Ebola shows we learned too little from AIDS

The largest Ebola outbreak ravages out of control in Africa as WHO considers declaring a public health emergency on suspicion of the disease reaching Saudi Arabia.

Ebola is a health and humanitarian disaster, and a serious infectious disease threat, but a separate WHO action shows systematic weaknesses in how new drugs are researched, developed, approved, and delivered to patients. On August 6, WHO announced an ethics panel to decide if and how to use experimental therapies for Ebola.

If this all sounds a bit familiar, it should. In the depths of the AIDS crisis, patients clamored for access to new drugs with unknown risks. There were no protocols in place. Haphazard experimentation on patients is illegal as well as unethical. But people were dying. Patient advocates created the political will to overcome these obstacles, and let patients choose risks using the meager information available. The result: many, many lives saved.

What did we learn from the AIDS crisis about how to better manage medical research? Approximately nothing. AIDS remains an exception in healthcare research, in every sense of the word. For example, NIH-funded AIDS research still has separate deadlines and mostly separate review from all other medical research. In our thinking, we've quarantined the whole AIDS crisis itself, as an event. Sure, we rethought what "patient" and "clinical trial" meant for AIDS because we had to. But we're not going to let that infect our thinking in other areas of medicine.

Ebola has no cure or effective treatment. Our response to Ebola is essentially medieval, because we have nothing better. Vaccines and drugs have not been developed, because most people who get Ebola are poor. Clearly, the economic costs of Ebola outbreaks would justify significant development costs. The costs of fighting just this one outbreak will be in the hundreds of millions of dollars, and I suspect the total economic losses will be in the billions. So even though the people who get Ebola don't have much money, it still makes economic sense to prevent Ebola outbreaks. Why then don't we?

There is an experimental drug, ZMapp, that has been manufactured in very small quantities. It has been tried on two Ebola patients. Controversially, those patients were both white health workers. Some in Africa now demand that wider access to ZMapp be provided, or at least considered. If this sounds like AIDS all over again, well, it's not much different.

Getting an approved drug to market is expensive, perhaps a billion dollars, depending on how you count. (There are many ways to count, but they all lead to very large numbers.) A poorly-managed trial could prevent a drug from ever being approved. That means never helping many people, and not incidentally never making back money invested in development. So drug companies are nervous about offering unapproved drugs to desperate people, for both ethical and financial reasons.

Why is ZMapp in short supply? Is it hard to make? Yes and no. ZMapp is a combination of three antibodies extracted from transgenic tobacco plants. Tobacco plants grow as fast as tobacco plants want to grow, so while manufacturing of ZMapp is ultimately scalable, the lag to get more drug is real: somebody literally has to plant tobacco plants in a greenhouse and wait for them to grow.

Other, faster manufacturing platforms could be considered, but ZMapp's manufacturer has disincentives to do this: to get a drug approved by the FDA (or elsewhere in the world) only trials using material from the exact manufacturing process used for the production drug can be used to support approval. This is for good reason, of course, particularly for a biotech drug like ZMapp. For biotech drugs produced in yeast, even changing the size of the incubation chamber can change the impurities that must be filtered out of the final drug.

But these are some of the reasons that stack up a billion dollars in front of getting a new drug approved. The AIDS crisis showed us we need to change our thinking. We changed our thinking. Then, when the AIDS crisis abated, we changed our thinking right back. This Ebola outbreak and the resulting humanitarian, moral, and ethical crises show that we learned little from the AIDS outbreak.

We have to drive the cost of drug development back down, and get drugs into the hands of patients sooner. That means that patients will get drugs with safety profiles that are less well understood. This means that we will have accept that some of these drugs will have side effects, and some people will be hurt or killed by those side effects. We can work towards drugs with better side effect profiles, and in fact drugs like ZMapp will mostly be quite safe. Mostly. But not always. So only patients who face serious risks in the absence of treatment should be offered these therapies, and they should be fully informed of the risks.

This is not an abstraction for me. Someone close to me participated in several clinical trials to combat an extremely dangerous disease that ultimately killed them. One of those trials was for an antibody therapy. Overall, experimental drugs made a horrible and lethal disease manageable and survivable. At least for a while. But the disease ultimately proved fatal, and in this case a bad reaction to antibody therapy probably hastened the end. What I learned is that this is hard in the abstract, but at the individual level, it's even harder, because you really don't know what's going to happen.

The changes I outline here, which encompasses ideas of both adaptive and pragmatic clinical trials, integrate clinical trials into clinical practice. This happens in two ways. First, clinical trials themselves are designed to answer questions about clinical practice and real benefit to patients, and adapt to meet patient needs as they progress. Second, drugs are approved, sooner, but approval is contingent on continuing investigation of how patients react to the drug.

