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.

Good ol' aspirin as cutting edge colon cancer drug?

Aspirin may be able to dramatically reduce tumor growth in colorectal cancer patients, especially if they have genetic mutations in a certain gene. A Harvard-led research team published a study along those lines recently in the New England Journal of Medicine, and UAB oncologist Boris Pasche was asked to write an editorial on the study.

According to a recent UAB News article, the study separated patients with colorectal cancer into two groups: one with a missing or mutated version of the gene PIK3CA, and another with the functioning gene in place. The use of aspirin in patients with the gene mutation was associated with a dramatic 46 percent reduction in overall mortality and an 82 percent reduction in colorectal cancer-specific mortality. In contrast, aspirin use in patients without the mutation did not affect mortality.


With about one in six of the 140,000 patients diagnosed with this cancer each year, carrying a mutated PIK3CA gene, the impact of the study could be considerable.

Dr. Pasche is quick to point out, however, that the findings are still early. Larger, controlled studies will be needed before the work changes clinical practice, but the results once again argue for the value of genetic research in personalized medicine.

The Mix sat down with Dr. Pasche, director of the UAB Division of Hematology and Oncology within the UAB School of Medicine to get his take on the study, its importance and limitations.

Show notes for the podcast

1:05 Over the past decade, little progress has been made in the treatment of locally advanced colorectal cancer, cancer that has spread to nearby lymph nodes but has not metastasized, or spread to other organs.While several new drugs have proven useful in the treatment of metastatic colorectal cancer, only one of them has demonstrated efficacy in locally advanced colorectal cancer.

1:25 A number of studies over the years had found that patients taking aspirin after a diagnosis of colon were less likely to die over time (lower mortality) than those not taking aspirin.

2:11 More recently, several studies further showed that patients taking aspirin (because it is already known to protect against heart disease) had a lower risk of colon cancer metastases. Others suggested that aspirin may also prevent the spread of established cancer and prevent recurrence in a significant group of patients.

2:43 A major question has been which patients will benefit from aspirin therapy. A study published a few years ago in the Journal of the American Medical Association. by the same investigators at Harvard identified COX2 as one molecular signalling pathway that was overactive in colon cancer patients that benefited from aspirin therapy.
This makes sense because COX2 is an inflammatory pathway, and aspirin is known to block it.

3:12 The Harvard team's latest study set out to pinpoint the mechanisms by which aspirin therapy changed the action of genes known to influence the COX2 pathway. It turns out that a gene called PIK3CA may be an important arbiter in determining whether or not aspirin helps a given person fend off colon cancer.

3:27 The use of aspirin in patients with the gene mutation was associated with an 82 percent reduction in colorectal cancer-specific mortality. In contrast, aspirin use in patients without the mutation did not affect mortality. Why this is so remains to be seen.

4:00 The work represents, in Pasche's view,. an ongoing trend, where a better understanding of molecular pathways surrounding disease re-positions old drugs as targeted, 21st Century therapies that work tremendously well for people with the right genetic profile.

4:45 In recent years, researchers found that patients with colon cancer frequently had developed mutations, small, random changes, in their version of the code for the gene called PIK3CA.  Like many mutations though, it made no difference in whether or not patients were more likely to survive. Only in combination with aspirin therapy did this genetic difference become valuable.

6:00 The Harvard study measured both overall mortality (overall likelihood to die in general in a given time period) and colon-cancer specific mortality with respect to patients having the mutation and taking aspirin. Measuring both helps to confirm or dismiss the idea that a treatment is making people live longer by countering cancer specifically, versus just making people live longer through some general mechanism.

6:50 While this early study is in a very small number of patients, its results are intriguing, says Pasche, and he expects larger, randomized, follow-up studies to follow quickly.

8:24 Should the use of aspirin be validated, its addition would be welcome, says Pasche. Over the past decade, little progress has been made in the treatment of locally advanced colorectal cancer, which is defined as cancer that has spread to nearby tissue or lymph nodes but has not metastasized, or spread to other organs. While several new drugs have proven useful in the treatment of metastatic colorectal cancer, only one of them addresses local cancer that has advance. More options are needed.

