Technological leaps make multiple, kidney-swapping surgeries more common

Chronic kidney disease affects 26 million American adults, with millions of those affected unaware because there are no symptoms until the disease is severe. When a person’s kidneys fail, they can go on dialysis or try to get a kidney transplant, which provides a better quality of life. The latter options requires that a friend or family member be willing to donate one. Otherwise, they face many years on a waiting list. 

But what if you have a donor who is not a match, which means the donated organ will be rejected by your immune system?  

The answer in Birmingham is UAB’s paired exchange and incompatible transplant programs. Ann Marie Reynolds, Gwendolyn Goldsmith and Frank Peters each needed a kidney and had a donor lined up that turned out to be incompatible. The swapping enabling them to be entered into a database that made all participants more likely to get a kidney, and this powerful story by UAB’s Tyler Greer describes their recent three-way transplant surgery.   

Their multiple, living-donor transplant has made it possible for each patient to live free of the constraints of dialysis for what doctors hope will be at least a decade and maybe two. Each of those who donated the kidney did so even though they knew their organ would be going to someone other than their family member or loved one. By the end of 2013, UAB is expected to complete perhaps 30 kidney swap transplants as part of the program.

A team of UAB surgeons, physicians and researchers in UAB’s Kidney/Pancreas Transplant Center has assembled and developed the technologies needed to make the multiple surgeries successful. We thought to talk to one of the UAB surgeons who oversaw the three-way transplant that day, Dr. Jayme Locke, and to ask her about this emerging field and what it means for patients. 

Show notes for the podcast:

1:52  The kidneys filter the blood, divert waste into urine and return useful proteins to the bloodstream. but can be damaged by diabetes, high blood pressure and cancer. 

3:00 As diseases progress, the kidneys become less and less able to function until they fail, at which points patients either go on dialysis, a mechanical system that filters the blood, get a kidney transplant or die. 

3:51 The field has shifted over the years from implanting kidneys from a stranger who recently died to organs donated by living people known to the recipient. In the United States there are about 100,000 people waiting for a kidney, but only 10,000 and 15,000 transplants done a year. The need far outweighs the supply, and those who have a family member willing to donate a kidney instead of going on a waiting list (ten-year wait in Alabama for some) has a tremendous advantage.  

5:12 It is important to note that about 35 percent of people who come forward and volunteer to donate a kidney to loved one are found to be incompatible with their would-be recipient. They have a blood type that means the recipient's immune system will immediately attack the donated organ and prevent it from functioning. Another 11 percent of willing donors will be found to be tissue incompatible. So almost half of would be donors cannot donate to their intended recipient. 

6:10  Paired exchange and incompatible transplant programs were born to address this problem, and to make it possible for many to get kidneys that would not otherwise happen.

6:37:  Paired exchange programs started in single hospitals, and now national databases have begun.  At UAB, the list of would be donors and patients is so large that the database locally is effective at making swaps possible in Alabama.

7:37: Ann Marie Reynolds, one of three patients in the transplant swap described above, has had three kidney transplants over the last 25 years. Some patients need more than one transplant because of rejection (sometimes years later) or because a systemic disease comes back in the new organ. Getting a second transplant is more difficult than the first because patients become sensitized. 

8:44 We all have labels on our cells that say self (made of a protein called human leukocyte antigen or HLA). Our immune system looks for this tag and spares self-labelled cells from immune attack, whereas those with other tags like bacteria are targeted. Thus, the goal is to find a transplanted organ made up of cells with an HLA that matches pretty closely with the patient's own tags. In the last ten years, researchers have developed the technology that enables patients to overcome some degree of mismatch if their blood and tissue types are close enough.  

10:30 Dr. Locke discussed the work of UAB's Dr. Roz Mannon, whose specialty is keeping the immune system from attacking a transplanted organ over the long term. While the field has gotten very good at preventing transplant rejection in the first year, gradual damage can cause the organ to fail five years later.

11:10 One approach to preventing long-term rejection, says Dr. Locke, is to find people better blood and tissue matches in donated organs in the first place. By carefully testing the expanded pool of potential donors and recipients in a swapping system, the chances increase that each patient will not only get a kidney, but a better matched kidney.  

11:45 The transplant researcher community also continues to work urgently to improve immunosuppressive medications such that they stop immune attack on a transplanted organ without making patients overly vulnerable to infections. UAB is a national leader in this regard, participating in several, ongoing clinical trials. 

