Synthetic Genomics for the Quality of Life

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Synthetic Genomics for the Quality of Life

Introduction

For the scientific community the twentieth century was the century of physics. Some of the best minds used powerful new scientific tools to solve many of the mysteries of matter and energy (Dyson 1998). These “tools” were the products of advances in engineering, chemistry, and materials science; they include microscopes, X-ray and neutron sources, accelerators, and supercomputers. Physics still has its mysteries, for example, the recently discovered dark matter and dark energy, and physicists will still be wrestling with these mysteries for many years to come.

The Human Genome

Biology was the sleeper science of the 20th century. It was slow to embrace the use of high technology research tools and generally followed a narrow, hypothesis-driven research approach. It is also true that funding for biological research lagged behind the funding of the physical sciences, especially in the United States. The discovery of the double helix structure of DNA (Watson and Crick 1953) was followed by seminal advances in molecular biology. They ushered in a new era of biological research that came into full force with the advent of genomics. Much credit for this scientific revolution is given to the Human Genome Project (HGP), which was officially launched in 1990 and concluded in 2003. The principal goal of the HGP was to sequence the human genome.

It is not generally known that the proposal to sequence the human genome did not come from the mainstream biological science community. In fact, that mainstream community was threatened by the proposal, fearing the diversion of research funds away from its traditional and fragmented grants system. The proposal was put forward by scientists (DeLisi 2001) within the U.S. Department of Energy (DOE), the successor to the U.S. Atomic Energy Commission (AEC). Created at the dawn of the atomic era, the AEC considered the effects of ionizing radiation on human biology and gave birth to the field of nuclear medicine. The DOE scientists argued that only if the human genome was sequenced could the effects of ionizing radiation be determined, as it had become increasingly apparent that radiation damages DNA. The fact that DOE science has always been dominated by physicists, accustomed to complex and pricey projects, was also a factor.

The HGP changed the culture of biological research. It was biology’s first foray into “big science” research demanding the coordination of large teams, the handling of large amounts of data, and above all, the development of technologies for DNA sequencing (IHGSC 2001). A significant new private sector arose both for the development of the new tools for genomics research and ultimately for capitalizing on the potential of genomics to affect major sectors of the economy such as the healthcare industry (Venter et al. 2001). Deciphering human DNA opened the door to entirely new ways to diagnose, study, and treat human diseases.

Microbial Genomics

While most of the attention was understandably on human genomics, there was another quiet revolution taking place: microbial genomics. In fact the first free-living organism to have its genome sequenced was the microbe Haemophilus influenzae , sequenced in 1995 by Craig Venter and his team (Fleischman et al. 1995) at The Institute for Genomic Research (TIGR). Shortly thereafter the TIGR team sequenced Mycoplasma genitalium , considered the smallest genome of a free-living organism. The sequencing approach of the TIGR team is referred to as “shotgun sequencing” and has since been adopted for most genomic sequencing. The approach involves shattering multiple copies of the genome into smaller random pieces, sequencing those pieces, and employing a supercomputer to assemble the sequence based on overlaps in the edge pieces of the fragments.

Over the last fifteen years an avalanche of genome sequence data has been pouring into the public databases. Many are microbial genome data that have revolutionized the field of microbiology. It turns out that our microbiology knowledge was limited to those microbes that could be cultured in the laboratory, a very small percentage of this living world inside and outside of us. Genomics gave us the tools to peer into this wonderful world and discover an amazingly rich diversity. Over sixty percent of the Earth’s biomass is microbial in nature: on the living world’s representative “tree” only a tiny twig represents the families of multi-cellular creatures like us.

Our current understanding is that our Earth was formed about four billion years ago and that microbial life first appeared on it and in it about two billion years ago. Microbial life eventually inhabited every nook and cranny of this planet, including environments of extreme temperature, pressure, and radioactivity. In recent years, we have discovered microbes in all environments including deep sea vents, coal beds, and volcanoes. There are microbes that can survive a million times more ionizing radiation than what would kill a human being. Having perfected their life processes through evolution, microbes are the virtuosos of the living world. We are learning a lot by studying these creatures, and we are employing this knowledge to solve many of our global problems.

