'Synthetic' chromosome permits repid, on-demand 'evolution' of yeast

Sep 14, 2011
Frequently described as bow-tie-shaped, a yeast chromosome has two arms that are positioned similarly to the two sides of a bow-tie. Credit: Jef D. Boeke and Sarah Richardson, Johns Hopkins University

In the quest to understand genomes -- how they're built, how they're organized and what makes them work -- a team of Johns Hopkins researchers has engineered from scratch a computer-designed yeast chromosome and incorporated into their creation a new system that lets scientists intentionally rearrange the yeast's genetic material. A report of their work appears September 14 as an Advance Online Publication in the journal Nature.

"We have created a that not only lets us learn more about yeast biology and , but also holds out the possibility of someday designing genomes for specific purposes, like making new vaccines or medications," says Jef D. Boeke, Ph.D., Sc.D., professor of and genetics, and director of the High Throughput Biology Center at the Johns Hopkins University School of Medicine.

Boeke notes that yeast is probably the best-studied organism with a on the planet and is "already used for everything from medicine to biofuel," making it a good candidate for his team's focus.

In designing the synthetic yeast chromosome, Boeke says, the goal was to make it maximally useful to researchers by laying down some ground rules: First, the product could not compromise yeast survival; second, it must be as streamlined as possible; and third, it had to contain the capacity for genetic flexibility and change.

Using the already known full —or DNA sequences—of the yeast genome as a starting point, Johns Hopkins graduate student Sarah Richardson wrote a software program for making a series of systematic changes to the DNA sequence. The changes were planned to subtly change the code and remove some of the repetitive and less used regions of DNA between genes, and to generate a mutated "version 2.0" of a yeast cell's original 9R chromosome. The smallest chromosome arm in the yeast genome, 9R contains about 100,000 base pairs of DNA and represents about one percent of the single-celled organism's genome.

Building the actual chromosome started with stringing individual bases of DNA together that were then assembled into longer segments. Large segments of about 10,000 base pairs were finally put into live yeast cells and essentially swapped for the native counterpart in the chromosome, a process for which yeast are naturally adept. In addition to 9R, the team also made a smaller piece of the chromosome 6L. Yeast cells containing the synthetic were tested for their ability to grow on different nutrients and in different conditions, and in each case came out indistinguishable from natural yeast.

The Hopkins teams says what distinguishes this constructed chromosome from the native version — and sets it apart from other synthetic genome projects — is an "inducible evolution system" called SCRaMbLE, short for Synthetic Chromosome Rearrangement and Modification by Lox-P mediated Evolution.

"We developed SCRaMbLE to enable us to pull a mutation trigger — essentially causing the synthetic chromosome to rearrange itself and introducing changes similar to what might happen during evolution, but without the long wait," explains Boeke. Why build in the scrambling system? To change multiple things at once, says Boeke, which is anathema among experimental scientists who traditionally change only one variable at a time, Nature is never that well controlled, he says.

The team activated SCRaMbLE in yeast containing both the synthetic 9R and 6L chromosomes, then analyzed the DNA from the . Testing this population of SCRaMbLEd yeast fed various nutrients they found some grew fast, some grew slowly and others really slowly, and some of the fast-growing ones had very specific defects resulting from specific gene loss, showing that SCRaMbLE does indeed introduce random variation. When the team analyzed the molecular structure of the synthetic 9R and 6L chromosomes from this SCRaMbLEd population, they found chromosomes with small deletions, rearrangements, and other alterations, at wildly varying locations.

"If you think of the as a deck of cards, we now have a system by which we can shuffle it and/or remove different combinations of 5000 of those cards to get lots of different decks from the same starter deck," Boeke says. "While one derivative deck might yield good hands for poker, another might be better suited for pinochle. By shuffling the DNA according to our specifications, we hope to be able to custom design organisms that perhaps will grow better in adverse environments, or maybe make one percent more ethanol than native yeast."

Boeke says the 9R and 6L experiments are "the beginning of a big project, whose ultimate goal is to synthesize the whole genome (about 6000 genes) and SCRaMbLE the 5000 likely to be individually dispensable. And he wants to make the tool available to anyone who wants to use it, without intellectual property protection.

Explore further: Mycobacteria metabolism discovery may pave way for new tuberculosis drugs

More information: Sc2.0 project: www.syntheticyeast.org

Provided by Johns Hopkins Medical Institutions

4.3 /5 (3 votes)

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Nanobanano
1 / 5 (10) Sep 14, 2011
PANDORA

Some shit should be left alone.

Seriously, DOOM is hyperbole/science fiction we all know, but my goodness, let's not tinker around with the artificial chromosome idea.

We don't need a billion people infected with some sort of chimera pathogen from an experiment gone wrong.

