Creating a chromosome

01 April 2014

Interview with

Jef Boeke from New York University Langone Medical Centre

Broken chromosomesThis week, scientists have achieved what has been hailed as the biological equivalents of climbing Mt. Everest.  They've created a synthetic, fully functional copy of a yeast chromosome.  Jef Boeke from New York University Langone Medical Centre is one of the scientists who's leading the project. He explained the project to Chris Smith...

Jef -   We've made a brand new chromosome, starting from a design that we put together on a computer.  The original chromosome has about 316,000 base pairs, which you could think of as letters. Starting with that sequence of letters, we carved out sections that we thought would probably the yeast could do without.  We inserted some of these and we changed some of the letters in ways that were visible to us.  Then we engaged a class of students in the Build-a-Genome Class at Johns Hopkins University who strung together these letters into words, the words into paragraphs, and eventually, we built pages of letters so to speak.  And then chapter by chapter, we introduced one chapter of approximately 25,000 letters at a time and replaced the chromosome that was present in the normal yeast with the synthetic counterpart.

Chris -   So, you did this in an incremental fashion.  You didn't replace the whole chromosome at once.  You did little bits of it at a time.

Jef -   Precisely.

Chris -   Why was it necessary to do little bits at a time?  Why couldn't you just make a new one and put it in?

Jef -   Well, we are able to do that. But it was risky the first time to do that because by making so many changes to the sequence that we had, we did not know ahead of time what the outcome would be.  This was a way to make sure that there were no flaws in our overall plan.

Chris -   So, the yeast that you've made, it works, it's indistinguishable when you just look at it in the way in which it grows, running this artificial computer design chromosome compared with wild-type yeast - yeast you would find brewing beer which is the yeast you started with, isn't it?

Jef -   That's correct.  That's exactly right.

Chris -   You picked on yeast chromosome 3, or at least that what you said you've done in your Science paper; so why did you choose that one?

Jef -   Well, you might've thought we would start with the smallest chromosome, but chromosome 3 is actually the third smallest chromosome.  The reason is because it's actually a sentimental favourite of people who work on yeast and that's because like people, yeast comes in 2 sexes.  They're not called male and female, they're called A and alpha. And just like people, yeast can mate and give rise to progenies and the master regulator gene for this process lives on chromosome 3.  That's why it was also the very first chromosome whose DNA sequence was determined.

Chris -   So, this gives you an insight into whether yeast effectively make male and female forms and if you've made an artificial form of yeast and it still makes male and female forms, you know your chromosome is working, right?

Jef -   It's one of the many ways we know, yes.  There are many genes on this chromosome.  Over a hundred and basically, they all have to be working to some extent in order for the yeast to grow normally as far as we can tell.

Chris -   What are the implications of what you've done, of being able to produce and prove that you can successfully produce a chromosome and replace the entire chromosome in a living organism in this way?

Jef -   Well, two things.  Number one, we can obviously scale up.  We can make larger Telomeres on chromosomes DNAchromosomes and potentially, we could build chromosomes that could be introduced for example into plants and animals down the road, much smaller versions than the native chromosomes because the yeast chromosomes are quite a bit smaller.  But secondly, we've installed into this chromosome a kind of programme that will allow us to - by slipping a switch, a genetic switch - allow us to trigger the formation of thousands of derivative chromosomes, all different from each other.  I likened it to a system that automatically shuffles a deck of cards.  Only in this case, the deck contains 100 genes.  So, we can shuffle the chromosome and ultimately, we'll be able to shuffle the entire genome of this yeast.  By doing that, we think we can make greatly improved versions that can be very useful for practical purposes, not just making alcohol which we know that yeast does very well, but many other products like medicines and vaccines, and specialty chemicals.

Chris -   Jef Boeke from the NYU Langone Medical Centre.  He published that work this week in the journal Science.

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