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Inside the Human Microbiome Project

Dear Friends,

Can you name this Beautiful Creature?

Today, I will be taking you with me on a journey into the inner workings of the world of the Human Microbiome Project. When one dives into any new content area there is the requisite language/vocabulary to master. Over the last three weeks, as we have begun this journey into the HMP, we have touched upon The Roadmap, The Jumpstart Centers, The Reference Genome, Repository Sites, body sites, bacteria—genus, species and subspecies. In this email, we will add a few new terms such as the Collaborators, the PIs (Primary Investigators), Contigs, Nucleotides, Operons, and The Tree of Life.

I am honored to share with you a portion of my conversation with one of the HMP Collaborators and Primary Investigators—Joseph Petrosino PhD. Dr. Petrosino is an assistant professor of Molecular Virology and Microbiology within the Human Genome Sequencing Center at Baylor College of Medicine in Dallas, and he also plays an instrumental role as a Primary Investigator or Collaborator with the Human Microbiome Project. A PI or Collaborator is one who heads up a lab or a group of researchers involved in the Human Microbiome Project. Isn’t it interesting that they have chosen the label Collaborator for the leaders within the HMP.

Now let’s listen in to my interview with Dr. Joseph Petrosino

Q. Tell me about The Jumpstart Program, the four jumpstart centers, and your role in the HMP at Baylor.

A. The four jumpstart centers are Washington University in St. Louis, Baylor College of Medicine in Dallas, The Broad Institute at Harvard and MIT, and the J. Craig Venter Institute in Maryland. The Baylor College of Medicine is not to be confused with Baylor University. In 1967 they parted ways because of certain restrictions on government funding in regards to religious institutions. So BCM formed its own entity. These four centers were chosen for the jumpstart phase because each has been NIH sponsored sequencing centers in the US for many years and were responsible for achieving the completion of sequencing for the human genome and many of the sequences we have in data bases today.

The Human Microbiome Project started with what is called The Jumpstart Phase of the NIH Roadmap Project, which means that it has a high profile directive to spawn more research in this area through the many institutes at the National Institute of Health. Therefore they set aside a large bolus of money to send off to centers that are ready to hit the ground running. This phase of the project is called the jumpstart phase.

Q. What is the focus for each of these four centers?

A. All four centers focus on both components of the HMP research—the metagenomic analyses and the reference genome sequencing. My normal position at BMC is as an assistant professor in the Department of Molecular Virology and Microbiology. Within the HMP I function as one of the PIs (Primary Investigators) or Collaborators on the project. Specifically, I oversee the clinical DNA extraction lab. He co-directs with Sara Hylander PhD. I handle more the clinical body site sampling and analyses, while Dr. Hylander leads the Reference Genome sequencing. However, I have my hands in all aspects of the work. My expertise ranges from how to handle the samples to how to get more accurate information from them in terms of sequences to what does it all mean in the end.

Q How many body sites for microbial sampling are there?

A. There are 18 in women and 15 in men. For example there are 8 or 9 sites in the mouth (the saliva, tongue, hard pallet, soft pallet, the buccal mucosa, etc), four sites on the skin, three in the vagina and only one sampling method for the GI tract—multiple stool samples.

There has been much talk about using more invasive methods to get samples from specific site within the GI tract with a small group of volunteers. We were afraid that nobody would volunteer for the sampling because it would be like your worst doctors appointment ever. We wanted to make sure people actually enrolled. We have sequenced around 50 people now and are on the way to completing the 250 individuals who have enrolled.

Q. Describe the different finishing goals—Standard draft vs. High Quality draft?

A. The best way to describe [finishing goals] is when people suggest organisms that should be sequenced. There are several working groups involved in this. One of the things that they do is to take a look at the taxonomical tree of life and see how many organisms are in that genus or how many species within that genus have been sequenced and been looked at carefully. How discrete is that data—how many of the base pairs are known? [This then sets the stage for determining whether a draft or a high quality draft is called for] When we have a goal for a standard draft or a high quality draft, we are referring to the number of times or the number of passes that quality control goes over a genome. So for example, for a standard draft we will basically sequence the genome—the data comes off the machine, there is an assembly generated so the single reads are put into a longer set of what are called contigs—trying to get [the chromosome] to where you have one complete circle. For the most part, all bacteria have one circular chromosome, there are some exceptions, but in general most bacteria have one circular chromosome. If you look at the genome size (the total number of base pairs-nucleotides) and divide that by 1000 that will give you the number of genes for a bacteria. Most people assume that the average size of a gene for bacteria is around 1000 base pairs.

