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Move Over, Mother Nature

Synthetic biologists harness software to design genes and networks.

By | July 1, 2012

image: Move Over, Mother Nature GRAND VISION, ROUND 1: With Genome Compiler, you can look at your syntheses on a variety of levels, from the nucleotides to the peptides to the whole organism.Genome Compiler media team

GRAND VISION, ROUND 1: With Genome Compiler, you can look at your syntheses on a variety of levels, from the nucleotides to the peptides to the whole organism. GENOME COMPILER MEDIA TEAM

Working at the crossroads of biology and engineering, synthetic biologists are crafting genes, proteins, and organisms that evolution never came up with. They are creating bacteria that produce biofuels and yeast cells that manufacture medicines. They are swapping promoters, ribosome-binding sequences, and open reading frames as if they were Lego bricks.

“We are no longer constrained by what Mother Nature gives us,” says Claes Gustafsson, cofounder of the DNA synthesis company DNA2.0, in Menlo Park, California.

Now, the constraint is the toolkit. Traditional biologists can work with DNA sequences using a simple viewer or editor, but “the engineers need a whole new suite of tools,” says Natalie Kuldell, who teaches biological engineering at MIT.

The synthetic biologist’s mind-set is all about parts, those nucleic acid bricks they shuffle to design a desired gene or gene network. Previously, researchers dealt with plain-text sequences, in word-processing or spreadsheet files. Copying and pasting, “it’s very easy to make mistakes,” says Avi Robinson-Mosher, a postdoc who designs cancer drugs at Harvard’s Wyss Institute for Biologically Inspired Engineering. Synthetic biologists need computer-aided design tools akin to those used by other kinds of engineers.

Fortunately, many synthetic biologists have backgrounds in computers and engineering, and are developing software of their own. Some programs make drawing up the plans for a new plasmid so effortless that high school students and untrained bio-hobbyists can do it. Others include simulators so researchers can predict how a new genetic circuit will work. Several are open-source, so computer-savvy biologists can customize them.

For now, many researchers have to manufacture their own plasmids, but that will change as commercial DNA synthesis becomes cheap. Synthesis currently costs from 20 cents to one dollar per base pair. But Chris Anderson, of the University of California, Berkeley, predicts the price could drop to two cents per pair within the next couple of years. Some gene design programs already have a built-in “order” button.

Here, The Scientist profiles six programs to make your syntheses smooth and satisfying.

Genome Compiler: Wave of the Future

www.genomecompiler.com

Features
“We think that cloning is going to die, and we want to facilitate its death,” says Omri Amirav-Drory, founder of Genome Compiler Corporation in San Francisco. “We see a future where people can, and will, design and print huge pieces of DNA.” To facilitate the process, he is developing Genome Compiler, a sequence manipulation tool with a visual interface that was released in June.

Amirav-Drory envisions Genome Compiler users designing new organisms without ever examining the underlying nucleotides, unless they choose to directly edit the sequence. As an example, he likes to pull up the oak tree genome and drop in the firefly’s luminescence system for glow-in-the-dark foliage.

“It’s a grand vision,” comments Nathan Hillson of Lawrence Berkeley National Laboratory in California. At this point, the still-evolving software lacks many of the capabilities Amirav-Drory has planned, but “it paints a pretty compelling vision for where things are going to be going,” Hillson says.

For now, Compiler users can perform basic functions such as loading a gene or genome, zooming in on the nucleotides or out to the proteins, and editing and checking constructs. The program also interfaces with DNA synthesis providers to facilitate estimates and orders.

Best For
While the goal is for anyone to be able use Genome Compiler, the current version requires molecular biology know-how to design the constructs.

System Requirements
Mac/PC; web browser-based and iPad versions are planned.

Pros
• User-friendly visual interface
• Loads entire genomes quickly
• Will offer DNA synthesis estimates from multiple vendors

Cons
• The June release is a “minimal viable product,” Amirav-Drory says, with many features not yet included. For example, tester Shani Ben-Arye, a postdoc at Tel Aviv University, noted in May she was still waiting on crucial capabilities including “undo” and the locations of restriction sites.
• The program still needs some polish to be most useful, Amirav-Drory adds.

Open Source?
No

Cost
Free for most users; large companies may have to pay a fee, Amirav-Drory says.

