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1 An interview with J Craig Venter, the man who sequenced the human genome on Fri Nov 22, 2013 11:31 pm


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Craig Venter has been a molecular-biology pioneer for two decades.

Art Streiber

J Craig Venter has been a molecular-biology pioneer for two decades. After developing expressed sequence tags in the 90s, he led the private effort to map the human genome, publishing the results in 2001. In 2010, the J Craig Venter Institute manufactured the entire genome of a bacterium, creating the first synthetic organism.
Now Venter, author of Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life, explains the coming era of discovery.
Wired: In Life at the Speed of Light, you argue that humankind is entering a new phase of evolution. How so?
J Craig Venter: As the industrial age is drawing to a close, I think that we're witnessing the dawn of the era of biological design. DNA, as digitized information, is accumulating in computer databases. Thanks to genetic engineering, and now the field of synthetic biology, we can manipulate DNA to an unprecedented extent, just as we can edit software in a computer. We can also transmit it as an electromagnetic wave at or near the speed of light and, via a "biological teleporter," use it to recreate proteins, viruses, and living cells at another location, changing forever how we view life.
So you view DNA as the software of life?
All the information needed to make a living, self-replicating cell is locked up within the spirals of DNA's double helix. As we read and interpret that software of life, we should be able to completely understand how cells work, then change and improve them by writing new cellular software.
The software defines the manufacture of proteins that can be viewed as its hardware, the robots and chemical machines that run a cell. The software is vital because the cell's hardware wears out. Cells will die in minutes to days if they lack their genetic-information system. They will not evolve, they will not replicate, and they will not live.
Of all the experiments you have done over the past two decades involving the reading and manipulation of the software of life, which are the most important?
I do think the synthetic cell is my most important contribution. But if I were to select a single study, paper, or experimental result that has really influenced my understanding of life more than any other, I would choose one that my team published in 2007, in a paper with the title Genome Transplantation in Bacteria: Changing One Species to Another. The research that led to this paper in the journalScience not only shaped my view of the fundamentals of life but also laid the groundwork to create the first synthetic cell. Genome transplantation not only provided a way to carry out a striking transformation, converting one species into another, but would also help prove that DNA is the software of life.
What has happened since your announcement in 2010 that you created a synthetic cell, JCVI-syn1.0?
At the time, I said that the synthetic cell would give us a better understanding of the fundamentals of biology and how life works, help develop techniques and tools for vaccine and pharmaceutical development, enable development of biofuels and biochemicals, and help to create clean water, sources of food, textiles, bioremediation. Three years on that vision is being borne out.
Your book contains a dramatic account of the slog and setbacks that led to the creation of this first synthetic organism. What was your lowest point?
When we started out creating JCVI-syn1.0 in the lab, we had selected M. genitalium because of its extremely small genome. That decision we would come to really regret: in the laboratory, M. genitalium grows slowly. So whereas E. coli divides into daughter cells every 20 minutes, M. genitalium requires 12 hours to make a copy of itself. With logarithmic growth, it's the difference between having an experimental result in 24 hours versus several weeks. It felt like we were working really hard to get nowhere at all. I changed the target to the M. mycoides genome. It's twice as large as that of genitalium, but it grows much faster. In the end, that move made all the difference.
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One of the world's leading geneticists, Venter has innovated and infuriated in equal measure.

