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DNA Origami: 16 June 2017
- 1. DNA Origami and other bio-technologies By Ethan Sung
- 2. A brief history … ▪ Initially conceptualised by Nadrian Seeman in 1980s ▪ Envisioned three-dimensional structures formed from DNA ▪ Refined by Paul Rothemund from the California Institute of technology ▪ Uses 7000 bp M13 phage genome ▪ Allows far greater manipulation of DNA into a wider range of shapes ▪ Process refined in 2009 to create three dimensional structures
- 3. Applications to Drug Delivery ▪ Uses to deliver the Doxorubicin drug ▪ Treatment for cancer cells ▪ Created from M13 Phage DNA ▪ Resistant from immune system decomposition ▪ Effective in Human Cancer Cells
- 4. Nanorobots ▪ Detects cells through receptors ▪ Created using a program called Cadnano ▪ Highly specific ▪ Locked jewellery box technique ▪ Used for leukaemia treatment
- 5. Molecular Rulers and Fluorescence ▪ Used to create microscopic rulers ▪ Calibrates high resolution microscopes ▪ Fluorescent dye molecules used as tracers ▪ Chemical thermometers made from DNA
- 6. Gene Editing ▪ Used to deliver CRISPR-Cas 9 ▪ Deliver directly to cells ▪ Specifically targets genes ▪ Used to edit genome ▪ Larger delivery load
- 7. DNA Computing ▪ ‘Spider’ created using streptavidin & DNA legs ▪ More versatile than silicone computing ▪ Can perform the ‘travelling salesman problem’, an indicator of computationally ▪ Used in cockroaches in vivo
Editor's Notes
- The idea of DNA origami was initially conceptualised by Nadrian Seeman in the early 1980s from an M.C Escher illustration. This lead to him seeing the potential to apply DNA to a wider range of bio-chemical processes. This was intended to observe proteins using X-ray crystallography. From this, he created the DNA origami process, creating a microscopic cube from DNA, leading to him winning the 1995 Freynman Prize for Nanotechnology. This was limited, using only 150 base pairs to construct a relatively simple shape. This process was refined by Paul Rothemund of the California Institute of Technology, using the 7000 base pair M13 bacteriophage genome DNA to construct structures from anew. He was able to use the complementary base pairing of DNA to create ‘staples’, used to contort the molecule into various shapes. This creates a scaffold of sorts, allowing the structure to be formed, having been designed using a computer system. Enzymes are used to trim the DNA molecule into oligomers The shape is solidified through heating and cooling, condensing the structure and allowing the staples to alter the DNA shape. Presently, researchers from MIT, Arizona State and Baylor University have collaborated to develop an algorithm named DAEDALUS to compose the structure around a geometric shape, creating the structure far quicker and cheaper than previous methods.
- In Beijing’s National Centre for Nanoscience and Technology have created a method for delivering the Doxorubicin anti-cancer drug directly towards effected cells. This is somewhat similar to the ‘magic bullet’ method used by monoclonal antibodies in the respect that cells are targeted with precision, meaning normal cells are not damaged, as in chemotherapy. As this treatment relies solely on DNA nucleotides it is entirely bio-compatible, giving it another edge on other drug delivery methods. The origami is composed from the M13 phage DNA which when tested in vivo, allowed the drug to be directly directed to tumour cells. The origami can be folded and coated with a phospholipid, replicating the structure of a virus. This prevents the immune system from reacting and preventing the drug from being delivered. This has been observed to successfully work in mice, allowing the drug delivery device to remain in circulation for hours after first administration. The drug is attached non-covalently to the origami structure, which was successfully taken into human breast cancer cells at a faster rate than free samples of the drug. It was also observed to circumvent doxorubicin resistant cells, making this a potentially game-changing cancer cure.
- Another application of DNA origami is the nanorobot, which can recognise cells through receptors. These are designed in a program called Cadnano, creating a barrel shaped structure, even smaller in size than a virus. The presence of the cell causes nucleotide strands called aptamers to detect molecules on the cell’s plasma membrane, causing the nanorobot to alter its shape, releasing the contents of the robot. This ensures that this method of drug delivery is highly specific, leaving other cells unscathed from the chemicals contained inside the nanobot. The works like a locked jewellery box, in this analogy the key would be the molecules on the target cell’s membrane and the jewellery box would be the folded DNA. An example of this technology being implemented include a form of leukaemia treatment, where the nanorobot releases an antibody when leukaemia cells are detected, preventing multiplication. However, there are some potential drawbacks to this methodology. As this a newly conceived method, its effects in biotic systems have not been evaluated. It will not work for agents that infect a cell, as this only works when molecules are presented on the cell surface. It is also hypothesised that they can be destroyed by nuclease enzymes, preventing the nanotechnology from operating functionally.
- A bio-physician named Friedrich Simmel has used the DNA origami technology to create microscopic rulers to measure the distances at a molecular level. This allows high resolution microscopes to be calibrated, allowing precise observation of cells to diagnose cellular malfunction. This allows identification of objects smaller than 200nm, far better than other calibration methods, breaking the diffraction limit previously held. Additionally, fluorescent dye molecules can be bound to the DNA origami, allowing many in vivo cellular reactions to be traced. This allows scientists to fully observe how a cell operates. This would allow biologists to fully understand cellular processes, allowing intervention when metabolic procedures fail to prevent the onset of disease. This has been implemented in cockroach research, using markers that bind to haemolymph cells, observing their journey around the roach’s body. In a similar sense, chemists have developed a thermometer from the DNA origami technique which uses the theory that DNA folds and unfolds due to temperature variation. Optical reporters can be used in conjunction with this to produce an easily detectable reading. This allows us to detect temperature fluctuations in individual cells.
- The DNA origami technique may one day be capable of encapsulating the CRISPR-Cas 9 gene editing tool, allowing it to be directly delivered in cells where specific genes can be targeted. CRISPR stands for ‘clustered regularly interspaced short palindromic repeats’ allowing genomes to be edited with extreme precision. This allows genes of living cells to be permanently edited, which will eventually lead to genetic diseases being curable. Using DNA origami has the advantage over existing methods, like viral delivery, which have a restricted load. By contrast, the highly specific nature of DNA origami can detect specific markers on cells, whilst facilitating larger gene packages to be delivered to cells.
- Scientists have also developed a DNA ‘spider’ made from a streptavidin molecule and is capable of walking over DNA molecules using three-four ‘legs’ . These are able to detect and follow tracks of substrate molecules, sequentially moving like normal computational robots do. These are far cheaper and more versatile than using silicone-based systems, also operating at a far smaller scale. In the future, these might be able to collaborate together to perform more computationally advanced tasks. Presently, these devices are not intended to perform functions that a conventional computer can, nor tasks of a more demanding nature. This is because the DNA computers suffer from being sluggish and error-prone. They are also single use, performing the same computation over and over again, unlike conventional computing. Yet, these have been proven to perform the Travelling Salesman problem, an indicator of successful computation. This was conducted by Leonard Adleman in 1994, using polymerase chain reactions to amplify DNA and sorted by gel electophoresis. These have been successfully used in living cockroaches, allowing a molecule to be used to target particular cells. They can compute simple logical operations, which can eventually be used to diagnose or treat diseases in vivo. This has also been used to diagnose tuberculosis in the same vein of operation. It is also hoped that this technology can be applied to humans in the next five years.