11:27 One cause for concern is that aspirin is known to increase the risk of gastrointestinal bleeding and hemorrhagic strokes, but Pasche argues that it is among the most safe and well tolerated of drugs currently used in oncology.

For more information, visit the UAB Comprehensive Cancer Center site.

Microbe-made molecules may be future drugs

Our ancestors first “invited in” gut bugs 450 million years ago because it 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. Complex microbial communities occupy our skin, nose and mouth as well, and humans and their bugs may have become a single super-organism.

The subject made national news in June when the Human Microbiome Project, NIH-funded effort to catalog the mix of bugs living on and in Americans, reported its first results. With the typical set of bugs now outlined, researchers are searching for the bug profiles that correlate with diseases, including cancer.

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, and is featuring the chats as a podcast series.

Our guest for this last podcast in the series is James Versalovic, M.D., Ph.D., professor in the Department of Pathology and Immunology at Baylor College of Medicine. We talked about how new understanding of the mechanistic details behind human cell/microbial crosstalk may lead to new treatments.  

 

Show notes for the podcast

2:08 Different sites in the body play host to entirely different complex communities of bacteria and other microbes. 

2:45 The line is blurry between microbial cells and human cells because they constantly "talk" as they work together to do so many jobs in the human body. 

3:33  This conversation is really an exchange of biochemical signals, some of them carried by small molecules produced by microbes, the subject of Dr.Versalovic's presentation at the UAB retreat. Microbial small molecules were first studied because they interact with our immune system to cause inflammation.  More broadly, evidence is emerging that human organs evolved in such close cooperation with microbe-made molecules that such molecules have become critical to the ability of several organs to function.

4:34 As a baby is born, all the tools are in place for his or her immune system to develop, but those tools are not trained yet to work in the real world. Exposure to many bugs starts at birth, and in fact, the mother's bugs help to determine the baby's mix of bug species. 

4:48 One might think the most important lessons learned by a baby's immune cells are about which invading organisms to attack and destroy to protect the body from infection. In fact, much of the education is about tolerance. The cells develop in the presence of many helpful bugs, and learn not to become activated to easily to cause unwanted inflammation. A mature system only loses its cool when faced with a considerable threat. 

6:17  Just like some people who are quick to anger, some people happen to have a labile immune systems that too often and in the wrong context becomes activated. Not having had the proper education, such oversensitive system can lead to systemic autoimmune, allergic and inflammatory conditions like inflammatory bowel disease. 

7:25 Babies' microbiomes are getting off to different starts in life based on whether they are delivered vaginally versus through C-section.  A C-section baby is more likely to start with bacteria from a mother's skin, where the kid born via "natural childbirth" starts with the mother's gut bugs in his or her gut. Over time the babies' bodies compensate but there could be long-term consequences. 

9:09  Normally, the microbiome helps to keep the immune system in check, so that it is not constantly overreacting to cause systemic inflammation. Over time though, things like diet, obesity or smoking, perhaps a bad infection, may alter this balance.

10:25 A goal of Dr. Versalovic's effort to understand how microbial small molecules signal to the immune system may inform efforts to design drugs that calm down the immune system the same way a healthy microbiome does. Researcher may be able to synthesize compounds made by bacteria, or compounds in the diet changed by gut bacteria, which improve organ function. 

11:40 We feed our microbiome when we feed ourselves, so it pays to chose your diet carefully. As we understand it better, we will have better idea of how the molecules making up food interact with various microbial species to impact health and disease. 

12:25 The compounds produced by interactions between the gut microbiome and food may be affecting physiology throughout the body, including in the brain, where early work has tied diet-driven changes in the gut microbiome to behavioral changes. 

15:03 Dr. Versalovic recommends that students and researchers interested in finding out more about the microbiome visit the Human Microbiome Project's DACC site.

Please click on the following links to listen to the other podcasts in this series. 

Gut bugs drive cancer risk?

