There was quite a splash in the media in May concerning Craig Venter’s claims to have made a synthetic cell.
However, the media have not elucidated exactly what this ‘synthetic’ means, and Venter himself, in a blaze of self-promotion, used blatantly misleading language. He spoke of his ‘creation’ as “the first self-replicating species we’ve had on the planet whose parent is a computer”, and of its genome having been synthesized “by a machine” entirely from “four bottles of chemicals” and its being “booted up” in a host organism.
Arthur Caplan, Professor of Bioethics, University of Pennsylvania was impressed and thought this one of the most important scientific achievements ever:
All…deeply entrenched metaphysical views are cast into doubt by the demonstration that life can be created from non-living parts, albeit those harvested from a cell. Venter’s achievement would seem to extinguish the argument that life requires a special force or power to exist. In my view, this makes it one of the most important scientific achievements in the history of mankind.
And Julian Savulescu, professor of practical ethics at Oxford University, would like to nominate Venter as the Demiurge:
Venter is creaking open the most profound door in humanity’s history, potentially peeking into its destiny. He is not merely copying life artificially…or modifying it radically by genetic engineering. He is going towards the role of a god: creating artificial life that could never have existed naturally.
As we will see, these ethicists have clearly misunderstood what Venter has achieved. More sane soundings have come from those who are expert in bioengineering, for example Jim Collins, Professor of biomedical engineering, Boston University:
Relax — media reports hyping this as a significant, alarming step forward in the creation of artificial forms of life can be discounted. The work reported by Venter and his colleagues is an important advance in our ability to re-engineer organisms; it does not represent the making of new life from scratch. The microorganism reported by the Venter team is synthetic in the sense that its DNA is synthesized, not in that a new life form has been created. Its genome is a stitched-together copy of the DNA of an organism that exists in nature, with a few small tweaks thrown in…Frankly, scientists do not know enough about biology to create life…Although some of us in synthetic biology may have delusions of grandeur, our goals are much more modest.
We will investigate what Venter has done, but we must be clear that although what he has done was technologically advanced, it amounts to no more than tinkering with existing life.
Perhaps a couple of analogies will help.
Let’s say I don’t know where to start to write an effective dramatic play. So I take an old printed copy of an old classic, The Merchant of Venice, and, putting the leaves through a digital scanner with optical character recognition, I obtain a digital copy of the text on my computer. I do some very minor editing – removing the odd sentence that seems redundant and adding a few footnotes – and print out the resulting play using the four bottles of chemicals in my printer, being very careful to get all the pages in order, and bind it into new covers with the title Shylock in Venice. Can I be said to have created a synthetic play? After all, I’ve used a lot of technology, and there is none of the original paper and ink in the new volume.
Or, let’s say I don’t know how to design a motor car, so I take the engine out of a green Ford Focus, strip it down, and measure all the parts. I then produce CAD drawings of all the constituent parts and assemblies, and send the CAD files to machinists to reproduce all the pieceparts. I don’t bother to send out the files for a couple of brackets that I know are redundant on that model, and I make sure that I order a plate with a different engine number so that I can identify it as my own. Having received all the pieceparts, I assemble the parts into an engine, take the engine out of a red Ford Focus and fit in my new engine instead. I’ve used a lot of technology, and none of the materials of the original green car are now in the red car. Can I be said to have created a synthetic car?
Now consider what Craig Venter did. He measured the DNA sequence (genome) of an existing living bacterium to produce a full listing on a computer. He then edited out some of the sequence that he knew was redundant, and added in some markers of his own that did not affect the overall functionality. He then divided up DNA sequence into short blocks and had these fragments physically built to order by a commercial chemical synthesizing company. Using 100 billion yeast cells, Venter recombined all these fragments to form a DNA sequence that matched the sequence on his computer. He then took another living cell, removed its DNA, and transplanted the re-assembled DNA into this cell, having inactivated an enzyme in the recipient cell to prevent rejection of the donor DNA. Can he be said to have created a synthetic cell?
The DNA sequence was taken from a living organism, living organisms were used to combine synthesized DNA fragments, and the recombined DNA was introduced into another living cell. Venter needed to know the exact order to combine the fragments to make the DNA sequence: one transcription error, one missing ‘letter’ in over a million base pairs could be fatal, and indeed was, as Venter reports in his Science paper Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Initially, an error-containing 811-820 clone was used to produce a synthetic genome that did not transplant. This was expected since the error was a single base pair deletion that creates a frameshift in dnaA, an essential gene for chromosomal replication.
So Venter had to slavishly copy what was known to work in real life. He had no hope of being able to re-assemble all the base pairs without an original blueprint to copy.
Jim Collins, Professor of biomedical engineering, Boston University makes this clear:
Although [genome sequencing] has expanded the parts list for cells, there is no instruction manual for putting them together to produce a living cell. It is like trying to assemble an operational jumbo jet from its parts list — impossible.
And George Church, Geneticist, Harvard Medical School:
But has [Venter’s institute] created ‘new life’ and tested vitalism? Not really. The semi-synthetic mycobacterium is not changed from the wild state in any fundamental sense. Printing out a copy of an ancient text isn’t the same as understanding the language. We already had confidence in our ability to make synthetic DNA and get it to function in cells. The grand challenge remains understanding the parts of cells that help the DNA to function.
