Zidan Yang uses the latest advances in genome editing to unlock the secret memories of our cells
Memory formation and shortage, a notorious conundrum that human beings have been striving to understand for hundreds of years and still there is no definition universally accepted. Yet modern scientists embark on analysing memory at a digital and quantitative level. In the summer of 2016, biological engineers from MIT successfully devised an analogue memory storage machinery, which to some extent can shed new light on the interpretation of memory. This machinery is the first system that can be used to record both the duration and the intensity of events in human cells in real time. This remarkable innovation was inspired by none other than the famous genome editing system CRISPR, which consists of a DNA-cutting enzyme called Cas9 and a short guide RNA strange that directs the enzyme to a specific position of the genome to proceed its cuts.
In bacteria, where CRISPR originally evolved, the system records memories of past viral infection events by storing the inserted sequences from viruses, therefore, the bacteria can recognise and combat these invading viral genes when exposed to the same virus. Scientists, on the other hand, wish to adapt this system to record biological processes inside human cells.
Adroitly, instead of targeting invading genes, they manipulated the guide RNA to recognised DNA that encodes the exact same guide RNA as itself, a so-called ‘self-targeting guide strand.’ Directed by this self-targeting guide RNA, Cas9 cuts the specific DNA and generates a mutation which becomes a permanent record of this event. More importantly, once this DNA is mutated, it will produce a new guide RNA which leads to the deletion of that newly mutated DNA.
Therefore, as long as the self-targeting guide RNA is expressed and Cas9 is not degraded, this system could keep accumulating its mutation records in real time. Furthermore, once an exposure (e.g. an inflammatory process) is recorded, this piece of memory can be passed on to the next generation in the sense of epigenetics. By simply sequencing the DNA, scientists can determine where and how many mutations there were and what subsequent actions should be conducted regarding these prompts. This would be a potent tool that enables us to monitor disease progression and developmental process from embryos to adults, in addition, just as advanced CRISPR systems do, the researchers’ engineer cells to record multiple inputs to producing different self-targeting RNA guide strands in the same cell. Ideally, each guide RNA is specifically activated which its input presents.
Rather than regarding each individual cell as a digital storage machine, scientists perceive the entire population of cells as an analogue ‘hard drive,’ which massively expands the available storage of information.
“With this technology you could have different memory registers that are recording exposures to different signals, and you could see that each of those signals was received by cell for this duration of time or that intensity.” – Samual Perli SM, one of the lead authors of this new study.
However, we still have no idea about what the future will hold. Any off-target effects of the DNA manipulation should be taken into consideration. Any social or ethical arguments could also affect the overall development of this technology. Are we able to record the process of memory storage and retrieval procedure in our brain using this kind of digital device? What subsequent events would this mutative accumulation result in, which our neural circuit’s plasticity? Is it possible for the National Health Service to take this technology into public health index records? All these concerns mentioned are only a starting line of the long and winding road ahead.
From Issue 12