Craig Venter and colleagues have created a synthetic bacterial cell containing only the genes necessary for life, according to a paper in Science. Following previous work to create a synthetic cell by rebuilding the genome of naturally occurring bacteria, the team simplified and reorganized the genome to retain only 473 genes. The researchers say their method can be used to study the core functions of life and construct cells with desired properties.
Dr. Christopher Voigt, Professor of Biological Engineering, Massachusetts Institute of Technology (MIT) (webpage):
Expertise: Synthetic biology, systems biology, genetic circuit design, developing and applying genetic circuits to problems in biotechnology.
“This work is a big leap forward from an earlier paper six years ago, when the same group showed that they could build a genome from scratch, to where they are now getting towards designing the genome. In the earlier work they rebuilt a genome found in nature. In the more recent work they start to apply the human concepts of design and organization in order to create a more easily understood genome.
“Basically what they did was pick an environment where they want their organism to survive, then work out which genes were unnecessary and eliminate them. More interestingly, they started to reorganize aspects of the genome. Evolution has given us this mess of genetics that works, but is not easy to understand or manipulate. So, just like organizing a house, they took the different genes that encode different functions in the cell and started to sort them out, putting all the genes associated with a particular pathway in the same portion of the genome.
“This new work isn’t a milestone in terms of manipulation – other people have made minimal genomes in the past. Nor have they introduced a new method of genetic engineering – people have put synthetic DNA into cells before. But this concept of reorganizing what’s already there to make it simpler to understand and easier to manipulate is a new thing, and points to a future.
“Biologists might disagree with all this by saying that the complexity of natural genetics that came out of evolution is necessary for life. The question is whether there is an alternate way to encode the genome so it’s got all the human design elements – it’s simple, modular, organized – yet is still is viable in a living cell. If human designers can create an ordered, structured alternative to how life is found in nature, that would speak to the complexity of biology simply being an artefact of how it was shaped by evolution.”
Dr. Sriram Kosuri, Assistant Professor, Chemistry and Biochemistry Department, University of California Los Angeles (UCLA) (webpage):
Expertise: Biochemistry, systems biology and biological regulation, synthetic biology, molecular biology, genomics.
“I thought the work was a tour-de-force. They have been working towards these goals for years but it’s quite amazing to see the work in print now. Kudos to the team at the Venter Institute, as during the course of this work they’ve had to develop several new technologies in genome synthesis and transplantation, as well as hit upon biology that we are yet to learn about. I love their approach; people can argue over scientific results about whether or not a gene is essential, but the synthesis of this genome draws a line in the sand, and shows unequivocally what is possible.
“The major limitation is that this is the beginning of a very long road. It’s not as if this new minimal genome will automatically lead to either fundamental insights or industrial applications immediately. That said, they’ve created a self-replicating biological organism that might be a better starting point for such scientific and engineering goals than continuing to study natural systems.”
Dr. Adam Arkin, Director, Berkeley Synthetic Biology Institute, University of California, Berkeley (webpage):
Expertise: Evolutionary design principles of cellular networks and populations.
“It is a very profound result and very elegantly presented. It is profound in two ways: one is the technological achievement and the other is how they are using synthetic biology to test and understand the biological question of what it means to be minimally alive. What is the required set of genes to be a living organism? What they found in the paper was that there was a huge number of surprises even in that minimal genome which couldn’t have been found by looking at genome sequences, and they had to do this experiment to find these unknown gene functions.
“It is important to understand that this wasn’t creation of life from scratch. It was the culling of inessential functions from an organism, and reconfigurations of genes that make life happen. And they were unable to classify the function of 149 of the genes that were retained. But is it a huge step towards having the design tools that might start looking like true innovation? I think the answer is yes.
“However, a core barrier exists and that is the knowledge barrier. Using things found in nature we can amplify properties or delete properties from the genome. But we have a very hard time in designing truly new functions in a way that allows organisms to be stable and healthy. They tend to die on us!
