By CRG staff - interview with Steven Salzberg

Steven Salzberg, PhD, is a Professor of Medicine in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University.


Genome sequencing in 20 years:

Certainly things are very different than they were 20 years ago. Most of the changes have been incremental, but adding things up, it's been quite dramatic. Extrapolating forward, I don't know if there will be any revolutionary changes; but even with steady progress, 20 years is a long time, and things will look very different from the way they look now.

One thing that we need to solve, and something I've worked on, is the assembly of genomes. I'd like to think that in less than 20 years we'll have either solved it, or there will be such dramatic progress that it won't be a problem anymore.

We have sequenced thousands of species. Almost all of them, with the exception of some bacteria, are draft genomes. That means there are gaps in the sequence, and there are parts of the sequence that aren't really positioned correctly, they're not lined up along chromosomes; so we can stitch them together, but we don't know what the chromosome structure is. That's true of nearly every genome out there, and in fact there are still gaps in the human genome.

The advent of next-generation sequencing has dramatically sped up the rate at which we're tackling new species, but they remain draft genomes; in fact, the quality of draft genomes has probably gone down a little bit with next generation sequencing.

How we sequence the genome today (and tomorrow):

We break it into a very large number of pieces, and we sequence those pieces in very short reads of 100 base pairs or so. Then we use a program, like the programs my group develops, to put it all together. That process has various laboratory steps and very complicated computational steps that are imperfect, so you don't get the whole genome reconstructed at the end.

A better way to do it would be to just grab a chromosome and read it from one end to the other. You wouldn't have to assemble it; you'd just have the chromosome sequence at the end. And there are people who are working on ways to read longer and longer stretches of DNA-without any big breakthroughs lately, but somehow we've got to get there, and hopefully within the next 20 years we will. If we come up with better technology to help us sequence the genome, hopefully we'll be able to sequence more genomes even faster-and they'll be complete instead of drafts.

Discovering new genes:

We use a lot of indirect methods to try to figure out which parts of the genome are the genes, so we're constantly discovering new functional parts of genomes that are either genes or regulatory sequences that control genes; but it's very piecemeal. In a way, that makes it more exciting, because you never know what you're going to find-even looking at well studied genomes you can find lots of new things-but I'm hoping we'll develop new and better methods for figuring out which parts of the genome are important to the organism.

For humans, I would like to be able to see a full catalog of all the genes. We don't have a catalog of all the human genes yet. In fact, we don't even know the precise number of human genes. So sometime, maybe in the next 20 years, we'll actually be able to say that we have the complete list of human genes-that is, all the protein coding genes and all the RNA genes.

When the Europeans first landed on the shores of North America, you can extrapolate: well, eventually, they'll explore the whole thing. I would say that at the rate we're going, in 20 years there's a good chance we will have a catalog of all of the human genes. It's not certain, because it's very hard to pin them down, but there's a good chance.

Sequencing breakthroughs:

Whether we'll be able to sequence a new genome with a technology that lets us assemble it with no gaps-that will require some breakthroughs. Incremental steps will not get us there.

There are different ways it could happen, some probably that I can't envision. If you can come up with a sequencing technology that lets you read chromosomes in extremely long fragments-say a million base pairs at a time-that would be a breakthrough. Right now the best you can do is read one or two thousand base pairs at a time. If you had a thousandfold increase in that capability, that would let you sequence and assemble a complete genome very quickly. And I don't know how you do that-nobody knows.

Personalized medicine:

I think that individualized genome sequencing and individualized medicine is going to happen, and I think it will happen in less than 20 years. I think we will all be getting our DNA sequenced, to some extent. Whether it will be our whole genome or just parts of our genomes, we will have our own genomes sequenced, and we will see that information used by our own health care providers.

I think it's actually inevitable-20 years is maybe a little short, but I think it's inevitable that everyone will have his or her entire genome on their computer at home, and their physician will have it, and they will regularly turn to it to look things up.

When you go to a new doctor, you should be able to walk in with your genome on a thumb drive. Your risk for future diseases and your responsiveness to various treatments is very much affected by your genome, and we're in a large scale enterprise right now to collect all of that information and figure it out: how your genome predicts whether you'll respond well to a drug, how it predicts your risk of a disease ... this is all useful information for someone who is trying to take some action about their own health. So I think it will translate into the clinic pretty quickly.

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