All it takes is one freaking engineered yeast cell finding it's way into the food supply, and who knows what would happen.

"Open source" food poison bioweapon...

Sheesh...
grosyhpgrosyhpgrosyhp
3 / 5 (6) Sep 14, 2011
AGRICULTURE

Some shit should be left alone. Just let's not tinker around with the artificial SELECTION idea. We don't need a million people infected with some sort of chimera pathogen from an selection gone wrong. All it takes is one freaking SELECTED wheat grain finding it's way into the food supply, and who knows what would happen.
Mad evil SELECTIONISTS should stop!!
Nanobanano
1 / 5 (6) Sep 14, 2011
You don't get it at all dude.

"Selection" works only with genes that are already there naturally.

Genetic engineering is tampering with genes, inserting genes from other kingdoms and phyla, etc, and in this case just flat out engineering something from scratch.

Hopefully, nothing will EVER go wrong with this, but when and IF it does we're talking about the potential for a megadisaster beyond comprehension, like the spanish flu or the black death.

This isn't even remotely similar to selecting which natural corn crop to grow, or selecting natural genes of corn to grow.

This is cross-classification genetic engineering, and it has unknown consequences for pathology and the mutation of viruses and other life forms.

Unfortunately, laboratory experiments are too narrow in scope to predict real world consequences of these organisms in the wild, where these alien genes could become incorporated into pathogenic viruses and prions in unpredictable ways.
Nanobanano
1 / 5 (5) Sep 14, 2011
This stuff is potentially more dangerous than nuclear weapons.

A nuclear accident might destroy a city.

The right kind of biological accident, or biological sabotage, could destroy entire nation-states or continents.

It HAS happened before. Look at invasive species accidentally introduced by humans:
africanized honey bees
foreign lung fish in the Mississippi
Tallow Trees
Wild Swine

These are "natural" life forms which were accidentally introduced in environments they dont belong in, and have caused havoc in the ecosystems.

In the case of invasive foreign fish, in some cases, they actually are catstrophically destroying the environments...

How bad a screw up do you think some chimera laboratory experiment would potentially be if it accidentally escapes, or if a virus mutates in it and escapes with the warped genes?

"Oh, that'll neeeeeeeeeever happen..."

This is serious stuff...
GreyLensman
3.7 / 5 (3) Sep 14, 2011
AGRICULTURE

Some shit should be left alone. Just let's not tinker around with the artificial SELECTION idea. We don't need a million people infected with some sort of chimera pathogen from an selection gone wrong. All it takes is one freaking SELECTED wheat grain finding it's way into the food supply, and who knows what would happen.
Mad evil SELECTIONISTS should stop!!


Nicely done.
Deesky
5 / 5 (8) Sep 14, 2011
"Selection" works only with genes that are already there naturally.

Why the quotes? What is a 'natural' gene? You realize that genes change and mutate all the time and genes present today need not have been there in the past.

Genetic engineering is tampering with genes, inserting genes from other kingdoms and phyla, etc

'Tampering' is an unnecessarily emotive description. Organisms have acquired genes from the environment and other species through horizontal gene transfer since life itself began and is probably why it was so successful once it started. This is the same thing except we shape the change mechanism rather than leaving it to nature to sort out in its own time.

in this case just flat out engineering something from scratch

Yes and no, but either way, it's awesome research!
Parsec
5 / 5 (3) Sep 15, 2011
I have no doubt that man could engineer some kind of organism that would out-compete and out-perform what nature has developed in 4 billion years.

Ya right dudes.
aroc91
4.2 / 5 (5) Sep 15, 2011
Nanobanano-

Think about this for a second... WHAT IN THE HELL COULD POSSIBLY HAPPEN?

Seriously? What is your proposal of what this could lead to? You're just like every other opponent of genetic engineering, claiming that ridiculous outcomes not backed with science will magically happen.

"Oh noes, it'll create some sort of super pathogen!"

HOW? Explain to me HOW that could possibly happen. You seem to be an intelligent person otherwise. Explain to me the though process that leads to this type of conclusion, because you would be the first. I haven't seen one argument as to how genetically modified food can cause cancer, or hell, ANY health issue for that matter.
Skultch
not rated yet Sep 15, 2011
Apocalypse shmocalypse. I want better beer. :P
Ethelred
4 / 5 (4) Sep 15, 2011
"Selection" works only with genes that are already there naturally.
No. Selection works on NEW mutated genes as well as the ones already there.

Genetic engineering is tampering with genes
So is artificial selection.

we're talking about the potential for a megadisaster beyond comprehension, like the spanish flu or the black death.
Those ARE within my comprehension and it really should be within that of the people doing the work as well. The future belongs to those that learn how to do new things. Not with those that hide under a rock.