Art Streiber

Some of your peers were blown away by the synthetic cell; others called it a technical tour de force. But there were also those who were underwhelmed because it was not "life from scratch."
They haven't thought much about what they are actually trying to say when they talk about "life from scratch." How about baking a cake "from scratch"? You could buy one and then ice it at home. Or buy a cake mix, to which you add only eggs, water and oil. Or combining the individual ingredients, such as baking powder, sugar, salt, eggs, milk, shortening and so on. But I doubt that anyone would mean formulating his own baking powder by combining sodium, hydrogen, carbon, and oxygen to produce sodium bicarbonate, or producing homemade corn starch. If we apply the same strictures to creating life "from scratch," it could mean producing all the necessary molecules, proteins, lipids, organelles, DNA, and so forth from basic chemicals or perhaps even from the fundamental elements carbon, hydrogen, oxygen, nitrogen, phosphate, iron, and so on.
There's a parallel effort to create virtual life, which you go into in the book. How sophisticated are these models of cells in silico?
In the past year we have really seen how virtual cells can help us understand the real things. This work dates back to 1996 when Masaru Tomita and his students at the Laboratory for Bioinformatics at Keio started investigating the molecular biology of Mycoplasma genitalium—which we had sequenced in 1995—and by the end of that year had established the E-Cell Project. The most recent work on Mycoplasma genitalium has been done in America, by the systems biologist Markus W Covert, at Stanford University. His team used our genome data to create a virtual version of the bacterium that came remarkably close to its real-life counterpart.
You've discussed the ethics of synthetic organisms for a long time—where is the ethical argument today?
The Janus-like nature of innovation—its responsible use and so on—was evident at the very birth of human ingenuity, when humankind first discovered how to make fire on demand. (Do I use it burn down a rival's settlement, or to keep warm?) Every few months, another meeting is held to discuss how powerful technology cuts both ways. It is crucial that we invest in underpinning technologies, science, education, and policy in order to ensure the safe and efficient development of synthetic biology. Opportunities for public debate and discussion on this topic must be sponsored, and the lay public must engage. But it is important not to lose sight of the amazing opportunities that this research presents. Synthetic biology can help address key challenges facing the planet and its population. Research in synthetic biology may lead to new things such as programmed cells that self-assemble at the sites of disease to repair damage.
What worries you more: bioterror or bioerror?
I am probably more concerned about an accidental slip. Synthetic biology increasingly relies on the skills of scientists who have little experience in biology, such as mathematicians and electrical engineers. The democratization of knowledge and the rise of "open-source biology;" the availability of kitchen-sink versions of key laboratory tools, such as the DNA-copying method PCR, make it easier for anyone—including those outside the usual networks of government, commercial, and university laboratories and the culture of responsible training and biosecurity—to play with the software of life.
Following the precautionary principle, should we abandon synthetic biology?
My greatest fear is not the abuse of technology, but that we will not use it at all, and turn our backs to an amazing opportunity at a time when we are over-populating our planet and changing environments forever.
You're bullish about where this is headed.
I am—and a lot of that comes from seeing the next generation of synthetic biologists. We can get a view of what the future holds from a series of contests that culminate in a yearly event in Cambridge, Massachusetts—the International Genetically Engineered Machine (iGEM) competition. High-school and college students shuffle a standard set of DNA subroutines into something new. It gives me hope for the future.
You've been working to convert DNA into a digital signal that can be transmitted to a unit which then rebuilds an organism.
At Synthetic Genomics, Inc [which Venter founded with his long-term collaborator, the Nobel laureate Ham Smith], we can feed digital DNA code into a program that works out how to re-synthesize the sequence in the lab. This automates the process of designing overlapping pieces of DNA base-pairs, called oligonucleotides, adding watermarks, and then feeding them into the synthesizer. The synthesizer makes the oligonucleotides, which are pooled and assembled using what we call our Gibson-assembly robot (named after my talented colleague Dan Gibson). NASA has funded us to carry out experiments at its test site in the Mojave Desert. We will be using the JCVI mobile lab, which is equipped with soil-sampling, DNA-isolation and DNA sequencing equipment, to test the steps for autonomously isolating microbes from soil, sequencing their DNA and then transmitting the information to the cloud with what we call a "digitized-life-sending unit". The receiving unit, where the transmitted DNA information can be downloaded and reproduced anew, has a number of names at present, including "digital biological converter," "biological teleporter," and—the preference of former US Wired editor-in-chief and CEO of 3D Robotics, Chris Anderson—"life replicator".
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After developing expressed sequence tags in the 90s, Venter led the private effort to map the human genome.

