A DNA master chef, cooking up genomes

Daniel Gibson makes synthetic genomes in his lab at J. Craig Venter Institute. He hopes to make genomes that can be used in the next generation vaccines.
Written by Boonsri Dickinson, Contributing Editor

Daniel Gibson can synthesize genomes the way the Iron Chef whips up a mean dinner dish.

At the J. Craig Venter Institute -- famous for creating the first self-replicating, synthetic bacterial cell -- Gibson can be found mixing concoctions of DNA that could one day end up in the next generation of vaccines.

We spoke to him about what it's like to be on the forefront of genetic research.

SmartPlanet: What is your day like?

I arrive at JCVI at six a.m. and then hurry up and get my office work done so that I can spend the rest of the day in the lab.

Before entering the lab, I make a list of all the lab work I want to get done and then optimize the schedule in my head so that I can carry out many experiments at once.

SmartPlanet: Can you explain how synthesizing genes could help produce faster vaccines? Why is it important to make a virus that can keep up with the mutation of the flu virus to make vaccines faster?

Influenza vaccines become less effective annually because the influenza virus genome rapidly mutates. This often leads to structural changes allowing it to evade the host immune response. Currently, the virus causing the epidemic or pandemic is used in vaccine production by injecting it into fertilized chicken eggs.

This process can take more than a month. However, by combining the powers of our new rapid DNA synthesis method with reverse genetics cell-based methods, flu vaccines can be made much faster.

The genome sequence of the virus can be downloaded and built in the laboratory. These sequences can then be expressed to produce the virus, which is used in vaccine production.

The amount of time saved will be especially critical in response to a pandemic. We believe these approaches extend beyond flu and can be applied to other ever-changing pathogens as well.

SmartPlanet: How does your team plan on making synthetic vaccines?

We are taking a synthetic genomics approach in producing cells with valuable properties.

In this approach, we synthesize and transplant complete bacterial genomes to produce cells based on a DNA sequence that we design at the computer. Complete genome synthesis allows for extensive re-engineering of existing organisms.

These organisms can be tailored for efficient production of energy, pharmaceuticals and industrial compounds. Our new method can be used to accurately and rapidly synthesize DNA.

The synthesis of genes and genetic circuits, and even genomes, is no longer a bottleneck. Now we need to better understand how to turn a synthetic DNA sequence into something useful.

We are creating computational tools for pathway design and optimization for this purpose. Our DNA sequence databases are filling up with novel genes and pathways waiting to be identified, optimized and expressed.

Bioinformatics tools will certainly aid this process.

SmartPlanet: How do you construct a large DNA sequence that is error-free?

Most errors are produced at the first step of the DNA synthesis process when the individual DNA bases -- G, A, T, and C -- are strung together into oligonucleotides.

The key is to start by synthesizing short stretches of DNA and catching these errors early on. We start by synthesizing 60-base oligos and stitch these together into 300-base pair fragments.

At this stage, we sequence the molecules and weed out any that have mutations. We then take the error-free molecules and begin assembling them. Because our assembly method does not usually produce errors, we can carry out the process very far before sequencing again to confirm that no new errors have been introduced.

SmartPlanet: Why did you start with the mitochondrial genome?

There are many diseases including diabetes, cancer, blindness, and deafness that are caused by mitochondrial deficiencies. Demonstrating that we can rescue these deficiencies by installing a synthetic mitochondrial genome into defective mitochondria could possibly allow for gene therapy strategies and therapeutic drugs to be more logically engineered.

SmartPlanet: What is it like creating a genome sequence? What do you think will be possible in the future?

It is a lot of fun especially now that we are getting really good at it. No matter how many times I do it, it always amazes me that I can design a DNA sequence at the computer and then build it in the laboratory.

My guess is that, in the future, all DNA synthesis methodologies will be completely automated from the four bottles of chemicals that make up DNA all the way up to complete bacterial genomes.

And, I would be surprised if the equipment that automates this process wasn’t small enough to fit on a lab bench.

SmartPlanet: What inspires you to do this type of research?

By constructing synthetic cells, we will learn how to improve upon already existing life. It will also allow us to better understand how life works. There is not a single biological system that is completely understood. Every gene function for even the simplest bacteria is not defined.

But, now that we can produce synthetic cells, we can synthesize minimal genomes and make minimal cells where we understand the function of every gene in that cell and what DNA is required to sustain life in its simplest form.

SmartPlanet: Do you worry that someone might use this research and use it to create something harmful?

We are concerned and have been thinking of the policy and societal implications of our work since the earliest experiments. We understand that any new area of science or technology they can be used for positive purposes. In the case with synthetic genomics, new biofuels, new vaccines, pharmaceuticals and clean water. [There's always a chance] they can be used in a negative way.

We have worked hard since the earliest days (of our research program to create a synthetic cell nearly 15 years ago) to engage in dialogue about our work [with a diverse group]: bioethicists, governments U.S. and foreign, congressional members, laypeople, educators, students and the media. This area of science has had considerable amount of review and we believe that it has great potential for good for society if used wisely.

We intend to be leaders in making this a reality.

SmartPlanet: What's the hardest part about the research you are doing?

The hardest part is putting several weeks of effort into something only to find out that the experiment did not work. The disappointment lasts until the next great result or good idea comes about.

SmartPlanet: What is the last book you read?

Who has time to read books when you’re synthesizing genomes?

This post was originally published on Smartplanet.com

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