Mar 29 2016

Engineering A Minimal Genome

Minimal genomeCraig Venter’s team has crossed another milestone in their quest to engineer artificial life – they have engineered a bacterium that can survive and reproduce with just 473 genes. This is the smallest genome of any free-living thing (so that does not include viruses).

The purpose of this is to create a minimal starting point for later genetic engineering. Venter says this minimal bacterium is like a frame onto which specific modules can be placed. He envisions a future in which you can have made-to-order genetically engineered bacteria in which you plug in specific functions.

The Basic Science

This research program is also interesting from a purely basic science perspective. The bacterium used in Venter’s research is Mycoplasma mycoides. The choice of a Mycoplasma bacterium was obvious, as the species in the wild with the smallest number of genes is the related Mycoplasma genitalium, which has 525 genes. The new bacterium has 52 fewer genes.

The process was mostly one of trial and error – removing a gene and seeing what happens. They discovered a few different classes of genes with this process.

Some genes are essential to life. If you remove them, under any circumstance, the bacterium cannot live and reproduce.

Some genes are quasi-essential. If you remove them the bacterium can still live and reproduce, but is much less robust. Venter kept these genes in, so they are part of the 473 remaining genes.  That makes sense if you are trying to engineer a useful bug, you don’t want one that is sickly and slow.

Some genes are essential but redundant. These were interesting, because on the first pass it seems like you can remove them without any harm. But when you also remove a companion gene, the bacterium can no longer survive. One of the two genes is needed.

Then, of course, there were genes that could be removed without hampering the cell’s ability to survive and reproduce. These were all removed.

One outcome of this research is the identification of 149 genes that are essential to life but have completely unknown function. These genes can now be targeted for further research to discover what they do.

It is interesting that a cell can have robust function with only 473 genes, some of which are redundant and some of which are only quasi-essential. While this is still complex, it seems manageable that we can learn what each of these genes do and how they interact.

Once we really understand this system it seems likely that we will be able to alter the base system itself, making new versions of the minimal genome. But even if we don’t the minimal genome is a great research tool.

Practical Applications

The practical purpose of this research is to facilitate the genetic engineering of bacteria for industrial use. As Venter says, the minimal genome is like a frame, and now we can plug in specific functions.

Bacteria are tiny biochemical factories. They are already used for a variety of functions, such as manufacturing drugs and chemicals used for other industrial purposes. Used in this way they are extremely cost effective. They reproduce themselves, and carry out their reactions with high efficiency.

Insulin is a great example. For decades after its discovery medical insulin was purified from cattle and pigs. It could be synthesized chemically, but not mass produced. In 1978, however, insulin became the first human protein made with a genetically engineered organism, a modified E. coli bacterium. This made the insulin cheaper and safer.

Bacteria can also be engineered to do useful things like eat plastic, or clean up oil spills or toxic waste. They could possibly be engineered to produce biofuel.

The technology has many potential uses, and if Venter has his way his research will fast track their development.

Conclusion

Life is a very complex machine that has evolved over billions of years. That is a lot of trial and error, not easily reproduced. It makes sense that we should avail ourselves of that massive store of practical knowledge.

The key to that knowledge is genetics. Yes, we have to also understand the biochemical and physiology, but it all starts with the genome. This is why genetic engineering is one of the emerging technologies that is likely to dramatically shape our future. The technology is already is widespread use, but I think we are just scratching the surface of its potential.

Imagine how much we will understand about the genome in a century.

There are some who are scared by the technology, but that is always the case. I think we need to respect the power of the technology, like respecting the power of nuclear technology, but that does not mean we should shy away from using it carefully and responsibly.

15 responses so far

15 Responses to “Engineering A Minimal Genome”

  1. Rikki-Tikki-Tavion 29 Mar 2016 at 8:30 am

    Yes, let’s engineer a bacterium that thrives on plastic. What could possibly go wrong?

  2. Steven Novellaon 29 Mar 2016 at 9:41 am

    Yes, let’s pump explosive gas into residential homes. What could possibly go wrong?
    Yes, let’s let everyone operate 2 ton motor vehicles at high speeds on crowded public roads. What could possibly go wrong?
    Yes, let’s use self-sustaining fission reactions to generate heat for power generation. What could possibly go wrong?

    Some technologies have risks, but those risks can be managed.

  3. MaryMon 29 Mar 2016 at 10:04 am

    I’m far more impressed that Ebola, with 7 genes, can take down extraordinary numbers of humans. That’s remarkable.

  4. edamameon 29 Mar 2016 at 10:21 am

    Brace yourselves : how could this thing with all these paired dependencies among 400+ genes (any one of which if you remove hurts fitness) have evolved? It couldn’t: irreducible complexity, God, and all that. I’m saying, just have a response prepared because if they haven’t already, they will make this argument. Dembski probably already has.

    What is amazing is how many genes were needed. We need to remember that this is a minimal Mycoplasma genome. After all, Mycoplasma has been evolving for billions of years, so has had time for all the dependencies and quasi-essential genes to emerge.

    Using a single, even an extremely simple, organism to find key insights into the origins of life, must be taken cautiously because even the simplest living organism has been evolving for billions of years and had time for all sorts of genetic baggage to accumulate that we don’t understand.

