SynBioFromLeukipposInstitute

Eukaryotic microalgae are an incredibly diverse group of organisms whose sole unifying feature is their ability to photosynthesize. They are known for producing a range of potent toxins, which can build up during harmful algal blooms causing damage to ecosystems and fisheries. Genome sequencing is lagging behind in these organisms because of their genetic complexity, but transcriptome sequencing is beginning to make up for this deficit. As more sequence data becomes available, it is apparent that eukaryotic microalgae possess a range of complex natural product biosynthesis capabilities. Some of the genes concerned are responsible for the biosynthesis of known toxins, but there are many more for which we do not know the products. Bioinformatic and analytical techniques have been developed for natural product discovery in bacteria and these approaches can be used to extract information about the products synthesized by algae. Recent analyses suggest that eukaryotic microalgae produce many complex natural products that remain to be discovered.

Natural medicines, made to order in space

An MIT spinout, Synlogic, is aiming to create a new class of medicines, by re-programming bacteria found in the gut as “living therapeutics.”
Based on research by its co-founders, MIT professors Tim Lu and Jim Collins, Synlogic creates so-called synthetic biotics, which sense and correct metabolic abnormalities that underlie some major diseases and rare genetic disorders.  
Human intestines are filled with trillions of bacteria, collectively called the microbiota, that carry out vital health functions. Synlogic’s synthetic biotics — capsules, liquid suspensions, or other dosage forms that can be taken regularly — augment the microbiota with new metabolic capabilities or complement lost functionality in organs such as the liver.
“Over the past decade or so, the intricate connections between microbes and our bodies have become clearer and clearer, and it’s well known now that the bacteria that live in our gut have a major influence on human health,” says Lu, an associate professor of electrical engineering and computer science and of biological engineering, and head of MIT’s Synthetic Biology Group, who serves as scientific advisor for Synlogic. “We leverage that interface as a way of treating human disease.”
Last month, Synlogic raised an additional $40 million in venture capital and secured its first industry partnership with pharmaceutical giant AbbVie. For the partnership, Synlogic will collaborate with AbbVie to develop synthetic biotics for the potential treatment of inflammatory bowel disease, which may include probiotic microbes programmed to detect intestinal inflammation, and produce anti-inflammatory molecules or break down pro-inflammatory effectors.
Two of Synlogic’s main candidate drugs, expected to enter clinical trials during the next 12 months, treat rare genetic metabolic disorders. One drug candidate is for treating urea cycle disorder (UCD), which is caused by an enzyme deficiency that leads to a buildup of toxic ammonia in the blood. The other is for treating phenylketonuria (PKU), which involves a dangerous excess of the amino acid phenylalanine due to a mutation in another metabolic enzyme. In both cases, Synlogic’s drugs process and flush out the toxic metabolites from the body.
Think of Synlogic’s drugs like biological thermostats, says Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Department of Biological Engineering and Institute for Medical Engineering and Science, who also chairs Synlogic’s scientific advisory board. Instead of identifying and regulating the temperature of a room, he says, “The synthetic biotics detect and regulate the amount of an enzyme or metabolic byproduct in a patient’s body.”
Programming E. coli
For more than a decade at Boston University and MIT, Collins and Lu (who is Collins’ former student) have been developing “genetic circuits” for bacteria, which include on/off switches made with synthetic DNA or RNA sequences that instruct the bacteria to count, store memory, and even perform logic.
Collins and Lu have used these genetic circuits to program bacteria to seek and cure infection. In 2011, this approach earned Collins funding from the Bill and Melinda Gates Foundation to engineer bacteria to detect cholera and produce targeted antimicrobial peptides to treat it.
A few years ago, Lu and Collins, along with several venture capitalists, launched Synlogic to focus on commercializing “a new class of therapeutics based on living cells,” Collins says. In 2014, Synlogic came out of stealth mode, securing $30 million in funding from venture firms and the Gates Foundation.
Since then, Synlogic has worked primarily on programming E. coli Nissle, a strain of bacteria derived from the gut that is also used widely and safely as a probiotic. The programmed E. coli Nissle, Lu says, provides greater precision, safety, and efficacy for disease treatment, compared with traditional methods.
For inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, for instance, current treatments include small-molecule drugs or antibodies with anti-inflammatory properties. But the challenge is getting the right dosage, Lu says. “If you apply too little, it’s not going to work. If you apply too much, you have a chance you may immunosuppress the patient and cause side effects,” he says.
Synlogic can “program microbes to detect inflammation and make anti-inflammation molecules at the site of inflammation, as well as produce molecules that positively impact immune system function,” Collins says.
Then there’s the more rare but debilitating urea cycle disorder, which affects 2,000 to 6,000 people in the United States and impairs their ability to processes ammonia. If ammonia builds up too much and reaches the brain, it can lead to brain damage, coma, and death. The best available treatment option for people with UCD today is a liver transplant.
Synlogic aims to treat UCD with a daily biotic that functions in a surprising way: “It can decrease the ammonia in the bloodstream, without even contacting the blood,” Lu says.
Ammonia levels in the bloodstream, he explains, are dependent on ammonia production in the large intestine. Synlogic’s biotic converts intestinal ammonia into an amino acid, which is flushed out of the body through the stool, thereby dramatically reducing the flow of ammonia to the blood and reducing ammonia levels in the bloodstream.
Synlogic’s biotic for PKU, which affects 13,000 people in the United States, functions in a similar way, to regulate the processing and extraction of phenylalanine. PKU patients must adhere to a lifelong, extremely low-protein diet that can result in serious developmental disorders, because they can’t eat normal foods that contain phenylalanine — including many meat, dairy, and seafood products. “If we can degrade phenylalanine with convenient administration of this probiotic, that will change the course of this disease,” Lu says.
Collins says Synlogic has potential to treat many other rare genetic metabolic disorders. But the recent AbbVie deal, he says, also “opens up possibilities of using these microbes to produce biologics or other small molecules to treat a range of conditions.” These include cardiovascular disease and autoimmune, oncology, and central nervous system disorders, which have been linked to metabolic dysregulation. 
Reaching clinical efficacy
Part of the reason that probiotic treatments are not used for serious diseases is their lack of clinically validated efficacy. Synlogic, on the other hand, aims to overcome these efficacy issues with potent and precision-programmed synthetic biotics, Lu says.
For example, in engineering the safe and easily programmable E. coli Nissle, Synlogic engineers have designed the microbe to consume a massive amount of toxic metabolites. The E. coli Nissle strain that forms the basis of Synlogic’s UCD program, for instance, can consume orders of magnitude more ammonia than natural E. coli can, Lu says. “For this treatment to work for patients, you want the max performance you can squeeze out of any one of these biotics,” he says.
Based on their preclinical data, Synlogic’s treatments have the potential to reach “clinical levels” of efficacy not seen often in synthetic biology, says Collins: “Synlogic is programming these probiotic microbes to consume ammonia or phenylalanine for example, and they are reaching levels that are expected to be clinically meaningful, which is quite remarkable.”

