A three-dimensional covalent organic framework (COF-505) constructed from helical organic threads, designed to be mutually weaving at regular intervals, has been synthesized by imine condensation reactions of aldehyde functionalized copper(I)-bisphenanthroline tetrafluoroborate, Cu(PDB)2(BF4), and benzidine (BZ). The copper centers are topologically independent of the weaving within the COF structure and serve as templates for bringing the threads into a woven pattern rather than the more commonly observed parallel arrangement. The copper(I) ions can be reversibly removed and added without loss of the COF structure, for which a tenfold increase in elasticity accompanies its demetalation. The threads in COF-505 have many degrees of freedom for enormous deviations to take place between them, throughout the material, without undoing the weaving of the overall structure.
In this third part of our review of 2015, sourced from synthetic biology community, we cover five aspects that relate to developments in automation and commercialization. Synbio is booming, a 2014 report estimated the market could be worth $38 billion by 2020. The responses we received reflected the excitement within the community, but they also highlighted some of the challenges that must be addressed in order to prevent the bubble bursting.
Graves' disease is an autoimmune disorder that causes hyperthyroidism because of autoantibodies that bind to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, triggering thyroid hormone release. The physiological control of thyroid hormone homeostasis by the feedback loops involving the hypothalamus-pituitary-thyroid axis is disrupted by these stimulating autoantibodies. To reset the endogenous thyrotrophic feedback control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis by monitoring thyroid hormone levels and coordinating the expression of a thyroid-stimulating hormone receptor antagonist (TSHAntag), which competitively inhibits the binding of thyroid-stimulating hormone or the human autoantibody to TSHR. This synthetic control device consists of a synthetic thyroid-sensing receptor (TSR), a yeast Gal4 protein/human thyroid receptor-α fusion, which reversibly triggers expression of the TSHAntag gene from TSR-dependent promoters. In hyperthyroid mice, this synthetic circuit sensed pathological thyroid hormone levels and restored the thyrotrophic feedback control of the hypothalamus-pituitary-thyroid axis to euthyroid hormone levels. Therapeutic plug and play gene circuits that restore physiological feedback control in metabolic disorders foster advanced gene- and cell-based therapies.
Complex biomedical analyses require the use of multiple software tools in concert and remain challenging for much of the biomedical research community. We introduce GenomeSpace (http://www.genomespace.org), a cloud-based, cooperative community resource that currently supports the streamlined interaction of 20 bioinformatics tools and data resources. To facilitate integrative analysis by non-programmers, it offers a growing set of 'recipes', short workflows to guide investigators through high-utility analysis tasks.
Since the 1980s, scientists have worked on designing genetic codes to reinforce containment and control of genetically engineered microbes. New mechanistic studies of “deadman” and “passcode” gene circuits provide a flexible platform to build new safety switches.
On July 16-17th 2015 scientists from around the world will convene in New York City at the New York Genome Center to discuss progress in synthetic yeast genome engineering as well as a broader discussion of other genome engineering efforts,...
London designer and researcher Shamees Aden is developing a concept for running shoes that would be 3D-printed from synthetic biological material and could repair themselves overnight – It would react to pressure and movement created when running,...
Can the powerful gene-editing tool CRISPR help cure diseases? Drug companies are racing to find out.
A recently announced $300 million joint venture between Bayer AG and startup CRISPR Therapeutics—to develop new drugs for blood disorders, blindness, and congenital heart disease—is just the latest indication that the pharmaceutical industry is eager to find and develop new cures using CRISPR. But it’s far too early to grasp the full potential for CRISPR-based therapeutics, and much of the near-term focus will be on developing ways to deliver the gene-editing system to specific targets in the body.
CRISPR Therapeutics is one of three high-profile startups—the others being Editas Medicine and Intellia Therapeutics—aiming to use CRISPR to engineer new cures. All three are collaborating with or have garnered investments from larger drug-making companies, and the dealings over the past year have revealed broad disease areas where drugmakers see opportunities for applying the new tool.
