"Intellectuals in their self-flattering wish-fulfillment say that knowledge is power, but the truth is that knowledge further empowers only those who have or can acquire the power to use it."

Biopunks deplore restrictions on independent research, for the right to arrive independently at an understanding of the world around oneself is a fundamental human right. Curiosity knows no ethnic, gender, age, or socioeconomic boundaries, but the opportunity to satisfy that curiosity all too often turns on economic opportunity, and we aim to break down that barrier. A thirteen-year-old kid in South Central Los Angeles has just as much of a right to investigate the world as does a university professor. If thermocyclers [DNA copying machines] are too expensive to give one to every interested person, then we'll design cheaper ones and teach people how to build them.

What does the ability to copy DNA or knowledge of a genetic sequence give to someone who lives in a community plagued by violence and poverty? Who is benefiting from the push for DIYbio? Who are the actors "democratizing" science? By and large, the people participating in DIYbio are current students at elite colleges and universities or recent graduates, often even with advanced degrees in science and engineering and have worked or are currently working in university labs. They are also more often than not white, middle class, and primarily male (with notable exceptions, like Meredith). DIYbio can perpetuate social divisions in science and engineering even when on the surface claiming to break them down.

Moreover, the myth of the Victorian Gentleman Scientist permeating the rhetoric of DIYbio is a powerful one--a scientist pursuing a "pure" science not because of an interest in money and free of any state control but because of a deep curiosity with the power of the natural world. But the Victorian Gentleman is also independently wealthy off of money he didn't make himself, living in a house taken care of by women who have no voice or education. Where does the money come from for the modern home scientist? Who can afford to do unpaid work in the first place, not to even mention self-funded research in molecular biology? Science isn't and shouldn't be the sport of the privileged, and institutional labs today are staffed with people of many different socioeconomic and educational backgrounds (although it's still going to take a lot more to be truly equal).

What if instead of trying to work outside the system, overhyping the possibilities of biological technologies and at the same time devaluing the scientific labor that happens around the world in many different institutional environments, we worked towards an even better structure for science? The emphasis on open, shared work is wonderful and starting to be embraced by many in academia, what if we could have a real open, collaborative scientific enterprise across disciplines and academic or industrial barriers? What if there were more opportunities for high-paying technical jobs in science for people without advanced degrees? What if there were more biotech vocational programs to learn the skills you would need to work in these jobs? What if it were easier and cheaper for groups of scientists and engineers everywhere to turn ideas and hypotheses into technology and knowledge? What if there were real ways for knowledge to become power for that kid living in South Central LA?

Anyone can do science and garage biotechnologists and grad school dropouts will likely come up with powerful technologies and perhaps even empires to rival those of Microsoft, Apple, and Google that emerged from a culture of computer hacking forty years ago, but for knowledge to be power, for science to be truly democratic, we're going to need a lot more than cheap thermocyclers.

There are a lot of examples of biomimetic robots, robots that have components built to resemble biological structures but made of non-biological materials. Joseph Ayer's group at Northeastern builds biomimetic underwater robots that look and act like lobsters or lampreys, that have electronic brains built to function the way that networks of neurons do in the brains of animals. Using complex signal processing they can swim around and follow different stimuli.

There are tons of amazing videos of other biomimetic robots on YouTube, like the RoboBees:

BigDog:

AquaPenguin:

None of these robots, however, use actual biological components (yet). Biological engineers and robot scientists are currently thinking of ways where the unique properties of living cells could be used as components in small robots. The Cyberplasm project aims to do just that.

In this fish-shaped robot, the eyes are made of synthetic biological sensors, engineered strains of yeast or bacteria that are able to sense chemicals in the water and send a signal to the electronic "brain." These electronic circuits then send signals to muscle cells engineered to respond to signals coming from an electronic "nerve" rather than a biological one, causing the fish to swim towards the chemical signal.

I have to admit that when I think about these robots sometimes I feel like I'm in that part of Terminator II when the skynet scientist are inadvertently setting the course for their own demise at the hands of killer robots, but at the same time I think they are just totally amazing and fascinating. These are hardly self-replicating murderous robots (they're hardly more than ideas at this point), and technology that incorporates biological systems that can do things more efficiently and with less energy than electronic or mechanical components can be enormously beneficial. Being able to create better interfaces between electronic and biological components may also help in designing better medical devices like pacemakers, brain stimulation devices for treatment of Parkinson's and other serious chronic neurological diseases, or devices that can monitor health and release drugs precisely when needed. They're also just plain cool.

