Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
Now, since the finishing of the Human Genome Project, we’ve actually spent more time sequencing the genomes of other creatures to inform the function of human genes, than we have spent sequencing different humans in a disease context. This is a small part of the menu of all the creatures that have been pushed into this pipeline; and each one has its own story and own justification. Together, I think with the other centers and other parts of the international program, there’s probably a hundred species possessing larger genomes, extending far up the tree of life, that are well advanced in having their genomes sequenced. And of course, many more hundreds if you count microbes and small eukaryotes.

So today I’m barely going to talk about any of these. But I do like to just touch on a couple of them to give you this flavor: on the genomic side of this genome medicine equation, we’ve still got a genomic enterprise that is about sequencing the genomes of animals to help inform our direction through biomedical research via comparative genomics.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
Example number one is this creature here, the Tammar Wallaby, which my friend and colleague, Marilyn Renfree, here is catching. Below, there’s its embryo. And I told a remarkable story, I think at our meeting last week, of how all these offspring are born on the same day of the year—all the members of the species. So that’s one piece of remarkable biology. But the other thing I didn’t talk about is the antibiotic requirements for a creature that essentially does its development in the pouch, rather than in utero.

You know, these are not placental mammals, these are marsupials. So this thing develops most of its early life period outside or in the pouch. So at that time, it has a brother or sister who shares the pouch. So it [female parent] has two teats, one which produces a remarkable range of beginning-to-be-discovered antibiotics that can allow it [offspring] to survive in that period, and another which has other nutritional requirements. So what an opportunity for investigation in reproductive and early life biology.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
Here’s another one of these creatures. This is the sea urchin, which probably some of you, or a few of you, might have worked on in some lab rotation at some stage. Of course, it’s a model for development and another not too far distant eukaryote. Amongst the many things we discovered in the long, drawn out genome project was that there are eighty or so genes in this creature which really can now be used and studied as disease orthologs. If you’re working on a particular human genetic disease and you know the gene, you can now consider the sea urchin one of the creatures that you might want to look at to investigate the biology of that gene.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
And the last example is the macaque, which we finished recently, as David mentioned. These primates, of course, are extremely popular and important laboratory models. They’re used in neuroscience and vaccine studies, but also they’re used in behavioral studies. What fabulous creatures, and how similar to us they are. Those of you who own dogs probably think that dogs are almost the perfect models for human behavior. It takes very little for a non-primatologist to see these primates in action and start to engage them as fellow creatures in the kingdom, for which we would love to understand much of their dynamics and how they work.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
So we studied the macaque, and along the way deciphered—using just its raw genome sequence and comparing it to the chimp and human genome sequence—features about the rate of primate evolution based on different chromosomal events. It turns out that as chromosomes have changed across the species tree, the changes have slowed down a little bit in the human part of the lineage, more so than in any other primate. This, together with other data, is very informative about the dynamics of these genomic changes across evolution. This is a long study; I’m not going to tell you much about it.

Another highlight was the few genes we were able to eke out of that genome by comparing it to chimps to humans, and asking, of the changes that we see, how many of those changes reflect the pattern of action of positive selection across the lineage? Because those are the genes, of course, which we suspect are most important in saying why we’re humans and chimps are chimps, and macaques are macaques.

Some of those genes have even been duplicated as the genome has gone through its efforts to make that part of the genome more conservative, more important through the evolutionary process.
* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Figure adapted from original publication: Rhesus Macaque Genome Sequencing and Analysis Consortium. (2007). Evolutionary and Biomedical Insights from the Rhesus Macaque Genome. Science, 316 222-234.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
So we’re continuing, of course, all these studies in these other creatures to drive our use of sequence and genome analysis to inform human biology, to make more sense of the human genes, to make more sense of the human phenotype, and to allow us to make more inference. When you talk about something to do with a human gene, what does it mean for the human biology?

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
So as we’re all geared to do in the genome world, we kind of make it sound easy, okay? But in fact, it’s not. It’s still an expensive and clumsy, growing science to produce whole genomes. And without going into the ugly details to prove that, to really exemplify it, I’ll just tell you that to use those machines upstairs, it still costs about 10 million dollars to generate that raw data, and it still takes six months, which is remarkable, since it was a 15-year project using multiple centers the first time.

But it’s still six months, and that’s no diagnostic test, right? And that’s just to generate the raw data. You’ve still got to get a team of people that you can barely find and train to do the assemblies and put the stuff together, and do the quality control and annotate the data, and then do all that stuff that makes a genome. And if you want a genome like the human, which is actually a very refined and high quality piece of scientific product, it’s about the same effort again to get to that finished state. So the bottom line is, this is still a raw and underdeveloped science. There’s still a lot of work to do just in this basic effort of genomics. Having said that, the programs have not been restrained in what we and they are trying to do with sequence as a basic discovery tool. And that’s illustrated by a couple of things I’m going to just mention, but not talk about in any detail today.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
First, Copy Number Variation Studies - Jim Lupski will talk about this in this series. And what he will tell you is that following up his earliest discoveries are demonstrations that genome duplications indeed can drive genetic disease. That’s quite controversial. Jim really nailed that maybe ten years ago. That, plus the observation by many others that parts of mammalian genomes are naturally polymorphic in their quantity. That is, you can look along the genome and find a part which is duplicated in one person maybe three times and you can go to another individual and it’ll be duplicated five times. These can be large pieces of genome, with function, with genes contained within them. So the concept of copy number variation, CNV, plus this notion of the engagement in disease, has led to other programs which, in some instances, are using microarrays and other techniques. But in other cases, investigators are actually using sequence to drive the discovery of a full catalog of these events.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
Here’s another program, called the Human Microbiome Project. We actually have a lot of this project anchored here [at Baylor College of Medicine] through George Weinstock’s efforts, and he’s going to talk to you, too. The idea is that since sequencing of bacteria is getting pretty routine, let’s sequence them all. Now of course, you can’t culture many of them, so that presents a big problem. So, the initial thrust is to sequence the 600 or so that are in the catalogs of all culturable and non-culturable bacteria, plus several non-bacterial microbes, and use this reference sequence, plus additional samplings of different body sites, different orifices and different groups of people, obtaining raw sequence to better understand the ecology of these positions in the body. This catalog is being built, and this is now an NIH [National Institutes of Health] Roadmap Program. This is going to be a big deal, and is going to impact on this whole concept of genomic medicine when we move past the human and the human genotype into other areas of sequence and those kinds of activities.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.

Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
And of course, here’s kind of the mother of all additional projects, the Cancer Genome Sequencing Project. This is another NIH [National Institutes of Health] initiative that was launched a couple of years ago. The idea is, “let’s extend the sequencing model, and let’s sequence a whole bunch of tumors. Let’s extend our notion of characterizing different cancer diseases to a full and comprehensive understanding of genomic changes and the range of genomic changes that can affect those diseases. And let’s use that to drive discovery of what loci might be important in those diseases when we haven’t found those loci already.”

This is controversial and well worth at least a one hour group discussion and meeting already. But suffice to say, it’s off the ground. We have trials. Three diseases have been chosen by the larger program: glioblastoma (GBM), ovarian cancer, and squamous lung carcinoma. There’s actually another whole component that was funded by a pilot before this, characterizing a lung adenocarcinoma. So this is all really rolling along.

* Notes in this slide presentation are adapted from the transcript of “The Pathway to Genomic Medicine,” a presentation by Richard Gibbs, PhD, given in August 2007, as part of Baylor College of Medicine’s Department of Medicine Grand Rounds Human Genetics Symposium.