The Fabulous World of Bio-Fabs ArrivesMalaria kills 853,000 children under the age of five every year. Some 3.2 billion people in 107 countries are potentially at risk for catching malaria. Up to 500 million people contract the disease every year, and more than a million deaths are directly caused by it.
This is made even more tragic by the fact that there is a cure for malaria. It’s called artemisinin and is a natural compound found in the sweet wormwood tree in northern China.1 It completely eliminates the parasite from the body. So why isn’t it being distributed worldwide?
The answer is that the tree doesn’t make enough artemisinin to extract it on an industrial scale. Before even a dent could be made in the treatment doses needed, all the sweet wormwood trees would vanish from the earth.
You might suggest that the compound be synthesized, and that would be a good idea ? except for one thing: To do that requires copying the collection of genes, known as the genetic pathway, that makes artemisinin in the tree. Those genes, once copied,would have to be inserted into a suitable organism that could grow the compound, such as yeast cells.
If that sounds like genetic engineering, it is. Yet despite the fact that we’ve had the basic techniques of genetic engineering mastered for several decades now, it’s not as simple as it sounds.
For one thing, the genetic pathway for producing artemisinin consists of nine genes. Each gene has 1,500 DNA bases on average. If scientists wanted to create an artificial way of making the drug, they’d have to try out various versions of the pathway and discover one that would make more of it than the tree does ? preferably lots more. That means assembling different combinations of nine genes with 1,500 bases each, or roughly 13,000 bases for every new version of the complete pathway.
In addition, they’d want to make variations of each gene in the pathway to fine-tune the production for peak efficiency. Making just two versions of each gene would require 512 constructs, or six million nucleotide bases. The task of testing genetic pathways rapidly becomes overwhelming using today’s manual techniques for synthesizing DNA.
In the 1980s, a scientist at the University of Colorado developed a way to synthesize DNA. DNA is made up of nucleotides, which contain the so-called bases: adenine, cytosine, guanine, and thymine. Each base has a different level of attraction to the others, and the researcher used that property to assemble the DNA. The technique is still in use.
First a nucleotide is attached to a styrene bead floating in liquid. A new nucleotide and some acid are added to the liquid, and a bond is formed. Then the new nucleotide is exposed to acid, which encourages it to form a bond with a third nucleotide.
This laborious process is repeated over and over until the desired gene is assembled. The error rate is about one incorrect base in 100, or 1 percent. That would yield 130 errors in the genetic pathway for artemisinin, and that would render the pathway useless. Typical living organisms, manufacturing DNA molecules, do so at a speed of 500 bases per second with an error rate of one base in a billion, roughly a trillion times better performance than the best man-made gene synthesis technique available today.
But what if you could automate that entire process? Better yet, what if you could do it all on a chip?
Enter the micro-array, the equivalent of a large computer chip that uses the natural properties of DNA and RNA to let scientists determine the expression level of thousands of genes in a single pass, with the results being read by computer.
A team of scientists called the Bio Fab Group has come together from institutions across the nation. The team has modified this technology to help them assemble and test the genetic pathway for creating not only a cure for malaria, but for AIDS and numerous other diseases as well. And the bio-fab movement is taking the world of genetic engineering by storm, according to Scientific American.2
The members of the Bio Fab Group founded a company called Codon Devices in Cambridge, Massachusetts, which is applying the engineering principles of the computer chip manufacturing sector to synthetic biology. It is their aim to transform biotechnology, especially gene synthesis and manipulation, into an industrial mainstay of the scientific and medical worlds.3
Synthetic biology stands today at approximately the place that electronic engineering stood at the end of the 1950s, when integrated circuits were still soldered together by hand. In 1957, Jean Hoerni of Fairchild Semiconductor invented what’s known as planar technology, which is the lithography technique in use today for making computer chips.
All at once, electronic circuits could be printed automatically and reliably, instead of laboriously assembled with a high error rate. It wasn’t long before there was an entire library of standard circuits that engineers could simply plug together for various uses. The result, as we all know, was the rapid growth of computer power and shrinkage of circuit size characterized by Moore’s Law.
This technology, known as chip fabrication or chip fab, has proven to be one of the most successful methodologies in history.
Today, genetic scientists are still, in effect, hand-soldering together their circuits of DNA components. Moreover, the methods and tools aren’t standardized.
That’s where The Bio Fab Group and Codon Devices come in. They’ve created the technology to build up a bio-fab industry in which standardized modular segments of DNA will be manufactured and used the way standard types of computer chips are used today. This will free the scientists to deal with the larger issues they’re trying to address instead of, in effect, working as technicians in their own labs.
One of the things that makes real biological systems fast and accurate at assembling genes is that they run many different operations in parallel. The Bio Fab Group adapted existing micro-array technology to run such parallel operations at densities of a million DNA fragments per square centimeter.
These fragments are then chemically assembled into the desired gene sequences. By creating modular sequences of nucleotides, they can then readily assemble any combination to produce the desired gene.A series of chemical washes removes any imperfections from the micro-array slide, thereby reducing the error rate. They now have that rate down to one in every 1,300 bases.
They use a new technique called MutS, L, H, which employs DNA’s own error-correcting properties to reduce that further to one in 10,000, which is sufficiently accurate to move ahead to the next step: industrial scale production.
According to the journal Science Letter,4 Codon recently completed its pilot program under a National Institutes of Health grant to create a library containing every human and mouse gene, which had been synthesized with its automated system. In order to do that, the system had to faithfully reproduce 65,000 nucleotides.
