personalized medicine, but I promise you it won’t stop there. I want this blog to cover the amazing range of biomedical research—from a cell biologist developing new insights into the intricacies of signal transduction to a medical doctor investigating new therapies in a clinical research trial.

Sometimes I’ll look at how large, multidisciplinary teams of scientists are enabling us to move research forward at a pace unimaginable just a few decades ago. On other occasions, I’ll show you how a single brilliant investigator, perhaps working in a field that seemed obscure to most, has hit upon a finding that substantially expands our understanding of life and health. Also, as I come across cool scientific images or fascinating facts about biology or health, I plan to share them with you, right here on this blog.

I hope you get a charge out of this! I look forward to hearing from you, and from everyone who is excited as I am about the future of biomedical research.

Francis S. Collins
Director, National Institutes of Health