So instead of blindly inserting a group of cells hoping they are all cardiac muscle, he is using CRISPR to insert marker genes - such as a gene that includes a glowing, green fluorescent indicator - to be able to clear out every other non-heart cell in mouse models.
Earlier methods of performing genomic surgery had barriers of high costs and low flexibility that kept many researchers from adopting them.
"Then CRISPR started coming out, and since then it has absolutely exploded," said biologist Montserrat Anguera of Penn's School of Veterinary Medicine. "CRISPR seems to be the easiest and fastest way for labs to edit the genome."
She studies how embryonic stem cells develop into specialized cells within organs such as the liver or heart. Using CRISPR, she can delete regions of the stem cell genome to help decipher their function in human development.
Bao first began his work with sickle-cell disease using older systems such as zinc finger nucleases, but has since switched to CRISPR - and he is a believer.
"I call them nanoscissors - a truly amazing tool," Bao said.
Anguera joined Penn's faculty a year and a half ago after a postdoctoral fellowship at Harvard Medical School, where CRISPR-guided research flourishes. Both she and Epstein hope to grow Penn's community of users, now just a handful.
The Broad Institute, a Harvard-MIT biomedical research collaborative, holds the patent for the tool's components and methods. Its main inventor? A 32-year-old neuroscientist, Feng Zhang. Early last year, Zhang and his team were the first to demonstrate the system's search-and-edit capabilities in the cells of mice and humans.
Researchers at the University of California, Berkeley, first used CRISPR to make targeted DNA cuts. After more work by Zhang, CRISPR has become the powerful tool seen today, with a proven record in many animals and plants.
"The analogy would be like the search-and-replace function in Microsoft Word," Zhang said. "In the genome, we don't have a biological search function, so we use a specific string of letters."
This string of 20 letters, or bases, is used as a template to search for a specific matching section of the genome, which is no small feat. In humans, double-stranded DNA is made up of three billion base pairs. But once you engineer the special 20-letter-long code, or guide RNA, the CRISPR system will target the desired gene by searching along the DNA until it makes a match. Once locked in, an enzyme then acts like DNA scissors and cuts the two strands.
Because many CRISPRs can act at once, you can delete whole regions or cut and paste from different areas of the genome. The tool can also exploit the cell's natural DNA repair mechanism and weave a new piece of genetic code into a gap.
Zhang has cofounded a Cambridge, Mass.-based start-up, Editas Medicine, to develop new treatments using CRISPR.
"In areas of research, CRISPR can help us understand and identify genetic mutations that can lead to disease," he said. "Clinically in the long run, we might be able to use it to repair mutations."
Zhang also notes that real-world applications abound beyond medicine too: making better crops or biofuels. But experts say it will be years before genomic surgery comes to a hospital near you.
"It may take 10 years, could be shorter," Bao said. "The most important challenge is off-target cutting - not only cutting where you want to cut, but also at other locations you don't want."
For instance, if 19 out of 20 letters match up, the guide RNA may still bind and cause the enzyme to cut the wrong gene. Zhang is working on ways to make the search more stringent, such as increasing the number of letters.
And even when the correct edits are made, an organ could have other issues. Researchers recently regenerated damaged heart muscle in monkeys using an older gene editing technique, and found that the animals had episodes of irregular heartbeats after the procedure.
Still, Epstein remains optimistic about CRISPR's future, and predicts it will be available to patients within a decade.
"It's not pie-in-the-sky anymore, it's real," he said. "Changes can occur in surprising, quantum leaps."