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Where will the century of biology lead us? A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development and prospects for public approval.

The quality of our future will depend on the direction society takes regarding complex issues such as health care, sustainability, the economy, and national security. Successful resolutions to these complex issues will to some extent depend on the pace at which scientists and entrepreneurs develop technologies.

Over the past decade, venture capitalists, governments, foundations, and the private sector began evaluating synthetic genomics--more commonly referred to as synthetic biology--as a potential industrial revolution. In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.

Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field? Along with the technology push of societal benefits is the activist's pull with concerns for health and environmental risks. Are activists' concerns about synthetic biology's risks reasonable? And if so, how might scientists and policy makers address those concerns?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts--oligonucleotides composed of 50-100 base pairs--which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes, removing the need for specialized knowledge.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

The twentieth century was the century of physics, partially due to the successful interactions between theoretical and experimental physics. When aeronautical engineers developed early aircraft, they used flight simulation for the interaction of aircraft and the environment. The interplay between theoretical and experimental biology is currently less developed. Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore's law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore's prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18-24 months, and productivity in reading and writing is independently doubling at a similar rate. Consequently, we are approaching the point where major developments in synthetic biology should occur.

Genomics Now--and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

* Avian Influenza Vaccines. Most influenza strains originate in Asia and travel around the world as the flu season progresses. Although bird flus do not frequently infect humans, in nature they can spread from birds to mammals.

In 2013, scientists linked the avian influenza A (H7N9), a new strain of bird flu that emerged in China, to a father who had visited a bird market the week before becoming sick, then infecting his daughter. Both later died, but other close contacts were not infected. When one person infects another, this typically indicates the early stage of a pandemic, as was the case in 1957, 1968, and 2009.

In the traditional approach to making vaccines, developed in the 1940s, scientists culture and grow an influenza virus in chicken eggs. When introduced into the human body, the virus stimulates the production of antibodies. Ideally, vaccines reach consumers before the influenza season begins. With the H1N1 strain in 2009 (the "swine flu"), most doses became available only after that pandemic had run its course.

After identifying a viral strain and its genetic code, researchers are now able to use rapid computerized sequencing and grow large quantities of vaccines in culture. This method provides a more effective response to seasonal and pandemic flu outbreaks, shortening the production time from months to days.

Using this method, Novartis and Synthetic Genomics Vaccines Inc. will work together to develop a bank of synthetically constructed seed viruses ready to go into production as soon as the World Health Organization identifies flu strains. The use of synthetic biology will reduce the vaccine production time by up to two months, which is particularly critical in the event of a pandemic.

* Malaria Drugs. Malaria infects an estimated 300 million to 500 million people annually, and it is fatal to roughly 1.5 million of those. Until malarial drugs were developed, people in areas prone to the disease have used mosquito nets and head coverings, drained marshy areas where mosquitoes lay their eggs, and used the insecticide DDT, which is now banned in many countries. Physicians used a synthetic form of quinine and sulfur drugs as treatments until the Plasmodium parasite developed resistance.

During the Chinese Cultural Revolution in the 1960s, the Chinese government launched a project to investigate the properties of plants used in traditional herbal medicines. Chinese herbalists treat fevers with Qing hao, also known as Artemisia annua or sweet wormwood, which is indigenous to China and Vietnam. Farmers extract the active ingredient artemisinin from its dried leaves, which releases oxygen-based free radicals that destroy the Plasmodium parasite while in the red blood cells of the host.

Artemisia annua has a nearly 90% efficacy rate against parasites resistant to other antimalarial drugs. But isolating and extracting artemisinin from plants is an expensive and laborious process. In 2004, the World Health Organization endorsed artemisinin combination therapy (ACT), the use of several antimalarial drugs, which reduces the chances of the parasite developing resistance. ACT is more expensive, however, and the supply is not meeting the demand. WHO estimates that up to 50% of malarial drugs sold in Africa and Asia are from the black market; these drugs provide a sublethal dose, helping the disease to develop resistance. So speculators are stockpiling the wild plant.

Most patients in need of antimalarial drugs are from developing countries and unable to afford them. In response, the Bill & Melinda Gates Foundation granted $42 million to University of California at Berkeley professor Jay Keasling to create a vaccine using synthetic biology. Keasling is redesigning the genetic circuits in the metabolic pathways of E. coli and yeast to code for all of the enzymes to produce the precursors to artemisinin. Sanofi Aventis, which is producing the drug on a not-for-profit basis, has agreed to scale up production of the drug by growing gene cassettes in fermenting vats in a process similar to brewing beer.

Although malaria patients benefit from bioengineered drugs, activists are concerned because bioengineered artemisinin will displace thousands of Asian and African subsistence farmers who cultivate the plant. Rather than disrupt the livelihoods of thousands of small farmers, according to Elias Zerhouni, director of global research and development with Sanofi Aventis, the company has decided to release the synthetic drug when the natural production does not meet the demand.

