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.