The Power and Potential of Gene Tuning

After a lifetime in the field of epigenetics, and nearly 20 years after my colleagues and I coined the term “genome editing,” I will be the first to admit that describing the “epigenome”—a marvelous biological process that guides what our genes do—takes a bit of explaining. I find that thinking about the genome and epigenome in terms of music and sound-mixing can be helpful here.

We experience all sorts of music as we go through life, from Bach and Brahms to Laufey and Lizzo. It is remarkable that you can do so many different things musically from just a few basic components. You have a defined set of notes, which can be played separately or together in an enormous number of combinations and time signatures. Those notes can be played at different volumes—some louder, some softer. And finally, those same notes can have different textures. The note of A as played on a violin sounds very different when played by a distorted, death-metal guitar. Each has the same number of vibrations per unit time, but our experience of them is not the same at all.

 So now, let’s turn to genes. Humans have around 20,000 of them—which is not many more than the total number of genes in a fruit fly. Initial estimates were far higher, at around 120,000, because we thought that more genes are needed to make more complicated organisms. Our thinking was wrong. The wondrous complexity we observe emerges out of combinations of genes, functioning with a certain order and timing—rather than all of your genes doing “everything, everywhere, all at once.” Our body consists of several hundred different cell types (red blood cell, skin fibroblast, neuron), and about 8,000 genes in a given human cell come together, each at a specific volume, timing, and texture to bring it to life. Scientists call this gene “expression”—a term aptly borrowed from the arts. What coordinates it?

Consider a music score for a song—whether it’s Taylor Swift’s Love Story or Schubert’s Message of Love. In both, you would see notes on a musical stave, with specific markings for rhythm, volume, and pitch. For our genome, every four bars of music would be accompanied by four pages of guidance on how to play them correctly. Scientists have discovered that in addition to 20,000 genes, our genome contains about 3 million sets of instructions on how to express them (akin to dials on a soundboard); together, these cover a quarter of human DNA. Our body contains about 40 trillion cells and in each one the genes are expressing themselves in a distinct way (a blood cell makes different proteins than a liver cell than a lung cell). And now think of setting each dial on a soundboard to the exact position you need for the music to sound like Swift or like Schubert. The epigenome is the total set of “dial settings” for all the genes that are expressed in a given human cell and give it its biological identity.

Health from harmony, disease from distortion

On a fundamental level, health (or the lack of it) is created and maintained through a kind of epigenomically-mediated harmony.

If you’ve ever heard a beginning violinist working through a simple piece, you’ll know it's sonically grating. We hear the lack of harmony, and it's painful.

But what is lack of harmony? It could simply be the wrong note played at the wrong time. But it can also arise from a failure of coordination. Any time you have more than one instrument on stage, if they're not coherent (you might picture a middle-school orchestra, here), it just hurts.

Music can also be ruined when the relative volumes within it are wrong. (“Why are the drums so loud in this mix? We need less vocal and more bass!”) In music, it seems intuitive to us that the various notes and instruments must come together at the correct volumes, and in the right rhythm. And so it is with gene expression in relation to health and disease.

Read More: The Gene-Editing Revolution Is Already Here

We have had access to the complete, human genome sequence since 2003. Our DNA is long; reading one letter of human DNA per second, it would take you a century to read the whole genome. Think 500 textbooks, stacked one atop the other. Now imagine reading different versions of that text—each unique to different people and populations, and asking: where are the genes that make us sick? Where are the genes that lead to heart attacks, or irritable bowel syndrome?

As it turns out, many of the genetic signatures that cause us to develop such common and degenerative conditions are not actually located inside the genes themselves.

Now if that statement inspires some confusion, then you are not alone. We scientists were just as confused at first. But what we've essentially figured out is this: Few of the common diseases we suffer from—be they cardiovascular, autoimmune, or neurodegenerative—are the direct result of broken or defective genes (or keeping within our musical metaphor, broken or defective instruments). The pianos are fine. The guitars are fine. They are simply being played in the wrong way.

Conducting the orchestra of gene expression

Soon after the first sequence of the human genome was determined, scientists started a large effort to compare DNA between individuals with and without certain diseases. This approach—called a Genome-Wide Association Study (or GWAS) has been applied thousands of times for every imaginable human trait difference, including whether someone is a “morning person” or whether a given individual is likely to get celiac disease. What these studies found was this: susceptibility to practically every, major, non-infectious disease rarely lies in the genetic “notes” themselves. Rather, about 90% of it lies in the instructions of how to play those notes.

Armed with this knowledge—and empowered by the development of CRISPR-based proteins that can edit both genome and epigenome—scientists across academia and industry have been racing toward the goal of a new class of genetic medicines. Medicines that can help patients retune the ill-timed notes or imbalanced volumes leading to disease.

The basic idea is this: if discord of gene expression leads to disease, could we not simply re-tune this orchestra of gene output to restore harmony in health?