12:57 A unique team at UAB makes multiple swap transplant operations possible. In some cases, six operations are underway at the same time, which requires skilled support by teams of nurses, anesthesiologists, pharmacists, etc., both in preparation and follow up to surgery. This tremendous and coordinated effort by UAB Nursing is led by people like Katie Stegner who runs the operating rooms and Debbie Sparks, the nurse manager on the kidney floor. 

15:35 The living donors that make the swapping system possible are willing to sacrifice part of themselves for their loved ones, a choice that has Dr. Locke's respect. Beyond that are those that chose to donate an organ into the system in honor of a family member or friend, hoping the swap system can give an organ back to that loved one. 

17:28  Dr. Locke would like to see a truly national swapping system develop, one that was not for profit. The huge size of such a database would make a great difference for many more patients in need of transplant. 

 

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.

Key to immunogenomics value: embed research in healthcare system

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

We recorded interviews with nationally recognized experts in this area 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 meeting presenter Robert Plenge, M.D., Ph.D., assistant professor of Medicine at Harvard Medical School – and Director of Genetics and Genomics within the Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital.

We discussed how immunogenomics has provided a flood of new clues about the genetic quirks contributing to many diseases, but the field must now, with the quirks as a guide, delve back into cells to learn the details of how such changes cause disease. To do so, they must collect human cells from patients known to have a given disease, and related efforts will accelerated the trend toward "embedded" genomics research.



Show notes for the interview:

1:01 Genomics is the study of DNA, RNA and the proteins that code for and how they contribute to health and disease. Immunology is the study of how several cell types fight infection, and why they attack our own tissues in some case to cause inflammation as part of inflammatory and autoimmune diseases. Immunogenomics then is the study of how these components work together, the genetic programming of the immune cell sets.

1:54 Plenge's work focuses on determining the genetic basis of predisposition for autoimmune diseases, and for rheumatoid arthritis in particular. Past genomic studies have determined some of the genes that contribute risk for rheumatoid arthritis, but immunogenomic studies are going further to determine the effect that genetic variations are having in cells, and at what that says about disease mechanisms.

3:19 The last few years have seen the rise of genome-wide association (GWAS) studies, where researchers use genomic technologies to examine every coding unit in the entire genomes of two sets of people (one with a disease, one without) to reveal every small genetic difference. They use tool called microarrays to look at large numbers of genetic sequences all at once, and to find small variations called single nucleotide polymorphisms (SNPs) associated with any given disease.

3:35 But GWAS studies only show that certain families have certain genetic variations that make them more susceptible to certain disease. They do not tell how or why the variations cause disease.  The next step then for Plenge and others will be to roll up their sleeves, go into the lab with this GWAS information and study the cells of people with disease-causing genetic variations to reveal disease mechanisms that can be countered with precision designed therapies.

4:29 Plenge's presentation talks about the importance of biomarkers, the physical measures that show a disease is underway or that a drug is countering it.. These are the tests that give meaning to clinical trial results. Researchers hope that new biomarkers will help them predict who will respond to a given treatment for rheumatoid arthritis based on their immunogenomic profile.

5:12 Plenge is working with the Pharmacogenomic Research Network (PGRN), organized by the National Heart Lung and Blood Institute, part of the Institutes of Health, to see if genomic patient profiles can be used to predict which patients are likely to respond, for instance, to an important category of treatments for rheumatoid arthritis called anti-TNF biologic drugs.

5: 47 It may be that most clinical trials will soon come to benefit from the addition of immunogenomic tools that predict any given patient's response to treatment, or their likelihood to experience a given complication of side effect.

6:22  It's easy to think of the immune system as involved in fighting infection, or even in autoimmune diseases like rheumatoid arthritis where the system mistakenly recognizes its own tissue as foreign and attacks it. Mounting evidence argues, however, show that "mistakes" by the immune system bring about inflammation at the root of cardiovascular disease, neurodegeneritive conditions, cancer, pulmonary disease, etc. A profound understanding of the interplay between genomics and immunology will offer tremendous opportunities to develop new therapies, says Plenge.

