Serendipity, invention and innovation at X-VAX

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The science fiction author and biochemistry professor Isaac Asimov once observed that the most exciting phrase in science is not “eureka!” but “gee, that’s funny,” because stories of scientific discoveries are full of lucky coincidences – from the stray mold spore that landed on a Petri dish and led Alexander Fleming to discover penicillin, to Wilhelm Röntgen’s chance detection of X-rays while testing whether cathode rays could pass through black cardboard.

Serendipity, the notion of researchers seizing upon an unintended and unexpected occurrence, has also played an important role in the discovery of our candidate vaccine ∆gD-2 (delta gD-2). However, serendipity is no accident. It takes curiosity and determination to follow through and turn that discovery into an invention.

Finding what wasn’t being looked for in the first place

Pablo Gonzalez was a postdoctoral researcher from Chile who came to William “Bill” Jacobs’ lab at Albert Einstein College of Medicine in New York to study how to genetically manipulate mycobacteria and develop vaccines against viruses. Bill’s lab had pioneered the genetic manipulation of BCG (the vaccine against tuberculosis), and both Bill and Betsy Herold had discussed the idea of cloning herpes genes into a BCG vector. As part of the collaboration, Pablo began learning mycobacteria genetics from Bill’s lab and herpes virology from Betsy’s lab. Pablo was a successful genetic engineer and had introduced several different herpes genes into recombinant BCG, but none of these successfully protected mice from herpes.

The herpes simplex virus (HSV) contains a protein on its surface known as glycoprotein D (gD), which is needed for the virus to enter host cells. At one of Betsy’s lab meetings, Natalia Cheshenko, who led research in uncovering the herpes virus cell entry mechanisms, mentioned that she needed to make an HSV-2 strain that was deleted in gD to better understand its role in triggering the signaling cascade involved in viral entry. Pablo volunteered to make the virus, and the gD-deleted virus helped answer the question about viral entry, which led to the first collaborative publication where the ∆gD-2 virus was described.

One day Betsy, Bill and Pablo were pondering the disappointing results with the BCG vaccine vector, when they decided to follow through on an inspiration: “Now that we have this gD-deleted virus, what if we immunize the mice with it?” This was a heretical thought as decades of research in herpes vaccine development had focused on gD as an essential target for immune protection, because that protein elicits the dominant neutralizing antibody response in natural human infections. The researchers were wondering if deleting gD could stimulate a different immune response. They knew the virus would likely be safe as it lacked the gene for the surface protein needed for viral entry and therefore could not spread after injection.

Two months later Pablo got the results of the first experiment: complete protection! And thus began the collaborative studies between the Herold and Jacobs labs, led by the two talented graduate students Chris Petro and Clare Burn, into why deletion of gD led to this surprising and functionally distinct protective immune response. Further research revealed that ∆gD-2 induces non-neutralizing antibodies that mediate the killing of infected cells. It appears that the gD surface protein interferes with the immune response as part of a viral immune evasion mechanism; deleting that one gene seems to “unmask” several other protective antigens. A patent application was filed, and later X-VAX licensed the invention for further development and commercialization.

Innovation is taking an invention to market

At X-VAX, creativity and an interdisciplinary culture foster the unexpected. We look for connections that may not be obvious. For our lead herpes vaccine program, we plan to transform the scientific invention of ∆gD-2 into an innovation that meets the needs of patients, physicians and payers in the marketplace. It involves the disciplines of developing and launching a product that has regulatory approval and insurance reimbursement, and that people want.

We believe that innovation doesn’t come from a single mind but from team players who appreciate diversity and want to be surrounded by people who enjoy different opinions and ideas. Often, it is a conversation over lunch or while having a coffee that can lead to the decisive spark for a new concept. Innovation happens at the crossroads of serendipity and knowledge. Or as Louis Pasteur put it, “chance favors only the prepared mind.”