We have a strong “yes” as an answer in the recent development of a cure for sickle cell disease. This medicine does not involve repairing the mutation that causes the disease –a mutation that breaks a gene that makes oxygen-carrying hemoglobin in our red blood cells. Instead, guided by a GWAS for genetic variants that protect against this disease, scientists figured out how to "wake up” a gene called fetal hemoglobin that normally goes silent after birth. In this work—a collaboration between Dr. Stuart Orkin, scientists at the University of Washington, and a group led by myself—altering one of the epigenetic switches in the “symphony” of how our body makes hemoglobin restored health to sickle red blood cells. In fact, to date, this has helped over 50 persons living with sickle cell disease!

Where this really gets exciting is that there are a vast number of diseases like this— in which otherwise healthy genes are being played at the wrong volume, at the wrong time, or in the wrong combinations. For each of these, we can move the sliders to shift the timing, volume, and texture of what each individual gene “sounds” like. And critically, we can do it without having to rewrite the music.

Gene tuning for common, chronic, and severe disease

The emergence of this new transformative therapeutic power begs the question: what are the areas of most need, and how could we put this to the best, possible use?

It makes sense for the first focus to be on severe disease.  Take, for example, someone with devastatingly high cholesterol, at a high risk of early death from cardiovascular disease. If they do not respond to the usual medications, what are we to do? And what of chronic viral infections like Hepatitis B, for which there are treatments, but no effective cure? What options are there for those who face a lifetime of liver disease, a high risk of liver cancer, and no long-term prospects beyond liver transplant?

Read More: How Gene Editing Could Help Solve the Problem of Poor Cholesterol

 Could we just remove a gene, rip out the page wholesale? Yes. I'm a gene editor, and I firmly believe that gene editing has the potential to cure hundreds, if not thousands of rare, single-gene diseases—a potential recently demonstrated in several clinical trials. But I will be the first to admit that once you have gene-edited somebody, you’re done. There is no way back—you are gene-edited for life. If you are facing an otherwise untreatable condition, you might be fine with that. But for those with partly manageable conditions like high cholesterol or chronic viral infection, there may be less enthusiasm in some folks for this all-or-nothing approach.

With gene tuning, we can place an X mark over a precise part of the music score and say, “Don’t play this.” You can turn this gene up, turn that gene down, and observe the hoped-for benefit. And if something goes awry you can – at least in principle – reverse the effects.

Besides the potential benefit of reversibility, gene tuning also offers control over duration of effect. For example, a remarkable new wave of cancer treatments has emerged recently from work by physicians and scientists at the University of Pennsylvania in which the patient’s own immune system cells are reprogrammed to attack a blood cancer. Once they have done their job, you may want those same cells to calm down and return to standby mode—lest they cause collateral damage through their persistent (albeit well-intentioned) hyperactivity. Gene tuning is built for precisely this kind of nuance, allowing you to raise or lower the volume of one or more genes gradually, or for a fixed, desired duration of time.

Same tune, less cowbell

Beyond this, there is another reason why gene tuning could transform the application of genetic medicine. Put simply: tweaking and editing single genes will only get you so far.

The majority of common and chronic diseases involve expression changes in multiple genes. To tackle these, we will have to re-tune not just one instrument, but a whole section of the orchestra.

Take the case of chronic, age-related autoimmune conditions. Imagine retuning multiple, immune-system genes to turn “attack yourself” music into “protect yourself” music. We actually know which genes to tune for that. And the ability to set their volume gauges to zero, to 10,000, or anywhere in between is ultimately where the next generation of therapeutics are headed.

For the vast majority of disease, we don't need the genes to be off, we just need them to start performing at the right volume. Same tune, only less cowbell.

Looking ahead at the next decade, I see it as an important window of opportunity for gene tuning to go after diseases where multiple levers need to be adjusted on the soundboard—and where the adjustment level needs to be a graded one, rather than all-or-none.  This is not to say that gene editing cannot do similar things. But sometimes you just need to match the problem to the solution best configured to solve it. You could play the intro to the Jaws theme on a flute – but it will sound better on a double bass.

So when can we expect these gene-tuning therapeutics to actually become available to patients?
In a time where genetic therapy for cancer is becoming the standard of care, and where we have an approved CRISPR medicine for the most common genetic disease on earth, we are closer than ever. The number one thing we have learned from that history is every new technology stands on the shoulders of previous ones,

The first clinical trials for gene tuning are likely to happen very soon - perhaps within the year.  Encouraged by the exponential growth in the broader gene therapy space, many academic scientists and biotech companies are working hard to bring therapeutic gene tuning to patients. Clinicians and regulators worldwide have learned to appreciate the power and potential of gene editing, and I am hopeful we will see a similar phenomenon for gene tuning as well.

The second half of John Lennon’s classic Strawberry Fields Forever was sped up by the Beatles’ producer, George Martin, to sound right—one of countless examples in the history of music where small tweaks to the score made a big difference. Gene tuning is just getting started on a similar journey to bring harmony to human health—a big challenge, to be sure, but one, I sincerely hope, we can work out.