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Lipinksi Rules, Biotech Bootcamp and Sharktank

Back about 20 years ago, a medicinal chemist named Lipinski came up his “Rule of Five” for whether a chemical compound had “drug like properties”. Never mind what they are, unless you’re planning to start a lab in your garage. There have been variations on the “rule of five”, like, do you really need a drug right out of the starting gate? Why not look for lead-like compounds? What are the properties of those? And how did you come up with these rules anyway?

The bottom line answer is, well, after you’ve seen a bajillion compounds coming out of high throughput screening and have worked on thousands more, you just know. You can look at a compound and say, ehhhh, that’s never going to be a drug. The tailpiece has too many carbons or the scaffold is too skimpy or that compound is promiscuous. (Um, that’s as sexy as drug design gets by the way). In general, this comes with years of experience and lots of practice.

But now there is a different Lipinski involved in drug discovery. This is Dan Lipinski, the Democratic representative from Illinois, and he’s all about making drug discovery more appealing to vulture capitalists. His latest initiative, hooking up labrats to the money, is profiled in a recent article in Nature called Biotech Bootcamp. It made me throw up a little. Here are some money quotes:

David Johnson was just one minute into making his pitch when the interruptions started.

“Why do I care?” barked a bespectacled man at the back of the seminar hall. Johnson, chief executive of the California biotechnology start-up GigaGen, blinked. He had condensed his company’s story into a neat ten-minute presentation for I-Corps, a nine-week course designed to teach business skills to entrepreneurial scientists like him. Now his talk was derailed.

At first Johnson did not understand the question. He thought it was aimed at the therapy that GigaGen, based in San Francisco, plans to develop for people with weakened immune systems.

“No. You. Why do I care about you?” the man demanded.
Johnson was not the only one getting gruff treatment at I-Corps’ kick-off meeting in Chevy Chase, Maryland, last October. When another team squandered a few precious minutes elaborating on the need for new therapies to treat pain, I-Corps creator Steve Blank pounced. “If you spend the next ten weeks telling us about pain, you’re going to be in pain,” he said.

Drug discovery, meet Sharktank.

You know, I just want to reach into the journal and strangle this Steve Blank guy. Here he is barking at a dude who has probably spent untold years doing research on the subject and all that matters is the bottom line. What have you done for me lately? What’s in it for Steve Blank?

It gets better, or worse, depending on your perspective:

It will take years to find out whether the approach and theory behind I-Corps is adaptable to the unique challenges of drug development. But it was already clear by the conclusion of the inaugural class last December that many of the 19 teams had learned some unexpected lessons: several companies were told to drastically change course, and in some cases to abandon promising science for something more market-savvy. “You can be a great researcher and you can think you have great ideas,” says Congressman Dan Lipinski (Democrat, Illinois), who had pushed to see Blank’s approach implemented for government-funded research. “But until you’re forced to talk to a potential customer, you never really know.”

Yes, I’m sure that’s what Watson and Crick thought when they worked on the structure of DNA. Who’s going to buy this thing?

“So, I said to Francis, who cares what we can do with it? It’s just f***ing awesome!”

They probably thought they had great ideas. Ha! What did they know? What’s really important is how much money can they make for the investor. How is this ball and stick model of some stupid polymer going to change my world? What has it got to do with me?

This quote was gobstopping:

Lipinski has long been concerned about the quality of research funded by the US Small Business Innovation Research (SBIR) programme. The funds are intended to stimulate translation of scientific discoveries into the marketplace, but critics have raised questions about how effective the programme is. A 2013 analysis by Nature found that the top earners of such grants were rarely focused on commercialization. “Sometimes it seems like SBIR is being used in many cases not to further a business, but to continue research,” says Lipinski.

That’s right, sometimes biotech startups will do anything to get the money to further their research. They’re utterly shameless.

Anyway, read the whole thing. I’m not saying that this approach doesn’t have some merit. But in the industry, we call them project reviews. Things *do* get cut on a fairly frequent basis. The difference is that research is (was) still thought as having intrinsic worth. It isn’t always clear to the business community why science should pursue something but each little revelation may become extremely important to someone else in another company 15 years from now. Lipinski, Blank and the sharktank approach don’t seem to get that. So, I have to ask, who put Dan Lipinski in charge in the first place??*

Derek Lowe of In the Pipeline summed up the Silicon Valley attitude to drug discovery research the other day in Silicon Valley Sunglasses, and while Derek and I have differing views on the role of government in drug discovery, we do agree on the basic problem with putting Silicon Valley entrepreuers in the driver’s seat:

There’s another problem that’s not unique to the Valley, although it does tend to give people a bad case of it. That’s the “Clearly I’m smart and successful, so clearly I have something to offer in this other field over here” one. We all succumb to that one now and then; it’s human nature. You can watch Mark Cuban display it here, with respect to medical testing.

