Bacterial Cell with a Chemically Synthesized Genome

buddhakan

I guess I am not as optimistic as Yggdrasil that Venter or anyone else will have such good luck with arbitrary genomic implants into arbitrary hosts, unless the genome's source and the host are quite closely biologically or phylogenetically related to begin with. Certainly one would not expect a prokaryotic genome to function in a eukarotic host or vice versa since the genetic regulatory machinery is so different, not to mention the cellular organization itself. I even doubt if a Mycoplasma-type genome implanted into a typical prokaryote like E. coli would work for the same general reasons. Eventually, such heterologous transplants might be made to work by engineering into the introduced genome all the necessary regulatory sequences required for expression by the particular type of host or recipient cell used, when these are already known. However, I still expect some really daunting problems even with homologous transplants as investigators try to move up the phylogenetic ladder to more complex cell types.

Ygggdrasil

Quote by rhody

Dr Venter's company is on the cutting edge of Genomic research, that fact is without question. How will the results his team was able to achieve to be independently verified, or has it already been done ?

Given the large amount of work involved and the great expense required to construct synthetic genomes, I don't really foresee many other groups using this technology, at least in the near future. However, as the price of gene synthesis goes down, other groups may attempt to use these techniques for other applications.

Quote by buddhakan

I guess I am not as optimistic as Yggdrasil that Venter or anyone else will have such good luck with arbitrary genomic implants into arbitrary hosts, unless the genome's source and the host are quite closely biologically or phylogenetically related to begin with. Certainly one would not expect a prokaryotic genome to function in a eukarotic host or vice versa since the genetic regulatory machinery is so different, not to mention the cellular organization itself. I even doubt if a Mycoplasma-type genome implanted into a typical prokaryote like E. coli would work for the same general reasons. Eventually, such heterologous transplants might be made to work by engineering into the introduced genome all the necessary regulatory sequences required for expression by the particular type of host or recipient cell used, when these are already known. However, I still expect some really daunting problems even with homologous transplants as investigators try to move up the phylogenetic ladder to more complex cell types.

You bring up some good points, and I agree with many. I also doubt that the mycoplasma genome would function if transplanted into E. coli. However, I think there might be ways to make this work. For example, from Shinya Yamanaka's work on induced pleuripotent stem cells, we know that injecting a set of 4 transcription factors is sufficient to reprogram any human cell into a stem cell. Maybe it's possible to find a small set of mycoplasma transcription factors that, when introduced into host with the genome, would reprogram the host to allow the mycoplasma genome to "boot up" correctly. Of course, this approach would not be so general because it would be dependent on the specific genome being used.

cesiumfrog

There's a bit more detail in Venter's own press release, on the front of the TED site.

The work I'm more interested in is figuring out how these smallish genomes produce "life", that is, what is the individual task performed by (and physical mechanism employed by) each molecule that the genome codes for? Can anyone point me to where this sort of "reverse engineering" is done?

rhody

Ran across this today in the news today, May 23 2010, from: guardian.co.uk The Observer

Quite lengthy article that chronicles Venter's life: begins in 1968, in Vietnam during TET Offensive, interesting that he did not pursue his patent efforts after success in the Human Genome Project, but deferred to the requests of President Clinton, if he hadn't he would be one of the world's richest men by now:

excerpt:

He caused further outrage when he said he would not only beat that establishment club to the solution but patent the results. He eventually – arguably – made good the first part of that boast but, under pressure from President Clinton, gave up on the latter and agreed a joint declaration of the triumph with the official team in the millennium year, losing a fortune in the process. (Asked how he felt to have deciphered human life, Venter, who had designs on being "the first billionaire biochemist", replied: "Poorer.")

Since I am a physics admirer, I thought this observation by Freeman Dyson was interesting:

Freeman Dyson, the physicist, captured the full range of academic sentiment in this dry appraisal: "This experiment is clumsy, tedious, unoriginal. From the point of view of aesthetic and intellectual elegance, it is a bad experiment. But it is nevertheless a big discovery… the ability to design and create new forms of life marks a turning point in the history of our species and our planet."

and what others have said:

It's very easy to mock Venter," Jones suggests. "When he first appeared, people just kind of sneered at him. But they stopped sneering when they saw his brilliance in realising that the genome was not a problem of chemistry but a problem of computer power.

The last sentence above is particularly telling, a personal opinion that I share with Venter, not out of ego or wanting to be recognized, Ray Kurzweil and other noted leaders have stated for sometime that technologies ability to assemble large amounts of data is growing at an exponential rate, the Genome project, the four main experiments at the LHC and now research into this new area of Genomics cry out for a radical improvement in computing power, on the order of super exponential growth, tens of thousands of times faster then we have now, farms of distributed supercomputers sharing the load are simply inadequate to process what we have now. Not to mention the human coordination and communication required to create and maintain software required to do so. That is another technical and logistic nightmare in and of itself, not to mention actually processing the data from experiments.