7:25 Immunogenomics may help to lessen the massive time and cost necessary today to conduct the average clinical trial. Plenge hopes that emerging techniques and advances will create efficiencies in medical research.  Treatments that address inflammation in rheumatoid arthritis may also prove to have utility in reducing inflammation contributing to say diseased arteries. The potential for this becomes greater the more profound the field's understanding of genomic/immune system interplay.

9:27 Many of the past studies in immunology and genomics were done in mice meant to serve as models of human disease.  But mice are different than humans. There are now many more opportunities to do what Plenge calls "embedded immunogenomics," where registries collect cells and data from human patients for study as part of routine clinical care.  The research is embedded in the healthcare system. If patients consent for a quick blood draw, researchers gain access to details of subsets of cells and genes linked to diseases, and can follow changes over time.

11:13  One emerging trend may be the uncoupling of such genetic registries from a doctor's office visit. People participating in the new registries may just stop by a lab (e.g. Quest Diagnostics) for testing whenever they don't feel well.

12:20 Plenge recommends that researchers interested in learning more about this area look into a database under development called Immunobase, which is working to catalog inherited genetic variations contributing to a wide variety of diseases. The work underway at Sage Bionetworks and  i2b2 (informatics for integrating biology and the bedside), an NIH-funded biocomputing initiative, represent other interesting initiatives. Patients interested in participating in research might look up 23andMe, and those with rheumatoid arthritis, the Arthritis Internet Registry.

Tune in next Friday to hear our talk with John O’Shea, M.D., chief of the Molecular Immunology and Inflammation Branch with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health.

Human immuno-genome interview series: UAB's Casey Weaver

Most of the time The Mix covers general research topics, but for the next several Fridays we will feature a podcast series focused on the emerging field of immunogenomics.

We recorded the interviews live 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.

Immunogenomics as a field is using new genomics tools to unravel the complexity of the human immune system and related diseases, which are now known to include heart disease, neurological disease and cancer because of their interplay with inflammation. The work promises to improve diagnostic tools and offer new treatment approaches.

Among the most important of genomics tools are microarrays, which enable researchers to measure the expression levels of many genes at once, and bioinformatic programs, which identify patterns in the massive data sets generated during genomic analysis of individuals and populations.

Our guest for this podcast is meeting presenter Casey Weaver, M.D. professor in the Department of Pathology within the UAB School of Medicine. We discussed how immunogenomic tools have helped researchers to finally grapple with and begin to dissect the complex workings of the immune system, and specifically, of T cells.


Show notes from the podcast:

:57 Our view off the immune system has been zooming in for years, from early studies that looked at the system at the cellular level, to studies that examined the relevant molecules inside cells, and now, to studies looking at the genes that control it.

2:00 Weaver's team has been trying to understand how T cells, one of the workhorse cell types of the precise, thorough and massive adaptive immune response, are controlled by genes that code for cytokines, signaling proteins that ramp the immune response up and down as needed. The team is also interested in the process by which more stem-cell-like T cells "decide" to become one of several more specialized cells, depending on the kind of bodily invader encountered.

2:24 CD4+ T cells are the "master regulators" of the immune response, and Weaver studies how these cells decide to mature into different types of immune cells depending on the kind of immune response needed. His work in recent years has been aimed at mapping the genes expressed in each scenario.

2:45 Weaver's team is working to genetically engineer mice in which researchers can see a readout of which genes are expressed in which immune cells and when. It has became clear how limited the current understanding is of how immune genes are controlled in T cells.

4:13 Every kind of microbial challenge (virus, bacterium, fungus) requires a different kind of immune response to eliminate it. CD4+ T cells differentiation adapts to each threat, matching up with so that it can oversee the right response.

5:11 Along with genes controlling T cell responses, there are often small pieces of genetic material that regulate when and where genes turn and of.  Weaver's team has spent time identifying several of the regulatory genetic elements that control T cell cytokine genes. Several of these elements are cis (lie alonside) the genes they control.  

5:51 Rapid advances in genomic data and technology have enabled researchers to establish correlations between small changes in genes, and in the regulatory elements that govern them, and susceptibility for many diseases.

6:19 How susceptible a given person is to an immune-mediated diseases may depend on small changes in certain genes, so-called single nucleotide polymorphisms or SNPs, but the field is not sure of their data.  Does a certain SNP cause disease, or is it just in the same region as something else that does?

6:59 One way to answer that question is to test the impact of a SNP in a live organism where the immune system is at work. Part of the strategy in Weaver's lab then has been to put part of a human cytokine gene with a SNP associated with a disease into a mouse model, and to see if it has the predicted impact.

