I’m part of a team at bluebird bio developing transformational new technologies and I love it. The current pace of technological innovation in biotech has ushered in new possibilities at an unprecedented rate. We find ourselves in a position not unlike aviation engineers some 60 years ago. For example, the SR-71 Blackbird was a technological leap forward in aircraft design, built to go fast and fly undetected. This remarkable plane, first flown in 1962, still holds the record for the fastest airbreathing engine piloted aircraft. So, what does this Blackbird of the cold war era have to do with bluebird and the gene therapy era? Simply put, mission and capabilities, and – when it comes to our gene editing program – stealth.
The Blackbird was the first aircraft to incorporate stealth technology to reduce radar signature and fly undetected. If you were to ask someone to describe bluebird bio, they might say we’re a gene therapy company or perhaps a rare disease company. If you asked them what we do, they may describe our transformative lentiviral gene delivery platform. Our lentiviral technology applied to our investigational cell therapies has shown promise in functionalizing red blood cells in patients with beta thalassemia or sickle cell disease and may provide hope to parents with boys diagnosed with cerebral adrenoleukodystrophy.
What might get missed amongst this incredible array of candidates in clinical development is that we are also researching and pioneering gene editing technologies. bluebird is building a new generation of therapies centered around precision gene targeting using an entirely separate biological platform. And not only are we applying our gene editing technology ex vivo, akin to our lentiviral platform, we are actively developing ways to perform gene editing in vivo, to make corrective genetic alterations in situ – in cells where they reside within the human body.
Under the cover of bluebird’s success, the gene editing program flies in stealth mode like the Blackbird, avoiding detection but performing mission critical work. Off the radar we are reimagining approaches to diseases once thought intractable and developing novel tools to bring hope to patients.
The Blackbird was the first plane to employ novel stealth technology to enhance flight mission capabilities. Similarly, meganucleases, the basis of bluebird’s investigational gene editing platform, was the first gene editing technology to demonstrate the ability to make targeted double strand DNA breaks—an advancement that enhanced the incorporation of exogenously provided DNA. This seminal work formed the tenets of the current gene editing paradigm being used in labs across the globe.
However, like stealth technology, gene editing also saw the rise of newer, technologically distinct platforms. As academic and industrial groups sought to develop programmable DNA recognition and cleavage systems to drive scientific discovery and ameliorate disease, new gene editing platforms were established. Meganucleases, Zinc Finger Nucleases (ZFN), Transcription-Activator-Like Effector Nucleases (TALEN), and Clustered Regularly Interspersed Short Palindromic repeats and associated proteins (CRISPR/Cas9), listed in the order of their discovery to cleave a DNA target of interest, are all being developed for clinical gene editing approaches.
Our meganuclease platform has several characteristics that we hope will allow it to fly. We can append a TAL DNA binding domain to a meganuclease core (called a megaTAL) enhancing its already favorable DNA binding specificities and cleavage activities. The monomeric architecture and small size of the megaTAL nuclease requires the delivery of a single component to make double strand DNA breaks. Moreover, unlike other nuclease platforms, megaTALs break DNA leaving 3’ overhanging tails, enhancing transgene insertion. Our megaTALs are small, specific, powerfully active, easily delivered and yet fly stealth through a biotech landscape driven by investment in the newest model plane.
Throughout my scientific career I have had the somewhat rare experience of utilizing all four gene editing platforms in my research. I can say they all work, they cut DNA and can be used for various end purposes with their incumbent advantages and challenges. So why do I choose to fly stealth?
The sense of community and commitment to patients at bluebird is tangible, it is real. It does not merely exist in the platitudes of some company slide deck. I and the amazing team here believe it to our core, and it drives us. Our commitment to excellence causes us to do the hard science and prevents us from putting any old therapy out there because it is “gene editing.” If it’s not transformative then it is not worth it.
I fly stealth because success, not recognition, motivates not only me but the whole gene editing team, from the protein scientists who create the megaTALs to the engineers and biologist tasked with delivering them to cells and characterizing their function. The gene editing team at bluebird, like the rest of the company is enthusiastic, authentic, hardworking and caring. Moreover, we are supported by a company culture that encourages personal development, believes in work-life balance and actively encourages challenging the status quo; critical “life” support systems when flying fast and on the edge of technological space.
We are hopeful that the success of bluebird’s gene editing program will see us emerge from stealth mode. We strive to become visible and clinically impactful as we seek to bring our own vision of what new types of treatment could look like to those who need it most. Like the Blackbird now on display in museums across the country, our emergence will be testament to the hard work and dedication of a talented team—building something historic.