Edited Transcript from “The Pathway to Genomic Medicine,” Richard Gibbs, PhD*
We live in very different worlds—those of research and clinical practice. Genomic medicine, of course, infers that we’re going to bring together genome information and genetics and clinical practice. I feel like much of the time, we know so little about each other’s worlds [clinical and research], even though we’re here [at Baylor College of Medicine] probably nestled together more closely and more intimately than in any other institution in the world. No one else can match our sheer mass of individuals on both sides of that fence.

So I think we have this extraordinary opportunity, to overcome some of the enormous barriers to what we do. So that’s why I jumped at the chance to come and talk here. I feel like every time we collaborate, we add one more little dot in the big mosaic that we’re building. And maybe one day we’ll all stand back and look at that mosaic, and we’ll know exactly what genomic medicine is. In the meantime, I think we kind of have to struggle through to make our own definitions. So what I really want to do today is to give a bit of reality to some of the elements of the whole enterprise, and set the framework from the genomic point of view, as well as outlining how the study of genetics is unfolding in informing human disease.

* 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 so of course it’s all directed to this magic model where somebody walks into your clinic, and I guess this is the near-term model, where you [the physician or researcher] send their sample over for a complete human genome sequence, and you use that to inform your decisions. The further-term model will be that they will actually walk in with that little device, or you’ll look at it online, and they’ll already have logged in their family genetic information, their own DNA sequence, and you’ll just have to look it up to get it.

* 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*
If you subscribe to that model, which of course we all did at the beginning of the Human Genome Project, then you had to subscribe to this pretty simplistic model of how all this was going to work. That is, there would be a primary data discovery, the sequence of the human genome. This would easily lead to discovering genes and inferring their function, and we would just use that information to modulate and cure disease and do diagnostics and prognostics.

* 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*
Of course, we all knew that that was a very naive model, and it had much more complexity to it. In fact, this big box on the left actually represents all of the biomedical research, and what everybody’s been doing all along. I think what we’ve been doing since is really adding layers and layers, and smaller and smaller tics to this diagram, while acknowledging the importance of the integration of simple genomic approaches into the complexity of biomedical research and disease phenotypes.

* 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*
Within the framework of genomic medicine, the technology has been critical. That is, every step in the development of the whole model has been enabled constantly by technology. That continues to be the theme. And at each point, the only real reality check we’ve had is to sit back and look and say, “Well, what have we achieved in terms of development of data sets and development of knowledge about individual disease?”

* 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 that’s the framework, as I already said, that I want to address today, in the context of these three questions.

How are we doing with this idea that a lot of DNA sequencing and analysis of genomes—and the follow up from that—can actually drive knowledge discovery?

In particular, how are we doing that in the context of genetics and disease?

What should we do next, particularly here at Baylor?

* 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*
The first question is actually pretty easy to answer. We’re really doing pretty well. This is my favorite slide from 20 years ago, when we did the first PCR direct analysis of a gene and found heterozygous mutations that caused a direct disease. It was a nice illustration of the first application of multiplex polymerase chain reaction, in combination with fluorescent sequencing, to find all the gene’s structural mutations and to say that the rest of the gene wasn’t affected, because we’d looked at every coding base in it.

* 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’ve gone from that now through sequencing the whole human genome, and here’s the scene from the White House where everyone had a group hug, saying, “It’s all done and the private and public sectors have all agreed to disagree about certain things, but the datasets speak for themselves.” That’s the shortest history of the Genome Project I’ve ever been able to deliver—down to about ten seconds?

* 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 after that, we came home and figured that we had a lot of Ts, Cs, As, and Gs, and didn’t really understand them, and asked ourselves the critical question, “How could we begin to interpret these data and eke out what was inside of them?” And we pretty much came to the conclusion that what we needed more than anything else was actually more sequence data, in order to drive comparative genomics and to generate some sources of genetic variation and so forth.

* 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 from that period, I guess it’s now six years since that first draft of the human genome appeared, and four years since the finished genome, and we’ve continued to build the enterprise of being able to sequence DNA in the way that we learned to do it in the context of the Human Genome Project. So for those of you who’ve been upstairs—and if you haven’t, you’re certainly invited to come and look—we now have this big machine. It’s three floors of this building, and it has 200 people, and it has a floor full in instruments and computers. And its job right now is to produce about a one times coverage of a mammalian genome every month [9/2007]. So in some contexts, that’s remarkable.

Because through the Genome Project, we started doing a very tiny fraction of that, and wondered how we could do this entire job. Now we can cover a whole human in one month. Normally, for reference, when we sequence a mammal, such as a human, we would do a six-fold coverage. In six months a facility like ours can actually push out a human genome sequence, equivalent to what the Human Genome Project offered, at least at its first phase. And so that’s a number to keep in mind, please. We have a three billion—base genome. You have two copies of that. You have six billion bases; three billion from your mother and three billion from your father. And that’s about the number of raw bases we can push out from the Genome Center.

* 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.