* Printing Human Tissues and Organs. The exponential acceleration of computing power applied to developments in genomics and 3-D printing has opened up the possibility of printing human body parts. Using custom-designed printers that can create both a synthetic scaffold and materials, bioengineers have printed prototype heart valves, artificial bone, joints, vascular tubes, dental implants, and skin grafts.

Cornell University biomedical engineer Lawrence Bonassar's lab is printing ears. He first takes a 3-D image to determine the ear's geometric pattern. Then, he prints ear tissue in layers composed of ink with living cells. For real applications, the patient's body would accept the new ear since it is composed of its own cells.

Even with the success of organ transplants, the supply of donated organs can't keep pace with the demand. If we could print them, then waiting for a donor match could become a thing of the past for the millions of patients in need of organ transplants every year. But the challenge is that human organs are complex structures with dozens of cell types.

Chinese researchers have printed miniature replicas of human kidneys. They use human kidney cells cultured in large volumes and blended with hydrogel. The mini kidneys are able to function in exactly the same ways as human kidneys--they can break down toxins, metabolize, and secrete fluids. However, researchers need to solve the problem of how to print blood vessel networks within organs.

In North Carolina, a team at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine has built custom bioprinters that can print numerous cell types. The 3-D printer has multiple cartridges for liquefied plastics and for cells cultured from the patient. The printer creates layers of alternating synthetic material and living cells in whatever shape a computer program specifies. The Wake Forest researchers envision some custom implants becoming available within in the next decade.

* Biofuels and Bioplastics. The oil industry and the U.S. Department of Energy are major investors in the initiative for the transition from the oil-based to the bio-based economy. In order to reduce the carbon footprint, they are developing biofuels created from biomass derived from crops and agricultural waste. Bioengineered microorganisms provide a quicker, more cost-efficient method than traditional chemical processes for breaking down biomass from crops and converting it into biofuels.

This shift not only involves fuels, but also oil used to produce numerous plastic products we use every day, such as carpeting, car parts, packaging for food, and apparel. Sustainable manufacturing is a trend for manufacturing companies developing their brands. Manufacturers are increasing the percentage of their plastic production to bio-based feedstock and ultimately hope to move away entirely from oil.

In 2005, then-CEO Charles O. Holliday Jr. wore a pinstripe suit made from DuPont's Sorona fibers, a polymer created by bioengineered bacteria and yeast that ferment corn sugars. These fibers are stain-resistant and more durable than nylon. They also require less energy to produce and emit less carbon dioxide. Nike is making shoes using polyurethane made from plants. Ford is using plant-based plastics for car parts. Similarly, Nestle, Coca-Cola, Pepsi, Odwalla, Heinz, and Procter & Gamble are using plant-derived plastic packaging. The biodegradable plastic containers are free of toxic BPA and endocrine disruptors that impact human health.

Bioplastics and biofuels have many potential benefits, but currently are more expensive than oilbased products. In order for biofuels to compete, a carbon tax will be required on oil, gas, and coal to reflect the cost of externalities. Industrialscale production of biofuels and bioplastics requires biomass. When the biomass comes from crops, this competes with food production, which increases the cost to consumers.

Feedstock from biomass requires land, water, and fertilizer. DuPont built an industrial biorefinery in Tennessee that turns 6.4 million bushels of corn annually into 100 million pounds of plastic. Growing the corn for just that one biorefinery requires 40,000 acres.

Crop production for biofuels and bioplastics is also accelerating deforestation, runoff, and water contamination and increasing atmospheric pollution. Bioplastics release methane, a greenhouse gas, during decomposition. As Friends of the Earth points out, if you take into account the life cycle analysis of biomanufacturing, synthetic biology is not a panacea for the environment.

* Investigating Life on Mars. Current conditions on Mars are not conducive to life as we know it on Earth. However, numerous missions to Mars have detected the chemical building blocks of life: nitrogen, oxygen, and carbon. So scientists have not ruled out life existing in the past.

With evidence of frozen water on Mars at 4-8 km depth and the possibility of previous life, researchers would like to discover it, bring it back to Earth, and study it. However, this research project faces numerous challenges.

NASA must find a way to drill into the ice, transport equipment and vehicles to Mars, and successfully return the samples back to Earth--a process that would take an estimated three years. Assuming discovered Martian life is based on DNA, genomics pioneer and entrepreneur Craig Venter has an alternative plan of action. In the Mojave Desert, he is developing robots to isolate microbe samples from soil on Mars. Once scientists obtain the samples, DNA sequencers will decipher their genomes.