Scientists at the University of Oxford have created synthetic tissues that possess functional properties controlled by light — including the ability to “switch on” the expression of individual genes.

Made up of hundreds of interacting water droplets, these light-activated synthetic tissues could be developed into a platform to study how cells interact, for drug delivery, or even to control living tissues.

The work has demonstrated that it is possible to create synthetic tissues that comprise patterned networks of interconnected compartments, each with a minimal cellular functionality that can be externally controlled by light.

The big news this past week was something so significant and remarkable that it should have been the topic of conversation at every water cooler everywhere. While Microsoft’s AI bot tweeted out racial insults to anyone that would listen, and the circus of U.S. presidential election candidates exchanged even more schoolyard insults, a genius named Craig Venter managed to create a synthetic cell with the smallest genome of any known, independent organism. After 20 years of research, Mr. Venter created an entire new species that we can build upon to create cells that produce drugs, biofuels, chemicals, and anything else we can dream of.
So how is this different from back in 2010 when Mr. Venter first created a synthetic life form? The difference is that when this first synthetic life form was created, it simply involved inserting an existing bacterial genome into another cell. This resulted in a truly artificial life form but one that was still very complex. Since then, Venter’s team has been deactivating genes one by one to see which genes were required for life to exist. Notice how this involves adding and subtracting genes, not editing them.
Gene is a segment or a portion of DNA molecule while genome is the total DNA content in a cell.
Venter used a bacteria called “mycoplasma mycoides” that exists in the stomachs of vegetarian mammals like cows or goats. By adding and subtracting genes from their target genome for this bacteria, Venter was able to isolate the minimum number of genes required for life to still exist which turns out to be 473 genes. This is a remarkable feat and should cause us to ask, how can we invest in this technology? This particular type of technology is called synthetic biology and we’ve compiled a list of 7 Synthetic Biology Stocks that you can invest in. However, just one of these 7 stocks is the company founded by Mr. Venter himself; Intrexon (NYSE:XON). If you want to invest in the genius behind this recent achievement, buy stock in XON. It’s up just 20% from their IPO in August 2013:

