Thursday, October 25, 2012

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.

Wednesday, October 24, 2012

Nobel Prizes recall promise of and obstacles to stem cell medicine

Sir John Gurdon of the University of Cambridge and Shinya Yamanaka of Kyoto University were recently awarded Nobel Prizes for their work with induced pluripotent stem cells.

We used the occasion to ask Tim Townes, Ph.D., chair of UAB’s Department of Biochemistry and Molecular Genetics, for his comment on the state of the iPSC field, its wondrous potential and the remaining obstacles to human treatment.

Gurdon discovered in 1962 that an entire living tadpole could be created from an already mature frog intestine cell using a technique called nuclear transfer. But his technique required the use of an embryo, and led to the controversy over the potential use of human embryonic stem cells. Yamanaka’s work ended the controversy by showing you could turn skin cells into stem cells just using proteins called transcription factors (no embryos needed).

“Proving that a fully differentiated bodily cell could be turned back into a stem cell, and determining all the steps necessary to do so, were absolutely phenomenal accomplishments worthy of a Nobel Prize,” says Townes.

Just after Yamanaka did his Nobel-winning work in 2006, Townes’ team, in collaboration with scientists at the Massachusetts Institute of Technology (MIT), "cured” sickle-cell disease in mice using genetically altered induced pluripotent stem cells. This was the very first demonstration that researchers could not only take a differentiated cell back to a stem cell, but could also fix a genetic problem in iPS cells and transplant them to cure a disease.

In a perfect world, says Townes, you could take a few skin cells from a patient and coax them back along the differentiation pathway to become stem cells, which are capable of becoming many kinds of cells. Then you would program the stem cells to become, say, red blood cells to treat sickle cell anemia, or white blood cells to replace those causing leukemia. You might be able to make stem cells that attack tumors, or even keep them on ice for years to fight a disease you don’t have yet.

The problem is that the field must prove such cells are safe and potentially effective in humans before they are ever given to humans, even in clinical trials. Stem cells in our body rarely move backward from being fully mature differentiated cells to immature stem cells. Some kinds of tumor cells are among the exceptions, so it pays to tread carefully.

The traditional solution is to create a model of the disease in mice — for instance, ones genetically engineered to have a human gene responsible for a disease. But mice and humans have evolved to have considerable differences, and many treatments that work in one do not work in the other. Researchers are currently debating whether or not studies in a larger animal like a pig are needed to better ensure safety. Furthermore, how long do you wait after giving stem cells to an animal before you declare the treatment to be safe? It may be a few years, says Townes.

In the meantime, he and others are studying whether they can make the treatments safer by using more mature stem cells. After a certain point in the process of maturing, stem cells can no longer move backwards along the pathway to become immature (potentially cancerous) again. Treatments based on mature stem cells would not provide a permanent cure for a disease like sickle cell. Patients might need a monthly infusion, but it could potentially still bring considerable relief.

For those interested in learning more about induced pluripotent stem cells, Townes recommends the National Institutes of Health's stem cell website and its research site. Also see Yamanaka’s recent GEN article, which warns against putting stem cell treatments into human patients too soon, or without proper proof in place. Then there is the iPSC content offered by Genetic Engineering & Biotechnology News.

Friday, October 19, 2012

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.

Monday, October 15, 2012

UAB team sets sights on neuroprotection

Neurological diseases are notoriously complex, and drugs have not improved significantly in decades. The main drug treatment for Parkinson's disease, L-DOPA, was first approved for use in 1970. It temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations. Patients with Parkinson's die at twice the rate of those without the disease.

For these reasons, researchers have been urgently seeking for years to understand Parkinson's to the point where they can begin to design drugs that go beyond symptom relief to counter the inflammation and nerve cell death at the disease's root. A team of researchers from the University of Alabama at Birmingham gave a presentation today at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans,  in which they revealed that they may be approaching that point. The researchers have designed a set of experimental drugs called LRRK2 inhibitors that show evidence of protecting nerve cells, at least in the rodent and cell culture studies they have carried out so far, which are meant to approximate human disease.

But these are still just models, and therein lies the problem. Despite the excitement among researchers, when should patients begin to raise their expectations?

The UAB research team, and the field of neurology in general, is excited just to have identified an enzyme like LRRK2 against which they can design drugs that could reverse underlying disease processes. That would be a first for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinson’s disease, it is the same kind of enzyme (although not the same one) that has been successfully targeted by existing cancer treatments, including Herceptin. On the other hand, the UAB team's LRRK2 inhibitors are still years away from human clinical trials. They must pass several basic tests (e.g. toxicology tests) before even being considered for human trials, and a great many drug candidates fail at this stage.

Perhaps the best we can do is to set down the facts, and offer just enough hope while avoiding hype.

The Mix sat down with Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation today at Neuroscience 2012. We wanted his take on what has been accomplished so far, and on what lies ahead. Also please take a look at our related press release on his meeting presentation.

Show notes for the interview:

1:00 Patients are surprised to hear that there is today no treatment that reverses the underlying disease processes related to Parkinson's disease, and that the focus for decades has been on symptom relief only.