Minimal Genome

Genomes are long stretches of “base pairs,” the building blocks of DNA usually represented by the letters A, C, G, and T. Genes are parts of genomes responsible for the production of proteins, which are the workhorses of cells. Individual genomes can include thousands of genes that turn on and off much like instruments in an orchestra. Despite our many advances we still have no clue as to the functions of many genes in each of the genomes we have sequenced, including the intensely studied human genome. Even the tiny M. genitalium genome, that is 582 thousand base pairs long with roughly 482 genes, contains at least a hundred genes of unknown function. From the time that this genome was sequenced we asked the question: how much smaller can the genome be and still maintain its free-living status? Thus was born the concept of a “minimal” genome (Fraser and Venter 1995).

Despite valiant efforts using the latest of molecular biology tools, the “minimal” genome proved elusive. As a result there arose another advance in basic research: the launching of synthetic genomics. It was argued that if we could synthesize a genome from the four chemicals A, C, G, and T, we could then determine the “minimal” genome by selective omission of the segments that included the not-absolutely-necessary-for-survival genes. Gradually, we realized that if we were successful in synthesizing genomes, the benefits would grow far beyond establishing just a “minimal” genome.

Although the term “synthetic biology” entered the scientific vernacular just a few years ago, it actually describes several of the molecular biology techniques that over the past few decades have been applied to tweaking various genes. The tweaks have enabled such products as human insulin produced by pigs, genetically engineered corn that resists the herbicides to control threatening weeds, and synthetically produced pharmaceuticals to combat malaria. Synthetic genomics gives us the weapons to go beyond the tweaking of various genomes to the system-wide restructuring of genomes in order to achieve much larger scale improvements in the ways we produce medicine, clean energy, and renewable chemicals, and in ways to clean up the environment.

Synthetic Genomics

On May 20, 2010 Craig Venter announced an accomplishment that will stand as a significant milestone in biological research (Gibson et al. 2010). Building on a series of molecular biology breakthroughs, the Venter team synthesized the genome of the organism Mycoplasma mycoides that is roughly twice the size of Mycoplasma genitalium . The synthetic genome was then inserted into the cell of a related species microbe, that of Mycoplasma capricolum , that eventually “booted up” the host cell and assumed the identity of Mycoplasma mycoides . This was the first research confirmation that DNA is indeed the software for the cell’s hardware. As one team member correctly noted, this was the first organism whose parent was a computer!

News of the first synthetic cell, named Mycoplasma mycoides JCVI-syn1.0 received worldwide attention. The scientific and business communities quickly realized that biotechnology had acquired a powerful new tool that could be applied to a variety of applications. In the fundamental research arena, the fifteen year-old dream of creating the “minimal” genome was now much closer to reality. Along with that achievement will come new ways to determine the properties and functions of a multitude of genes of unknown function. It will become possible to rearrange the locations of genes of existing genomes in order to achieve greater efficiency in metabolic functions within cells. Versatile robotic systems will be designed and built in order to rapidly integrate many combinations and select for optimal function. Ultimately, we can look ahead to the creation of entirely new genes and genomes that, properly harnessed, can be put to use to solve some of the global problems of our time.

Dark Side

Every new technology also has its dark side, and new biotechnologies are no exception. Bioterrorism has been the concern of governments and societies for decades especially after the advances in recombinant DNA methods in the seventies. Bioterrorism was also a threat during the cold war and more recently after the September 11, 2001 attack that was quickly followed by the anthrax attacks on the U.S. Congress. In 2003 particular concern emerged when the Venter team successfully synthesized the virus phi X in a few days (Smith et al. 2003). Informed of this development, the Bush Administration quickly convened a high level group that deliberated long and hard about whether the synthesis methodology should be classified. The emerging consensus was that the benefits of keeping the science in the public domain outweighed the risks of various parties using it for nefarious purposes. Both the Obama Administration and the U.S. Congress have adopted a similar position after the announcement of the synthetic cell.