Almost ten years ago, Freeman Dyson ventured a wild forecast:  “I predict that the domestication of biotechnology will dominate our lives during the next fifty years at least as much... read more

All the baby pictures, financial transactions, funny cat videos, and email messages that we hoard often require technology companies to build sprawling data centers.

A new technique could shrink the space needed to store digital data that today would fill a Walmart supercenter down to the size of a sugar cube.

The team of computer scientists and electrical engineers has detailed one of the first complete systems to encode, store, and retrieve digital data using DNA molecules, which can store information millions of times more compactly than current archival technologies.

THE DIGITAL DATA IS CHOPPED INTO PIECES AND STORED BY SYNTHESIZING A MASSIVE NUMBER OF TINY DNA MOLECULES, WHICH CAN BE DEHYDRATED OR OTHERWISE PRESERVED FOR LONG-TERM STORAGE.

In one experiment outlined in a paper presented in April at the ACM International Conference on Architectural Support for Programming Languages and Operating Systems, the team successfully encoded digital data from four image files into the nucleotide sequences of synthetic DNA snippets.

More significantly, they were also able to reverse that process—retrieving the correct sequences from a larger pool of DNA and reconstructing the images without losing a single byte of information.

The team has also encoded and retrieved data that authenticates archival video files from the University of Wsahington’s Voices from the Rwanda Tribunal project that contain interviews with judges, lawyers, and other personnel from the Rwandan war crime tribunal.

“Life has produced this fantastic molecule called DNA that efficiently stores all kinds of information about your genes and how a living system works—it’s very, very compact and very durable,” says coauthor Luis Ceze, associate professor of computer science and engineering at the University of Washington.

“We’re essentially repurposing it to store digital data—pictures, videos, documents—in a manageable way for hundreds or thousands of years.”

The digital universe—all the data contained in our computer files, historic archives, movies, photo collections, and the exploding volume of digital information collected by businesses and devices worldwide—is expected to hit 44 trillion gigabytes by 2020.

That’s a tenfold increase compared to 2013, and will represent enough data to fill more than six stacks of computer tablets stretching to the moon. While not all of that information needs to be saved, the world is producing data faster than the capacity to store it.

DNA ARCHIVES
DNA molecules can store information many millions of times more densely than existing technologies for digital storage—flash drives, hard drives, magnetic and optical media. Those systems also degrade after a few years or decades, while DNA can reliably preserve information for centuries. DNA is best suited for archival applications, rather than instances where files need to be accessed immediately.

[FASTER LASERS COULD REVEAL BETTER DATA STORAGE]

The team from the university’s Molecular Information Systems Lab in close collaboration with Microsoft Research, is developing a DNA-based storage system that it expects could address the world’s needs for archival storage.

First, the researchers developed a novel approach to convert the long strings of ones and zeroes in digital data into the four basic building blocks of DNA sequences—adenine, guanine, cytosine, and thymine.

“How you go from ones and zeroes to As, Gs, Cs, and Ts really matters because if you use a smart approach, you can make it very dense and you don’t get a lot of errors,” says coauthor Georg Seelig, an associate professor of electrical engineering and of computer science and engineering. “If you do it wrong, you get a lot of mistakes.”

The digital data is chopped into pieces and stored by synthesizing a massive number of tiny DNA molecules, which can be dehydrated or otherwise preserved for long-term storage.

RANDOM ACCESS
The University of Washington and Microsoft researchers are one of two teams nationwide that have also demonstrated the ability to perform “random access”—to identify and retrieve the correct sequences from this large pool of random DNA molecules, which is a task similar to reassembling one chapter of a story from a library of torn books.