1:37 The other surprise facing newly diagnosed patients is that most of the treatments in use today were developed at least 50 years ago, so it's frustrating for them to learn about how limited their options are.

1:48 Traditionally, researchers have seen the death of nerve cells that make dopamine, the signaling chemical that contributes to our ability to control our movements, as the relentlessly progressive disease process underlying Parkinson's disease. This would explain how the disease, as it gets worse, eventually overwhelms older drugs that seek to relieve symptoms by replacing lost dopamine.

2:07  In recent years, however, the field has learned that although loss of dopaminergic neurons is important, disease processes may well affect pathways beyond dopamine.

2:48 In 2004, population studies found genetic mutations in the gene for an enzymne called LRRK2
in families at greater risk for an inherited form of late onset Parkinson's disease. The mutation most closely associated with the disease makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.  The question still to be answered is whether or not LRRK2 represents a key controller of Parkinson's severity in all patients with the disease, including those that develop it for reasons unknown in their sixties.   

4:09  While there are still years to go before LRRK2 inhibitors could become available to patients, West says the field is further along in the process of developing a specific target to design drugs against than many Parkinson's researchers ever thought would happen.  

5:05 One of the challenges in neurodegenerative disorders is that humans may be the only creature to get certain diseases of the brain. And yet, to test whether an experimental drug is worthy of human trials, you need to try it first in animal models that mimic the human condition. West says the field is now making progress on creating such models, which may quicken the pace toward human studies. 

6:04  When it comes to developing drugs in the face of stricter regulations, industry and academia have learned in recent years to do more experiments on drug candidates early on, before research teams even apply for permission to start a clinical trial. West's team is repeating its experiments right now to be sure of its data, and to ensure that the team's would-be drug has strong effects in a model that mimics human disease. 

7:17  LRRK2 gets researchers excited because it is rare to find enzymes that are both proven to have a role in a disease of the brain, and that are structured such that a drug can change their action. LRRK2 is the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

8:49 Inherited forms of disease can hide from evolution if they start late in life. They do not keep anyone from reproducing so there is no evolutionary pressure to weed them out of the gene pool.  

10:47 Researchers cannot differentiate between the symptoms of inherited Parkinson's disease linked to a LRRK2 mutation and symptoms in those who develop PD late in life for reasons unknown. That creates at least the possibility that LRRK2 may have a role in all of PD and that a drug fine-tuning LRRK2 could be helpful in all cases. West says he was shocked when it came to light that a disease as complicated as inherited Parkinson's could be caused by a mutation in a single gene.

12:00 Along with whatever is triggering Parkinson's disease, the idea has emerged in the field that the body's reaction to that trigger, the response of the immune system, may be making the disease worse by causing inflammation. LRRK2 may be a critical switch to deciding whether or not inflammation makes the disease worse. 

13:46 Getting a drug into clinical trials today requires a massive investment, so it does not pay to enter clinical trials prematurely. A rushed trial that fails because of poor design can result in a "black eye" for that drug target, making it harder to find funding for related research projects after that.  

15:22 West's team has been working with LRRK2 for several years now, and has been refining  proposed drug candidates that inhibit it. Their latest lead drug candidate overcomes many of the limitations of earlier generations of proposed drugs. It is capable of having its effect in the brain, and targets only LRRK2, and not any of the hundreds of enzymes it might interact with to cause side effects. 

16:32 West recommends that those interested in Parkinson's disease and related research look up the relevant webpage from the National Institute of Neurological Disorders and Stroke. Also very helpful are the websites for the Michael J. Fox Foundation, the Parkinson's Disease Foundation and the American Parkinson's Disease Association

Friday, October 12, 2012

Immunogenome meets computing power

Welcome to the second podcast in the new series from the Mix on the emerging field of immunogenomics.

I recorded the interviews on the subject with national experts from UAB, Harvard, Stanford and the NIH at a recent symposium organized 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 is using new genomics tools to unravel the complexity of the human immune system and related diseases. 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.

Our guest for this podcast is meeting presenter Stephen Quake, D.Phil., professor in the Department of Bioengineering at Stanford and a Howard Hughes Medical Institute investigator. Quake specializes in microfluidic large-scale integration (LSI), in which he use his "lab on a chip" (a fluid-containing maze of channels, valves and wells on a microchip) to achieve high-speed, automated analysis of biological problems.

Our discussion covered how, by coming up with technologies that more precisely measure biological processes, the field has revealed new laws of nature at work in the body.

Show notes from the interview

:49 Immunogenomics, says Quake, can be defined as the sequencing and study of genes involved in the performance of the human immune system — genes whose expression pattern is in constant flux.

1:45 Right now you can't go to the doctor and ask him or her to give you a molecular diagnostic test measuring the health of your immune system, but such tests may be coming with the help of immunogenomics. In the future, such tests may be used in combination with therapies that adjust your immune response when it's too sensitive (autoimmune disease) or too weak (vulnerable to infectious disease).

2:52 Technology development is part and parcel with advances in immunogenomics. Quake's original training was in physics, with its 300-year tradition of precision measurement, which helped him to develop new measurement technologies for biological systems.