Gene Designer: Codon-Perfect

www.DNA20.com/genedesigner2

DRAG, DROP, PLACE YOUR ORDER: Gene Designer shows you the DNA code and open reading frame translations, and helps you fit the codons to your organism of choice.
DRAG, DROP, PLACE YOUR ORDER: Gene Designer shows you the DNA code and open reading frame translations, and helps you fit the codons to your organism of choice.
DNA2.0

Features
When DNA2.0 first launched, Gustafsson found himself working as a human “gene designer,” helping customers organize their open reading frames and restriction sites using clumsy text files. The company developed its own software to streamline the process. Users can drag and drop elements, such as promoters or open reading frames, to build the construct they want. Designers can then hit the “order” button.

DNA2.0 has devoted much of its research to codon optimization. The same protein could be encoded by thousands of different sequences, but having the right codon combination can double protein expression, Gustafsson says. For example, the software can reverse-translate a human kinase amino acid sequence into the ideal nucleic acid bases to work in E. coli. 

Best For
Gene Designer can be used by anyone, from students to advanced researchers. It’s best for people making more than a few genes but less than a genome, says user Martin Hällberg of the Karolinska Institute in Stockholm.

System Requirements
Mac/PC/Linux

Pros
• Easy-to-use graphic interface
• Codon optimization
• Direct ordering

Cons
• Accessing the most advanced codon optimization requires users to work directly with, and order from, DNA2.0.
• It can handle only small genomes (a few hundred kilobases) at this point.
• Competing DNA synthesis companies may not sell Gene Designer-based sequences.

Open Source?
No

Cost
Free

Clotho: It’s What You Make of It

www.clothocad.org

CHANNELING STEVE JOBS: Like an iPhone for your DNA constructs, Clotho offers individual apps to manipulate sequences at the touch of a button.
CHANNELING STEVE JOBS: Like an iPhone for your DNA constructs, Clotho offers individual apps to manipulate sequences at the touch of a button.
CIDAR LAB AT BOSTON UNIVERSITY

Features
Clotho is a program to access parts registries and manipulate DNA sequences. Developer Douglas Densmore, of Boston University, compares it to an iPhone: users download apps to work with the sequences. It’s convenient, says user Robinson-Mosher, because he can examine and alter his sequences in any kind of app, without having to copy and paste the code between programs. Clotho comes with a few apps already on board, such as a sequence viewer and a spreadsheet-like tool to manage your freezer samples.

Densmore’s group provides more apps, and users can also write their own. For example, Robinson-Mosher encoded a plug-in to interface with j5, another DNA-design program (see below). Another plug-in, called Optimus Primer, helps design primers. There are more than 30 apps available, says Densmore, who developed Clotho when he was a postdoc at Berkeley, working with Chris Anderson.

Best For
Molecular biologists with the computer know-how and the desire to customize their experience

System Requirements
Mac/PC/Linux running Java

Pros
• It’s easy to share data with other Clotho users.
• By the end of 2012, Densmore and Anderson plan to have a training module about using Clotho built into the program itself.

Cons
• At this point, “There is a learning curve to it,” Densmore says.
• It’s limited to apps written in one language, Java.

Open Source?
Yes

Cost
Free, although Densmore may sell some apps in the future.

GenoCAD: Grammar Rules

www.genocad.org

Features
GenoCAD is a tool for molecular biologists to stitch together DNA out of parts from public databases or personal libraries. It is the first element in what developer Jean Peccoud, of the Virginia Polytechnic Institute and State University in Blacksburg, plans as an integrated suite of “Genetic Design Automation” tools to streamline DNA assembly, control a microscope to characterize protein expression, and check designs for sequences from dangerous organisms such as bioterror agents.

Users can design different templates, or “grammars,” for their constructs. Like a grammar-check warning that a sentence lacks a period, GenoCAD will apprise users of a missing termination codon or other crucial element. In addition, GenoCAD includes a simulator, so researchers can predict how several genes might work together.

Best For
Molecular biologists at any level of expertise

System Requirements
GenoCAD uses a web interface and works with Internet Explorer, Firefox, and Chrome.

Pros
• It’s simple to use and makes it easy to keep your sequences organized, says Christopher Overend, a virologist in Peccoud’s lab.
• GenoCAD monitors public databases, such as GenBank, and will warn you if a sequence you’re using changes, perhaps due to a correction.

Cons
• Peccoud designed the program for researchers to keep their data on his servers, but scientists concerned about the security of their data might want to install it on their own machines. While this is possible, it’s not trivial, Peccoud says.
• The simulation is based on binding constants and other data scientists enter, which may or may not be accurate. “How good these simulations are, nobody knows,” Peccoud says.