Until recently, no one had looked at carboxysomes under the microscope in cells that were still alive. My labmates Dave and Bruno developed a way to label carboxysomes with fluorescent proteins and track them under a microscope as the cells grow, and their amazing paper in Science details some of the fascinating systems they discovered about how carboxysomes are controlled.

They noticed something very interesting right away: the carboxysomes in live cells are all lined up, evenly spaced, down the central axis of the rod-shaped bacteria. They hypothesized that there must be something holding the carboxysomes in place, preventing them from diffusing through the cytoplasm. All bacteria have a "skeleton," a mesh of proteins that maintains their shape, helps them divide, and can hold chromosomes and other cellular parts in place. When they deleted one of these mesh proteins out of the genome of the photosynthetic bacteria they saw that the cells would become rounder, not able to hold their shape as well, and that the carboxysomes weren't evenly spaced any more (figure B). When they knocked out a different skeleton-associated protein, parA, they saw that it seemed to exert special control over the carboxysomes. Deleting this gene allowed the cells to stay rod-shaped, but the carboxysomes weren't lined up anymore (figure C).

In the mutants without parA and no even carboxysome spacing, sometimes when a cell divided, one of its daughter cells wouldn't get any carboxysomes. Without the machinery to capture carbon dioxide, the cell grew much slower until it was able to get enough protein together to make a new carboxysome. In the video below you can see this happening. The red arrow points to a cell that gets no carboxysomes after division, and the white arrow points at its sister cell that got them all. The empty cell doesn't divide again until it forms carboxysomes (the green dots), while the cell that got the carboxysomes has already divided by that time. This shows why the cell would invest so much energy holding the carboxysomes in place; without even spacing a certain number of cells wouldn't be able to grow at the optimal speed, decreasing the fitness of the whole population.

When they fluorescently tagged parA in wild type cells, they saw something amazing: this "skeleton" protein isn't just a static structure that the carboxysomes cling too, but an oscillating wave, ping-ponging back and forth down the length of the bacteria. As the wave moves through the cell parA makes sure that the carboxysomes are evenly spaced along the whole axis. In other species of bacteria, this skeleton wave can control the even spacing of genetic material along the length of the cell or keeps proteins associated with the tips of rod-shaped bacteria where they belong. You can see the wave traveling through the cell in the second video, where the carboxysomes are labeled in red and the wave protein in green.

With a deeper understanding of the cell biology of the carboxysomes and how they are controlled in the cell, as well as the genetic tools that Bruno and Dave developed for putting the fluorescent proteins into the photosynthetic bacteria, synthetic biologists in our lab and others will be better poised to engineer the carboxysomes for any number of synthetic purposes, to design novel bacterial micro-factories.

In The Guardian article, plant scientist Eoin Lettice points out that most of the genetically modified (GM) plants brought to market today primarily benefit giant multinational corporations rather than the consumer. Tomatoes designed to last longer during long-distance shipment end up tasteless and mealy, and the most common genetically modified foods are designed to be resistant to the weed killer that Monsanto produces, the chemicals in which may actually contribute to health problems (although the numbers in the one study are worst than shaky and a lot more work needs to be done). Moreover, Monsanto and other GM producing corporations aggressively patent their products, holding back research in plant science by not allowing university researchers to use naturally occurring plant gene regulatory sequences that they have patented, and forcing small farmers around the world out of business. Government delays in approving the use of GM products cause a lot of problems for these corporations, and it is in their best interest to make their products seem natural and good and their opponents seem crazy and stupid. Lettice puts it well when he writes:

Perhaps I'm being presumptuous, but I can't imagine many Irish or European consumers lying awake at night worrying about lost revenues for [the German chemical company] BASF. What Irish consumers are interested in, however, are real and tangible benefits from their foods.

