M.Eng. Capstone Project Highlight: Applied Rejuvenative Therapies

By Iris Wu

Rewind time. Repair damaged tissue. Reverse the effects of aging.

Aging — a problem we’re all familiar with

As the human body ages, stem cells become less capable of repairing damage. One notable cause for this is senescence. Senescence occurs in stem cells due to the accumulated damages caused by everyday use. When potentially oncogenic stimuli are brought on by these damages, the cells will shut down proliferation and cease dividing to ensure cancer does not occur. When these stem cells senesce, inflammation is initiated to promote the body’s immune system to eliminate the senescent cells. This inflammation at low concentration is beneficial — assisting the repair of tissue. Over time, however, the accumulation of damage caused both by this inflammation and other accumulated stresses lead to a feedback loop that further impairs tissue function. This is one of the potential causes for the aging we see today.

But what if there was a way to improve aging? Every culture has dreamed of finding the fountain of youth.

The Conboy Lab’s research on aging and rejuvenation is a step in the right direction towards making that dream a reality. The fastest growing segment of the American population are those older than 65 years of age — a segment growing faster than the total population in the US. Tissue damage due to trauma is the 5th leading cause of death for people over 65. Now more than ever, translational approaches to aging are necessary to stem the costs of an aging population.

Research & Solution

Aging and disease share many of the same symptoms including degeneration of tissue integrity, DNA damage, and chronic inflammation. In many ways it is meaningful to characterize these two conditions as being essentially the same thing. This is the paradigm that this Master of Engineering Capstone Team* adopted in the Conboy Lab, run by Irina and Mike Conboy.

Their research focuses on the rejuvenation of tissues affected by aging and disease. This includes studying diseases caused by genetic disorders, like Muscular Dystrophy which results in a degenerate state that shares many of the characteristics of aged tissue. Much of their research in the Conboy Lab is aimed at reversing these harmful phenotypes. Their goal is to eventually apply these findings to human diseases while pioneering a new understanding of aging.

Two projects are at the center of their research:

  • A dual drug approach to alleviating the aged phenotype
  • The use of muscle dedifferentiation and CRISPR technology to treat Duchenne Muscular Dystrophy.

*A core part of the UC Berkeley Masters of Engineering experience is the Capstone Project, where students develop real-world solutions to address crucial industry, market or societal needs.

Rejuvenating Aged Tissue

The M.Eng. students and researchers in the Conboy lab are working on a dual drug approach to tissue regeneration which has proven to be effective at improving brain, liver, and muscle function. Experiments in old mice who received simultaneous injections of these drugs showed improved cognition and learning over untreated animals. Improved health was also seen in aged mice injected with both drugs as compared to untreated mice.

Thanks to the mechanisms through which these two drugs harmonize and their proven viability in humans, they have potential therapeutic application once more research is performed. The lab is currently fine-tuning the mechanism through which the drug functions as well as optimizing it’s performance. This project is currently in late stage development with a publication and patent in the works.

Treating Muscular Dystrophy

Muscular dystrophy is a genetic muscle wasting disease which affects roughly 200,000 people in the United States each year. At present, there is no true cure for muscular dystrophy. While many treatments focus on alleviating symptoms, the best opportunity for a cure comes in the form of gene therapy which would cure the disease at its source.

Current attempts to treat muscular dystrophy with gene therapy have had difficulties with two main challenges, both of which regard proper delivery. First, current delivery methods such as Adeno-associated virus (AAV) and lipofection come with their own associated risks such as cell death or immune response.

The second problem involves the muscle itself. Because muscle cells do not divide, even if the tissue is treated, there is no guarantee that enough of the tissue will have functional physiology.

Our technology combines CRISPR/Cas-9 gene editing technology with cellular dedifferentiation.

Myotubes are terminally differentiated cells. They no longer progress through the cell cycle and undergo “permanent” changes in gene expression, cell morphology, and function. Gene editing with CRISPR/Cas-9 currently depends on the natural cell cycle, requiring repair mechanisms only active during cell growth to assimilate corrected genetic material into the genome. Their solution in the Conboy Lab is to revert muscles cells to an earlier state in their lifecycle. This is done chemically as opposed to genetically which is more common in other labs in the field. The benefit of chemical alteration is the avoidance of unnecessary changes to the genome which can be associated with cancer.

Most diagnoses of Duchenne Muscular Dystrophy occur around the age of five when the majority of the muscle in the body is already terminally differentiated. With the science being pioneered in the Conboy Lab, treatment for muscular dystrophy may be possible for people of all ages.

Meet the Team

Alan (left) and Aaron (right) presenting their research at the Berkeley Master of Engineering Capstone Expo

Aaron Blotnick

Aaron Blotnick is a Biologist turned bioengineer in the Master program at Berkeley. He majored in Biology and Spanish focusing on molecular biology and linguistics respectively. His insatiable curiosity has now led him to the Conboy Lab where he works to elucidate the pathways influencing the aged tissue niche. His decision to switch in focus from biology to biotech occurred while performing genetics research to improve crop viability. Experience in high-throughput genetics research inspired the pursuit of a career in science which was not only innovative but also applicable to real world problems.

Alan Borelli

Alan Borelli is a Master’s student in the bioengineering department. He was a religion major at Princeton University and wrote his senior thesis on the question of faith in the films of Ingmar Bergman. Then as is now, Alan is interested in exploring the mysteries of life. He considers it a great privilege and incredibly exciting to be part of the cutting edge research being done at the University of Berkeley and the Conboy Lab specifically. It is his goal to earn a PhD in bioengineering and pursue further research in the field.