“One of the great findings but also the great caveats of this work is that it allowed them to discover how much we don’t know, even about the core sections of the genome. That is exciting, scientifically. This work may be a great platform for applications but it also presents a moment for reflection about how we’re going to approach a better understanding of life.”
Dr. Takanari Inoue, Associate Professor, Department of Cell Biology, Johns Hopkins School of Medicine (webpage):
Expertise: Synthetic cell biology, cell signaling networks, how cell morphology affects biochemical functions in cells.
“Those offering the paper only a quick glance might have the initial impression that scientists have succeeded in creating a new life form, but a closer examination will reveal that this is not quite the case. What has been made is a chimeric bacterium whose genome has been reduced significantly without compromising the cell’s ability to self-replicate. Even this, however, is an impressive feat which has no doubt required the integration of enormous resources, exquisite skills and extensive knowledge.
“I personally found the work significant because of the insights it has into basic biological principles. For example, the authors deduced that some of the quasi-essential genes in a cell are often actually necessary for it to function efficiently. Furthermore, the group annotated individual genes that are sufficient for self-replication, attributing functional consequences to each element of the complete cellular genome.
“Importantly, the work also discussed limitations of the chimeric bacteria. Although they do contain a minimal genome that allows them to self-replicate, this is probably only sufficient for survival in an optimal environment. It remains untested whether these chimeras can evolve to fit into a new environment – a capability that is found in most organisms to some degree.
“The bioethical issues should not be neglected. Advances in computer graphic technology once approached the point where animation characters looked impressively real. However, this realism induced a sense of uneasiness in viewers: a phenomenon referred to as the “uncanny valley”. Similarly, reports such as this one might mark the scientific community’s entry into an uncanny valley that is inhabited by synthetic life forms. We will need to spread public awareness that can effectively catalyze society to deal with the potential risks inherent to this type of work.
“For example, the current study introduces an artificial genome into an existing bacterium without any apparent safeguard mechanisms in place. Since there are still many factors in the bacterium that are not under control by scientists, it is unclear if we fully understand how the sum of these two components (natural and synthetic) will behave.”
Dr. Samuel Deutsch, Head of DNA synthesis and Assembly, DOE Joint Genome Institute (webpage):
Expertise: DNA synthesis and Assembly, Pathway refactoring, Genotype to Phenotype modeling.
“Hutchinson et al., describe the results of their efforts to identify a minimal set of genes that can support independent life. Using experimental data to ascertain which genes are essential for life, combined with biological knowledge and multiple iterations of the ‘Design, Build and Test’ (DBT) cycle, the authors were able to re-boot viable cells with a highly reduced genome (~50% of the parental bacteria). The resulting strain, which they called JCVI-syn3.0, is a good approximation of the minimal complement of genes required for life, and represents a remarkable landmark in terms of the ability to deconstruct and understand complex biological systems.
“In the process of generating JCVI-syn3.0, which required multiple iterations before obtaining viable cells, the authors perfected their previously published methods for genome synthesis. As such they have made it possible to apply manufacturing paradigms such as the DBT cycle to whole genome-engineering. This will facilitate future efforts for prototyping designer cells with new properties, although this still remains well beyond current capabilities.
“JCVI-syn3.0 displayed substantial defects in growth and morphology that suggest it is extremely unlikely that such a cell would survive outside of the laboratory. Hence any potential risks associated with JCVI-syn3.0 are minimal.
“The authors claim that access to DBT ‘can be applied to the construction of a cell with any desired properties’. This seems a stretch since no significant designer features have been incorporated at this point and the theoretical underpinnings required to design substantive functional features will take many years to develop, namely: (i) an understanding of how the genome functions and is regulated and (ii) robust whole-cell computational models. The remarkable study reported in this paper nevertheless constitutes an important step forward in that direction.”
Declared interests (see GENeS register of interests policy):
No interests declared.
‘Design and synthesis of a minimal bacterial genome‘ by C.A. Hutchison III et al, published in Science on Thursday 24 March, 2016.