Attitudes are also changing at Western agribusinesses, some of which used to dismiss poor farmers as mere "seed pirates". As developing countries develop GM crops of their own, these firms are now pursuing public-private partnerships or joint ventures with local firms and otherwise softening their stance. Monsanto, a hard-nosed pioneer of transgenic crops, is donating its drought-resistant technology to a coalition called Water Efficient Maize for Africa, for example.

Bacteria themselves are much smaller and much simpler cells, performing many of the same cellular functions without the spatial organization of organelles, all the cell's enzymes and genetic material are instead floating freely in the cell. Some types of bacteria, however, do have compartments that have specialized functions, separating certain enzymatic activities from the rest of the cytoplasm. These compartments are surrounded by a protein shell, not a membrane, so they aren't technically organelles, but they're still pretty amazing.

Many species of photosynthetic bacteria (the precursor to the chloroplast organelle that makes plants photosynthetic) have protein-bound compartments that separate the carbon dioxide capturing machinery from the rest of the cell, called carboxysomes. The enzyme that captures the carbon dioxide and turns its carbon atoms into chemical forms that the cell can use is called RuBisCO and it kind of sucks. Every carbon atom in a photosynthetic cell comes from this enzyme's function, but the reaction happens much much slower than most enzymatic reactions and if there's too much oxygen around it doesn't happen at all. In the carboxysome, RuBisCO is so tightly packed that oxygen can barely fit through the cracks, and the high concentration of the enzyme can help to overcome some of the inefficiency of the reaction. The carboxysome protein shell is made up of interconnecting proteins shaped like hexagons and pentagons that link together to form a complex polygon, kind of like a soccer ball.

This soccer-ball protein geometry is also used by some species of viruses to form a protective shell. Some carboxysomes have a geometry that is more complex than the standard icosahedral viral capsid, indicating that carboxysomes may have not actually originated from the same common ancestor as the virus, but that their similarity is the result of convergent evolution. However, the question of whether carboxysomes are the result of endosymbiosis between bacteria and viruses that have evolved over billions of years is still open. This matryoshka doll concept of evolution and cellular substructure, with animal cells housing bacteria housing viruses is wonderful and fascinating, pointing to a rich diversity of interspecies cooperation in nature.

There's still a lot that we don't know about carboxysomes, and there's a lot of active research going on in my lab about how carboxysomes are formed and controlled inside of photosynthetic cells, with the goal of being able to engineer special protein substructures inside any bacterial cell. Stay tuned for more on that shortly!

We designed a metabolic circuit in bacteria that produces hydrogen (a potentially useful fuel) from natural precursors in the cell. The proteins in our synthetic pathway work to make hydrogen by transferring high-energy electrons from pyruvate, a common metabolite, to protons that are freely floating in the watery cytoplasm. The electrons transfer between the proteins through quantum-mechanical tunneling, which makes hydrogenases and other electron transferring proteins some of the craziest enzymes ever.

This tunneling happens so fast once two electron carrying proteins (of which there are many different types in the cell) hit each other, that it's difficult to make sure that all of the electrons from the original metabolite are getting to hydrogen. While sometimes the analogy between synthetic biology and electronics can be a bit tricky, in this case we really have to "insulate" the "wires" that are transferring electrons by preventing them from connecting to other "wires" and "shorting" the "circuit" (sorry to go overboard with the quotation marks but you get the idea). We tested a bunch of different biological methods to insulate the pathway, and all of them made small but significant improvements in the amount of hydrogen that we could produce. These methods can be used not only to optimize the amounts of hydrogen that we can make biologically, but can be applied to many other synthetic biology circuits that use electron transfer to get things done.

Lyrics after the jump!

Muldoon: What about the lysine contingency? We could put that into effect!

Dr. Ellie Sattler: What's that?

John Hammond: It is absolutely out of the question.

Ray Arnold: The lysine contingency - it's intended to prevent the spread of the animals is case they ever got off the island. Dr. Wu inserted a gene that makes a single faulty enzyme in protein metabolism. The animals can't manufacture the amino acid lysine. Unless they're continually supplied with lysine by us, they'll slip into a coma and die.

Dr. Ellie Sattler: How could we cut off the lysine?

Ray Arnold: No real trick to it. Just stop running the program, leaving them unattended.

