Image post 4: nanodiamonds may solve implant problem

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Here is an image of nanodiamonds currently being studied as a potential coating for artificial joints. UAB researchers are exploring whether such coatings can reduce wear on joints made of metal alloys. The work is important because more than 400,000 knee replacements and 300,000 hip replacements are performed each year in the United States.

The grinding force placed on joints causes the artificial versions to shed debris that can cause pain, limit mobility and hasten joint failure. Debris particles are absorbed by scavenging immune cells called macrophages, which then secrete chemicals that cause swelling and pain. This inflammation turns on bone-eating cells near implants, and bone-loss increases the likelihood implants will break loose and require a second surgery.

Diamond coatings may significantly reduce such shedding, and studies are underway to confirm that they are safe and effective. For more information on the work led by Yogesh Vohra, Ph.D.,  director of the UAB Center for Nanoscale Materials and Biointegration, read this 2012 article.

The price of not having worms

It seems we may be missing out on the benefits of worm infection in our too-clean world. For a long while in human evolution, gut worms helped to train and balance our immune systems, and their absence may make some of us more likely to develop an oversensitive gut-based immune reactions.  

For instance, developed nations have the highest rates of inflammatory bowel disease or IBD, where the immune system mistakenly attacks intestinal cells. Such autoimmune diseases occur when processes meant to attack foreign invaders (e.g., viruses, bacteria, parasites) mistakenly attack healthy tissue and cause inflammation. Crohn's disease and ulcerative colitis are the two main kinds of IBD.  

The Mix chose to broach this somewhat nauseating subject because researchers just published a study in the journal PLOS Pathogens that found giving worm eggs to monkeys protected them from the simian version of IBD.  

That article, covered by Scientific American, also mentioned that worm-based IBD treatments will soon be tested in human trials. Specifically, researchers are looking at whether or not whipworm eggs that infect pigs (but never humans) could trigger a worm-specific immune response that counters human IBD. Worm eggs may be able to trick the immune system into thinking it has a worm infection, and to trigger a specific kind of worm-related response that happens to counter gut inflammation. 

We asked UAB’s Peter Mannon, M.D., professor in the UAB School of Medicine’s Division of Gastroenterology and Hepatology, for his take on the study and on the rise of worm-based medical therapies to counter gut inflammation.

One benefit of living in a world where we are regularly infected by viruses, bacteria and parasites is that they teach our immune system what to attack, and what to ignore, says Mannon.  The immune systems of mice raised in germ-free conditions never mature, and become less capable of fighting off infection in their intestines.

Mannon is also an expert in the gut microbiome, the complete set of bacteria inhabiting the human gut. Many are commensal, having co-evolved alongside the human body to help it digest foods. Interestingly, the abnormal gut inflammation in IBD not only damages human cells, but also the helpful bacteria we keep in our guts on purpose. Thus, studies underway seek to describe specific changes that take place in gut microbiomes when they are exposed to inflammation.  

“I think, given the strong consumer interest in products like probiotics, that the potential use of such worm-egg therapies would be acceptable to most patients, as long as they know the cannot possibly get worms from them," said Mannon.

Next gen sequencing a lens on bug-driven cancer risk

The bacteria, viruses and fungi living on our skin, up our noses and in our guts have a profound impact on our chances for developing cancer and other inflammatory diseases. Every one of the many millions of individual bacteria in our gut, for instance, contains genes that serve as instructions for the building of proteins. These molecules constantly interact with our own cells, helping to do everything from digest food to mistakenly triggering immune responses linked to cancer risk.

With these interactions in mind, the UAB Comprehensive Cancer Center chose "cancer and the microbiome" as the theme for its recent research retreat. The Mix interviewed several retreat presenters, each a nationally recognized expert in the area, and is featuring the chats as a podcast series over the next few weeks.

Our guest today is Michael Crowley, Ph.D., director of the sequencing operations in the genomics core within UAB's Heflin Center for Genomic Science. Before researchers can understand how our complex microbial communities either help or harm us, Crowley says, they must determine which species are present and what they are up to. Much can be revealed by determining the makeup of microbial genes, which offer clues to the molecules and chemicals they release into our bodies, with the help of high-speed sequencing and genotyping tools.