3:12 Biology was revolutionized time and time again in the 20th century by new technologies, from chromatography in the early part of the century to gene sequencing and genomic technologies in the latter half.

4:20 High-speed testing, or high-throughput technologies, have allowed for complex, massive experiments that could never have been conceived before their advent. The modern era is characterized by continual leaps in computing power, and that same type of technological scaling has now moved into the analysis of genomic information.

5:34 Computing power helps to resolve the complexity of the human immune system (now recognized as more complex than originally understood) and to pursue simple ideas.

5:59 The field of immunogenomics is young, perhaps starting with a zebrafish model paper out of Quake's lab in 2009. His early work in immunogenomics was focused on answering basic questions about the immune system, such as how many antibodies the human body contains.

7:13 The next big milestones in the field will include figuring out how to intrepret immunogenomic data in the context of a given event, like getting vaccinated or contracting an infectious disease. Lots of labs are working in this area, and it will be exciting as they reach their conclusions.

8:22 Immunogenomics is still focused on basic questions about how to measure the immune system with genomics tools. It will be some time before the field can launch an immune version of the Human Genome Project (the Human Immunogenome Project?).

9:03 With the field being so new, there our no textbooks on it nor are there yet review papers to recommend, although some are being written right now. For those with a deep interest, says Quake, the best course may be to search the literature by keyword using PubMed, and he invites all to look up his papers, which are listed by topic at his website.

About the podcaster:

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

The first podcast in the immunogenomics series, which debuted on Oct. 5, 2012, featured S. Louis Bridges Jr., M.D., Ph.D., director of the Division of Clinical Immunology and Rheumatology within the UAB School of Medicine.

Tune in next Friday, when we will talk with symposium presenter Casey Weaver, M.D., professor in the Department of Pathology with the UAB School of Medicine.

Friday, October 5, 2012

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.

Thursday, October 4, 2012

"Virtual rehabilitation" making strides

Check out this video featured recently by the magazine Wired showing a man walking with the help of robotic leg braces controlled by his thoughts. Specifically, an able-bodied researcher controlled the braces by picturing the act of walking on a treadmill.

I am fascinated by attempts to link the brain, computers and mechanical limbs — and in general the science of brain-computer interfaces, or BCI. The Wired article picked up on work published by researchers at the Long Beach Veterans Affairs Medical Center and the University of California, Irvine, in the open-access research archive arXiv.

The California team’s device, and the field it represents, have a long way to go before future devices help paralyzed people to walk again, but the progress is heartening, says Cali Fidopiastis, Ph.D., director of UAB’s Interactive Simulation (iSim) Lab, which is part of the Department of Physical Therapy in the UAB School of Health Professions.

Fidopiastis has some neat work under way that involves navigating computer programs (e.g. opening folders, starting apps) with thoughts or eye blinks, and developing devices that would allow soldiers to alert their teams to danger — or to pilot drone aircraft — simply by thinking about it.

While progress is being made toward applying thought-pattern control to prosthetics, Fidopiastis says, research needs to proceed carefully because the faulty translation of such patterns into movements could be very dangerous for a disabled person walking through his or her neighborhood with the help of such a device.

The robotic braces in the above video are controlled by electrical impulses fired along nerve pathways in the brain and captured by electroencephalogram, or EEG, electrodes placed on the scalp. Programs called “classifiers” identify the user’s intention to move from the EEG signal, but they are not yet nearly sensitive enough, says Fidopiastis.

Classifiers are learning programs that recognize patterns and make decisions. If they recognize the wrong thing, however, they can generate unintended movement in an attached prosthetic. Furthermore, a classifier must be trained by the person using it. This is done by repeating over and over the movement that the prosthetic should make until the program can accurately spot the accompanying EEG signature.

Unfortunately, today's classifiers cannot reliably transfer that training from day to day or task to task. How useful is a prosthetic if it takes hours of training before it can turn a corner, walk up a ramp and climb some stairs on command, and if it must be retrained every time you use it?

The real leap in the new study, says Fidopiastis, may be in taking brain-computer interfaces that were developed to improve communication and adapting them to enable movement. Traditionally, brain-computer interfaces have been used to enable patients with motor nerve conditions like Lou Gehrig’s disease to type a message on a keyboard by thinking about each key. The new work applies those methods, tools and techniques to mobility.

Motion-enabling prosthetics may also be useful in the emerging field of “virtual rehabilitation.” Past studies have argued that when a therapist moves a patient’s paralyzed limb, the movement may help to re-wire the brain for the possibility of self-directed movement. Edward Taub, Ph.D., in the UAB Department of Psychology, did some of the early work along these lines, showing that movement therapy applies to patients with multiple sclerosis as well as to stroke survivors. Perhaps it applies to any patient whose disease or injury has compromised their ability to move? Future studies will tell.

Fidopiastis recommends that those with an interest in this field take a look at The Wadsworth Brain-Computer Interface System or the mixed-reality rehabilitation projects under way at the E2i studio and the University of California at San Francisco.

About the blogger

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