I argued that organisms engineered with alternate genetic codes, who need an external source of unnatural amino acids in order to survive, would not be able to survive in the wild where these unnatural amino acids do not exist, just like the "lysine contingency" in Jurassic Park. Of course, humans can't make their own lysine either, requiring it in our diet in order to survive (this is why it is an essential amino acid), and thank goodness lysine is everywhere in the environment, in the proteins of the plants and animals that we eat. In the case of unnatural amino acids it is possible to design chemicals that don't exist in nature, and molecules that cannot be made enzymatically. While it may be possible that in many many millions of years a biological pathway could evolve to create such an unnatural amino acid, it is vastly more likely that the escaped synthetic bacteria will have died first, its atoms scavenged by other micro-organisms that can't even read its DNA. Moreover, the mutations introduced are small, incremental changes to protein structures that better allow us to understand how proteins work rather than give the cells any vastly new behavior. In many respects, the products of synthetic biology are almost identical to natural cells. We shouldn't bush off concerns over safety with eye-rolling, but we also shouldn't let unrealistic fear take over either. What do you think?

But what if instead of mutating individual tRNAs, you could make a whole parallel genetic code in a living cell? An awesome paper in this week's Nature makes progress towards this goal, by using directed evolution to design a ribosome that reads four letter codons instead of the normal three. With a four letter code, you could potentially program 256 different amino acids, to create altered proteins or entirely different biological polymers. For a lot more detail on how the researchers went about "reprogramming the code of life" check out the webcast of a presentation by the senior author, Jason Chin.

Expanding the genetic code to include unnatural biological building blocks is an interesting problem for synthetic biology. Most synthetic biologists aim to recombine natural systems in unnatural ways, making new connections between existing or slightly modified proteins to create a new function. Using different chemical building blocks has the potential to create totally new chemistries with fascinating implications for how we understand and use living systems. An editorial in the most recent issue of New Scientist addresses some of the typical concerns that arise with any new synthetic biology technology:

This is a fundamental advance that could lead to new drugs, materials and energy sources. But tampering with life's operating system will inevitably raise safety concerns - and it's true that we have no way of predicting the fallout of this work. Synthetic biologists need to confront openly and honestly public fears that they are "playing God". If such deeply felt concerns go unanswered, the huge potential of this breakthrough could come to naught.

In many ways, the use of unnatural nucleotides and amino acids in laboratory strains of bacteria has the potential to actually create safer synthetic systems. Unnatural amino acids have to be chemically synthesized and supplied to the cell in the growth medium, thus preventing the cells from being able to grow in the wild if they were to escape. More importantly, wild-type cells would be unable to "read" the synthetic genes in a cell with an expanded genetic code, so any gene transfer between engineered cells and natural cells would make protein "gibberish" (most random protein sequences don't actually fold in the cell, and thus would not lead to any new function). Instead of simply relying on the hand wave-y argument of "lab strains are already probably unfit for survival in the wild", these sorts of "failsafe" systems may soon be feasible to ensure environmental health and safety for all new biological designs.

(via New Scientist)

David Benqué, a student in the Design Interactions program at the Royal College of Art in London, explores using hypothetical genetically engineered plants to create an acoustic sound garden. Bugs engineered to chew specially designed nuts in rhythm, whistling termites, lilly pad speakers, and popping seed pods populate this imaginary garden.

This Acoustic Botany is fascinating in terms of synthetic biology, rethinking and expanding the potential scope of genetic design, as well as having implications for how we think about natural ecologies of sound. As Nick writes over at Noise For Airports:

Primarily, this seems like a very interesting way to create an opposing form of acoustic ecology. Most work in acoustic ecology is about reducing human sonic influence in nature, and protecting "natural" soundscapes. Genetic engineering (or at least the implausibly specific and sonic version Benqué describes) offers another way to get into nature's sounds and alter the soundscape.

(via we-make-money-not-art, via Noise For Airports)

You would think that yeast, being so single celled and bread-y, wouldn't be able to tell us much about human biology or anything as complex as aging, but many of the cellular processes that happen in our cells exist in yeast, and it's a lot easier to study yeast than it is to study humans (you certainly couldn't make a "daughter arrester" in humans). A lot about what we know about how cell growth is controlled (with huge implications for our understanding of cancer) comes from studies done in yeast, and more recently yeast has emerged as a useful model system for understanding mechanisms of cellular aging.