Show notes for the podcast:  

2:15 Fred Sanger came up with the first technique for determining the sequence of the coding units making up human DNA in 1977, and while it has undergone changes, its chemistry is basically the same today, says Crowley.  The technique reveals the order in which the DNA units, or nucleotides, line up to serve as coded instructions for the building of a human being. Initially, the scientists could sequence just a few nucleotides at a time, and then a few hundred. With advances in next-gen sequencing technologies, researchers can now sequence the entire set of genetic information for a person, three billion coding units, in 10 days for $5,000. In way of contrast, it took the Human Genome Project roughly $3.8 billion and six years to do the same thing 10 years ago.

3:47 Crowley is an expert in next-gen sequencing, which analyzes a great many small pieces of DNA in one area all at once on a glass slide. It's like looking at the night sky, seeing all the stars at once, and keeping track of which stars are changing.

4:36 Crowley's next-gen sequencing operation at the Heflin Center is mostly concerned with analyzing genetic material collected from patient samples. The information currently gives researchers clues to how diseases and medications change the microbiome, but in the future, the data will help clinicians adjust care and treatment.

6:11 The most important tool in microbiome and genome sequencing, says Crowley, comes from a company called Illumina, and is called the Genome Analyzer 2X. This second-generation tool enables the team to sequence 95 billion base pairs of information at one time from hundreds of microbiome samples on a single glass slide.

6:33 The question to be answered by this type of analysis changes with researcher that comes in seeking Crowley's help with a microbiome sequence. Often the question is "how has a patient's microbiome changed as he or she developed a disease, or what changes has chemotherapy made in a person's microbiome?"

7:46 Crowley's lab has assisted researchers conducting genomewide association studies, a type of analysis made possible in recent years by the availability of computing power and high-speed sequencing technologies. Such studies compare the genetic makeup of a patients with and without a disease. They determine the variations present at each spot in the genetic code for each person and the degree to which any variation contributes to disease. Crowley's team can look, in real time, at up to five million of these variations, called single nucleotide polymorphisms, or SNPs, which are different for each individual and can be associated with particular diseases.

8:39 The problem with GWAS studies is that they only show that one trait is somehow linked to a disease, not whether or not one can cause the other. Furthermore, associations from GWAS studies can only account for about 5 to 10 percent of the risk of inheriting many diseases. This has been termed the problem of "missing heritability."

8:59 To find this missing genetic risk, the NIH funded the ENCODE project, which has linked diseases to areas of the genetic code, not just to specific genes. The ENCODE project picked up where the Human Genome Project left off in 2003, seeking to understand which bits of the genome have an active role in human biology despite not being genes. While the 20,000 or genes discovered during the Human Genome Project are a central part of the “blueprint for human biology,” ENCODE has helped to confirm that genes represent less than 2 percent of the genome. Genes, it turns out, are surrounded by vast stretches of code, some of which control when, where and how genes turn on and off. Problems with such regulatory sequences have now been implicated in many diseases.

11:36 Sequencing operations in the genomics core within UAB's Heflin Center for Genomic Science work closely with the UAB Microbiome Core in a model where researchers grounded in many disease areas can gain unfettered access to next-gen sequencing expertise and instruments.

13:10 For those interested in reading more on microbiomic genetics, Crowley recommends the NIH's Human Microbiome Project and the National Human Genome Research Institute websites. He also recommends searching Google, which turns up articles including In Good Health? Thank Your 100 Trillion Bacteria (New York Times, @ginakolata), Finally, A Map Of All The Microbes On Your Body (National Public Radio, @robsteinnews) and Discover the Frenemy Within (Wall Street Journal, @ronwinslow).

Do gut bugs drive cancer risk?

So far, 2012 has been the year of the human microbiome. That's the set of bacteria, viruses and fungi living on our skin, up our noses and in our mouths and guts. The subject made national news in June when the Human Microbiome Project, a massive, NIH-funded effort to catalog the mix of bugs living on and in Americans, reported its first results.

Our ancestors first “invited in” gut bugs, for instance, 450 million years ago because doing so let them harness bacterial enzymes to get more energy from more kinds of food. Today, microbes contribute 360 times as many genes responsible for the human ability to convert food into energy as human genes themselves. Humans and their bugs may now represent a single super-organism.

