New DNA Base-Editing Approach Can Potentially Treat Thousands of Hereditary Diseases

New DNA Base-Editing Approach Can Potentially Treat Thousands of Hereditary Diseases

EDITING HUMAN DNA 

If in the near future thousands of hereditary diseases that affect us today were no longer an issue, how would this information impact our society? If you can change a person’s DNA so that they will never experience getting sickle-cell anemia, cystic fibrosis, hereditary blindness, or countless other diseases that can limit one’s life, how valuable would this technology be to humanity? The answer is that it would profoundly affect how we view our health and how we live our daily lives. 

Dr. David R. Liu and his team at the Broad Institute at MIT and Harvard have pioneered editing individual
DNA letters in the human genome to make this possible, perhaps in the not-so-distant future. With the help of Dr. Merkin’s newly formed Merkin Institute for Transformative Technologies in Healthcare at the Broad Institute, Dr. Liu’s continuing research on his revolutionary “base editing” technique and its potential to eliminate thousands of hereditary diseases could transform medicine.

We must possess a basic comprehension of DNA’s structure to understand how it works. Consider the human genome contains six billion DNA letters (3 billion pairs). Four bases in DNA make up the letters A (adenine), C (cytosine), G (guanine), and T (thymine). These letters pair off to form DNA’s double helix. Adenine always pairs with thymine and cytosine always pairs with guanine. These letters are used for the sequences of fragments of DNA and are the code for genetic information. If there is one mistake or mutation in just one single letter within a pair, it can have a significant impact on our health.

Dr. Liu and his team at the Broad Institute utilize base editing, unlike gene editing which requires cutting strands of DNA, with a modified version of CRISPR that allows them to alter a single letter at a time without breaking its structure. To explain the use of conventional CRISPR, it would be like replacing an entire paragraph whereas the modified CRISPR 2.0 would allow the ability to replace a single word. “Of more than 50,000 genetic changes currently known to be associated with diseases in humans, approximately 32,000 of those are caused by the simple swap of one pair for another,” Liu said. Their first base editing tool that converted a cytosine (C) to a thymine (T) has the potential to correct 14% of human diseases associated with a single-letter mutation. The new base editor can convert the base adenine (A) into the base inosine (I), which acts as a guanine (G). This tool will allow them to address an additional 48% of these diseases, offering new opportunities for therapeutic applications.  

INITIAL CHALLENGES WITH ADENINE
In the initial stages of discovery, Liu and his team had challenges in creating an editor that could alter an adenine. Like most scientists who look to nature for answers to create and alter certain proteins and genes to move their research forward and escalate their findings, they had to resort to evolving their own enzyme in the lab that would convert adenine (A) into inosine (I) in DNA. After much trial and error, post-doctoral fellow Nicole Gaudelli was able to generate an enzyme that can convert AT base pairs to GC base pairs in human cells. This effort would take more than two years to accomplish, but their efforts resulted in an average of 53% efficiency with almost no errors. While this method is not a perfect solution, it offers a significant improvement compared to other methods currently used to address point mutations (mutations that affect only one or few nucleotides in a gene sequence). 

Lab Experiment #1
Using the adenine base editor, Liu’s team decided to target a point mutation from cells extracted from a patient with hereditary hemochromatosis (also known as HHC). HHC causes a build-up of iron in a patient’s blood and can be fatal. The team was able to correct the mutation using adenine.  

Lab Experiment #2
Another example of using adenine was the team’s experiment to install a pair of mutations that activate genes that make up the code for the production of fetal hemoglobin. Fetal hemoglobin genes, while silenced at the time of birth, can be used to protect against certain types of blood diseases like sickle-cell anemia if they were to remain active throughout the course of a person’s life. 

THE FUTURE: ALTERING DNA IN LIVING HUMANS
While these discoveries seem promising, base editing DNA to treat genetic diseases in living humans will still require years of research and experimentation, most experiments with base editing are done on cells grown in a petri dish and not on actual living tissue. Liu and his team will need to figure out the best possible methods for delivery to the right tissues in the body’s cells. They will also have to determine the right time to deliver a certain gene therapy and measure its efficacy. While we may be years away from treating diseases in humans, having a machine that enables base editing is an important step to helping solve genetic diseases. Having this new technology available will offer hope and help transform the healthcare outcomes for many illnesses and diseases that currently do not have a known treatment or cure. 

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What is CRISPR? 

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) 

It is the unique organization of short, partially palindromic repeated DNA sequences found in the genomes of bacteria and other microorganisms.

CRISPR-Cas9: A molecular scalpel that can edit or delete whole genes within the DNA structure.

Base editing: An improved and more precise DNA editing tool that allows editing one letter of DNA at a time more efficiently than with CRISPR-Cas9, and with far fewer undesired random insertions or deletions.

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David R. Liu, Ph.D.
Richard Merkin Professor and Director of the Merkin Institute for Transformative Technologies in Healthcare, Core Institute Member, Vice Chair of the Faculty, Director of the Chemical Biology and Therapeutic Sciences Program at Broad Institute of MIT and Harvard

Professor and Director of the Merkin Institute for Transformative Technologies in Healthcare, Dr. David R. Liu at the Broad Institute of MIT and Harvard, is also a professor of chemistry and chemical biology at Harvard University and a Howard Hughes Medical Institute (HHMI) investigator. His research combines and integrates chemistry and evolution to enhance and program biology. He and his lab developed a new approach that includes the evolution of intracellular delivery of proteins with next-generation therapeutic potential – developing and applying genome-editing agents, and the discovery of therapeutically relevant synthetic molecules and synthetic polymers through DNA-templated organic synthesis. 

Liu graduated first in his class at Harvard University with a Bachelor’s degree in Chemistry before entering the Ph.D. program at UC Berkeley. He earned his Ph.D. in 1999 and became Assistant Professor of Chemistry and Chemical Biology at Harvard in the same year. He was promoted to Associate Professor in 2003 and to full professor in 2005. Liu was also appointed as a HHMI Investigator in 2005 and joined the JASONs, academic advisors to the U.S. government
on science and technology, in 2009.