But here are a couple of recent examples of the more localized problem. I wrote last year about Emerald Therapeutics, an outsourced-lab-assay company backed by Peter Thiel (who may also be interested in their antiviral therapy ideas). Here’s another article on them, and it asks, in so many words, “Why is new drug development so comparatively torpid when app development is so torrid?”. I couldn’t provide a more succinct version of the Silicon Valley/biopharma disconnect if I tried.

According the article, the folks at Emerald “. . .think it comes down to the difficulty of running experiments in the life sciences”. But I’d like to propose that this difficulty, at least for early-stage work like Emerald is proposing to do for people, is largely a matter of contrast. If you’re used to being able to sit down and bang out code, any time, anywhere, with all kinds of tools (libraries, compilers, virtual machines, what have you) at your fingertips, then yeah, working up a new assay protocol in a cell line is going to seem agonizingly slow. Multibillion dollar ideas can be cranked out in the coding world very quickly, if you hit the right place at the right time, but just you try that in the lab. Now, I have no problem with Emerald running assays for people, although it may yet be harder than they’re thinking. But they’re not removing as much of a bottleneck as they might think. The real bottlenecks are figuring out what assay to run, and what to do with the data once you have it. Can’t outsource those.

That’s what I think has been Valley-ized there, the idea that very, very soon now something will just wildly, exponentially take off. As much as I might like to see something like that happening in biopharma, though, I can’t quite make myself believe it. Technology, Silicon Valley style technology, is human-designed and human-optimized for other humans. As human beings, we’re playing on our home turf there. But the biology of disease is an away game if there ever was one. The inner workings of cells and the ways that they work together are flat-out alien compared to anything we’ve ever built ourselves. People who are used to coding up apps have never experienced anything like it, and many of them don’t seem to realize that they haven’t. Expecting the sorts of behavior that you get from human-built technologies, and expecting the same effects from the techniques that work to optimize them, is an expensive accident waiting to happen.

Derek is understating the challenges of research here. The thing that really ticks off the beancounters, as I have seen from personal experience, is the number of iterations researchers have to go through to understand something. It takes multiple assays, multiple rounds of synthesis, multiple trips to the syncrotron for dataset collection, multiple attempts to make the protein. There are just a lot of steps and they have to be repeated over and over again. Each one costs money. Some of them lead to dead ends but the only way to know that is to actually do the research, presumably with your small business loans. Those steps and the costs associated with them freak MBAs out. They carve a significant dent in “shareholder value”, therefore, they must be investigated, limited and controlled. And that is when researchers find themselves in a real bind because there can be no breakthroughs without the annoyingly slow, agonizingly expensive tests, assays and datasets. Public flaying of nascent biotech CEOs is not going to make this better. Ok, maybe you’ll eventually hit on another Cialis. Other than that? I have serious doubts unless there is an unusual degree of kismet involved.

Silicon Valley entrepreneurs aren’t the only ones who have no idea how complex biopharma research is. Congress seems to be buying into this mindset that these geeky researchers just need to start thinking like fast and nimble Silicon Valley types and  MBAs on steroids. They are making the challenge of drug discovery even more difficult than it already is. It’s already a long, hard slog without money.

I just hope that the presidential candidates take some time to work through these issues. Private capital is probably not going to be enough to save the drug discovery research infrastructure at this point. What is needed is long term investment, stability and continuity of research, and a lot fewer people trying to get rich quick on someone else’s backbreaking labor of trying to find that new antibiotic.

* It just occurred to me that Dan Lipinski’s thought process is more messed up than I thought. There is a pervasive misunderstanding that academic groups do basic research and they pass on their fully developed drugs onto private companies that develop them. This is wrong. Small companies, big companies, multinational companies do real research. They need to do real research because academic groups pass on frequently little more than nuggets of leads and hints of ideas with a soupçon of druggy goodness. It is very rare for an academic group to produce the fully monty. So, if Lipinski is shocked, SHOCKED that a biotech would use its small business loans to do real research and doesn’t understand why that’s necessary, we have a serious problem on our hands. That means the whole Congressional approach to funding is based on a lie.

That’s going to hurt.