The rapid delivery time and error-free operation demonstrate that a cure for malaria and other diseases is much closer. But this automated technology for gene synthesis, which is called the BioFAB platform, will also have a profound impact on molecular biology, drug discovery, vaccine development, pharmaceutical manufacturing, agriculture, and renewable energy, just to name a few.
The same technology that creates new genes can be tailored to make new proteins for industry, such as chemical catalysts or proteins that degrade environmental pollution. It can also build enzymes that will destroy disease organisms or even cancer cells. By using the BioFab methods, a protein-based vaccine could be created on the fly for anything from SARS to bird flu. This would produce a vaccine much faster than even the most reliable traditional methods.
In another bold move, the Bio Fab Group members established a non-profit foundation they’re calling BioBricks to create a vast library of components that will allow biological engineers to simply reach for the shelf in assembling more complex or multi-cellular devices.
This registry now contains more than 1,000 components, which the team is calling BioBricks, including biological versions of inverters, switches, oscillators, counters, amplifiers, and input-output display components. For example, in one experimental device, a complex of these components makes up a small area of cells that will glow fluorescent green when it detects the volatile chemicals given off by explosives.
Based on these successes, the Bio Fab Group began to teach a course in fab-style engineering with ready-made biological components in 2003 and started the International Genetically Engineered Machine contest, a competition that will involve the best talent from 30 universities this summer. Among the notable entries are a biofilm that can record and then display a photograph, and a digital counting device made of DNA that can count up to one million.
If that sounds trivial, consider that the counting device is now being incorporated into sensors that will monitor the production of the drug artemisinin, which will ultimately cure malaria.
Given this understanding of the bio-fab trend, we forecast the following four developments:
First, by 2020, genetic engineering will become a fully mature industry. Until now, it has proceeded by fits and starts, much as the computer industry did between World War II and the 1970s. At that time, there were numerous companies of varying sizes making computers and electronic components. All the technological pieces of the puzzle existed, but they had not yet been brought together or fully exploited. Moreover, no oneyet knew which companies or business models would succeed or fail. Just as Fairchild failed to reap the rewards of the technology it pioneered, look for companies that are analogous to Intel, Microsoft, and Apple that can find and exploit the “sweet spots” in the value chain.
Second, in the next 10 to 20 years, we will see an intense period of rapid development in the bio-fab industry, which is actually the convergence of several fields that share common technologies. Already, dozens of labs exist that are creating drugs, vaccines, biological computers, sensors, and industrial chemicals through this means. As a systems biologist at Harvard pointed out in a recent Knight Ridder report,5 scientists can now encode DNA to do virtually anything you can think of.
Artificial viruses are a reality, and scientists at State University of New York are programming an artificial bacterium, which is orders of magnitude more complex than a virus. Companies are springing up everywhere, claiming to do “synthetic biology” better than the other. And, it’s only a matter of time before someone creates an artificial animal.
Third, expect a backlash as people express their fears of misusing genetic engineering, followed by an era of enormous progress. The journal New Scientist,6 for example, recently explained how a terrorist could manufacture the smallpox virus by reengineering genetic material that can be ordered on the Internet. Add this to the controversy we’ve already seen regarding cloning and human embryonic stem cell research, and you have a major controversy on your hands. When the dust settles around 2020, synthetic biology, properly overseen and controlled, will combine with the burgeoning field of nano-technology to virtually eliminate the diseases we’ve known throughout history. For example, using genetic engineering and synthetic biology, there is no reason that a human liver couldn’t be grown in a pig and then transplanted. The process would begin with the patient’s own DNA, thus eliminating any possibility of rejection.
Moreover, with industrial scale bio-fab technology, it will become cost-effective to target cures for every disease for which there is a known cause, even those that afflict only a few hundred people each year.
Fourth, by 2050, whole new classes of living materials that combine nanotech properties with synthetic biological capabilities will be in use. For example, smart clothing that not only provides heating and cooling, but also cleans the wearer and the clothing itself will be commonplace, as will carpeting that literally eats dirt. Crops will use photosynthesis to create starch and sugars, and then use a parasitic yeast-like organism to ferment it, thereby turning sunlight directly into ethanol for fuel. And artificial life forms that live off of various forms of pollution will rehabilitate the environment on a continuous basis. References List :
1. Scientific American, June 2006, “Engineering Life: Building a FAB for Biology,” by David Baker, George Church, Jim Collins, Drew Endy, Joseph Jacobson, Jay Keasling, Paul Modrich, Christina Smolke, and Ron Weiss. ⓒ Copyright 2006 by Scientific American, Inc. All rights reserved. 2. ibid. 3. For information about the NIH pilot program discussed in Science Letter, visit the Codon Devices website at: www.codondevices.com 4. Scientific American, June 2006, “Engineering Life: Building a FAB for Biology,” by David Baker, George Church, Jim Collins, Drew Endy, Joseph Jacobson, Jay Keasling, Paul Modrich, Christina Smolke, and Ron Weiss. ⓒ Copyright 2006 by Scientific American, Inc. All rights reserved. 5. Contra Costa Times, November 19, 2005, “Artificial Biology Gives Reasons for Both Hope, Fear,” by Robert S. Boyd. ⓒ Copyright 2005 Knight Ridder, Inc. All rights reserved. 6. New Scientist, November 12, 2005, “The Peril of Genes for Sale.” ⓒ Copyright 2005 by Reed Business Information, Ltd. All rights reserved.