Concerns about this new biotechnology transcend the bioterrorism threat. The first foray into recombinant DNA in the seventies triggered fears of engineered organisms escaping and causing environmental disasters. The launching of the HGP anticipated the problems of revealing human genetic information that could cause discrimination in employment and insurance. As a result, a fraction of the HGP budget was earmarked for in-depth studies of the ethical, legal, and social implications of sequencing the human genome. Significant resources were also invested in educating the broader communities of scientists, policymakers, and citizens on genomics including addressing the risks of learning the details of genetic predisposition to various diseases. Today, there are safeguards in place to protect against the nefarious use of genomics, and laws have been passed to protect against genetic discrimination. However, there is still much work ahead to ensure against abuse of this biotechnology.

Finally, there is what can be called the Prometheus danger. For some, the successful creation of a microbial cell conjures up a future of cloned or engineered human beings that violates the basic tenets of humanity and invites the “wrath of the gods.” Given the scientific challenges, such a future could not be imminent, but even if it were, there are boundaries that should not be crossed, and humanity needs to deliberate on how to draw those boundaries. The future is unknowable, and it is possible that in a distant time these boundaries will need to be reconsidered if humanity is to survive. Consider, for example, the case of a planetary emergency, such as a comet on a collision trajectory to Earth posing a global annihilation danger from which only a “sample” of humanity can be salvaged.

Future

Synthetic biology and synthetic genomics make the immediate future both brighter and more complex. The new biotechnology adds to our toolkit for dealing with many of the global problems facing our world today including the threat of anthropogenic climate change. It offers ways to petroleum alternatives such as using synthetic organisms that can efficiently convert various feedstocks (for example cellulose or carbon dioxide) into clean and renewable fuels. Removing carbon from the world economy and sequestering it away from the atmosphere is now seen as more possible given the synthetic genomics tools. Research is underway to exploit this technology for rapidly producing vaccines for pandemics and other diseases. Biotechnology will also enable us to meet the food, water, and energy needs of an expanding human population expected to level off at roughly nine and a half billion by the middle of this century.

Biology has now taken center stage in the pantheon of the sciences and, powered by genomics, will be playing a major role in enhancing the quality of our lives. It is fitting to reflect on the historical record of the Greek philosopher Aristotle, considered the “father of biology.” When his pupil, Alexander the Great, embarked on his campaign to the east he followed his teacher’s instructions to send samples of the flora and fauna that he encountered. Aristotle recorded the different samples, perhaps becoming the first human heralding the living world’s remarkable biological diversity.

Bibliography

DeLisi, C. 2001. “Genomes: 15 Years Later. A Perspective by Charles DeLisi, HGP Pioneer.” Human Genome News 11:3-4. Oak Ridge National Laboratory.

Dyson, F. J. 1998. Imagined Worlds. Cambridge, MA.

Fleischman, R. D. et al. 1995. “Whole-genome Random Sequencing and Assembly of Haemophilus Influenzae.” Science 269 (5223):496–512.

Fraser, C. M. et al. 1995. “The Minimal Gene Complement of Mycoplasma Genitalium.” Science 270 (5235):397–404.

Gibson, D. G. et al. 2010. “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome.” Science 329 (5987):52–56. Originally published online in Science Express, May 20, 2010. http://www.sciencemag.org.

International Human Genome Sequencing Consortium. 2001. “Initial Sequencing and Analysis of the Human Genome.” Nature 409 (6822):860–921.

Smith, H. O. et al. 2003. “Generating a Synthetic Genome by Whole Genome Assembly (pHi)X174 Bacteriophage from Synthetic Oligonucleotides.” Proceedings of the National Academy of Sciences, 100 (26):15440–15445.

Venter, J. C. et al. 2001. “The Sequence of the Human Genome.” Science 291 (5507):1304–1351.

Watson, J. D., and F. H. Crick 1953. “Molecular Structure of Nucleic Acids; a Structure for Deoxyribose Nucleic Acid.” Nature 171 (4356):737–738.