In the mid-nineteenth century, Louis Pasteur conducted the famous experiments refuting the theory of spontaneous generation, according to which spontaneously living organisms could originate from inert, organic or inorganic matter. It was a belief, already noted by Aristotle, which was accepted almost universally, although some scholastics, with Thomas Aquinas at the head, raised objections from a philosophical angle. Following Pasteur’s experiments, the theory was abandoned, and from then on, the principle omne vivum ex vivo (all life comes from life), also formulated as omnis cellula e cellula (all cells come from cells), was accepted.

The remarkable advances in biology during the last century, which have provided greater insight into cell structure and functions, revived the hope of finding a specific spontaneous generation, i.e., the possibility of creating an artificial cell from the molecules that make up a cell with the minimum essential properties of a living organism: the ability to assimilate nutrients from the outside, to grow and reproduce.

After several attempts along these lines, on 20 May 2010, the journal Science published an article authored by Craig Venter (one of the pioneers in human genome sequencing) and 23 other scientists as a fast-track paper. The title of the article was: “Creation of a bacterial cell controlled by a chemically synthesized genome” (1). Venter himself spoke of the creation of a “synthetic cell” and the news spread quickly. In fact, the next day, 21 May, the headline in British newspaper The Times read: “Scientists create artificial life in lab”. Many other media talked about the “creation of life”, of “artificial life”, the abolishment of the axiom omnis cellula e cellula, of one of the most important findings in the history of humanity, and even of the doubts that this research raises regarding the existence of the human soul.

Venter and his team used Mycoplasma capricolum, a bacterium that causes infections in goats, related to the one that causes human pneumonia, and extracted its DNA, which, as we know, is the carrier of genetic information. They also chemically synthesized the DNA of Mycoplasma mycoides, another very similar bacterium. Chemical synthesis of DNA has long been common practice. In 1984, a gene had already been synthesized, and automated DNA synthesis platforms are available. The improvement by Venter’s group was that the DNA of M. mycoides is almost 1,100,000 nucleotide pairs instead of the 300 that were assembled in 1984. This was undoubtedly a breakthrough, both in the technical and basic fields.

This synthetic DNA was introduced into the other bacterium, M. capricolum, devoid of its DNA. This process also represents a technical advance. Once the aforementioned difficulties had been overcome, the results were as expected: the bacterium thus formed began to use all its machinery to follow the instructions contained in the introduced genes, including those that direct its reproduction. In fact, the bacterium divided countless times and the genetic information it expressed was that contained in the introduced DNA.

A year later, a consortium was formed to develop a project (Synthetic Yeast Genome Project, Sc2.0) aimed at achieving “synthetic cells” of the yeast Saccharomyces cerevisiae, a simple eukaryotic organism, but much more complex than bacteria. In fact, it consisted of artificially modifying the chromosomes of this organism to change some of its phenotypic characteristics. Through a well-designed process, the modification of two yeast chromosomes was achieved. The modified genes were transcribed with good fidelity, but the viability of the resulting cells was not like that of the unmodified yeast (2).

After a few years without further progress than the modification of other S. cerevisiae chromosomes using the same technique employed in 2011, in 2019, a team of researchers from the Swiss Federal Institute of Technology in Zürich (Switzerland) led by Matthias and Beat Christen managed to synthetically “rewrite” the genome of Caulobacter crescentus, a gram-negative bacterium. Following a procedure that improved upon the one used by Venter’s group in 2010, they obtained Caulobacter cells, whose DNA was synthetic. Effectively, it was a new species, since by changing many aspects of its genetic information, phenotypic changes were expected. They called this new species Caulobacter ethensis. The specific name was coined using the initials of the institution where the research was conducted (Eidgenössische Technische Hochschule in German). The modification of many genes of the native bacteria allowed the researchers to determine their essential nature and conclude their article by saying that “our results highlight the promise of chemical synthesis rewriting to decode fundamental genome functions and its utility toward the design of improved organisms for industrial purposes and health benefits” (3).

All of this research was summarized in a review published by Venter himself and other members of his team in 2022 (4). The article focused on the methodology used by the different authors and ended with some ethical considerations, such as the necessity of not releasing genetically modified organisms or cells with synthetic genomes due to the unpredictable environmental consequences.

