As the world grows more complex, we see hopeful signs of progress in the field of gene-based medicinal therapy. In particular, the famous CRISPR-Cas9 gene-editing technique has been gaining significant traction due to its simplicity and versatility. On October 28th, Dr. Lu You’s team at Sichuan University in Chengdu successfully implanted cells containing CRISPR-edited genes into a patient with lung cancer. While this may seem like a small step, it is a result with heavy implications for the future of biomedical research. Carl June, an immunotherapy specialist at the University of Pennsylvania, described the implications of this progress best, calling the possibility for an ensuing international duel in biomedical research “Sputnik 2.0.”
To understand the implications of this, it is important to understand what exactly CRISPR is. Broadly speaking, various sequences of DNA are arranged in particular forms and patterns, and DNA is built from four base components: adenine, guanine, cytosine, and thymine. When looking at a single strand of DNA, we can identify the ordering of the bases by identifying them through the first letters of their names. For example, ATCGGCTA is a sequence of “adenine thymine cytosine guanine guanine cytosine thymine adenine”. How do we get from these simple bases to what we call “genes?” Think of these DNA sequences as encoders of the gene data that makes organisms what they are. Through complex processes that are still being researched, cells can use their internal machinery to transcript and translate these genes, decoding their information and using the resulting blueprints to build the scaffolding, infrastructure, defenses, and behaviour of the cell.
Now we look at a small microorganism: bacteria. What is special about the DNA of bacteria is not necessarily that they vary in complexity, but that they are easily studied and manipulated. Bacteria have their own “immune system,”—completely unlike our own vascular system–—that is based on cellular machinery and chemical processes that work in tandem to keep out viral particles that could otherwise harm them. This “immune system” is controlled by short, palindromic gene sequence clusters in the bacterial genome, and works by attacking and eradicating the genome of an invading virus. We give a special name to these sequences, “Clustered Regularly Interspaced Short Palindromic Repeat” sequences—CRISPR sequences! However, as the name reveals, these clusters are spaced intermittently. Between them lie “spacers,” which are sequences of old viral genetic material incorporated into the bacterial genome, serving as something like a memory system for previous attacks.
First, the DNA of an invading virus is incorporated and “saved” as a spacer. Then, the cellular machinery transcribes this new spacer sequence, creating a single-stranded CRISPR RNA molecule. Finally, this CRISPR RNA molecule is cut into pieces, and attached to certain types of cellular machinery that act as defense mechanisms, guiding these biological weapons to destroy the virus. Because this CRISPR RNA is the result of transcription over old viral DNA, the RNA strands are perfect guides, guaranteed to deliver the machinery to the right place in order for the viruses to be destroyed.
This looks like what one would expect from a very primitive bacterial immune system, but what makes CRISPR so convenient and useful is the extreme precision of CRISPR RNA’s “targeting.” In bacterial immune systems, CRISPR RNA served as guides to bring molecular defense mechanisms to their precise targets. What is now being developed in the lab is a way to use this precise targeting for gene editing purposes. Molecular geneticists synthesize unique RNA strands that precisely match DNA sequences in an organism’s genome, in the same way that CRISPR RNA precisely matches viral DNA strands. These RNA strands can again be used as “guides,” but instead of delivering destructive cellular machinery to the location like with the bacterial immune systems, they can deliver machinery that silences or alters gene sequences with extreme precision. This is an extremely powerful technology, and it gives scientists the freedom to edit sequences like words in a word document (with enough funding and resources, of course).
The problem lies in how easily accessible and cheap CRISPR is. Heralded as a revolution in the life sciences, there has been some concern among scientists about the breakneck speed at which its use is being expanded, at the potential expense of ethical concerns. Indeed, April 2015 saw a study published in Nature involving the use of CRISPR on human embryos, which stirred up controversy over its use on the human genome.
But what has been an overall positive platform for this technique has been the world of clinical biomedicine, which is precisely where the work of Dr. Lou You’s team fits in. After getting through setbacks and time issues due to longer-than-expected wait times for collecting and amplifying some of the immune system cells isolated from the patient, the team used the CRISPR method to attach a DNA-cutting protein to an RNA guide. Using this method, the team was able to make a precise cut at a gene that encodes a “breaking response” on the immune response of an immune cell. These edited cells, now with a more relaxed breaking response, could potentially fight the patient’s cancerous lung cells.
The edited, amplified cells were injected back into the patient successfully, and Lu says that there will be ten more patients receiving two to three injections each. Typically, there can be complications with injecting these cells back into the body—like the body outright rejecting them—but in this situation, the edited cells were sufficient enough to not cause excessive problems. Lu does state however, that the continued tests will involve careful monitoring for adverse effects, rejections, or a degeneration of the patients’ health.
Other clinical scientists have expressed a combination of excitement and wariness at these results. CRISPR’s ability to revolutionize genetic-medicine approaches to cancer treatments is unquestioned, but there is controversy around whether or not the treatment is scalable. It requires a lot more time and resources to grow and amplify entire cells over similar immunoresponse components like antibodies. Despite this, there is a lot of hopeful buzz around CRISPR’s use in anti-cancer treatments, and there will be no doubt that it will soon become a technology in biomedical treatment.