[A contig–from the word “contiguous”–is a series of overlapping DNA sequences used to make a physical map that reconstructs the original DNA sequence of a chromosome or a region of a chromosome. A contig can also refer to one of the DNA sequences used in making such a map.]

For the bacterial chromosome think of a railroad track in a circle. We will know some of the base pairs but won’t know all of them—there will be gaps. There will be certain levels of uncertainty at certain positions. With a Standard Draft there is a threshold of uncertainly that all the sequencing centers hold to. Anything above that limit must receive further reads so as to scrutinize these unknown bases. All bacteria will receive a Standard Draft, which will complete the circle, and many will receive what is called a High Quality Draft, which gives a more detailed accounting of each base in the chromosome.

I will close this portion of the email sharing a bit of our conversation regarding genes, proteins, pathways, evolution and probiotics. I had asked Dr. Petrosino how many of the genes in a bacteria’s 1000 gene collection produce the same protein—is there a redundancy? He seemed to confirm that primarily each gene produces a different protein, but one thing led to the next….as you will see.

A. There is a lot of protein production redundancy is some bacteria depending on the niche that an organism is living in. Sometimes if the host or surrounding bacteria are providing nutrients that the organism needs over a course of evolution certain genes won’t be needed. For example lets say you need a specific sugar metabolized and you are growing in nature you would need to have all the enzymes in that pathway, all the proteins in that pathway to be able to breakdown that sugar. Where as if you find you are in an environment with a host where you have landed in a spot in the body, over the course of evolution where the metabolite is right there then you don’t need all those genes to create the metabolite and those genes will start to eventually mutate and evolve away. Or acquire mutations that will inactivate those genes and then as time passes (many eons) it will be hard to distinguish that the genes were even there. Perhaps rearrangement will occur that will eliminate those parts of the genome entirely. Depending on where an organism lives will sort of dictate the genes that that organism has. If they have just happened to become a human symbiont then they may have more genes than they need for their new environment. Depending on the environment that a bacteria finds itself living in it has regulatory mechanisms available to itself that can switch genes on or off to enable them to adapt to that habitat- like using fermentation as a pathway for energy verses respiration in a more oxygen plentiful environment. Cytocines are proteins and so are most chemocines. Metabolic pathways are the result of a cell, whether it be a human cell or a bacterial cell producing proteins that will take a complex molecule like a protein or a sugar and clip off a small part and pass it on to the next enzyme in the pathway. Metabolic pathways are basically assembly lines with proteins being the stopping points on the assembly line.

OK, that is enough. I realize this last paragraph is a bit of a potpourri of ideas. But I wanted to posit these thoughts here for you, as they are coming from a Collaborator, whose on the bench, in the lab, doing the work of discovery for all of our benefit. Thank you Dr. Petrosino!

Sincerely yours,

Seann Bardell

Clinical Note:

To all of you, as our customers, thank you for your patience with our shipping over the last two weeks, as we have been moving our warehouse from Portland to Los Angeles. We are thrilled with our new warehouse’s capacity. Friday, last week we began shipping again—full throttle.

I want to encourage you to expand your thinking a bit when it comes to dosing with our synbiotic formulas. Have you tried mixing our different probiotics formulas? For example this morning and for the last week, I take one tablespoon of the Beta Glucan Synbiotic Formula and one teaspoon of the No. 7 Systemic Booster in a large glass of water—I like what it does, I like how my body feels with it. Try it. It even tastes quite good. With this mix I am getting a combination of our American collection of pedigreed good bugs (Beta Glucan Formula) with our Bulgarian collection (No. 7 Systemic Booster). Check what is in each of these formulas.

Another of our customers representing a large consortium of health practitioners suggests we follow a protocol of 1 teaspoon of our Original Synbiotic Formula in the morning and 1 capsule of our Supernatant Synbiotic Formula in the evening. With this regime, patients are getting both the American and Bulgarian collection with fiber and metabolites. Check this one out.

The Last Quiz Answer: Cinereous vultures, also called Eurasian black vultures, are the largest raptors in Eurasia, and boast an impressive 8- to 9-foot wing span. These vultures are considered “vulnerable to extinction” in Europe by the World Conservation Union. Current estimates put the global population at about 4-6,000 individuals. These impressive birds breed in mountainous and steppe areas from Spain to Mongolia and south to the Himalayas. They have been spotted on Mount Everest at altitudes of up to 23,000 feet. They form long-lasting pair bonds, and can live to be 38 years old.

Welcome to the Talking Glossary of Genetic Terms from the National Human Genome Research Institute.

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