Massive computing power reveals gut bug/cancer links

Next gen sequencing reveals bug-driven cancer risk

Gut bugs and estrogen-related cancer

Evolving in a sea of microbes

2012 was the year of the microbiome, the set of bacteria, viruses and fungi living in our noses, mouths and guts. It made national news in June when the Human Microbiome Project first reported on what the bug mix looks like on and in a typical, healthy American.

New understanding of our 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.

For these reasons the UAB Comprehensive Cancer Center chose "cancer and the microbiome" as the theme for its recent research retreat, and The Mix interviewed retreat presenters for a podcast series.

Today's guest is George Weinstock, Ph.D., professor of Genetics at the Washington University School of Medicine.  We talked about his leadership role in genomics revolution, including his contribution to the design of both the Human Genome Project and the Human Microbiome Project.

Show notes for the podcast

1:12 Our world has been dominated by microorganisms for three billion years. All life then involved in this sea of microbes, and humans are no exception.

1:45  Having evolved in a world awash with microbes, the human body is colonized by specific sets of them that provide us with hundreds of times more functions than our own genes can't deliver. Human cells, for instance, have borrowed signalling pathways from microbes that help us digest our food, protect us from being infection, etc.

2:39 Insects have microbiomes too, they they are much simpler than ours. One related theory is that our immune system is more sophisticated because it had to learn to safely handle the many bugs we "invited" to help us digest our food. Taking the idea a step further, some experts think the immune system’s ability to repel unwelcome invaders might represent a lucky, evolutionary after-effect of its more ancient role — managing a stable of helpful bacteria.

3:58 At the heart of Weinstock's decades-long career is DNA sequencing, the technology that enables researchers to determine the order of DNA coding units as a step toward understanding the function of each DNA snippet. The same methods were used to do this for 25 years, but then in 2006 new methods matured that made possible to vastly accelerate the pace of sequencing.  Weinstock's lab can now do in a day what it once took years to do.  For instance, his team can determine the sequence of several human genomes in a day, each requiring the analysis of 3 billion units of code.

6:06 The new high-speed technologies have made possible massive undertakings in genomics, including the 1,000 Genomes Project, The ENCODE project and the Human Microbiome Project.

7:06 Weinstock is among the pioneers that helped to launch the Humane Genome Project, which ran from 1998 to 2003 and offered the first estimate of the 20,000 or so genes present in the human blueprint. Before that project, he was among the very first to sequence a genome from any creature, in his case the bacteria responsible for causing syphilis.

9:36 Weinstock also helped to organize the Human Microbiome Project, which this summer published a series of reports in Nature and several Public Library of Science journals that revised the understanding of how microbes drive either health or disease. Researchers from 80 institutions spent five years collecting and sequencing samples from 242 healthy volunteers.

11:07 Bugs don't colonize humans one by one, but instead as part of large, complex communities.  They interact so thoroughly with each other and our cells that they must be analyzed together. Newly available technologies made it possible to analyze the genes of thousands of organisms at once, and the National Institutes of Health decided to invest heavily. The goal is to quickly advance the understanding this huge aspect of human health driven by our microbes. The NIH funded several genome centers to sequence bacterial genomes, with Weinstock's lab among them.

11:34 Beyond just looking at bacteria, the project funded a number of clinical researchers to study how each person's microbiome affects everything from acne to urinary tract infections to the risk for inflammatory disease in premature babies to cancer.

12:28  While the NIH did not think the project would instantly cure diseases (the genomics are too complex), they did hope to understand how you study the microbiome and what resources would be required. 

Gut bugs' relationship with estrogen-related cancer

The human microbiome made news earlier this year when the Human Microbiome Project reported its first results on the typical set of microbes living on and in the average, healthy American. It's still in the news because researchers keep finding new ways in which our bacteria, viruses and fungi interact with our bodies to drive disease risk.

Along those lines, the subject of today's podcast is the emerging evidence that each woman's particular set of gut bacteria may influence how she processes the hormone estrogen. One theory holds that some bug species produce enzymes that increase a woman's lifetime estrogen exposure, and potentially, her risk for estrogen-related cancers.  