With funding from the U.S. Department of Defense's research agency DARPA, Venter is developing a prototype Digital Biological Converter that can transmit digitized DNA information as electromagnetic waves near the speed of light. The journey from Mars to Earth would take roughly 4.3 minutes. Also in development is a receiver that uses 3-D printing to recreate living cells here on Earth. This method would also eliminate the risk of Martian life forms contaminating Earth life.

* Bioweapons. Now that genome sequencing and synthesizing technologies are more affordable and powerful, researchers frequently perform research that involves sequencing and synthesizing genomes of deadly pathogens. In order to better understand the various strains of bird flu, scientists are extremely interested in the Spanish influenza virus that killed an estimated 50 million people in 1918. Researchers have placed the genome of this deadly pathogen and others in the online database GenBank maintained by NIH for other researchers to use.

With the pathogen's genome sequence online and the availability of DNA synthesizers (a used machine could be purchased for less than $10,000 on eBay), someone with technical or graduate-school training in molecular biology could recreate a deadly virus. In a report financed by the Alfred P. Sloan Foundation, a group of scientists and policy analysts concluded that terrorists would find it easier to work with naturally occurring pathogens than synthesizing them. However, as a protective measure, the synthetic biology community is boycotting DNA-synthesizing companies that do not use DNA-screening software for customer orders.

Given the dual-use nature of synthetic biology, the Department of Homeland Security has taken precautions to prevent the increasing number of DIY garage biologists from creating bioengineered pathogens for biological warfare. After analyzing the potential for bioterrorism, President Obama's Bioethics Commission encouraged pursuing the benefits of synthetic biology, but with prudent vigilance. This entails monitoring the industry and updating regulations as needed.

The U.S. National Science Advisory Board for Biosecurity and the World Health Organization have determined that the benefits of disseminating information through articles and Web sites outweigh the risks. The best way to develop responses to bioterrorism, they reason, is to perform synthetic biology research.

* Bioremediation Organisms. Researchers are investigating the use of bioengineered enzymes in microorganisms to break down industrial wastes, oil, heavy metals, radioactive material, and pesticides in contaminated soil and water.

The 2011 tsunami in Japan and subsequent Fukushima Daiichi nuclear accident resulted in more than 1,000 tons of contaminated water and radiation exposure. Bioengineers have modified Deinococcus radiodurans--a bacterium with rapid DNA repair mechanisms enabling it to live in environments with very high levels of radioactive material--to consume and digest the hazardous chemicals in radioactive nuclear waste.

To clean up messes like the 2010 BP Deepwater Horizon oil spill--one of the worst environmental disasters in America's history--researchers can create synthetic algae to break down the destructive chemicals in the oil that impact the flora and fauna in the Gulf of Mexico.

Both of these cases required releasing modified organisms into the wild. As a precaution, these bioremediation microorganisms are infertile and have suicide genes to prevent unintended effects to the environment. Even with safeguards in place, activists see the bioremediation organisms as a potentially invasive species with emergent properties resulting from the interaction of genes.

Gaining Public Acceptance for Synthetic Biology

Through automation, bioengineers are currently making strides in developing vaccines and printing human body parts. However, the development of bioplastics, biofuels, bioweapons, and bioremediation organisms all raise legitimate concerns.

A coalition of more than a hundred international environmental and human-rights organizations--led by ETC Group, the International Center for Technology Assessment, and Friends of the Earth--initially lobbied to persuade regulators to impose a moratorium on synthetic biology research, due to unknown environmental and health risks. When this strategy did not work, the activists are now advocating greater oversight and regulation of the field, referred to as the precautionary principle. This approach requires that companies demonstrate health and environmental safety through lengthy studies. But this approach will slow the field's development, delaying any potential social benefits.

Ideally, each bioengineered product would undergo extensive testing not only for health risks, similar to testing in the pharmaceutical industry, but also for environmental risks. However, the costs involved are prohibitive to the development of most industrial products. Even with the time and costs dedicated to pharmaceutical clinical trials, a 1988 study reported in the Journal of the American Medical Association revealed that roughly 106,000 people die each year in American hospitals as the result of side effects from medications. Compare that with the estimated 40,000 annual traffic fatalities over the last twenty years. The activists seem to hold synthetic biology development to a higher standard than other technologies.

But, rather than focusing on the negative aspects of emerging technologies, addressing complex global issues requires solving these challenges. To address activists' concerns with bioengineered products, James Greenwood, president of the Biotechnology Industry Organization, proposes that regulators pursue both risks and benefits. Using the proportionality approach for the problem that agencies seek to address, regulators must demonstrate that they are not squandering resources and delaying social benefits in order to address negligible risks for nominal gains in safety.

Randall Mayes is Field Editor for Wild Cards at TechCast Global,, and the author of Revolutions: Paving the Way for the Bioeconomy (Logos Press, 2012), from which this article draws.
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Author:Mayes, Randall
Publication:The Futurist
Geographic Code:1USA
Date:May 1, 2014
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