This isn't even remotely similar to selecting which natural corn crop to grow, or selecting natural genes of corn to grow.
Nonsense. We even cross strains to create hybrids. Most modern crops ARE hybrids that cannot reproduce.

and it has unknown consequences for pathology and the mutation of viruses and other life forms.
The lab is the right place to learn the consequences.

Ethelred
Thex1138
not rated yet Sep 15, 2011
'I'mmmmm Meltinggggggg......!!!' Said the man testing the lab-fabricated genome that he spilt onto his hand...
Ethelred
1 / 5 (1) Sep 15, 2011
That was LSD.

Ethelred
Nanobanano
1 / 5 (2) Sep 15, 2011
HOW? Explain to me HOW that could possibly happen. You seem to be an intelligent person otherwise. Explain to me the though process that leads to this type of conclusion, because you would be the first. I haven't seen one argument as to how genetically modified food can cause cancer, or hell, ANY health issue for that matter.


Remember the "Hybrid" H1N1 flu strain? You know, the one that "somehow" picked up genes of both bird flu and swine flu, and then killed about a thousand people in mexico and caused the world wide epidemic? It's unknown how many died from it, because a lot of cases probably went undiagnosed and were presumed to have died of other forms of illnesses.

Certain viruses COULD pick up artificial genes or transgenic DNA from an engineered organism during their natural life cycle. Some virus lie dormant hiding inside cellular genetic material for multiple cellular life cycles. That is an opportunity for the virus to obtain the gene, by chance, just as in H1N
aroc91
5 / 5 (4) Sep 15, 2011
Nanobanano, I saw you rated my comment 1. I'm interpreting that as a white surrender flag, because you obviously can't think of any logical reasons as to how this would do anything.

Do you realize the complexity and the amount of work that would be required to create any sort of pathogen artificially, let alone some end-of-the-world variety one you're imagining? We're not yet to the point where scientists can go "I'm bored. I think I'll make a super-infectious, super-deadly strain of yeast today." We don't have the knowledge to do that and you seriously think there's even the slightest possibility it'll happen by accident?

I'm not sure you understand the complexity of biological systems. Evolution creates specific systems that have many parts working in conjunction to do some task. The chances of these artificial genes jumbling in just the right way in, hell, even 1000000 generations, in order to create a system of proteins that makes some sort of super toxin is next to nil.
aroc91
5 / 5 (4) Sep 15, 2011
That's a bad example. That hybrid flu strain uses billions and billions of existing, time-tested and selected mutations.

There is absolutely nothing unique about the DNA these researchers have created. It's probably mostly nonsense DNA anyway. There's no way they could be able to put together a functional protein by just stacking together random nucleotides with interspersed known transposons and deletion/other rearrangement factors in any sort of recognizable time frame.

Certain viruses COULD pick up artificial genes or transgenic DNA from an engineered organism during their natural life cycle. Some virus lie dormant hiding inside cellular genetic material for multiple cellular life cycles. That is an opportunity for the virus to obtain the gene, by chance, just as in H1N


You still haven't proposed a mechanism. How would that lead to anything catastrophic? As stated before by Deesky, this happens all the time and has been for millions of years, with functional genes.
Telekinetic
1 / 5 (2) Sep 15, 2011
In 1956 African bees were brought to Brazil so that scientists there could try to develop a honey bee better adapted to tropical areas. Unfortunately, some of the bees escaped and began breeding with local Brazilian honey bees. Since 1957, these bees and their hybrid offspring, Africanized Honey Bees, have been multiplying and migrating to other regions.
The first swarm of Africanized bees in the United States was documented in 1990 at Hidalgo, Texas. As of this writing, Africanized Honey Bees can be found in most of mid and southern Texas, about one-third of New Mexico, all over Arizona, the southern half of New Mexico and the southern third of California. They continue their northward migration.
You dopes are so enamored with the corporate conceit of beating Mother Nature at her own game, it will be human error, not breakthrough R&D, that determines our future.
Deesky
5 / 5 (2) Sep 15, 2011
In 1956 African bees were brought to Brazil so that scientists there could try to develop a honey bee better adapted to tropical areas. Unfortunately, some of the bees escaped and began breeding with local Brazilian honey bees.

Natural selection at work, what's your point? We have a very narrow view of 'invasive species'. Long before humans came on the scene, environments and habitats have been exploited by new species, the very species we later came to think of as indigenous. Indeed, humans themselves are perhaps the most invasive species of all.
aroc91
not rated yet Sep 15, 2011
Telekinetic-

Again, bad example. What's the parallel between NATURAL invasive species and a sequence of nonsense DNA that would need billions of generations worth of mutation to produce ANY sort of viable protein, which even then, would only be capable of herping and derping its way around the cell without countless iterations and selection, let alone be responsible for an entire sequence of intricate proteins and subsequently intricate events capable of ANY pathogenic behavior?
Telekinetic
1 / 5 (2) Sep 15, 2011
In 1956 African bees were brought to Brazil so that scientists there could try to develop a honey bee better adapted to tropical areas. Unfortunately, some of the bees escaped and began breeding with local Brazilian honey bees.