So, what was new in what Venter did? Not copying a complete DNA sequence, for sure: Arthur Kornberg and colleagues copied the DNA of the phiX174 virus in 1967, though not by synthesizing it from basic fragments as the DNA sequence was not deciphered for another 11 years.
Nor introducing a full DNA sequence into another living cell, or in removing or replacing little fragments of DNA – this is done all the time with genetic modification, using naturally occurring DNA or short synthesized fragments. No, Venter’s achievement was in building up the whole DNA sequence from individual tiny fragments. To use the motor analogy: previous operators had replaced whole engines into existing cars or made modifications to existing engines – substituted improved sparkplugs or camshafts, for instance – but no-one had gone the whole hog and built an engine entirely from copied parts.
The DNA fragments that Venter put out to a commercial synthesis company, Blue Heron (Bothell, Washington), were short sequences of nucleotides (i.e. oligonucleotides). Nucleotides are the ‘bases’ that pair up on the double helix of DNA: adenine (A) with thiamine (T), and guanine (G) with cytosine (C). These bases A, T, G and C or their derivatives or precursors, are the “four different bottles of chemicals” referred to by Ventor, from which Blue Heron built his oligonucleotides to specification. For example, a short sequence of 18 base pairs (‘letters’) could be
Effectively, this is information, just as are the sequence of letters to make up the words of a play, or the sequence of ‘1’ and ‘0’ in computer files. The code for operation of one of the simplest living cells, as used by Venter, is just over a million base pairs long. It is three billion base pairs long for humans.
Venter and Gibson describe their procedure:
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.
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.
Certainly this is an impressive technological feat: it took 15-20 years’ work and $40 million of investment. The feat is the assembling from contituent base pairs, themselves synthesized, of a complete DNA sequence of a living organism (with a tiny bit of genetic modification as ‘tags’ or ‘markers’).
Kornberg was able to make a straight ‘carbon copy’ in 1967, but he was though unable to read the genome, and thus built it up from scratch. In the 1970s, biologists ‘cut and pasted’ single genes, using what was naturally available. Then in the 1980s, biotechnology moved to the stage of being able to synthesize genes that were not naturally occurring, e.g. genes of 300 base pairs (K.P. Nambiar et al, 1984). Venter and Gibson say
Kornberg did not create life in a test tube, nor did we create life from scratch. We transformed existing life into new life. We also did not design and build a new chromosome from nothing. Rather, using only digitized information, we synthesized a modified version of the naturally occurring Mycoplasma mycoides genome. The result is not an “artificial” life form.
Venter’s synthesis was limited to the genome, the DNA sequence, as is indeed claimed in the Science paper, Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome, which states
We report the design, synthesis and assembly of the 1.08-Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting from digitized genome sequence information…
Rather unhelpfully, Venter translates the ‘synthetic’ terminology into the cell itself, for he says in the Wall Street Journal article How We Created the First Synthetic Cell
We refer to the cell we have created as being a “synthetic” cell because it is controlled only by a synthetic genome assembled from chemically synthesized pieces of DNA. Even though the cytoplasm of the recipient cell is not synthetic…
Well, that’s all down to definitions. Jim Collins, Professor of biomedical engineering, Boston University, takes issue with this concept:
Imagine if bioengineers could program genes and cells to grow into a functioning “synthetic” heart that saved a patient in need of a transplant. The recovered patient would not be considered a synthetic organism or a form of artificial life; he or she would be viewed as a lucky individual with a synthesized heart. Venter’s microorganism is analogous to the recovered patient, albeit with a transplanted, synthesized genome.
The following statement by Venter thus appears to be grossly misleading:
This is the first synthetic cell that’s been made, and we call it synthetic because the cell is totally derived from a synthetic chromosome, made with four bottles of chemicals on a chemical synthesizer, starting with information in a computer.
Of course, the cell itself that Venter ended up with when he introduced the synthesized genome wasn’t ‘totally derived’ from a synthetic chromosome. He has gone from the cell’s being ‘controlled only by a synthetic genome’ to being ‘totally derived from a synthetic chromosome’. Venter’s get-out and sleight of hand for this is to point to the progeny of the recipient cell, where
The properties of the cells controlled by the assembled genome are expected to be the same as if the whole cell had been produced synthetically.
So, Venter is essentially claiming that progeny cells are ‘totally derived’ from the synthesized DNA because they should have the same properties as one in which he had been able to synthesize its cytoplasm as well.
And from there it is just a short step to the nonsense claims of ‘synthetic life’ reported in the media. Thus the Financial Times report Scientists create a living organism
Scientists have turned inanimate chemicals into a living organism in an experiment that raises profound questions about the essence of life.
And the Daily Telegraph report Scientist Craig Venter creates life for first time in laboratory sparking debate about ‘playing god’
Artificial life has been created in a laboratory for the first time by a maverick scientist. Dr Craig Venter, a multi-millionaire pioneer in genetics, and his team have managed to make a completely new “synthetic” life form from a mix of chemicals.
Needless to say, such newspaper reports are ignorant and sensationalist hogwash.