In the near-term, CRISPR is attractive for use in experimental therapies for certain genetic diseases or cancers. These therapies entail removing cells from the body, modifying their DNA, and reintroducing them. But all three companies are also intent on developing technologies for delivering CRISPR to cells in the body without having to remove them—a substantially more complicated challenge which if met would open the door to a much broader range of potential therapies.
One major objective of Bayer’s joint venture with CRISPR Therapeutics will be to develop new delivery technologies which will be “critical” to future drugs meant to target cells inside the body, says Rodger Novak, CEO of CRISPR Therapeutics. It’s not a small challenge. To work, the drug first has to find the right organ or tissue. Once it’s there it must deliver the payload into the right cells in a safe way.
“The ultimate need” of any of the players trying to make CRISPR drugs is for technologies that can increase CRISPR’s specificity, so that it edits only the target DNA sequence, says Axel Bouchon, head of Bayer’s newly launched LifeScience Center, who will lead the joint venture. The basis of CRISPR technology is a biological system some bacteria use to remove unwanted viral DNA sequences (see “Genome Surgery”). One of the molecules that locates and cuts the DNA has evolved to be somewhat nonspecific so it can be flexible enough to address a range of different viruses, says Bouchon.
That’s not a problem for some applications involving engineering cells outside the body, or ex vivo, says Bouchon. “If you want to go in vivo you have to make sure that it is highly specific” to the targeted sequence, he says. He says Bayer holds proprietary technology as well as the in-house expertise needed to achieve that specificity.
Once the system is specific enough, there could be several ways to get it into the right cells, such as by using viral vectors or nanoparticles. Delivering it to the right tissue might be as simple as licensing a syringe for injecting into the eyeball, or a stent for delivering the drug to the heart, says Bouchon. But none of the players trying to make CRISPR drugs have yet been able tackle all three challenges—delivering the drug to the tissue, the cells, and ultimately to the target sequence with the necessary specificity, he says.
Bayer is a leader in treating certain genetic diseases of the blood, including the clotting disorder hemophilia, and Bouchon says the shortest route to developing a CRISPR drug may be in the treatment of a portion of those diseases that could be treated ex vivo. Treating the other disorders will require delivering a drug to cells in the liver, but that requires a “huge step,” says Bouchon.
Treating genetic eye disorders is another attractive near-term application because the eye is less susceptible to immune reactions, and because some methods for injection into the eye are well established (see “CRISPR Gene Editing to be Tested on People by 2017, Says Editas”). A CRISPR-based drug for congenital heart disease, meanwhile, is a “moonshot” idea, says Bouchon. Delivering CRISPR to the right cells in the heart, or in other similarly complex organ systems, presents challenges that will likely take more than a decade to solve, cautions Novak.
Indeed, though the technology “will be game-changing for medicine,” says Novak, “these are really early days.”
Successful synthetic biology efforts rely on conceptual and experimental designs in combination with testing of multi-gene constructs. Despite recent progresses, several limitations still hinder the ability to flexibly assemble and collectively share different types of DNA segments. Here, we describe an advanced system for joining DNA fragments from a universal library that automatically maintains open reading frames (ORFs) and does not require linkers, adaptors, sequence homology, amplification or mutation (domestication) of fragments in order to work properly. This system, which is enhanced by a unique buffer formulation, provides unforeseen capabilities for testing, and sharing, complex multi-gene circuitry assembled from different DNA fragments.
A versatile technique for editing genomes has been called the biggest biotechnology advance since the polymerase chain reaction (PCR), and the US Patent and Trademark Office (USPTO) is set to determine who will reap the rewards.
On 11 January, the USPTO granted a request to review a key patent awarded for the technique, known as CRISPR–Cas9. The outcome of the ensuing proceedings, called a patent interference, could be worth millions to the research institutions that are at war over the relevant patents. It might also influence who is allowed to use the technology — and under what terms.
“This is an absolutely humungous biotech patent dispute,” says legal scholar Jacob Sherkow of New York Law School. “We’re all waiting with bated breath.”
On January 14, Eric S. Lander published an article in the journal Cell celebrating the “heroes” of CRISPR-Cas9, a revolutionary DNA-editing technology that may be the most important genetic engineering development in decades.