    My hope, with this project, was that they would find about 50 genes, and this would really narrow things down in terms of origins of life research.

    OTOH, this is just one organism! Let’s say they run this kind of experiment with multiple simple organisms, and then do comparative analysis, find the intersection of genes conserved, then we might be able to do some clever inferences to try to find the true minimal genome that we could build in the lab to build the first true artificial living thing “from scratch”.

    That could provide a lot of useful constraints on origins of life experiments of the Miller-Urey type, something to aim toward with the bottom-up chemical approach.

  5. Steven Novellaon 29 Mar 2016 at 11:00 am

    Keep in mind, this was the minimal genes necessary for robust life and reproduction, not any life. They want these to be functional for industrial uses.

    With fewer genes, perhaps much fewer, it would be able to limp along, barely survive and reproduce.

    But you are also right – this is the fewest for a bacterium (at least this bacterium, but maybe bacteria in general). Bacteria are highly evolved. That won’t stop the IDiots from claiming exactly what you predict.

  6. GrahamHon 29 Mar 2016 at 12:12 pm

    I wonder if we can reduce the minimal to 42, that could exist under conditions of minimal threat to its existence?
    42 is a good number :).

  7. pdeboeron 29 Mar 2016 at 12:48 pm

    Thats a good answer GrahanH, but what about the universe and everything?

  8. daedalus2uon 29 Mar 2016 at 12:55 pm

    Also, keep in mind that this is for an “organism” that replicates itself (using certain media) in a certain time frame.

    We don’t know what the primordial soup consisted of. Maybe some of the essential proteins that are products of “essential” genes were already present in that primordial soup, generated by non-living processes.

    If there were non-living processes that generated ATP (for example pyrophosphate can substitute for ATP in many reactions), then the ATP generation pathways are non-essential in primordial soup, but are essential in modern environments where ambient ATP levels are near zero (because organisms consume it).

    If the time for replication were extended, to days or months, or even years, that gives life a starting point with a greatly reduced degree of difficulty.

  9. Robneyon 29 Mar 2016 at 7:03 pm

    I have a couple of questions.

    1) Would it be possible to apply selective pressures on cultures of bacteria to reduce redundant genes and let evolution do our work for us?

    I suppose the problem is if you want fewer genes to become fixed in a genome to replace the function of what was previously performed by multiple genes, you need new genes to accumulate to be selected from thereby increasing the total number of genes in the process. And evolution has shown that it is a messy process that tends to accumulated redundant genes because they have no selective pressure acting on them.

    2) Is it possible we could use computer models to predict the outcome of genetic modifications and eventually genetically engineer entire genomes (and the emergent organisms) in a computer simulation?

    I suppose this is possible in principle but in practice how far off are we in terms of computational power and our understanding of genetics?

  10. Lukas1986on 30 Mar 2016 at 2:21 am

    Great article. Creations however are already claiming this as a proof of the doom of evolution:

    “Mycoplasma mycoides Just Destroyed Evolution
    “We’re Showing How Complex Life Is”

    Call it Mycoplasma mycoides lite—researchers have established what is approximately a minimal organism by removing about half of the genes from the Mycoplasma mycoides genome. The result is a set of 473 genes which, collectively, appear to be required for any kind of reasonable performance. That is an enormous level of complexity. Furthermore, about one third of that minimal gene set is of unknown function. As J. Craig Venter put it, “We’re showing how complex life is, even in the simplest of organisms. These findings are very humbling.”

    Yes, humbling, if you are an evolutionist. This is because this result shows how astronomically impossible evolution is in its hypothetical early stages. Simply put, there is no way such an organism is going to randomly evolve.”

    Source: http://darwins-god.blogspot.sk/2016/03/mycoplasma-mycoides-just-destroyed.html

    I do not agree with the author, Cornelius Hunter a member of the Discovery Institute but just let you know about this how can this be twisted in to a way to support their religion.

  11. Average Joeon 30 Mar 2016 at 7:32 am

    1) unknown. In the wild, there is no correlation between genome size and rate of cell division.
    2) Systems Biology + Synthetic Biology are the fields of study

  12. Rikki-Tikki-Tavion 30 Mar 2016 at 10:53 am

    Steve, I am a rocket engineer. I work on designs for turbopumps that move large quantities of oxygen just a few centimeters from a large supply on hydrogen. I know that technologies have risks. But creating a life form, that eats materials that we employ for the very reason that they are not currently digestible by life forms seems to me like the definition of a very bad idea. Less like a nuclear reactor and more like a nuclear powered airplane.

  13. edamameon 30 Mar 2016 at 11:43 am

    Lukas thanks for that link: creationists are more predictable than Mycoplasma!

  14. RickKon 30 Mar 2016 at 11:14 pm

    “Darkness Falls” – Kyle Mills

    Thriller involving terrorists who get their hands on bacteria that eat plastics.

  15. Lukas1986on 31 Mar 2016 at 11:42 am

    There is already a bacteria that eats plastic:

    “Ideonella sakaiensis is a bacterium from the genus Ideonella and family Comamonadaceae capable of breaking down PET plastic which was isolated from outside a plastic bottle recycling facility.”

    Source: https://en.wikipedia.org/wiki/Ideonella_sakaiensis

    There are more links to this when you use its name in Google.

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