Art Streiber

What kind of things can you do now with this kind of technology?
The most obvious is to distribute vaccine in the event of an influenza pandemic. In 2009, when the World Health Organization declared H1N1 influenza (swine flu) to be the first pandemic in more than 40 years, there was the fastest global vaccine-development effort in history. Within six months, hundreds of millions of vaccine doses had been produced. But it was not fast enough. The traditional method of manufacture relies on growing the viruses in fertilized hen eggs. In all, it takes around 35 days. As a result, around 250,000 people died from H1N1, most of them young. Had this virus been more pathogenic, the lag time in vaccine availability might have resulted in strife, disorder, and social breakdown.
How can the process be speeded up?
Synthetic Genomics, Inc, and the J Craig Venter Institute are working with Novartis to accelerate the production of influenza seed strains, backed by the US Biomedical Advanced Research and Development Authority. We are using a method called "reverse vaccinology," which was first applied to the development of a meningococcal vaccine by Rino Rappuoli, who is now at Novartis. The entire genome of an influenza virus can be screened using bioinformatic approaches. Next, particular genes are selected for attributes that would make good vaccine targets, such as outer-membrane proteins. Those proteins then undergo testing for immune responses. We and Novartis have produced vaccines in fewer than five days. Since the completion of a proof-of-concept demonstration in 2011, the process has been successfully repeated for multiple additional influenza strains and subtypes.
And you also have superbugs in your sights.
The fear has been expressed again and again that we may be facing a return to a pre-antibiotic era. One approach is to revisit phage therapy, in which bacteriophages that are specific to a certain bacterial strain are used to kill microbes. Every few days, half the bacteria on Earth are killed by phages. Can we enlist their help?
Unlike traditional antibiotics, which can cause collateral damage by killing "friendly" bacteria in our bodies, phages are like molecular "smart bombs," targeting only one or a few strains. That is not to say they are easy to use. As with antibiotics, cells can mutate to develop resistance to phages. Humans also clear phages rapidly from the bloodstream. With our new DNA synthesis and assembly tools, we could design and synthesize 300 new phages per day.
My greatest fear is not the abuse of technology, but that we will not use it at all
What's next for "teleportation"?
At this point in time we are limited to making protein molecules, viruses, phages, and single microbial cells, but the field will move to more complex living systems. I am confident that we will be able to convert digitized information into living cells that will become complex multicellular organisms or functioning tissues.
Why is this technology going to change how we explore Mars?
We could send sequence information to a digital-biological converter on Mars in as little as 4.3 minutes, that's at the closest approach of the red planet, to provide colonists with personalized drugs. Or, if NASA's Mars Curiosity rover were equipped with a DNA-sequencing device, it could transmit the digital code of a Martian microbe back to Earth, where we could recreate the organism in the laboratory. We can rebuild the Martians in a P4 spacesuit lab—that is, a maximum-containment lab—instead of risking them crash-landing in the Amazon. I am assuming that Martian life is, like life on Earth, based on DNA. I think that because we know that Earth and Mars have continually exchanged material. There are many people (often religious) who believe that life on Earth is special or unique, and we are alone in the cosmos. I'm not among them.
Why are you so confident about life on Mars?
Well, it has been estimated that Earth and Mars have exchanged on the order of 100kg of material a year, making it likely that Earth microbes have traveled to and populated Martian oceans long ago and that Martian microbes have survived to thrive on Earth.
One of our teams at Synthetic Genomics, in collaboration with BP, spent three years studying life in coal-bed methane wells in Colorado. We found remarkable evidence, in water samples from one mile [2.2km] deep, of the same density of microbes as are found in the oceans (one million cells per milliliter). Simple calculations indicate that there is as much biology and biomass in the subsurface of our Earth as in the entire visible world on the planet's surface. The same could be true for Mars.
And beyond, presumably?
If it works, then we will have a new means of exploring the universe and the Earth-sized exoplanets and super Earths. To get a sequencer to them soon is out of the question with present-day rocket technology—the planets orbiting the red dwarf Gliese 581 are "only" about 22 light-years away—but it would take only 22 years to get the beamed data back. And if advanced DNA-based life does exist in that system, perhaps it has already been broadcasting sequence information.
Where else is digitized DNA information taking us?
Creating life at the speed of light is part of a new industrial revolution. Manufacturing will shift from centralized factories to a distributed, domestic manufacturing future, thanks to the rise of 3D printer technology.
Finally, where is this great endeavor taking you?
Since my own genome was sequenced, my software has been broadcast into space in the form of electromagnetic waves, carrying my genetic information far beyond Earth. Whether there is any creature out there capable of making sense of the instructions in my genome, well, that's another question.
Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life by J Craig Venter is published by Little, Brown. Roger Highfield, former editor of New Scientist and current director of external affairs at the Science Museum Group, was external editor of the book. This interview was conducted in a series of conversations and e-mails over the past year.
J Craig Venter's Firsts
One of the world's leading geneticists, Venter has innovated and infuriated in equal measure. His most significant achievements include:
Mapping the human genome: In 1998, Venter founded Celera Genomics to sequence the human genome using techniques called shotgun sequencing and expressed sequence tags. Using the most powerful civilian supercomputer at the time, Venter managed, in three years, to achieve his goal. However, Celera initially decided not to publish certain sections of the genome, copyrighting them instead. But, faced with public and scientific outcry, it backtracked.
Creating the first synthetic organism: Venter is founder, chairman, and CEO of the J Craig Venter Institute, which is working on artificial life-forms with functions such as producing biofuels. In May 2010, his team synthesized the genome of the bacterium Mycoplasma capricolum. Venter's own showmanship has at times overshadowed the project: a fellow synthetic biologist told the New York Times that the only regulation their field needed was "of [Venter's] mouth". (MV)]

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