8:15 Part of the difficulty of analyzing gene expression traditionally has been that transgenic techniques (putting human genes in a mouse) may end up putting that gene into the mouse genome in several places and randomly.  That makes it hard to pick up the subtle readouts you need to tell whether or not a SNP is contributing to a disease. Weaver's solution, one used by other labs as well, is to insert entire genes into the genome that include the SNP under study, in effect creating a level genetic playing field on which to judge the contribution of each SNP to disease.

11:06 Weaver recommends those interested in more information on the field see the National Center for Biotechnology Information and the UCSC Genome Browser.

New series on the human immunogenome

Most of the time The Mix covers general research topics, but for the next several Fridays we will feature a podcast series focused on the emerging field of immunogenomics. Guests will include nationally recognized experts in this area from UAB, HudsonAlpha, Harvard, Stanford and the National Institutes of Health.

We recorded the interviews live 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.

Immunogenomics as a field is using new genomics tools to unravel the complexity of the human immune system and related diseases, which are now known to include heart disease, neurological disease and cancer because of their interplay with inflammation. The work promises to improve diagnostic tools and offer new treatment approaches.

Among the most important of genomics tools are microarrays, which enable researchers to measure the expression levels of many genes at once, and bioinformatic programs, which identify patterns in the massive data sets generated during genomic analysis of individuals and populations.

Our first guest in the series is S. Louis Bridges, Jr., M.D., Ph.D., director of the Division of Clinical Immunology and Rheumatology within the UAB School of Medicine and deputy director of the UAB Comprehensive Arthritis, Musculoskeletal, and Autoimmunity Center. Tune in next Friday, when we will talk with Stephen Quake, D.Phil., professor in the Department of Bioengineering at Stanford.




Show notes for the interview:

1:09 Immunogenomics can be defined as the use of the tools of genomics to study human immune cells, and to define the mechanism by which immune-related diseases damage the body. 

2:02 Rheumatoid arthritis is the most common autoimmune disease, in which immune cells called antibodies come to target the body's own tissues.

2:47 In many ways, RA represents a cogent example of the intersection between immunology and genomics in that about 30 percent of the risk for the disease is based on your genes. In addition, small changes in more than 35 different genes contribute to that risk.

3:39 Bridges and colleagues founded the CLEAR registry, which stands for Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis. The registry compares the incidence and severity of RA in African-Americans against other ethnic and racial groups over time to better understand how immune-system mechanisms cause damage. Past studies have found that RA is more severe in African-Americans than in whites.

4:42 Researchers are working to understand the genetic basis of RA severity in African-Americans in part by examining single genes (RANK ligand, peptidase) known to be associated with disease severity or early onset. Bridges and colleagues have also been conducting genome-wide association studies, which look at every piece of code making up every gene (nucleotide) in a group of people to identify the differences seen only in people with a certain condition. In many cases, such studies reveal that networks of genes contribute to a disease, as opposed to a problem with the code of any single gene.

5:40 All races share 80 to 90 percent of the genetic background leading to RA, so perhaps 2 to 5 percent of genes vary by race, says Bridges.

6:02 In some whites, a gene called PTP-N22, for instance, has randomly undergone a small change in its code called an SNP (single nucleotide polymorphism). People who happen to have that change in PTP-N22 are 1.9 times as likely to develop RA.

7:09 A change in a single piece of code out of 3 billion base pairs making up the human genome, if it's in the wrong spot, can contribute to either the incidence or severity of RA. Such changes may predict which patients will go on to see their joints destroyed.

7:56  Immunogenomics work will have its first impact in the clinic in the form of a new wave of identified biomarkers that predict which patients will do well on which treatments. Further down the road, Bridges sees the field identifying more specific subsets of cells most responsible for RA-related damage, which could in turn lead to the development of more targeted treatments.

9:44 Bridges recommends that members of the general public interested in learning more on RA and related research visit the Mayo Clinic's RA pages. Researchers may want to look up the work of Robert Plenge, M.D., Ph.D., assistant professor of medicine at Harvard Medical School, whose interview is coming up as part of this podcast series in a few weeks.

About the podcaster:

Greg Williams @gregscience @themixuab is research editor within Media Relations at the University of Alabama at Birmingham.