Bioscientists often liken the human body to an exquisite machine whose intricate workings are governed by DNA, RNA and proteins.
Assistant professor of bioengineering Stanley Qi is helping to invent tools and techniques to tweak this molecular machinery in increasingly sophisticated ways. Qi specializes in the use of CRISPR-Cas, best known as a sort of molecular scissors to cut and splice genes with unprecedented precision. But Qi, also a professor of chemical and systems biology in the School of Medicine, and a member of the faculty of Stanford ChEM-H, believes that snipping away at DNA is just the start.
Below, he explains three ways his lab is developing variations of CRISPR-Cas to make it a more useful tool to do research, treat disease and, perhaps one day, rejuvenate worn-out body parts.
Our lab has linked CRISPR-Cas9 to other proteins in ways that enable this basic technology to do more than target and cut genes. We’re developing CRISPR variants to find, and then fine-tune, specific genes to modulate their functions, like twisting a faucet to turn it on or off or regulate the flow precisely. Scientists call this up-regulating and down-regulating genes. We’re also adding new functions to the CRISPR toolbox to study what is called gene regulation — which genes are active at a given time in a given cell. Very few diseases are caused by a mutation or defect in a single gene, where you can just come in and fix that one part. Most diseases result from malfunctions in a system of interacting genes. We’re doing the basic research that would allow us to one day use CRISPR-Cas to study all of the active participants in a disease-causing system and, eventually, modify the activity of any problem-causing genes in that system.
In recent years researchers have become increasingly aware that the location of DNA inside the nucleus of a cell can influence how the DNA functions. The nucleus is not a uniform space. It has many compartments, and different compartments can induce different behaviors. If DNA moves to the outer edges of the nucleus, some genes appear to be silenced or shut off. Other compartments can boost the expression of certain genes. Several types of cancer are known to be caused by the aberrant movement of DNA inside the nucleus, causing genes to be expressed abnormally. We’re developing a tool called CRISPR-GO that seeks to not only track DNA in the nucleus but move it to a specific desired location. Obviously, we’ve got a long way to go, but we are studying whether this approach might be able to prevent or reverse certain pathologies that result from aberrant DNA movement.
As we learn how to use CRISPR-Cas to study DNA as a system, it becomes possible to imagine one day developing safe techniques to treat many adverse consequences of aging. Take a person’s knees, for instance. In a young person cells known as chondrocytes secrete collagen to help build up a gel-like tissue called the meniscus, which acts like a force absorber connecting the bones. But as people age, the old meniscus cells undergo subtle changes in their genome that render them incapable of producing sufficient force-absorbing collagen. As a result, the knee joint gradually decays and becomes brittle. If we can develop CRISPR-Cas tools that allow us to control and reactivate the youthful self-repair ability of these cells, we might be able to rejuvenate the joints. There will be limits to how far we can with such techniques. We could not reprogram the entire body, or enable people to live forever. But if we can repair some of the body’s worn out parts, that would allow us to enjoy a higher quality of life as we age.