With the typical set of bugs now outlined, researchers are searching for the bug profiles that correlate with diseases. New understanding of our complex microbial communities is laying the foundation for advances in the treatment of infectious, autoimmune and inflammatory diseases, including the process by which inflammation contributes to cancer. The work could even make possible prescription fecal transplants that replace disease-causing microbiomes.

Against this backdrop, the UAB Comprehensive Cancer Center chose "cancer and the microbiome" as the theme for its recent research retreat. The Mix interviewed several retreat presenters, each a nationally recognized expert in the area, and will feature the chats as a podcast series over the next few weeks.

Our guest today is Casey Morrow, Ph.D., professor in the UAB Department of Cell, Developmental and Integrative Biology and the retreat’s organizer.




Show notes from the podcast: 

0:45 We would be unable to digest most of our food without our microbiome — and it may have helped to establish our immune system. The wrong bugs, though — or our immune system’s reaction to them — also help to drive many infectious and inflammatory diseases, possibly including heart disease and cancer.

1:25 The microbiome is a name for the complex communities of microbes found on and in the various habitats around the body. Over the last 10 years, the field has found that a person's mix of bugs can be extremely helpful or dangerous to them.

2:24 Human microbes have become a subject of greater interest with the realization that we exist in symbiosis with them; that they are a part of us.

2:57 Along with aiding in the digestion of food, these bacteria, viruses and fungi have a complex and ancient relationship with our immune system. In one sense, they teach our immune system how to tell the difference between helpful and destructive bugs, and whether or not to ramp up an immune response. The latter is a crucial decision, because immune responses fight disease in the right context, but they also cause unwanted inflammation when they misfire.

3:12 The field has come to recognize that inflammation caused by an overactive immune system, sometimes in reaction to helpful gut bacteria, contributes to a variety of diseases, including cancer. Beyond triggering immune responses out of turn, some bugs may also release compounds themselves that damage DNA and contribute to cancer risk.

4:16 The team organized this retreat based on the UAB Cancer Center's strategic plan, which reflects work in many labs showing that a person's bug profile not only contributes to inflammation, cancer and obesity, but that all of them influence each other.

5:19 Dr. Morrow and colleagues established a UAB Microbiome Core within the Cancer Center with the help of Cancer Center director Edward Partridge, M.D., but the core is in the process of expanding into a university-wide effort.

6:42 The core is set up such that UAB researchers can easily add microbiome analysis to their ongoing studies of many diseases with a "one-stop shopping" approach. Researchers can bring in samples of microbes from mouths, guts or other habitats in patients or study animals, and the team will analyze the microbiomes. After core scientists prepare the DNA for the client, they hand it off to Michael Crowley, Ph.D., and his team at UAB's Heflin Center for Genomic Science. These researchers determine the sequences of the DNA chains in the bug genetic material, and then send the vast amounts of genetic data they generate through high-speed sequencing techniques to Eliott Lefkowitz, Ph.D., who leads UAB's Molecular and Genetic Bioinformatics Facilty. His team then provides the client with the identities of the bugs in the sample.

8:19 As they conduct clinical trials, researchers interested in diabetes, cancer and obesity can collect samples, store them for later analysis with the microbiome core, and look for associations between microbiomes and pathology. Such analyses promise to help track microbial communities in a given person as he or she goes from health to any given disease state.

9:43 The consensus now is that microbial communities are actively driving health and disease. We even have currently available cultures, yogurts and pills that change the microbiome in the mouth or gut to improve health, part of a billion-dollar industry.

11:25 Presenters at the UAB symposium were among the pioneers that showed the differences between the gut microbiomes of obese and thin people. The UAB microbiome core works closely with UAB's Gnotobiotic and Genetically Engineered Mouse Core, led by Casey Weaver, M.D. Gnotobiotic mice are genetically engineered and raised to have no gut microbiome, and fascinatingly, can be made to gain significant weight if the microbial gut community from an obese human is transplanted into them.

12:29 The gnotobiotic facility offers a system for studying how you can transplant microbiomes from healthy individuals to obese ones, which becomes vital when the goal is to perform such transplants in humans a few years down the road.

