Why aren’t all those breakthroughs translating into cures?

One of the ways that science journalism continually fails the public is by ignoring the Valley of Death that lies between discovery and product development. The problem is especially acute in healthcare, where the maddening complexity and unpredictability of clinical responses dooms most “breakthroughs” to failure.

The problem is less ignorance on the part of journalists than a combination of laziness and cupidity. Stories about high schoolers curing cancer are easy to write and are a good bet to generate ad revenue. So those stories get written, but the stories of how discoveries actually get turned into treatments are just too hard to write and sell. That’s a shame.

The article I linked to above was written in 2011, and reported legit studies of nanoparticles in cancer treatment. It’s now 2019, and this review of nanoparticles in medicine says that “Nanomaterials have the potential to overcome some of the major issues in the clinical world which may include cancer treatment….” If after 8 years you are still talking about potential, then maybe that breakthrough wasn’t quite the step forward that was depicted.

All of this is to say that it’s no surprise that the public has no idea how hard drug development is, and are perplexed that we have so many breakthroughs yet so few cures. After all, if teenagers are curing cancer, what are all these fancy scientists at greedy drug companies doing? How hard can it be?

That’s the background for questions like this one that I got on Quora:

Can’t I just drop a mixture of phages into a vat of MRSA and harvest the ones that multiply? Why is finding a phage alternative to antibiotics harder than this?

Dropping phage into a vat of MRSA is R&D. Finding a phage alternative to antibiotics is product development. There is a huge gulf between the two.

Killing bacteria in a test tube is easy. We’ve been doing it with phage (and any number of other compounds, both natural and synthetic) for well over a century. If that was the hardest step in creating medicines that cure infections, then no one would ever be sick.

So here is a list of the barriers that lie between finding a phage that kills bacteria and creating a medicine that actually cures people. The list is in increasing level of difficulty.

1. Finding a mixture of phage that kills all strains within a species of bacteria. Bacteria, unlike animals, have highly divergent genomes. The “core” genome of S aureus comprises only about 75% of its total genes (vs >99% in humans). This diversity means that not all strains are susceptible to any one particular phage. Few phage successfully infect more than about 70% of clinical Staph strains. Getting >95% coverage of these strains requires developing a “cocktail” of a half-dozen phage.
2. Developing manufacturing methods that deliver phage products of consistent potency and purity. Phage constantly mutate and evolve; making sure that batch 100 performs exactly as batch 1 did is not a trivial challenge. In addition, phage have to be purified away from bacterial products that cause inflammatory responses. Several recent case studies of phage therapy report that phage doses were limited by these contaminating endotoxins.
3. Developing a realistic animal models of disease. Rodents don’t get sepsis the way humans do, and sepsis is the leading cause of death from bacterial infectious disease. Most animal studies that purport to show efficacy of phage therapy simply treat the animals like test tubes: bacteria are injected, phage are injected soon thereafter and wipe out the bacteria. But that’s not how infectious diseases present in the clinic. Clinical infections are usually well-established in one or more locations and then spread to other tissues. Bacteria in an established infection are physiologically very different from bacteria in a test tube, and what works for test tube bacteria may not work at all in a real infection.
4. Those animal models are also needed to determine if the phage can get to the site of infection, and persist long enough to find the target bacteria and attack them. Most antibiotics have half-lives on the order of several hours. The half-life of phage in the bloodstream is just a few minutes before they are scavenged and destroyed and excreted. Phage are viruses, and your body is very good at detecting and eliminating viruses. Formulating phage to perfuse infected tissues and persist there is a major challenge.
5. Developing rapid diagnostics and getting clinics to use them. Nearly all antibiotic prescriptions are written in the absence of any microbiological testing. Because antibiotics have a fairly broad range of activity, doctors can usually guess which antibiotic will have at least some clinical value. Standard micro workups take 2–3 days, and no doctor will wait for these results before prescribing. In contrast to antibiotics, phage are very narrow-spectrum (see #1 above). Prescribing an anti-Staph phage therapy for a Strep infection would do no good at all. No doctor (or patient) will want to wait for more than a few minutes, or pay more than a few dollars, for test results that are needed to guide phage therapy. Until we have rapid (and cheap and accurate) diagnostics, it’s much easier to just write a prescription for antibiotics.
6. Making the economics work. Despite the very real crisis of antibiotic resistance, antibiotics (either first- or second-line) work > 90% of the time. Antibiotics are also relatively cheap, rarely costing more than a couple hundred dollars for a course of therapy. This means that the market for phage therapy is relatively small and that manufacturers can’t charge high prices to make up for it. Why should drug companies and venture capitalists invest in a high-risk, low-return product?

You’ll notice that FDA/regulatory hurdles aren’t anywhere on my list. That’s because any outfit that takes care of #’s 1–4 will have no problem with the FDA. A package of high-quality analytical, pre-clinical and clinical studies presented by a manufacturer with a strong quality system will sail right through the NDA process.

Phage therapy is not unlike many of the other “breakthroughs” we read about in health news: it works great in the lab, but is difficult to translate into an actual treatment that is safe and effective. Making discoveries is relatively easy; making medicines is very, very hard.

And writing stories that reflect this reality appears to be even harder. Or at least, less remunerative.