Saccharomyces cerevisiae is known as budding yeast, meaning that when it multiplies it doesn't split in half like many other asexual organisms, but rather that a new cell "buds" off of the old one. The "mother" cell will keep budding off more "daughters", which will themselves become mothers when they get large enough. A mother cell can only bud off so many times, however, before it starts to slow down, age, and eventually die. The mechanisms controlling this aging process are not well understood. Why can't the cell divide indefinitely? Is the aging "programmed" in the DNA or is it something else, like oxidative stress from metabolism? Can it be reversed or slowed down? It's difficult to study only older cells in a mixed culture of yeast, with millions of cells swirling around and budding constantly. Synthetic biology devices like the daughter arrester can therefore be useful for basic science research of aging by quickly isolating a population of aged cells for further study and characterization. As an engineered device, the daughter arrester can also be incorporated as one component in a more complex synthetic system where control of cell growth and death are necessary.

The game's plot is based on Atlas Shrugged; the underwater city was built by exiled creative geniuses frustrated with the repressive political, economic, and religious authority of the post-WWII time period. For a neat and uniquely overthought analysis of the comparison between the plot of Ayn Rand's novel and BioShock, check out OverthinkingIt, a blog written by some of my very smart friends.

Many people have discussed the politics, game design, and artistry of BioShock, but I find the scientific aspects to be fascinating. Much of the gameplay is focused around collecting and using different combinations of biological technologies. Your character must not only pick up guns and grenades and other traditional first-person-shooter weaponry, but must also collect ADAM and inject himself with specially designed plasmids found in vending machines that give him different super-human capabilities in fights against the Splicers and Big Daddies.

The biology of the BioShock world is clearly absurd--genetic engineering will never allow a person to shoot swarms of live bees or lightning strong enough to stop a Big Daddy out of their fingertips--but the biopolitics suggested by the storyline are compelling and important to consider as synthetic biology moves forward. Rapture is in shambles after a violent civil war fueled by the scarcity of ADAM and the subsequent stratification of the supposedly ideal underwater society into those who could afford the new genetic products and those who couldn't. There are obviously many ethical considerations before we start genetically engineering humans, "designing our own offspring" (perhaps too many to even try it), but one of the most important issues that emerges is that of class: Who will be able to afford genetically engineered children? What will happen to those who can't? Will genetic engineering technologies exacerbate class conflicts or be used to improve lives in developing countries and thus level the playing field? Will our future look like Gattaca or BioShock, or something else entirely (we can only hope that it's the latter)? Who gets to decide?

The science fiction stories told in BioShock may not be an accurate picture of feasible synthetic biological products and a future where they are deployed, but by addressing these questions they provide an interesting perspective on a conversation that too often focuses on very narrow (very white, middle class, male, American?) definitions of "safety", "security", and "progress." There's a lot to think and talk about, but I'm definitely looking forward to playing BioShock2 and having nightmares of shrieking hyper-fast zombie mutants chasing me.

Analyzing the history of a technology requires a complex look at the social, economic, and political context in which it emerged, and the reciprocal influences that the developing technology exerts on these factors. Predicting what the future of a technology will be like, how it will affect the economy and understanding the potential risks and payoffs is much much harder. Rob Carlson's new book, Biology is Technology: The Promise, Peril, and New Business of Engineering Life takes on this challenge, looking at the recent history and potential future of synthetic biology and biological engineering from the perspective of a biotech entrepreneur, discussing the science, the economics, and the politics of this emerging technology. Through a series of case studies, the book highlights many of the difficult contradictions inherent in the development of biological technologies.

