Author: Viktoria Sefcikova Edited by: Eleonora Lugara, Ruth Sang Jones
On April 4th, SIU London collaborated with UCL Biochemical Engineering Crook Society and UCL engineering society to host an event titled “From Idea to Start-up: Genetic Engineering and its Therapeutic Potential.” The event included lectures and engaging discussions from three experts on the use of genetic technology to better human life—whether it be by targeting aging, advancing development of DNA products, or editing the germline genome.
Dr Daniel Ives
Dr Daniel Ives is the founder and CEO of Shift Bioscience , a drug discovery company that investigates genetic causes of aging with the aim of extending the healthy human lifespan. Dr Ives began by discussing the “hallmarks of aging,”  which are 9 disruptions of cellular processes involved in the aging process. When genetically targeting aging, remedying a highly connected hallmark could have a beneficial effect on others. One such hallmark is mitochondrial dysfunction, which has a significant impact on the epigenetic aging clock, a highly accurate measure of aging quantified by epigenetic changes. Mitochondria are cellular organelles that produce the energy required for cell function. So their dysfunction, which occurs by accumulation of damage in the mitochondrial genome, will have negative consequences on energy generation as evident in aging.
However, it has been observed that cells can, in some circumstances, reduce the amount of their hosted mitochondrial genome damage. Dr Ives observed during his PhD that in A549 cell lines (rho degree cells derived from lung carcinoma) with both healthy and damaged mitochondrial DNA, the proportion of damaged mitochondrial DNA could be reduced when the cells activated a certain pathway. This is the shift effect. At Shift Bioscience, they have identified small molecule compounds known as “shift drugs”, which trigger this effect to occur faster than in the A549 cells.
Shift drugs have been applied to mouse models and were successfully shown to reduce aging by one-third on the epigenetic aging clock. The aim of this technology is to achieve “longevity escape velocity.” In this state, an individual can remain at an age with which they are content.
Currently, Dr Ives is working with single-cell aging clocks—a cell line engineered to report its age. With this, it is possible to generate a CRISPR screen to go through all your genes and see what is happening with the genetic clock.
Dr Paul Rothwell
Dr Paul Rothwell is Group Leader of Innovation at Touchlight Genetics, a company which has developed novel synthetic DNA vectors that can be used as delivery vehicles for genetic therapies. Dr Rothwell discussed the current market of DNA technology and the shortcomings of DNA manufacturing, which Touchlight has addressed for their competitive advantage.
Current plasmid DNA is used in a number of innovative healthcare technologies, such as CART genetic engineering for cancer treatment and constructing adeno-associated virus (AAV) tranfer plasmids as a therapeutic delivery vehicle. But the current plasmid DNA manufacture cycle is inadequate for a number of reasons:
-Fermentation and purification methods are slow
-Production is expensive
-Bacterial sequences generated are often unstable
Dr Rothwell explains how the company’s trademarked “doggybone DNA” (dbDNA) addresses these limitations by using a rolling-circle amplification methodology. The resulting DNA has greater stability. Dr Rothwell’s aim is to further increase the yield of dbDNA, which will in turn decrease costs. Touchlight is an excellent example of addressing a gap in the current market to improve therapies reliant on inherently flawed DNA technologies.
Dr Helen O’Neill
The final speaker was Dr Helen O’Neill, lecturer and molecular geneticist at the Institute for Women’s Health at UCL ,where she is a member of the Embryology, in vitro fertilisation (IVF), and Reproductive Genetics group. Dr O’Neill uses CRISPR genome editing to research treatment approaches for neuromuscular and sex-linked disorders. She describes CRISPR as a “Gold Rush” for biotechnology—evident in the technology’s high versatility. Research on CRISPR is able to shift discussions on a month-to-month basis.
Dr O’Neill’s work with CRISPR focuses on germline genome editing, particularly on methods to improve IVF. She explained that the future of IVF is going to be moving beyond screening for diseases to correction of diseases. A common controversy in the field is that editing the germline is permanently changing subsequent generations. However, Dr O’Neill raises the point that we are already making heritable changes with cancer radiation therapy and in cancer therapy, the germline is not just “edited” but rather destroyed. She also explained a common incongruency we see in the news ,whereby many advances reported involve use of older genome editing methods, such as TALENs or zinc-fingers, rather than CRISPR. The reason is that these older technologies have had significant time and resources invested into them, including FDA and clinical trial approval. This has led to some companies persisting with these preceding technologies; however, at the rate CRISPR is revolutionising the field, it is expected to have a key role in future genome editing.
The speakers offered additional insight about the challenges faced in their professions during a Q&A session. In summary, the public often has a fear and distrust of a new technology, especially when it is propelled very fast. On the other hand, legislation often does not move fast enough and countries vary in their demand for genetic therapies. The question of off-target effects for CRISPR is especially challenging because we need to know when the state of the technology is “good enough.” Quantifying what is worth the risk for genome editing is often a question of what is considered disabling by people who possess the trait.
A question was raised of how much business experience is necessary when translating one’s scientific ideas to a successful start-up. While it is possible to learn how to manage all aspects of your business yourself, bringing others onboard to fill in gaps in knowledge is also an effective solution. Dr Ives mentioned as a tip, to licence your work to third parties, but also not to let industries tax you too soon (i.e. before you know your product works). Flexibility is key in running a successful business and expect to fail 3-4 times before getting on the right tract. From Dr Ives’s experience, your second or third idea is generally better than your first. Genetic therapeutics has the appeal of a high profit margin, but also carrying a high risk. Having the ability to recognise when to change directions is a strength necessary to be able to transition when one project is not working out.
The event closed off with a networking session where event attendees had an extra opportunity to interact with speakers and enquire further about their work.
1.Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer, The Hallmarks of Aging, Cell, Volume 153, Issue 6, 2013, Pages 1194-1217, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2013.05.039 (http://www.sciencedirect.com/science/article/pii/S0092867413006454)