Recently, there has been a new development in the research in the Sc2.0 project, and in the final months of 2023, no fewer than ten critical articles were published in this regard (5–14). The scientific community was rocked in a way, as evidenced by the fact that they were immediately the subject of comments in important scientific journals (15,16). The impact of these papers was also reflected in the dissemination in the media. For example, on 13 November 2023, National Geographic published an article entitled “Scientists create synthetic life: an artificial yeast that could be the future of biotechnology”. The most striking aspect in this article and similar ones that were published was that yeast cells carrying several synthetic chromosomes could divide repeatedly. The yeast Saccharomyces cerevisiae normally reproduces by budding, i.e., after the replication of its genetic material — which in this case included artificially synthesized chromosomes — a bud begins to form on the cell surface, gradually growing in size; one of the copies of the genetic material is incorporated into this bud, while the other copy remains in the mother cell. When the bud reaches a sufficient size and transfer of the copy of the genetic material and the rest of the cellular components has been completed, the bud separates, constituting a new cell identical to the original one. The separation leaves a ring-shaped scar on this cell in the place where the budding occurred. In that regard, an image included in almost all the commentaries was one from the article by Zhao et al. (14), which showed a yeast cell visualized while it was producing a new bud; the striking thing, however, is that up to seven scars were observed on the mother cell, i.e., the cell was undergoing its eighth division.

All the research discussed herein is clearly of great importance from a fundamental point of view – an importance that would be difficult to summarize in this necessarily brief article – and, in the future, could lead to practical applications in the field of biotechnology or in health. Notwithstanding, some points must be clarified.

First of all, Venter was right when he pointed out that research studies such as these must be subject to ethical precepts. As mentioned, he only pointed out the need not to release these artificially modified species into the environment. Nevertheless, we must bear in mind that one of the first rules of research ethics is not to create false hope in the public or take the results obtained out of context.

Both in the media and in statements by the researchers themselves, there has been very frequent talk of “creation of life in the lab”, “creation of synthetic cells”, of “synthetic life” and other similar expressions. I think these statements are meaningless. Using an analogy, suppose we have a computer that contains many databases and all the programs required for them to work. Imagine now that we erase those databases and invent a new system to create a new database with data designed as we wish, and to transfer that data to the computer. The logical thing is that the computer uses the information entered and not the original data, which we have deleted. We could consider then that the computer with its operating system and its software is the cell, and the databases are the genes. It would not be reasonable to say that we have created a computer, nor that an artificial computer has been obtained, let alone that computer manufacturers will no longer be needed. The experiments discussed in this article have the undeniable merit of having achieved a system of synthesizing very large DNA molecules, introducing them into a cell and eliminating the genetic information that that cell previously contained. But we have not created a living cell. If the cell receiving the artificial genome did not have all its immense resources to replicate the genetic material, to read and correctly express the information contained in the genes; if it did not have all the subcellular organelles necessary to produce energy; if it lacked all the systems that allow it to assimilate nutrients from the environment and metabolize them, the information entered would be useless. Just as a database would be useless, no matter how perfect it was, if there was no computer with its functional hardware, with a good operating system and with programs capable of executing the information contained in that database.

In short, no life has been created, there is no artificial life, there are no artificial cells. There is only (and it is a lot) an artificial DNA, which can function as a natural one, at least up to a limited number of generations. What remains until a living cell is artificially produced is still a colossal challenge, one that may never be overcome. And, of course, there is no point in trying to make pseudo-metaphysical somersaults from these experiments.

There is still one issue that should be highlighted from an ethical point of view. It is a very frequent temptation among scientists that, in order to highlight the relevance of basic research, probably not understood by the vast majority of the public, we say things like “this study opens up new therapeutic possibilities in the fight against such and such a disease” or that “our research may enable further technological development”. These are expressions that, amplified by the public, can create the false hope that a particular disease is about to be eradicated, without taking into account the immense series of actions required in the translation from a laboratory finding to obtaining a health benefit. It is the leap that in English-speaking literature is graphically described as from bench to bedside, from the laboratory bench to the patient’s bedside. The same applies to the potential biotechnological application of the discoveries.

It hardly needs to be said that the present comments are in no way intended to minimize the value of the research discussed herein. They do aim, however, to ensure that all ethical criteria are correctly applied, not only when conducting research, but also when disseminating its results.

Luis Franco

Bioethics Observatory – Institute of Life Sciences

Catholic University of Valencia

Spanish Royal Academy of Exact, Physical and Natural Sciences

Royal Academy of Medicine of the Valencia Community

 

REFERENCES

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  2. Dymond JS, Richardson SM, Coombes CE, Babatz T, Muller H, Annaluru N, et al. Synthetic chromosome arms function in yeast and generate phenotypic diversity by design. Nature. 2011;477:471–6.
  3. Venetz JE, Medico L Del, Wölfle A, Schächle P, Bucher Y, Appert D, et al. Chemical synthesis rewriting of a bacterial genome to achieve design flexibility and biological functionality. Proceedings of the National Academy of Sciences of the United States of America. 2019;116:8070–9.
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