“It’s hard to recall a revolution that has swept biology more swiftly than CRISPR,” Lander, a biologist at MIT and Harvard’s Broad Institute, wrote, noting that, although nearly every molecular biologist is familiar with the technology that allows scientists to easily disable or change the function of genes, they are likely unfamiliar with the manpower that went into its discovery.
“Yet, the human stories behind scientific advances can teach us a lot about the miraculous ecosystem that drives biomedical progress,” he continued, “about the roles of serendipity and planning, of pure curiosity and practical application, of hypothesis-free and hypothesis-driven science, of individuals and teams, and of fresh perspectives and deep expertise.”
Programmed connection of amino acids or nucleotides into chains introduced a revolution in control of biological function. Reacting proteins together is more complex because of the number of reactive groups and delicate stability. Here we achieved sequence-programmed irreversible connection of protein units, forming polyprotein teams by sequential amidation and transamidation. SpyTag peptide is engineered to spontaneously form an isopeptide bond with SpyCatcher protein. By engineering the adhesin RrgA from Streptococcus pneumoniae, we developed the peptide SnoopTag, which formed a spontaneous isopeptide bond to its protein partner SnoopCatcher with >99% yield and no cross-reaction to SpyTag/SpyCatcher. Solid-phase attachment followed by sequential SpyTag or SnoopTag reaction between building-blocks enabled iterative extension. Linear, branched, and combinatorial polyproteins were synthesized, identifying optimal combinations of ligands against death receptors and growth factor receptors for cancer cell death signal activation. This simple and modular route to programmable "polyproteams" should enable exploration of a new area of biological space.
Davos 2016: Given that living matter can now be designed as the built environment, not for it, we need to advance a new kind of ecology where assemblies and mono-materials are eschewed in favor of multivalent wholes: a Material Ecology.
The intersection of design and synthetic biology is a powerful new direction of research and practice. Four early advocates and pioneers of what Ginsberg cal...
Synthetic biology offers possibilities of writing new DNA sequences and building biological components that are drawing even artists and designers to it. The field, however, is riven with ethical questions
The White Queen’s reply to Alice’s “one can’t believe impossible things” is one of the more popular quotes from the 19th century classic, Through the Looking-Glass. With imperious hauteur, she tells Alice, “I daresay you haven’t had much practice…Why, sometimes I’ve believed as many as six impossible things before breakfast.”
A new type of genetic circuit implanted in mice can treat psoriasis, an inflammatory skin disease.
Gene circuits created in the past typically monitored only whether a metabolic molecule A was present in their environment; if so, they produced a metabolic molecule X as a response. The new, more complex circuit can detect two molecules, A and B, simultaneously, and only if both are present does it produce the molecules X and Y.
“We have used cellular components to build an AND logic gate, as is familiar in electronics and without which computers could not function,” says Martin Fussenegger, a professor at ETH Zurich who led the project.
When researchers implanted a circuit with an AND gate of this kind into mice, the circuit was able to successfully suppress phases of psoriasis in the mouse model.
Fussenegger calls them molecular prosthetics: cells with specially developed gene circuits that can be implanted into an organism, where they take over metabolic functions that the organism cannot perform itself.
The new molecular prosthesis uses the language by which immune cells in the body communicate with one another: the language of the numerous messenger molecules that the immune cells can both produce and detect.
As the design of synthetic circuits and metabolic networks becomes more complex it is often difficult to know a priori which parameters and design choices will result in a desired phenotype. To counter this, rational design can be complemented by library-based approaches where diversity is introduced and then coupled with screening or selection methods. Here, we used a model of competitive growth to show that selection can rapidly identify library variants with near-optimal phenotypes. Many synthetic biology applications require phenotypes that balance multiple objectives, such as responding to more than one chemical signal. In addition, desired traits may be time-dependent, for example changing with the growth phase. By applying dynamic inputs to the selection, we show that it is possible to select for traits that satisfy multiple goals. Furthermore, we demonstrate that the underlying diversity in a library is heavily influenced by the initial circuit design. Overall, our findings argue that rational synthetic circuit design, coupled with diversity generation and dynamic selection are powerful tools for many synthetic biology applications.
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