As proof simply look how long it took the scientists an BNL to analyze and verify the collision data to finally announce discovery of Quark Gluon Plasma. I believe over two plus years. Not that the scientists were not being extremely careful in doing so, which may have accounted for some of the time. In any event, technological breakthroughs in this area are in demand, in the past some have risen to the challenge, and I have no doubt that it will happen again.

Rhody...

ThomasEdison

Quote by rhody

The last sentence above is particularly telling, a personal opinion that I share with Venter, not out of ego or wanting to be recognized, Ray Kurzweil and other noted leaders have stated for sometime that technologies ability to assemble large amounts of data is growing at an exponential rate, the Genome project, the four main experiments at the LHC and now research into this new area of Genomics cry out for a radical improvement in computing power, on the order of super exponential growth, tens of thousands of times faster then we have now, farms of distributed supercomputers sharing the load are simply inadequate to process what we have now.

Rhody, I completely agree with this assessment. When I first saw the headline, before even reading further or knowing about the process, my first thought was "computers can do that now?" I was also reminded of a statement Michio Kaku made on one of the more silly Science for Laymen TV shows on the Science Channel. I will paraphrase (I forgot the exact words):"The completion of the Human Genome project marks the start of a new era not of discovery but of mastery." In other words, using the information of genomes, which we already have, and building with them marks a new era in science. Much like the difference between the discovery of fire and finding creative ways of using it etc.

rhody

Quote by ThomasEdison

Rhody, I completely agree with this assessment. When I first saw the headline, before even reading further or knowing about the process, my first thought was "computers can do that now?" I was also reminded of a statement Michio Kaku made on one of the more silly Science for Laymen TV shows on the Science Channel. I will paraphrase (I forgot the exact words):"The completion of the Human Genome project marks the start of a new era not of discovery but of mastery." In other words, using the information of genomes, which we already have, and building with them marks a new era in science. Much like the difference between the discovery of fire and finding creative ways of using it etc.

Thomas,

Thanks, this has been gnawing at my soul now for the past two or three years, tapping some of the greatest minds out there through the wonder of Google/uTube/articles/professional papers has driven this point home again and again. I was planning to start a "discovery thread on emerging technologies in increasing computing power", I invite you to beat me to it. I am juggling two or three things right now personally/professionally and don't have time to do it the justice it deserves. I promise to contribute though, every time I find an interesting link, I squirrel it away for future use, I have a few ready to go.

Rhody...

ThomasEdison

Quote by rhody

Thomas,

Thanks, this has been gnawing at my soul now for the past two or three years, tapping some of the greatest minds out there through the wonder of Google/uTube/articles/professional papers has driven this point home again and again. I was planning to start a "discovery thread on emerging technologies in increasing computing power", I invite you to beat me to it. I am juggling two or three things right now personally/professionally and don't have time to do it the justice it deserves. I promise to contribute though, every time I find an interesting link, I squirrel it away for future use, I have a few ready to go.

Rhody...

Perhaps this is offtopic: Warning:

Go for it. I am probably too biased, too entirely pro-science and technology, to post a lot about these topics. I have been looking all over the internet for people's opinions relating to advances such as this one and I only see two camps of popular opinion. One camp is very luddite or religious/spiritual and the comments from it say that Scientists are always up to bad things and the same people love to make distinctions between what they regard as the "natural" order and what to them is "unatural." Not only do I disagree but I am not quick to make those distinctions anyhow.

I simply don't subscribe to the paranoia of "what are Scientists up to now?!?"
I also don't think that anything artificial must be bad and that anything natural must be good. The world is not that simple to me.

The other camp of popular opinion is more on the fence "Science is capable of great things, but in the wrong hands ... so we should be cautious" It is probably the most rational but I still don't agree. I would say this is a more nuetral stance.

So where are the pro-technology people? Where are the people cheering who say "Let's throw caution to the wind"? This may be an incorrect stance but that does not mean it should not be represented. From my position the balance of opinion about technology looks terribly skewed towards ludditism. I seem to be the only proponent (even if in an armchair fashion.)

I mentioned this article to several people I know and not one of them was excited or even thought it was a good thing.

Are there other people like myself who only see the good in advancement? Sometimes I feel like the only person with this viewpoint.

*ice109*

does anyone know if there is an expository paper somewhere that covers gibson et al 2008?

Ygggdrasil

Quote by cesiumfrog

There's a bit more detail in Venter's own press release, on the front of the TED site.

