Gene therapy to germline editing: Promises, challenges, ethics

A report this April rocked the scientific world: scientists in China reported editing the genomes of human embryos using CRISPR/Cas9 technology. It was a limited success: of 86 embryos injected with CRISPR/Cas9, only 71 survived and only 4 had their target gene successfully edited. The edits didn’t take in every cell, creating a mosaic pattern, and worse, unwanted DNA mutations were introduced.

“Their study should give pause to any practitioner who thinks the technology is ready for testing to eradicate disease genes during [in vitro fertilization],” George Q. Daley, MD, PhD, director of the Stem Cell Transplantation Program at Boston Children’s Hospital, told The New York Times. “This is an unsafe procedure and should not be practiced at this time, and perhaps never.”

As Daley detailed last week in his excellent presentation at Harvard Medical School’s Talks@12 series, the report reignited an ethical debate around tampering with life that’s hummed around genetic and stem cell research for decades. What the Chinese report adds is the theoretical capability of not just changing your genetic makeup, but changing the DNA you pass on to your children.

IVF (nevodka/Shutterstock)
IVF (nevodka/Shutterstock)

Concern started in the 1970s with the advent of genetically altered microorganisms and the birth of the first “test tube” baby, recounts Daley, also a pediatric hematologist/oncologist with Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Fast-forward to the 1997 birth of Dolly the sheep (the first cloned adult mammal) and the first isolation of human embryonic stem cells, from embryos discarded from fertility clinics, in 1998. Then, in 2006, the first cloned human embryo, consisting of four cells, was created and implanted in a womb. (The pregnancy didn’t take.)

While these startling events were going on, researchers were slowly but surely paving the way for gene therapy to correct disease-causing mutations. Today, clinical trials are introducing genes into patients with “bubble boy” disease, various blood disorders, metabolic disorders, eye disease and cystic fibrosis. The genes are brought in by engineered viruses introduced either into cells that are given to the patient or directly into tissues.

Wiskott-Aldrich syndrome WAS gene therapy Dana-Farber/Boston Children's Cancer and Blood Disorders Center
Gene therapy

And while debate swirled around embryonic stem cell research, scientists (including Daley) set about creating induced pluripotent stem cells—cells much like embryonic stem cells but derived by reprogramming ordinary skin or blood cells rather than using embryos. These cells are being actively used to model patients’ diseases in a dish for purposes of drug discovery.

Other recent developments include:

  • Mitochondrial replacement, a gene-altering form of IVF that is being considered in the UK for couples at risk of having a child with mitochondrial disease. The technique creates a “three-person embryo,” with the mitochondria coming from a donor’s egg cell.
  • In vitro gametogenesis, creation of eggs and sperm from stem cells. Daley’s lab created the first functional sperm cells from mouse embryonic stem cells in 2003, and in 2012, a Japanese team created mouse egg cells from induced pluripotent stem cells—then used them to produce healthy offspring. Though none of this has been done in humans, there’s much interest in this technique among infertile couples.

As for CRISPR editing of embryos, Daley thinks the technique has potential for rescuing embryos with life-threatening genetic disorders and believes the technical concerns raised by the Chinese study are surmountable over the coming decades.

George Daley (courtesy Rick Groleau)
Daley (courtesy Rick Groleau)

The ethical issues around CRISPR, especially in embryos, are thornier. The International Society for Stem Cell Research is revising guidelines for stem cell research to include germline genome editing, and the National Academy of Sciences and the Institute of Medicine just announced an international summit this fall to “explore the scientific, ethical, and policy issues associated with human gene-editing research.”

“There will be impassioned arguments from patient advocates,” Daley predicts.