Thursday, December 27, 2012

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.

Thursday, December 20, 2012

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.

Friday, December 14, 2012

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. 

Friday, December 7, 2012

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 ProjectThe 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.