Image post 3: dangerous clumps of fungus

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may help to diagnose and treat fungal infections.

Here is a scanning electron microscope image of the fungus called Aspergillus. It's in the process of germinating, or emerging from round spores (at the center) to begin growing. The fungus has sprouted long, branching filaments called hyphae.

Most people breathe in Aspergillus spores daily without incident, but those with lung diseases or weakened immune systems can contract Aspergillosis, symptoms of which range from allergic reactions to severe lung infections. The fungus is a major player in some forms of allergic asthma, as clumps of hard-to-remove hyphae build up in the lungs.

According to the CDC, fungal infections pose an increasing threat to public health because of the growing number of people with weakened immune systems, including AIDS, cancer and transplant patients. In addition, treatment-resistant fungal infections have emerged as a growing problem in hospitals. Global warming may be contributing to an increase in infections, as fungi thrive in warm, moist conditions. Please see the CDC fungal page for more.

Current treatments are largely incapable of reducing morbidity and mortality in Aspergillosis, said John Kearney, Ph.D., professor in the Department of Microbiology within the UAB School of Medicine. He and his team are developing a new kind of vaccine that could provide protection against invasive Aspergillosis. Bacteria elicit a stronger human immune response than fungi but contain some of the same proteins (e.g. chitin). Based on these common building blocks, it may be possible to develop a vaccine where bacterial protein vaccine ingredients are used to activate immune cells that also target a fungus and remove it from the body.

This image was made by Dr. Jeffrey Sides from the Kearney laboratory at UAB using an instrument made available by the UAB School of Engineering.

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

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).