There and Back Again

Mitchell Finer on the Journey of Biotech from Start-Up to Success

Editor's note: Mitchell Finer was a postdoctoral fellow with James M. Wilson, M.D., Ph.D., in Richard Mulligan's laboratory almost 30 years ago, where he began his work on gene therapy for disorders of globin expression. He emerged as a leader in the commercial development of gene therapy through his work in the biopharmaceutical industry. Mitchell recently stepped down as the chief scientific officer of bluebird bio. During a recent visit, Dr. Wilson asked Mitchell to reflect on his illustrious career and what he thought about the future of the field of cell and gene therapy.

Mitchell Finer, Ph.D,, is the former chief science officer of bluebird bio

Could you take us back to the days of the Mulligan lab at The Whitehead Institute when you started the work on beta globin gene therapy and discuss how it played out from there?

In the early days, we had very few tools to deliver therapeutic genes, and the field at the time focused on retroviral vectors. We had the sequence of the virus and knew some biology of the virus, although the work was mostly empirical—a lot of trial and error. Expressing the globin gene required use of genomic sequences in contrast to expression of complementary DNAs, which are the basis for most gene therapy vectors. The retroviral vectors we used do not normally encode introns that were necessary to include in our globin expression cassettes. In the end, the task took about 15 years from the work that I started in the Mulligan lab in the mid-80s together with Philippe Laboulch, now back in Paris, who expanded in detail the molecular basis of globin gene regulation and designed a globin gene expression cassette and completed this work in the early 2000s. Philippe ironed out how to get the vector to efficiently shuttle the globin gene into cells and how to get the gene to faithfully express in a tissue-specific fashion. It took a huge amount of researcher-years to get there.

How did you decide to work on beta globin during your postdoctoral fellowship with Richard?

When I was a graduate student at Harvard, I had some good friends in Tom Maniatas's lab, who had just published a great landmark Cell article starting to dissect the regulation of genes of the beta globin gene by transfecting plasmid in murine erythroleukemia cells. There was a beta globin project already in Richard Mulligan's laboratory, run by Elaine Dzierzak. Using retroviral vectors to introduce globin genes into hematopoietic stem cells was really the way to get at the true biology of the beta globin gene hematopoiesis, and so, upon starting my postdoctoral fellowship, I was all over the project. It was an exciting area, but clearer understanding of how to develop a therapeutic correction of beta thalassemia and sickle cell anemia could be gleaned by delivering the gene in the correct (hematopoietic stem) cells in the animal.

It is interesting that Tom Maniatas inspired you to do this because I met Tom while applying to graduate school in the Department of Chemistry at Cal Tech. He told me about his work in studying the regulation of the globin gene in eukaryotic cells. It suggested to me that the future of biology would be molecular and that one could do this work in eukaryotic systems rather than prokaryotic systems. I then moved from chemistry into the fields of biochemistry and biology and eventually developed my interest in gene therapy.

He is a very inspiring person. I seriously considered doing a postdoc in his lab. But I was at Harvard and ended up moving to the Whitehead Institute for biomedical research. Again, getting out of plasmid transfection, to be able to deliver genes into animals and see how they performed in the appropriate target cell, in vivo in mice, was a huge step up. It was well worth it.

Speaking of inspiring scientists, you and I did our postdoctoral fellowships with Richard Mulligan. Share with me an anecdote about Richard that typified our incredible experience there.

During our postdoc, Richard was emerging as a leader in biomedical research and, as a result, was traveling a lot and often away from the laboratory. Our laboratory group meetings were becoming less and less frequent. From what I recall, you and I decided to convene some group meetings when Richard was away just to help facilitate communications within the group. During one of our “renegade” group meetings, Richard, who was supposed to be out of town, showed up and blew a gasket that we had taken control of the laboratory! I think he was offended we did not invite him to his own group meeting, although, in the end, he was appreciative that you and I took the initiative.

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Human Gene Therapy, published by Mary Ann Liebert, Inc.,is the premier, multidisciplinary journal covering all aspects of gene therapy. GEN presents here one article "There and Back Again: Mitchell Finer on the Journey of Biotech from Start-Up to Success that was published in Human Gene Therapy Clinical Development." The views expressed here are those of the authors and are not necessarily those of Human Gene Therapy, Mary Ann Liebert, Inc., publishers, or their affiliates. No endorsement of any entity or technology is implied.