Talking on that theme in today's podcast is Claudia Plottel, M.D., clinical associate professor of Medicine in the New York University School of Medicine. She is an expert on the "estrobolome,"  the complete set of bacterial genes that code for enzymes capable of metabolizing estrogens within the human intestine. Her interview is the latest in a series recorded recently at a "cancer and the microbiome" research retreat held by the UAB Comprehensive Cancer Center. 




Shownotes for the podcast

1:00 Trillions of microbes, an immense community, live inside the human body and on its surfaces, interacting with the body to either help or harm it.

1:55 As a medical doctor who treats patients, Plottel has a unique perspective on microbiome research, and on how it may factor into patient care. Interacting with patients gives her a context to ask questions about the microbiome, while her research into the microbiome has made her more aware that any therapy is treating both the human body and its bacteria.

2:30 Beyond probiotics, there are few clinical treatments available that address a person's microbiome on the way to treating their disease, but several are on the horizon. For instance, approaches are under development that promise to restore a healthy population of microbes in a person, or even transplant them from a healthy person.

3:20 A major focus of Plottel's research is the interaction between each woman's gut microbiome and the hormone estrogen. It has been long known that estrogen, a vital hormone for human health, is processed in the liver, and that some of it enters the gut, where it interacts with each person's unique microbial community.

3:42 Also well established is that some of the estrogen entering the gut is recirculated through the body, while the rest of it is excreted. Evidence suggests that each person's mix of gut bugs determines how much estrogen is recirculated, making the microbiome a key regulator of each person's circulating estrogen levels over time.

4:27 Researchers know from studying large groups of women that the occurrence of certain cancers is estrogen-related, and that the incidence of these cancer types varies greatly across the globe. Microbial populations vary along with estrogen-related cancer rates, and projects under way in Plottel's lab seek to determine whether or not the two are linked.

5:22 One enzyme produced by certain bacteria, beta glucuronidase, is present in the guts of about 44 percent of women with healthy estrogen metabolism, so the thought is it plays a major role.

6:08 It has been established that antibiotic treatments change the make-up of the gut microbiome, and that it takes time for the community of helpful bacteria to recover after treatment. Some theorize that antibiotics throw off bacterial regulation of estrogen, and Plottel's team is currently running experiments to see if this is the case.

7:03 Plottel hypothesizes that women who happen to have gut bacteria with stronger or weaker enzyme function may have have higher or lower levels of re-circulated estrogens over their lifetimes, which in turn represents higher or lower risk for certain types of cancers. If this proves to be the case, researchers may be able to use prebiotics and probiotics to reduce risk.

9:00 Estrogen and cholesterol are chemical relatives, and some theorize that obesity, higher blood cholesterol, changes in gut bug profiles and higher risk for estrogen-based cancers are all related. In studies in mice, Plottel observed that antibiotic treatment that changes estrogen metabolism causes the mice to gain weight. Studies in women have also shown that obesity is a risk factor for estrogen-related cancers such as those occurring in the lining of the uterus (endometrial cancer) and in post-menopausal breast cancer. Plottel and others are working now to untangle these many threads.

10:10 The field of microbiome research is exploding in part thanks to the availability of new computational tools that can deal with its complexity, says Plottel. Most of the bacteria making up the estrobolome cannot be grown in culture for study by standard methods, so researchers must rely on genomic technologies and methods that have only become available in recent years.

10:58 Researchers need to look at cancer differently in the context of the microbiome, says Plottel. They should be looking more closely at the organ in which cancers occur, and seeking to determine if the microbial community specific to that organ is playing a role in cancer development.

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).

Massive computing power needed to unravel gut bug/cancer link

The human microbiome - the bacteria, viruses and fungi living on and in us - made news in June when the Human Microbiome Project first cataloged the mix of bugs for a healthy American.

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.

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 will be featuring the chats as a podcast series over the next few weeks.