The work I'm more interested in is figuring out how these smallish genomes produce "life", that is, what is the individual task performed by (and physical mechanism employed by) each molecule that the genome codes for? Can anyone point me to where this sort of "reverse engineering" is done?

You've just described the entire field of molecular biology. But, we know what many of the genes encoded by the genome do, and for some of the important ones, we have a very good mechanistic understanding of how they function. The really complicated part is figuring out how everything comes together. How are all of the functions of the cell coordinated? How do all of the interconnecting feedback mechanisms of a cell create a self-sustaining, homeostatic system? From a more mathematical point of view, we have a large system of coupled differential equations (representing chemical reactions, non-covalent bonding, etc.) and we want to determine what properties of this system create life. These questions are not likely to be answered soon, but hopefully research on synthetic life can help to frame some of these questions better and perhaps provide some insight.

Quote by ice109

does anyone know if there is an expository paper somewhere that covers gibson et al 2008?

Here are some writeups from the popular press:
http://www.wired.com/science/discove...nthetic_genome
http://www.nytimes.com/2008/01/24/he...e.9483638.html

And a short perspective on the paper by Biological Engineer Drew Endy (subscription required):
http://www.sciencemag.org/cgi/conten.../319/5867/1196

rhody

Thomas, and FYI to all,

Here is an older post link: The Language of Life: genes... Juan Enriquez TED Video Apr 2007 where I mention the subject of super exponential growth in processing the the end.
Cool TED video as well, highlights in the post, enjoy. Juan Enriquez is an engaging funny speaker...

Rhody...

*Count Iblis*

How far are we away from synthesizing an entire organism instead of just the DNA? So, if we can do this, then we can make a right handed version of the DNA molecule and all the left handed molecules in the cell will then also be right handed.

Andy Resnick

Quote by rhody

The last sentence above is particularly telling, a personal opinion that I share with Venter, not out of ego or wanting to be recognized, Ray Kurzweil and other noted leaders have stated for sometime that technologies ability to assemble large amounts of data is growing at an exponential rate, the Genome project, the four main experiments at the LHC and now research into this new area of Genomics cry out for a radical improvement in computing power, on the order of super exponential growth, tens of thousands of times faster then we have now, farms of distributed supercomputers sharing the load are simply inadequate to process what we have now. Not to mention the human coordination and communication required to create and maintain software required to do so. That is another technical and logistic nightmare in and of itself, not to mention actually processing the data from experiments.

I'm a little more jaded on this point. It's easy to generate PByte data sets- or datasets even larger. Unfortunately, our ability to extract information out of those datasets has not kept up with the rate we can generate data. Witness how 'genomics' has moved on to proteomics, metabolomics, immunomics, epigenetics, systems biology etc. etc. Each of those 'omics' can generate *far* more data than can be understood or digested. "science", especially in biology, is increasingly becoming the production of data that nobody ever looks at- including the teams that generated the data in the first place.

rhody

Quote by Andy Resnick

Witness how 'genomics' has moved on to proteomics, metabolomics, immunomics, epigenetics, systems biology etc. etc. Each of those 'omics' can generate *far* more data than can be understood or digested. "science", especially in biology, is increasingly becoming the production of data that nobody ever looks at- including the teams that generated the data in the first place.

Andy,

Not working in the biological field, the mention of: proteomics, metabolomics, immunomics, epigenetics is news to me. Did these fields even exist, say 5 to 10 years ago ? I remember Juan Enriquez saying in my post #27 above, the TED Video (and this was a few years ago as well) that the average genome startup company creates more data in one month than exists in the Library of Congress.

If understood your point, you are saying that not only is computing power an issue, but intelligently designed software to analyze the results (as applied to the emerging fields of study listed above), correct ? What are the major software players that exist today ? Say the top five in analyzing genomic data. What new software is being considered ?

This has to do with LHC data, I saw a news clip recently where a person responsible for LHC experimental data showed the audience a room filled with Disk arrays each in its own enclosure, a total of 128 Units with each unit having 10 Petabytes (edit: possibly Petabits, not quite sure) of data of collected LHC experimental data, I presume as backup. A lot of data to say the least.

Finally, a question for ygggdrasil, are all of Venter's experimental data and methods open for peer review by other Genome Companies/NIST/DOE, etc.. ? and if not, why not ?

Rhody...

Ygggdrasil

Quote by rhody

Not working in the biological field, the mention of: proteomics, metabolomics, immunomics, epigenetics is news to me. Did these fields even exist, say 5 to 10 years ago ?

All of the "omics" fields really started taking off only in the late 1990s-2000s.