Natural selection at work, what's your point? We have a very narrow view of 'invasive species'. Long before humans came on the scene, environments and habitats have been exploited by new species, the very species we later came to think of as indigenous. Indeed, humans themselves are perhaps the most invasive species of all.

That isn't natural selection, that's the irresponsible act of opening the lion cage door when school children are in the zoo. There are sea lampreys and Asian Carp decimating the indigenous fish species of the Great Lakes. They hitched a ride on foreign vessels. They don't belong here, nor does your misinformed sophistry.
aroc91
5 / 5 (2) Sep 15, 2011
That isn't natural selection


I beg to differ. The indigenous-ness of a species has absolutely no bearing on the natural differential survival and competition of species.
Telekinetic
1 / 5 (2) Sep 15, 2011
By using antibacterial soap products, we have created mutated "superbugs" that can't be killed by most, if any, known antibiotics. There is absolutely an enormous danger in the accidental/deliberate release of an out of control lab experiment. Because all of this seemingly harmless work is being done by highly trained researchers in lab coats, we're lulled into believing that they all know what they're doing.
Telekinetic
1 / 5 (1) Sep 15, 2011
That isn't natural selection


I beg to differ. The indigenous-ness of a species has absolutely no bearing on the natural differential survival and competition of species.

Tell that to the Native Americans who were deliberately given infected blankets by the armed forces of the white settlers.
aroc91
5 / 5 (2) Sep 16, 2011
But this doesn't concern an artificially selected superbug. This concerns yeast with junk DNA with induced mutation. There is a difference.

In the end, the mechanism of the invasion doesn't matter. There are a multitude of factors that could induce migration of a species and what happens happens. It's been happening for billions of years without our help.
Deesky
5 / 5 (2) Sep 16, 2011
That isn't natural selection, that's the irresponsible act of opening the lion cage door when school children are in the zoo. There are sea lampreys and Asian Carp decimating the indigenous fish species of the Great Lakes. They hitched a ride on foreign vessels.

You have stated nothing new, you just gave a different example of what you said before, therefore I have nothing new to refute. However, I'll make my earlier point easier for you to understand.

Natural selection works whether the introductory vector is derived through human assisted mechanisms or from purely natural ones. It doesn't matter if a new species of beetle, say, is introduced into a new environment by means of boat or by a cyclone. Once it gets there, it will either survive or die out - that's natural selection. The delivery vector is inconsequential.

They don't belong here, nor does your misinformed sophistry.

Ha, ha, ha.
Telekinetic
1 / 5 (1) Sep 16, 2011
Your argument, a kind of "let the chips fall where they may", doesn't address the consequences of carelessness. The examples I cited are costing the country billions to control the rampant destruction by foreign species. Try to get into California with a piece of fruit that you bought from outside the state.
Deesky
5 / 5 (1) Sep 16, 2011
Your argument, a kind of "let the chips fall where they may", doesn't address the consequences of carelessness. The examples I cited are costing the country billions to control the rampant destruction by foreign species. Try to get into California with a piece of fruit that you bought from outside the state.

I never made a value judgement, but my argument certainly addresses your claim that:

"That isn't natural selection".
cmn
5 / 5 (1) Sep 18, 2011
I personally welcome our new yeast overlords.
antialias_physorg
not rated yet Sep 19, 2011
Let's assess the difference between natural mutation and planned mutation (as per the article):

Planned mutation can be much more rapid (i.e. change more of the genome in a much shorter time), but that is just a quantitative difference to natural mutation - not a qualitative one.

Potential for danger arises when a pathogen is created that incorporates multiple new vectors of attack. Newly mutated species tend to change their envrionment (i.e. other organisms) as that environment adapts to them. With singular, natural mutations the chance for adaptation is high (to find a counter for M you mutate gene N).

With largely designed organisms the problem is a bit greater because now you can mutate sections A, B, C and D at the same time (requiring an adaptation by the 'victim' organisms of gene E, F, G and H at the same time). Natural mutation rates are very unlikely to produce that.

So while not totally different by mechanism from what occurs in nature there is a danger here.
knikiy
not rated yet Sep 19, 2011
I think humans' ability to tinker with stuff has always outstripped their ability to fully comprehend (or care about) the outcome of their tinkering - especially long term.