Biology is becoming easier to work with every day, enabling high school students and other non-experts to do work that was only accessible by elite level scientists only a few years ago. This democratization of science is seen by scientists and the general public as both a positive development and a potential threat. Having more people interested in and participating in biology will undoubtedly push the boundaries of our knowledge and our ability to engineer cells, but will also increases the likelihood of accidental or intentional release of dangerous pathogens or toxins. While describing how easy it has become to engineer biology in one's garage, Carlson also claims that the perceived threat opened up by easy access biological technologies is minimal, because it is still very hard to actually make any changes to genomes, especially to make something more dangerous than it already is. Carlson argues that further improvement of biological technologies is necessary to combat first and foremost natural pandemics--"nature is the bioterrorist"--as well as the possible emergence of synthetic threats from accidental release of biotech products or intentional malicious design of new pathogens, however unlikely they may be. This contradictory stance--biology is easy for me but too hard for terrorists--is common in the synthetic biology community that seeks to hype technological gains while minimizing the perception of risks.

The bright future of synthetic biology is described in terms of the trajectory of technological progress in other fields, extrapolated to reflect the likely development of future biological technologies. Carlson argues that progress in biological technologies will likely follow similar trajectories as aviation and computing in the twentieth century, following "technology lines" from dreams and tinkering, to mature direct design-to-build. Later in the book, however, Carlson warns about projecting the success of old technologies onto biotechnology. Biology isn't rocket science, and "we should be wary of inherited assumptions that the future of biological production will look like historical industrial production. Broadly distributed production using locally available feedstocks could fundamentally alter the way we think about logistics within our economy." Looking at the development of aviation and computers, two technologies that had a tremendous impact on the outcomes of the First and Second World Wars, respectively, may further complicate the extrapolation of technology lines. Carlson admits that "it is by no means clear that there can be a unified description of innovation or of the evolution of technolgy. Specific technologies arise in the context of history and the various social, economic, and political pressures of the day" (emphasis in original).

Given the difficulty of predicting the future of biological technology, what kind of scientific, economic, political, and social changes are needed to foster true innovation in biotechnology? As a small-scale "garage" entrepreneur working to design and market a "tool that provides a new quantitative capability in molecular biology", Carlson emphasizes the importance of having quantitative information about biological systems in order to adequately model new designs in a rigorous, predictive manner. Most current models of how biological systems work "lack quantitative predictive power, whereas engineering generally requires a framework of quantitative models based on quantitative experiments." Moreover, as a start-up entrepreneur, Carlson has a complicated relationship with the ideas of "open science", praising the efforts of the BioBricks Foundation, the Registry of Biological Parts, and iGEM for their emphasis on open access and free information, but is deliberately vague in describing his own work and bemoans the fact that much of the cost of developing a new product is in filing a patent. The book was finished before the announcement of the BioBricks Public Agreement and the BIOFAB, which are intended to provide a legal framework and a source of well-characterized, open-access parts for open synthetic biology, but many of the issues brought up in the book still remain. Can there be an open source science in parallel with large biotech companies with strong financial interests in new synthetic biology parts and devices? Do patents on biological technologies stifle or foster innovation? Will the biotech industry be structured like the computer industry, where small companies bring innovative new ideas to the market, but need the resources of much larger companies to develop the idea into a product and protect intellectual property? Will students, hackers, and hobbyists be able to contribute to biological technology the way that they contribute to software technology today?

The biggest question the book raised for me though was is biology really technology? In discussing Lawrence Lessig's belief that patents stifle creativity, Carlson writes: "These words are bold, provocative, and perhaps either offensive or inspiring, depending on the reader's point of view...But that is an argument to be made, not accepted outright." This is exactly how I feel about Carlson's assertion that biology is technology. Do we limit the power of biological systems by seeing them only in terms of human technologies? Are living things "special"? Do technologies "evolve"? Throughout the book the language used to describe biological systems is that of design, intent, purpose, and appropriation, while technology is described as progressing inevitably, outside of the control of human intent, literally evolving by natural selection. This is a dangerous view, one that privileges technological "progress" as special, revolutionary, and uncontrollable, while defining the control and appropriation of biology as "natural". Indeed Carlson goes so far as to make the bold and provocative statement that "Biological technologies in human hands are value neutral--neither intrinsically good nor bad--because the technologies that humans use are often adopted or adapted from nature rather than invented." For a book called Biology is Technology Carlson spends very little time making arguments for this controversial point, and I have to say, I'm not convinced.

There's a fun video of Karmella talking about her work on synthetic biology devices to track cancer cells and about careers in science streaming on the Teachers' Domain website. You should all check it out, she's an incredible scientist, artist, and teacher--a true inspiration!