To access the stored data later, the researchers also encode the equivalent of zip codes and street addresses into the DNA sequences. Using Polymerase Chain Reaction (PCR) techniques—commonly used in molecular biology—helps them more easily identify the zip codes they are looking for. Using DNA sequencing techniques, the researchers can then “read” the data and convert them back to a video, image, or document file by using the street addresses to reorder the data.

[TANTALUM SHOWS PROMISE FOR HIGH-DENSITY STORAGE]

Currently, the largest barrier to viable DNA storage is the cost and efficiency with which DNA can be synthesized (or manufactured) and sequenced (or read) on a large scale. But researchers say there’s no technical barrier to achieving those gains if the right incentives are in place.

Advances in DNA storage rely on techniques pioneered by the biotechnology industry, but also incorporate new expertise. The team’s encoding approach, for instance, borrows from error correction schemes commonly used in computer memory—which hadn’t been applied to DNA.

“This is an example where we’re borrowing something from nature—DNA—to store information. But we’re using something we know from computers—how to correct memory errors—and applying that back to nature,” says Ceze.

Microsoft Research, the National Science Foundation, and the David Notkin Endowed Graduate Fellowship funded the work.

Twist Bioscience Corporation, a company accelerating science and innovation through rapid, high-quality DNA synthesis, today announced the acquisition of Genome Compiler Corporation, an Israeli-based company providing software for genetic engineers, molecular and synthetic biologists. Twist Bioscience intends to leverage Genome Compiler's technology and expertise to drive a digital products portfolio, including an eCommerce solution with gene design capabilities, expected to be available in the second half of 2016.

"Twist's beta program is progressing well and our first customer shipments are underway," said Emily M. Leproust, Ph.D., CEO of Twist Bioscience. "Over the next few months we expect to scale our gene volume substantially, enabling us to offer market-leading production levels by this summer. We are delighted to bring the Genome Compiler technology, network and expert team into the Twist Bioscience organization. They are the leader in developing software that allows design of gene sequences for synthetic and molecular biology experiments. We intend to build an elegant, intuitive eCommerce solution with a deep pipeline of digital products to follow that will enable our customers to reimagine their research by providing seamless integration of the design and build of their synthetic DNA."

When the theoretical physicist Richard Feynman died, in early 1988, he left behind a maxim scrawled on the blackboard of his office at Caltech: “What I cannot create, I do not understand.” The words have been repeated often by scientists in many fields, but never so indelibly as when researchers at the J. Craig Venter Institute, in Rockville, Maryland, encoded them into the genome of a living organism, in 2010. Venter and his colleagues called their new entity syn1.0. It was a replica, with a few extra snippets of DNA thrown in, of Mycoplasma mycoides, a parasite that causes pneumonia in goats. Syn1.0 was the first human-engineered genome to be capable of controlling a cell, and Venter’s group used a custom alphabet of nucleotides to weave messages into it marking their own success. Revealingly but unintentionally, they mangled the Feynman quote, rendering it as “What I cannot build, I do not understand.”

Last week, in a paper published in the journal Science, Venter’s group unveiled the next step in their Feynmanian quest: syn3.0. For this edition of the parasite, their goal was to assemble as streamlined a new genome as possible. Humans have somewhere in the region of twenty-two thousand genes—more than a chicken, which has about seventeen thousand, but fewer than a grape, which boasts more than thirty thousand. Syn1.0, by comparison, had only nine hundred and one genes, and syn2.0 had five hundred and sixteen. By paring down their original synthetic genome even further, to four hundred and seventy-three, the researchers were able to produce what the Venter Institute’s Web site calls the world’s “first minimal synthetic bacterial cell.” Syn3.0 has the smallest genome of any self-replicating organism on Earth—that scientists are aware of, anyway—with “only the machinery necessary for independent life.” Within the discipline of synthetic biology, there seems to be little doubt that it represents an impressive achievement. Harvard’s George Church called it “a tour de force,” and Eugene Koonin, of the National Center for Biotechnology Information, described it as “quite a technical feat” and an “immensely satisfying development.”

