Craig Venter: Future Pathways for Synthetic Genomics

Is a Genomic Version of Moore’s Law in the Offing?

J. Craig Venter, Ph.D.

J. Craig Venter, Ph.D., is regarded as one of the leading scientists of the 21st century for his numerous contributions to genomic research. In addition to his past key positions, he is founder, current chairman, and CEO of the J. Craig Venter Institute (JCVI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic, and environmental genomic research, and the exploration of social and ethical issues in genomics.

Dr. Venter, who is also co-founder, executive chairman, and co-chief scientist of Synthetic Genomics (SGI) and co-founder, executive chairman, and CEO of Human Longevity, spoke to GEN.

GEN: Dr. Venter, you have been on the frontlines of genomics, synthetic genomics, and synthetic biology. Please talk about your research in synthetic biology and synthetic genomics?

Dr. Venter: JCVI’s synthetic biology program started in 1995, when my team sequenced the first genome. That same year we sequenced a second genome, the smallest one known (Mycloplasma genitalium) in collaboration with Clyde Hutchinson, who was then at the University of North Carolina. That led Clyde and I, along with our colleague Hamilton Smith, M.D., to start discussing the concept of comparative genomics and wondering what the most primitive and simplest genome that could exist would be.

That is basically how the field of synthetic genomics got started. We felt that the only way to answer this question would be to make a synthetic chromosome that contained all the necessary genes, and to use that to create a new life form.

That idea took close to 20 years to achieve. In 2010 we recorded the first synthetic cell. It involved making a synthetic version of, mostly, Mycoplasma mycoides. Although it contained a number of significant changes, it was primarily based on a pre-existing species, and with it we were able to show that the creation of a new life form was possible.

Ongoing work at JCVI with funding mainly by Synthetic Genomics (SGI), a company that was spun out of the Institute, and done together with Dan Gibson’s team at SGI, has been focusing on designing a species from scratch on the computer on first principles.

In our final design of this synthetic cell, more than 10% of the genes that are essential for life are of unknown function. That reality somewhat limits what can be done in terms of synthetic genomics. We define synthetic genomics as truly 

• designing biological processes and genomes and then 
• building them from scratch chemically, 

with the process improving as you gain more experience.

However, if we can’t design even the smallest organism based on first principles, because we don’t know what all the components do, the challenge is greater than we initially thought. This, though, should also alleviate a lot of people’s fears about the ease of being able to design super-bugs, super-organisms, and super-species. It’s proving hard to do with less than 500 genes, let alone at a much more complex level. 

GEN: Given this new reality, how are you now moving forward with your synthetic genomics program?

Dr. Venter: We are using a lot of computer metaphors and are in the process of defragging the genome. Two billion years of evolution have not been highly orderly; in fact, they’ve been quite messy. In any genome we have looked at there is not a lot of order to it except, for example, some symmetry around origins of replication that have been maintained. Despite what people used to think, that gene functions would be more organized, they tend to be scattered all over the genome based on changes that genomes have been subject to throughout evolution.

It’s analogous to what happens to a computer hard drive when it gets highly fragmented over time, with information stored haphazardly and not in any organized fashion. You can run a program to defrag your hard drive and organize the information back into files. We have been defragging the genome by rebuilding the chromosome and linking together related genes: for example, grouping all of the genes associated with glycolysis in a single cassette, and the genes associated with cell division in another cassette. In this way, future design can at least start with these cassettes. I suppose we will also have to create a cassette of genes of unknown function, at least until they get sorted out.

We think that this new fundamental cell, largely created by direct design, will be a great experimental tool. We are even thinking of creating a public contest around it and awarding a prize to whoever adds on the best evolutionary functions to the cell. This self-replicating cell represents an early, relatively primitive form of cellular life. If we add genes and complex functions to it we should be able to convert the cell into a much more complex organism.

During research I did while writing my book, Life at the Speed of Light, I came across some of the early history from researchers in the 1800s and early 1900s, where one French researcher said, essentially, give me a basic protoplasm and I will be able to recreate all of life. At that time it wasn’t known what was in the protoplasm—they didn’t know what DNA was or that proteins were discrete molecules—but the assumption was that it contained the building blocks of life.

Now we can attempt to recapitulate evolution on a much faster stage, and certainly use this ability as a very informative learning tool.

GEN: Focusing now on synthetic biology, how would you describe the progress being made and the direction in which this field is heading?

Dr. Venter: I think synthetic biology is more or less a redefinition of the field of molecular biology. And systems biology is, perhaps, a more modern term for physiology. People are largely doing the same things they were doing before, but maybe with a different goal in mind. People who were mainly doing fundamental molecular biology now claim that they are doing synthetic biology.

There are so many directions in which this could go. With the discovery of CRISPRs we have a new tool set to enable things perhaps to go faster and in a different direction than just taking straight synthetic approaches. I think the combination of CRISPRs and synthetic biology is pretty stunning.

One of the most important programs at Synthetic Genomics is the company’s collaboration with United Therapeutics, in which it is literally rewriting the pig genome to create pig organs that will survive in humans as replacement organs for transplantation, e.g., hearts, lungs, kidneys, and livers. Similar to what was done with monoclonal antibodies early on, in which they were humanized and replaced with human gene constructs, making it possible to grow human monoclonal antibodies in mice. Obviously, changing everything associated with rejection of allogeneic transplants is much more complex, but we have already had some limited success. We are literally starting at the design phase.

We have created a new, highly accurate version of the pig genome that we’ll be working with, which carries all of the genes that we have identified as being important, and we are going through and systematically changing those in the pig genome. For some of those we rewrite the gene and put a wholly new synthetic construct and a landing pad into the pig genome; whereas for others, when there are only minor edits needed between the pig and human genes, we use CRISPRs just to edit the genes and convert the pig sequence to a human sequence.

Dan Gibson at SGI made a big breakthrough early on in this process when he found that he could combine all of the different enzymes for all of the different processes in a single tube at a single temperature. This is called the “Gibson assembly,” and it allowed the process to be carried out by a robot. SGI has an instrument called the BioXp™, which is an automated DNA assembly robot that takes oligonucleotides or subsets and builds them into larger constructs. It is a commercial instrument currently being used in several labs. If we are not able to write large pieces of DNA, then there won’t be a lot of development in the field. 

"Future Pathways for Synthetic Genomics" is part 1 of a 2 part interview with Craig Venter. Part 2 will appear in the April 1 issue of GEN, and will focus on tools and technologies needed to advance synthetic genomics research.

ORIGINAL: GEN

Mar 1, 2016 (Vol. 36, No. 5)