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BURLINGTON, Mass. — When the first sequencing of a human genome was announced in 2003, a coalition of world leaders issued a statement declaring that researchers had “completely decoded all the chapters of the instruction book of human life.” They added that “this information is now freely available to the world without constraints.”

That big initial splash may have created unrealistic expectations for the field of genetic engineering. As Dr. Nessan Bermingham, former CEO and founder of Intellia Therapeutics, put it, “People say, ‘This is great. Can you give me a massive IQ? And I’d love to be taller, change my eye and hair color, etc….’ ”

Just getting started

Dr. Bermingham spoke during the daylong MilliporeSigma Scientific Symposium on Oct. 11. (Watch the video here.

Like other leaders in the field — including closing keynote speaker Dr. Charles Gersbach, Rooney Family Associate Professor of Biomedical Engineering at Duke University — Dr. Bermingham set a measured, sometimes sardonic tone. For all the promise of genome editing and directing cellular behavior, it’s important to remember that the technology is still in its infancy.

In fact, just a day after the symposium, Philadelphia-based Spark Therapeutics announced that the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee had recommended approval of the drug Luxturna, designed to treat an inherited retinal disease. If approved, it would be the first gene therapy for a genetic disease in the United States — 14 years after that first genome sequencing was completed.

Researchers still have much to learn. Humans have roughly 20,000 genes, which comprise only about 2% of the genome. The remaining 98% consists of what was initially called “junk DNA.” Researchers now believe that “junk DNA” plays an important role in regulating genes.

“If the 20,000 genes are the light bulbs,” Dr. Gersbach said during his keynote, “then there are approximately two million different dimmer switches involved in dialing those 20,000 genes up or down. That’s where we get the complexity of [human] biology.”

Adding to that complexity are genetic mutations, what Dr. Bermingham called “typos in the book of life.” The prospect of identifying and correcting those typos is tantalizing — until, he noted, “you realize that there are about 5,000 to 7,000 single-gene-driven diseases known today.” Nevertheless, he added, “There are tools that have been generated over the last 20 years or so that actually allow us to start modifying things. The convergence of technologies, tools and biological understanding sets the stage for a potential paradigm shift in patient treatment, giving us the potential for curative and potentially palliative treatments.”

An advance where you’d least expect it

One of those modification tools was discovered serendipitously. A decade ago, Danisco, a yogurt company, began researching ways to eliminate viruses that were contaminating cultures. They found that a certain percentage of the bacteria used in its cultures was virus-resistant.

“Turns out bacteria have a very neat little immune system,” Dr. Bermingham said. “It’s effectively comprised of two components. The first is analogous to a pair of scissors, or a scalpel, that allows it to cut genetic material. The second is effectively a zip code that sits on the pair of scissors targeting it to a specific site in the genetic sequence, ultimately leading to a targeted cut of the DNA.

This discovery raised the question of whether the DNA-cutting agent could be used for human therapeutic applications. The answer has come in the form of CRISPR/ Cas9 technology, which Dr. Bermingham compared to a Swiss Army knife, given the potential to effect different edit types within a cell depending on the desired outcome.

“The fascinating thing about it is that it doesn’t just allow us to target one part of your DNA,” he said. “We can hook up a lot of these scissors to a lot of different zip codes and send them throughout the whole genome to target different regions and do different types of edits. This is important when we start thinking about very complex diseases like neurodegeneration, bipolar disease or schizophrenia.”

This technology also has significant implications for personalized cell therapy. “We’ve been able to take an immune (T-) cell out of a patient and deliver into that cell new DNA that effectively acts as a seek-and-destroy tracker,” Dr. Bermingham said. “We put those cells back into the body, and that cell goes around the body scanning for cancer cells. When it finds a cancer cell, it grabs it, holds onto it and launches an immune response.

“This is the first example of where we have a very specific therapeutic application specifically targeting a cancer cell. It relies on genome modification, rather than genome editing, for the first generation; however, genome editing of those provides the potential for an enhanced response. Two of these types of drugs have recently been approved. The response rate in patients has been tremendous. This is a profound advancement as we think about treatments for cancer.”

Udit Batra, Ph.D., CEO of MilliporeSigma, the life science company that convened the scientific symposium, is also excited about the promise of personalized cell therapy, but highlighted that there are a few challenges that need to be overcome to get the therapies to patients efficiently and effectively. “We’re already working with innovators from biotech, academia and physicians from hospitals to figure out how we simplify and professionalize the manufacturing process to accelerate access to this therapy for many, many patients,” he said.

Moving to a health cure system

Genome modification, genome editing, personalized cell therapy, directed cellular behavior — all can be used not only to treat diseases, but also to prevent them.

“Moving from healthcare to an actual health cure system, there’s potential for a new paradigm,” Dr. Bermingham said. “There are significant social implications to this. Should we make permanent changes, not just for that individual, but also for the offspring of that individual?

“If you talk to a Huntington’s disease patient, they will tell you that the thought that their offspring can actually have Huntington’s disease — is a dreadful thought. They would like to figure out a way to ensure that they are not passing it on. However, we need to proceed cautiously.”

But genetic modification also brings to mind The Economist‘s “Editing Humanity” cover, which broached the possibility of customizing things like hearing, vision, IQ and other attributes. “Where do we actually draw the line?” Dr. Bermingham said.

The answer, to some extent, lies again in managing expectations. “If you look at IQ, no one gene or two genes or 10 genes drives that,” he said. “At best, one gene has about a 0.1% impact on your IQ. Reading to your kid every night before they go to sleep has a much higher impact on their IQ than any genetic modification that we could do today or in the foreseeable future.”

As we look ahead, people should focus on who will ultimately have custody of their genome sequences and how that data will be utilized. “The cost of whole genome sequencing has plummeted. As such, there is the potential for every child that is born to actually have a genome sequence versus the standard enzyme panel that’s run on the baby today,” Dr. Bermingham said. “There are already groups out there today looking at that from a  big-data standpoint.”

An exciting future

The race is on — not just to find cures for diseases that are killing millions of people worldwide every year, but also to determine who gets to decide the major questions regarding ethics and ownership. As in 2003, information regarding genome sequencing is essentially “freely available to the world without constraints.” No doubt, there will be more debate in the future about the regulation of genes.

“Not only is there an exciting future ahead for us in gene editing, but, as is often the case, an entire new field has opened through the research into those ‘junk’ sequences that aren’t junk at all,” said Dr. Gersbach.

Learn about MilliporeSigma’s new Life Science Center in Burlington, Mass., which officially opened on October 11, 2017.

MilliporeSigma recognizes the potential benefits of conducting properly defined research with genome editing because of the breakthrough therapeutic potential. Therefore, MilliporeSigma supports research with genome editing under careful consideration of ethical and legal standards. MilliporeSigma’s parent company has established a Bioethics Advisory Panel to provide guidance for research in which its businesses are involved, including research on or using genome editing.