But, in certain ways, syn3.0 must be classified as something other than a complete success. For a start, as Venter and his colleagues explain in their Science paper, they were able to build the genome but not, in Feynman’s words, create it. Their original designs failed to result in a viable cell. Instead, the researchers took syn1.0’s genome and reshuffled it, producing a lightweight variation on the original. At the same time, syn3.0 is not as minimal as it likely could be. It has fifty-two fewer genes than its nearest natural competitor, M. genitalium, a bacterium that infects the human urinary and genital tracts, but is still well above the theoretical lowest point. Koonin suspects that a truly minimal cell is something of an asymptotic target, one that synthetic biologists will edge closer and closer to, without ever actually reaching. Different creatures fulfill life’s essential functions differently, some with more brevity than others. Cherry-picking the best of each would be a Sisyphean task.

These issues aside, just how useful is Venter’s pursuit of minimalism? According to Christina Agapakis, the creative director of Ginkgo Bioworks, a bioengineering startup in Boston, the Institute’s techniques—particularly its gene-shuffling methods—will have important applications in the lab. But she was less convinced that, as Venter and his co-authors suggest in the Science paper, syn3.0 will reshape the biotechnology industry, which already relies on engineered microbes to produce everything from pharmaceuticals and food flavorings to detergent enzymes. “People have been doing industrial biotechnology for decades without a minimal cell,” Agapakis said. Yeast, for instance, has a larger genome than syn3.0, but it has been harnessed by humans for millennia, is well understood, requires little upkeep, can be grown at scale, and is relatively easy to genetically modify. It’s hard to imagine how syn3.0, which is raised on an expensive diet of cow parts within the cushy confines of a petri dish, could compete.

What it could do, however, is help scientists understand some of life’s most fundamental processes more completely. In 1996, when synthetic biology was in its infancy, Koonin wrote a paper in which he theorized that a cell with just two hundred and fifty-six genes, almost half as many as syn3.0, could be viable. Extrapolating backward from such a cell, he wrote, “may lead close to the origin of life itself,” shedding light on the nature of Earth’s last universal common ancestor—the simplest, most minimalistic organism, with none of the clutter of aeons of natural selection. In the past two decades, Koonin told me, Venter and others have done about as much extrapolating as is possible this way. But syn3.0 could still expand scientists’ knowledge of how existing organisms function. “Anyone who claims that she or he understands how a cell works is either ignorant or ridiculously arrogant,” Koonin said. “They don’t.”

Syn3.0 itself provides ample evidence of this: Venter’s group doesn’t know what nearly a third of its genes do. “Our main interest now is investigating those,” Hutchison said. For some of the mysterious genes, the researchers have a general sense of their purpose—removing toxins from the cell, for example—but not which chemicals are involved or why syn3.0 could possibly need six different ways of taking out the trash. For other genes, Hutchison said, “We don’t have a clue.” Answering that question will help demonstrate what functions are fundamental to life, if not how many genes they require.

One of the curious things about syn3.0 is that its stripped-down genome, although a marvel of human engineering, is poorly suited to life on Earth. It appears capable of all the essential functions, including reproduction, but it is already “en route to extinction,” Koonin said. Its wild counterpart, M. genitalium, has such a shrunken genome because it is far along what he called “a path of dependency”—as a parasite, it has outsourced many of its functions to its hosts, becoming less and less self-sufficient. It has lost genes in the process, leaving it vulnerable to the tiniest shifts in environmental context. “These particular organisms—they will not be on this planet for many hundreds of millions of years,” Koonin said. And yet, in its free-living state, even M. genitalium has some redundancies—non-essential genes that are, in fact, essential if the species is to mutate, evolve, and become capable of new behaviors. A minimal cell like syn3.0 is, by definition, doomed. Its DNA provides just enough information for a single organism to sustain its own life, but too little to insure the long-term survival of the species.

The American painter Ad Reinhardt, whose work had a major influence on the Minimalist movement, once wrote that “art begins with the getting-rid of nature.” Trying to engineer a minimal cell cannot help but run up against this dichotomy, which Agapakis summed up as the “conflict between the emergence of evolutionary novelty and the construction of designed novelty”—in other words, between the logic by which we seek to alter biology and the logic by which it alters itself. From this perspective, syn3.0’s relationship to life begins to resemble the relationship of Soylent to food. Both are facsimiles that serve mainly to show us the richness of the original.