From bedside to bench and back again: Review of “Cured” by Nathalia Holt

Cured cover

Innovation in pharma is a messy business. Drug R&D is risky, expensive, and slow – and that’s the easy part, once there’s actually a compound to test. Medical breakthroughs are even tougher in the “pre-drug” phase, for diseases where the underlying biology is complex and poorly-understood – but they do happen, which begs the questions of “how” and “where”. Big pharma, small biotechs, non-profits, and academia all have roles to play, but none has cracked the code in the earliest phases of biomedical discovery.

Luckily, there’s one reliable wellspring of innovation in medicine – the clinic. Doctors and desperate patients who face illnesses that “didn’t read the textbook” (or for which the chapter hasn’t even been written) often try untested therapies at the fuzzy intersection of science and patient care. And when we’re lucky, these micro-experiments pave the way for novel and important treatments.

In Cured: How the Berlin Patients Defeated HIV and Forever Changed Medical Science(Dutton), Nathalie Holt recounts two tales of innovation in the clinic.Timothy Brown, whose case is relatively well-known in the HIV community, received a bone marrow transplant in 2006 from a donor whose cells lacked CCR5, a critical co-receptor for the virus. Not only did his amazing clinical course significantly advance our understanding of HIV biology, but it also provided inspiration and validation for ongoing gene therapy approaches in other diseases.

The other Berlin patient, Christian Hahn (a pseudonym, as he remains anonymous), was treated with a “hit hard, hit early” approach that combined two anti-viral agents with hydroxyurea, an anti-cancer drug that had not been widely tested in HIV. Although Hahn’s treatment had a completely different rationale and method from Brown’s, the outcome was similar: Hahn was functionally cured of the virus, even after ceasing anti-HIV therapy.

These two patients’ stories are scientifically distinct, and in linking them together, Cured is predictably sprawling and complex. Holt interweaves the two stories with one another and other narratives of drug trials, basic gene therapy experiments, and related scientific advances, and although this non-linear approach sometimes helps bring out shared themes, it can be hard to follow. Add in the inherent challenge of explaining viral immunology to a lay audience, and you get a tale that requires a lot of patience and concentration.

Nonetheless, the main point of Cured comes through loud and clear: some ideas in medicine can only come from the clinic, one patient at a time. Heiko Jessen (Hahn’s physician) and Gero Hütter (Brown’s physician) had the right combination of insights, patient relationships, and grit to conduct single-subject “experiments” that would never have been pursued by an established company or organization. Gene therapy in particular owes a special debt to Hütter and Brown, whose “proof of principle” data were a direct ancestor of the exciting approaches being tested in the clinic today in cancer and other diseases.

But capitalizing on case study observations is not always easy, as illustrated by the 15-year effort to understand and systematize Jessen’s findings. We still don’t know exactly how the various components of Hahn’s treatment – his specific drugs, early initiation of therapy, “drug holidays”, and underlying genetic background, for example – interacted to yield such a robust response, and perhaps we never will. But even today, Jessen’s work continues to inspire further experimentation, and by recounting his story, Holt convincingly argues for the value of the process, not just the output, of clinical innovation.

Holt exposes another barrier to leveraging the power of “crowd-sourced” research: the cliquish biomedical research community. Without co-authors from the HIV “establishment”, Hütter’s work didn’t reach public attention for a year while it was rejected for publication and a meeting presentation. And this was in the context of a remarkable result – imagine the challenge if Brown’s outcome had been scientifically interesting, but a clinical failure? It’s sobering to consider how much medicine could benefit if all of these anecdotal, early, and incomplete findings were disseminated more quickly and openly.

Taken together, the two Berlin patients’ stories in Cured demonstrate the promise and challenges of “bedside-to-bench” research. Independent, iconoclastic physician-scientists like Hütter and Jessen can’t single-handedly drive medical innovation, but neither can established players like pharma and academia. The key is to figure out how to support real-world clinical experiments, disseminate the insights, validate the hypotheses, and develop new therapies. If we can do that more efficiently and effectively, that would be real innovation indeed.