Open Source?
Yes

Cost
Free

j5: Save Time & Money

j5.jbei.org

FOR HIGH-THROUGHPUT CLONERS: Why waste your time designing a cloning protocol when j5 can do it for you? Give it a plasmid like this one and it will give you the instructions.
FOR HIGH-THROUGHPUT CLONERS: Why waste your time designing a cloning protocol when j5 can do it for you? Give it a plasmid like this one and it will give you the instructions.
J5.JBEI.ORG

Features
Modern cloning techniques, such as Gibson cloning, allow molecular biologists to assemble many parts in a single reaction without using restriction enzymes. However, designing the required PCR primers is complicated. Hillson recalls it took him two days to make his first plan, for a relatively modest 10-part genetic circuit.

Hillson wrote j5 to do the designing for him. Give j5 the construct you want, and it will tell you the cheapest way to make each piece—by synthesis or by PCR. Users can input their designs as spreadsheets, or use the associated Device Editor program, a graphic interface.

Best For
The j5 program is particularly useful for high-throughput cloners making large combinatorial libraries, says user Will DeLoache, a graduate student at UC Berkeley.

System Requirements
A web browser to log in to the Internet-based program

Pros
• Saves time during design, and avoiding mistakes, is the greatest advantage, DeLoache says.
• The instructions from j5 work “almost all of the time,” says user Richard Heins, a postdoc at Lawrence Berkeley, compared to a 50–70% success rate with human designs.
• To really minimize person-hours, the output from j5 can be used to program a pipetting robot.

Cons
• There is no assistance in designing the constructs or checking that they will express properly.
• It’s rather technical, Heins says: “The moderate complexity could turn some users off.”

Open Source?
No

Cost
Free for academic, government, and nonprofit users; commercial users can purchase j5 from TeselaGen of San Francisco (www.teselagen.com). TeselaGen just started selling the licenses and had not settled on a price structure as The Scientist went to press; CEO Mike Fero estimated a large company might pay just shy of $20,000.

TinkerCell: Design & Draw

www.tinkercell.com

Features
TinkerCell is a modeling program in which researchers can design genes as well as networks such as signaling and metabolic pathways. Many researchers particularly like TinkerCell’s graphical interface, with a free-form drawing tool for sketching biochemical pathways. A user can connect genetic sequences to each component in a pathway, then zoom in on the DNA or zoom out to the complete circuit.

By activating the built-in simulator, users can watch as protein levels rise or fall, and predict how their genetic circuit might work. Researchers can also write plug-ins to customize TinkerCell’s functions.

Best For
Students and scientists who want to design genes, and draw or simulate pathways. “Hard-core” programmers may want to work via the command-line console, says developer Herbert Sauro of the University of Washington in Seattle, while the average user might prefer the graphical interface.

System Requirements
Mac/PC/Linux

Pros
• Easy to use
• TinkerCell checks your work and prevents silly mistakes, like connecting a metabolite to a ribosome binding site.
• Free-form canvas is ideal for drawing pathways.

Cons
• The capability to manage a library of samples in your freezer or program a liquid-handling robot is not built in.
• The simulations are only as good as the input parameters.

Open Source?
Yes

Cost
Free

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Comments

Avatar of: sagejohn

sagejohn

Posts: 2

July 12, 2012

Awesome!  Best advance that could ever happen to the human race!

The universe is a very dangerous place where current human life forms have little to no chance of surviving.

Avatar of: beijing water

beijing water

Posts: 1

July 12, 2012

still a long way to go if really wanna do something

Avatar of: Dov

Dov

Posts: 1457

July 13, 2012

Synthetic biologists harness software to design nature...

Genes are simply and obviously ORGANISMS, life's primal ORGANISMS.
Genomes are plainly and obviously ORGANIMS evolved by-for the genes.

Dov Henis (comments from 22nd century)

Avatar of: Tim Craig

Tim Craig

Posts: 1

August 8, 2012

Those look nice!

Avatar of: Andrew Gray

Andrew Gray

Posts: 1457

September 19, 2012

it was the next step for an amazing field of science. I still wonder how rushed this was. The first wysiwyg interface for this is needed but i just hope functionality prevailed over the need to come first. As our understanding of new genes and how they interact with different systems increases, an interface like this that is user friendly will be paramount.

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