Finding the "Just Right" in Genetic Medicine
The Goldilocks Principle of Genetics: Balancing Precision and Complexity
Some genetic diseases, like sickle cell anemia or Huntington's, are caused by a single malfunctioning gene.
Others, like heart disease or diabetes, are influenced by thousands of genetic variants working together.
The future of medicine lies in finding the "just right" approach to addressing both scenarios through advanced genome editing and polygenic risk assessment.
The recent FDA approval of the first CRISPR-based gene therapies marks a transformative milestone in biomedicine, validating genome editing as a promising treatment strategy 5 .
Simultaneously, the predictive power of polygenic risk scores (PRS) has improved considerably, accelerating their consideration for clinical use 6 .
The CRISPR-Cas9 system has revolutionized genetic engineering since its discovery as a bacterial defense mechanism 2 7 .
In 2019, researchers at the Broad Institute of MIT and Harvard developed prime editing, a more precise system that reduces off-target effects 1 .
Unlike CRISPR-Cas9, prime editing doesn't require making double-stranded cuts in target DNA. Instead, it uses a modified Cas9 that cuts just one strand, creating a flap where a new sequence can be inserted using a built-in template 1 .
Think of the difference this way: if CRISPR-Cas9 is like scissors that cut out problematic words and paste in new ones, prime editing is more like a word processor that directly rewrites individual letters without cutting the paper.
Scissors approach
Double-strand breaks
Word processor approach
Single-strand nick
Improved precision
Reduced error rates
Despite its advantages, prime editing still carried a small risk of creating unintended changes. After the new genetic sequence is copied, it must compete with the old DNA strand to be incorporated into the genome.
If the old strand wins this competition, the extra flap of new DNA might accidentally get incorporated elsewhere in the genome, potentially causing harmful mutations 1 .
With the most recent version of prime editors, this error rate ranged from one error per seven edits to one per 121 edits for different editing modes—a significant concern for therapeutic applications 1 .
MIT researchers recently engineered a solution that dramatically reduces this error rate. The team discovered that certain mutated versions of the Cas9 protein could make the old DNA strands less stable, causing them to be degraded more easily and allowing the new strands to be incorporated without errors 1 .
By identifying specific Cas9 mutations and combining them with proteins that stabilize the RNA template, the team created what they call vPE—a vastly improved prime editor that lowered the error rate to just one-sixtieth of the original 1 .
"For any drug, what you want is something that is effective, but with as few side effects as possible. For any disease where you might do genome editing, I would think this would ultimately be a safer, better way of doing it."
| Editing System | Low-Precision Mode | High-Precision Mode |
|---|---|---|
| Original Prime Editor | 1 error in 7 edits | 1 error in 122 edits |
| Enhanced vPE System | 1 error in 101 edits | 1 error in 543 edits |
| Improvement Factor | ~14x reduction | ~4.5x reduction |
Researchers first identified specific Cas9 mutations that showed relaxed cutting constraints, sometimes cutting one or two bases further along the DNA sequence.
These mutant Cas9 proteins were tested for their ability to reduce errors in the prime editing process.
Pairs of effective mutations were combined to create a Cas9 editor that lowered the error rate even further.
The improved Cas9 proteins were incorporated into a prime editing system with an RNA binding protein that stabilizes the ends of the RNA template more efficiently.
The final vPE system was tested in both mouse and human cells to confirm the dramatically reduced error rates 1 .
While gene editing addresses genetic issues at their source, polygenic risk scores (PRS) offer a way to read our genetic predispositions before symptoms appear.
PRS quantify inherited risk by integrating information from many common sites of DNA variation into a single number that represents an individual's genetic liability for a particular condition 6 8 .
These scores are calculated by summing risk alleles across an individual's genome, weighted by the effect size estimates derived from large genome-wide association studies (GWAS) 3 .
The predictive power of PRS has improved considerably in recent years, accelerating consideration for clinical adoption 6 .
A 2018 study examining polygenic risk scores in over 250,000 individuals from the UK Biobank found that 8% of the population had scores conferring at least a threefold increased risk for coronary artery disease 8 .
High Risk Population
≥3x increased riskModerate-High Risk
2-3x increased riskAverage Risk
Population baselineBelow Average Risk
Reduced riskA review of nine existing polygenic score reports found significant heterogeneity in how results are presented 6 .
Extended guide RNAs that both specify the target location and provide a template for the new genetic sequence 1 .
Proteins that can inhibit Cas9 activity, such as the LFN-Acr/PA system that helps turn off Cas9 after editing is complete 5 .
Donor DNA sequences used in homology-directed repair to enable precise gene correction or insertion 7 .
As with any powerful technology, genome editing and polygenic risk assessment raise important ethical considerations that researchers are actively addressing 4 9 .
The scientific community generally supports editing somatic cells (which don't pass DNA to children) but has expressed caution about germline modifications that could be inherited 2 .
Current research focuses on improving the efficiency and safety of these technologies.
The MIT team, for instance, is working on enhancing prime editing efficiency through further modifications of Cas9 and the RNA template, while also addressing the longstanding challenge of delivering editors to specific body tissues 1 .
"In principle, this technology could eventually be used to address many hundreds of genetic diseases by correcting small mutations directly in cells and tissues."
Looking ahead, these technologies promise a future where medical interventions can be increasingly personalized and preventive.
The journey toward finding the "just right" approach in genetic medicine continues, with researchers carefully balancing efficacy, safety, and ethical considerations to bring these revolutionary technologies to patients who need them.