Finally, a question for ygggdrasil, are all of Venter's experimental data and methods open for peer review by other Genome Companies/NIST/DOE, etc.. ? and if not, why not

All of the experimental data and methods for the results the institute has published are available in their papers (in addition to the Science papers, the institute has some methods papers in other journals describing the methods in more detail). Also, the sequences used in all of the published projects are available in the Genbank sequence database (for example, the sequence of the synthetic DNA implanted into the cell in this most recent paper is available at http://www.ncbi.nlm.nih.gov/nuccore/296455217).

*ice109*

Quote by Ygggdrasil

Here are some writeups from the popular press:
http://www.wired.com/science/discove...nthetic_genome
http://www.nytimes.com/2008/01/24/he...e.9483638.html

And a short perspective on the paper by Biological Engineer Drew Endy (subscription required):
http://www.sciencemag.org/cgi/conten.../319/5867/1196

i was hoping for something that was actually expository. the popular write ups aren't detailed enough and gibsons paper assumes too much. the problem is that i'm not trained as a biologist and while i can look up the words and understand them i don't know why he's using the techniques that he is. for example i don't understand why he gets the cassettes synthesized then puts them into a BAC vector plasmid then cuts them out again with a type 2 restriction exonuclease.

rhody

Good article in the Wall Street Journal yesterday: How We Created the First Synthetic Cell

Interesting approach, divide, overlap, reassemble at overlap points in three stages.

excerpts:

We started with the more than one million letters of genetic instructions for Mycoplasma mycoides, and then made slight modifications to its DNA sequence. First, we deleted 4,000 letters, which removed the function of two genes. We then replaced 10 genes with four "watermark" sequences. These watermark sequences are each over 1,000 letters in length and can be decoded to reveal the names of people, famous quotations and a website address. The entire sequence of DNA letters was then partitioned into 1,100 pieces, and each was synthesized using four different bottles of chemicals that make up DNA. These DNA fragments were designed such that adjacent pieces contained an 80-letter overlap, which facilitated the assembly process by providing unique regions where the synthetic pieces could join.

and

The synthetic Mycoplasma mycoides genome was assembled by adding the overlapping DNA fragments to yeast. Once inside a yeast cell, the yeast machinery recognized that two DNA fragments had the same sequence and assembled them at this overlapping region. The genome was not assembled from all 1,100 pieces at once but rather in three stages: 1,000 letters to 10,000 letters, 10,000 letters to 100,000 letters, and finally 100,000 letters to complete the 1.08 million letter genome. This assembled genome is the largest chemically defined structure ever synthesized in the laboratory.

Practical applications of this research:

We are currently working on the design of new cells that can much more efficiently capture carbon dioxide and "fix" (or incorporate) the carbon into new fuel molecules, new food oils, and new biologically derived sources of plastic and chemicals. We already have funding from the National Institutes of Health to use our synthetic DNA tools to build synthetic segments of every known flu virus so that we can rapidly build new vaccine candidates in less than 24 hours. We are also being funded to see if we can take sets of genes out of bacteria to design new synthetic pathways to make antibiotic compounds that are currently too complex for chemists to make.

Finally, a question for ygggdrasil, Andy Resnick,

It would seem that research (this question applies to the US) is well underway with work on "artificial life", a large number of Google hits confirm this. Do either of you know if said research is being done in the strictest of environments ?

I mean Biohazard Level IV (Doubly sealed, negative pressure buildings buried deep underground) Highly Secured Containment Facilities, and if so with oversight from official US agencies, NIST, DOE. One would hope so...

Rhody...

Andy Resnick

Quote by rhody

If understood your point, you are saying that not only is computing power an issue, but intelligently designed software to analyze the results (as applied to the emerging fields of study listed above), correct ? What are the major software players that exist today ? Say the top five in analyzing genomic data. What new software is being considered ?

I think that's about 1/2 right. Here's an interesting recent development:

http://www.livescience.com/technolog...scientist.html

I'm not expert enough to say much more than that. I guess my claim is that the complete analysis of data requires insight and creativity, features currently not sufficiently developed in software.

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cesiumfrog	There's a bit more detail in Venter's own press release, on the front of the TED site. The work I'm more interested in is figuring out how these smallish genomes produce "life", that is, what is the individual task performed by (and physical mechanism employed by) each molecule that the genome codes for? Can anyone point me to where this sort of "reverse engineering" is done?

ice109	does anyone know if there is an expository paper somewhere that covers gibson et al 2008?

rhody Recognitions: Gold Member	Thomas, and FYI to all, Here is an older post link: The Language of Life: genes... Juan Enriquez TED Video Apr 2007 where I mention the subject of super exponential growth in processing the the end. Cool TED video as well, highlights in the post, enjoy. Juan Enriquez is an engaging funny speaker... Rhody...

Count Iblis	How far are we away from synthesizing an entire organism instead of just the DNA? So, if we can do this, then we can make a right handed version of the DNA molecule and all the left handed molecules in the cell will then also be right handed.