Our guest today is bioinformatics expert Elliot Lefkowitz, Ph.D., associate professor in the UAB Department of Microbiology. We talked about how efforts to integrate research on cancer and the microbiome depend on bioinformatics, the high-powered computational analysis needed to reveal patterns within the mountains of data generated around the human microbiome. The data sets involved are many, many times larger than even the three billion coding units making up human genetic material.



Show notes for the podcast:

2:14  Researchers estimate that about 100 trillion microbes live on and in the human body, ten times as many as there are cells in the human body.

2:37  Research on the microbiome is revealing that, along with efforts by the human immune system to keep disease-causing microbes (e.g. bacteria) in check, certain sets of bugs in our body also help to defend against their pathogenic brethren.

3:11 Making matters more complex, the human microbiome is in flux, so it may change from a helpful mix of bugs to one that contributes to disease with changing circumstances. Being able to watch for that profile change would represent a medical advance. This change may be driven by a disease process, or may cause it in some cases.

3:33 The UAB cancer center is interested in changes in the microbiome because evidence suggests that bug profiles are changed by, and may change, cancer processes.

3:53 Bioinformatics is the computational analysis of biological data. Frequently, it deals with genetic sequence information, the DNA coding units that make up the genetic instructions for the building of a human. The order, or sequence, in which those units occur with DNA chains makes up the letters and words in these instructions. They are translated under the right circumstances into the proteins and regulatory elements that make up the body's structures and carry its messages.

4:30 After Michael Crowley, Ph.D., and his team at UAB's Heflin Center for Genomic Science, determine the sequences of the DNA chains in the bug genetic material, Eliott Lefkowitz, Ph.D., and his team at UAB's Molecular and Genetic Bioinformatics Facilty use bioinformatics to analyze them in different ways.

5:05  When Lefkowitz started in bioinformatics 25 years ago, the field was engaged in determining the sequence of a single gene, perhaps made up of about 1,000 coding units, otherwise known as codons.  It was a challenge with the computers of the day, but they did it. A few years later, Lefkowitz and others began looking at viral DNA sequences, which required them to analyze perhaps 200,000 coding units, and then bacteria, with perhaps 2 million coding units in play. With modern day next-gen sequencing, researchers may have to analyze 20 billion genetic units per sample.

7:11 The amount of information that researchers are having to analyze is so overwhelmingly greater that it was even five years ago that bioinformatics experts like Lefkowitz, even with leaps in computing technology, are having to create new computational techniques for using that computing power to get the job done.

8:20 For years, bioinformatics experts, including some at UAB, having been experimenting with concepts like cloud computing and Web 3.0, techie terms for massive stores of patient data and a unified system to analyze it. Lefkowitz and his colleagues work closely with the UAB Information Technology's Research Computing group (UAB ITRC), which makes available to research groups many resources, including the Cheaha cluster. It's a private network of individual data processors networked together to act like a supercomputer. When they need even more computing power, they turn to the cloud, in some ways like the networks that make Google searches so powerful.

10:00 To understand the impact of any individual's microbiome on that person's health, researchers need to know its make-up, the number of each kind of bug in comparison with others present, and what those ratios look like in a healthy person. A healthy microbiome is likely to vary by where you live, but there are some constants that could then be compared against those who have any particular disease.

10:58 Bioinformatics tools make it possible for researcher to compare the numbers and types of microbes in people who are healthy against those with each disease to see if different bugs dominate in people with a disease. Statistical associations promise to yield give clues that may lead researchers to create treatments that change microbes, rather than human cell signalling pathways, to treat human diseases.

13:00 Proteins, the workhorse molecules of human tissue, are made up of functional building blocks, many of which are used again and again by many different proteins. So when researchers see one of the known blocks in a protein of unknown function, it gives them some clues about what it does, especially when combined with bioinformatic analysis. Discovery of such repeating pattern often provides clues to overall biology.

14:20  In analyzing microbial communities, finding repeating patterns, like distribution of each bacterial types, and the ratios of one to the others represent patterns that can be compared between a person who is healthy and another with diabetes, for example. Lefkowitz can go even deeper and look at how at patterns in the proteins created by each set of microbes to see which are associated with disease or health.

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.

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.

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.

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. 

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.