Immunogenomics: more powerful the more it's used

Here we present the fifth and final interview in our podcast series focused on immunogenomics, a field that is using new genomics tools to unravel the complexity of the human immune system and related diseases.

We recorded interviews with experts on the subject from UAB, Harvard, Stanford and the National Institutes of Health at a recent immunogenomics symposium organized jointly by the HudsonAlpha Institute for Biotechnology and leading medical journal Nature Immunology. The symposium was sponsored in part by UAB and its Center for Clinical and Translational Science.

Our guest for this podcast is John O’Shea, M.D., scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and chief of the NIAMS Molecular Immunology and Inflammation Branch.

We talked about how immunogenomics will only achieve its potential when its tools become inexpensive and straight-forward enough that they can be folded into research efforts by non-genomics experts. O'Shea said early examples of that could be found in the symposium presentations, some of which provided insight into how the immune system drives disease while others predicted which patients should benefit most from new classes of drugs.

Show notes for the interview

1:01 Those who study the immune system have also closely studied genomics for years. What has changed in immunogenomics is the leaps made possible by new technologies. Immunologists now have the ability, given cheap, powerful tools, to conduct genomics studies as part of their research.

2:31 High-powered gene sequencing, bioinformatics and computing tools will only become truly powerful when immunologists, cardiologists and neurologists (non-genomics experts) start using them in their labs worldwide. Many presentations at the symposium represent examples of that starting to happen.

2:57 O'Shea's lab, which was a pure immunology lab five years ago, now includes several high-throughput sequencing machines, not to mention a dedicated computational biologist. Immunogenomics is changing the makeup of the average research lab.

3:34 Immunogenomics is important to O'Shea's research in particular because he works with immune cell signalling pathways that play a central role in autoimmune diseases like rheumatoid arthritis, where the immune system mistakenly targets and damages our own cells. It provides a whole new window on related mechanisms if you can understand which small variations in certain spots within our genetic code add risk for the disease.

4:03 Specifically, Dr. O'Shea is interested in immune signaling chemicals called cytokines that ramp up our immune response to infectious disease invaders, but that also trigger inappropriate immune reactions as part of autoimmune disease. Genomics tools helped the field determine that a certain cytokine signaling cascade called the JAK-STAT pathway was centrally involved in autoimmune disease. Now we know that small genetic changes, so-called polymorphisms, in STAT molecules confer risk for rheumotoid arthritis, lupus, Sjogren's syndrome, etc.

5:29 Interestingly, as the field tries to figure out what confers disease risk relative to the JAK-STAT pathway, a new class of drugs, the JAK inhibitors, are arriving on the scene. Some are under consideration for marketing approval at the U.S. Food and Drug Administration right now. With this arrival, new immunogenomics tools will help researchers understand which patients are more likely to respond to the new drugs, saving them time and misery.

6:08  O'Shea's presentation at the meeting was titled "Environmental Sensors and Master Regulators in the Emergence of Active Enhancer Landscapes." Put simply, all cells in a person have the same DNA, but all cells don't read the same sections of the instruction encoded in that DNA. To fulfill its specific functions, each cell reads certain parts of the same code, with mechanisms in place to open and close the right sections of the book. The mechanisms that control when genes are expressed are regulatory sequences, the subject of study in the science of epigenetics.

7:20 An increasingly popular theory is that the origin of many diseases, including autoimmune diseases, lies not with genes, but instead within the small pieces of epigenetic code, the enhancers and regulators, that control the process of when and where genes are turned on.

9:21 Genomics and epigenomics, the genetic cards we are dealt, have a great deal to do with our risk for disease, but our "environment" plays a big role as well. Environment in this context could mean sunlight, hormonal changes (estrogen versus testosterone), or how much inflammation a person has thanks to chronic disease. The excitement is around our new ability to measure the interplay between genetics and these other factors in disease risk using the new tools.

11:40 Over time, O'Shea and others have switched from using technologies that examine a single gene, to a few genes, and now, all human genes at once, the analysis of 3 billion coding units. As a result, many diseases are now known to be the result of changes in large networks of genes.

14;19 For more information on where immunogenomics meets epigenetics, O'Shea recommends the Nature website covering the ENCODE project, the NIH-funded effort to begin to map the regulatory portions of the human genetic code.