This results in a faster drug development cycle, benefitting patients sooner and cutting the cost of drug development, encouraging more drugs to be developed. But, initial patient populations are smaller, have clearer risk/benefit relative to taking the drug, and are more carefully monitored. So, side-effects are more likely to be found earlier, when fewer patients have taken the drug.

A perfect world? Hardly. But a better world, with safer, more effective drugs that are cheaper and more widely available. The drug industry is complicated enough that even this massive change would not solve all of it's problems. But it would make a great difference.

(For more information from people who've thought about this stuff a lot more than I have, google "pragmatic trial" and "adaptive trial".)

Refactoring the Human Genome

I I am pleased to announce my participation in a bold new effort to refactor the human genome. This effort is without a doubt the most ambitious project ever seriously attempted to ameliorate the long term burden of human disease. The potential benefits are vast.

The team behind this project is a biology A-Team that I'm honored to be a member of. Heading up this effort: noted evolutionary bioinformaticist Dan Graur. The core team also includes renowned bioinformaticists Yichen Zheng and Nicholas Price, talented genomic architect Ricardo B. R. Azevedo, and population geneticist Eran Elhaik. Advisers include Larry Wall, fresh off the successful Perl 6 project; noted computer language theorist Edmund Arranga, and celebrated biostatistician and data analyst Lawrence Sanna. Beyond the specific technology, important philosophical guidance was provided by Francis Galton. This project makes use of important work by Francois Pinard, although he is not directly involved in the project.

The thesis of this star-studded group is simple, but like many simple things hidden in plain sight, it takes a true genius like Graur to realize the potential that lies before us, within reach. When you ask Graur why nobody has proposed such a project before, he just smiles wryly and shakes his head. "The human genome is rife with dead copies of protein-coding and RNA-specifying genes that have been rendered inactive by mutation. It's time we stopped passively accepting this situation and did something about it."

Our project: refactoring the human genome. "Refactoring" is a term from computer science, meaning to reorganize the internal structure of a code base without changing the (intended) external behavior. This term has been borrowed into bioinformatics, where the meaning is equivalent: the reorganization of the structure of a genome without changing the behavior of the organism. As Graur eloquently observed, at least 85% of the human genome is plain junk. Most of it is not transcribed, and even much of which is transcribed is by definition nonfunctional, because it is not subject to purifying selection.

Why does this matter? Even though it is not important to our normal genomic lives, this junk DNA is an important source of disease. Most obviously cancer, but also genetic disorders such as converse errors that can cause acute adhominem ataxia.

From an evolutionary viewpoint, a function can be assigned to a DNA sequence if and only if it is possible to destroy the function by removing the DNA sequence. Put another way: by definition, eliding nonfunctional DNA does not change the organism's function. Since 85% of DNA is nonfunctional, suppressing it has no effect on normal biology. Why is it worth eliding? Studies by Graur's colleagues show that transcription of junk DNA is highly active in immortal cancer cell lines. The implication is obvious: the key to curing cancer is to attack it at the root: junk DNA.

Thus our project, dubbed RECODE (short for "Refactoring to Eliminate redundant non-CODEing regions") will use well-understood recombinant gene technology. The result will be a human genome that is between one third and one sixth the present size. The project is ambitious. The benefits clear. The savings in file storage alone amount to millions of dollars a year, and will only grow as genome sequencing becomes more common.

Technically, the project is straightforward, although the bioinformatics is a challenge. The hardest part, and the part I'm personally most excited about, is ensuring backward compatibility of the new genome which we've taken to calling "H. sapiens 2.0" with the present "H. sapiens 1.0" genome. Personally, I'm not sure backward compatibility is actually essential, but politically, it's probably indispensable. For one thing, there is the installed-base to think of.

As often happens, backward compatibility will involve compromises. In particular, rebalancing chromosomes will probably have to wait for a future "H. sapiens 3.0" project. But an elegant implementation of backward compatibility gives humanity a smooth upgrade path to a genomically more healthy future.

This project is so new, it doesn't even have a proper web site yet. However, basic information is available here.

Checklist Manifesto

What if surgeons operated on people like pilots fly airplanes? Atul Gawande's new book answers that question: fewer people would die on the operating table. Atul's new book is about how checklists can make surgery more disciplined without making it less creative or heroic. Atul tells literally gripping stories, among the most visceral writing I've seen on the very visceral subject of surgery.

But this book is about so much more than just making surgery better: it's about how complex processes fail, and the way we can make human processes that are still human, but produce the low rates of deadly mistakes we insist on. Atul is humble enough not to draw broad lessons that his data don't support, but he is bold enough to note that the question should be asked: in all kinds of complex processes, particularly during emergencies, how can we give people the tools they need to take effective action?

Atul Gawande is a great writer, a dedicated surgeon, and a creative health researcher. They are going to name buildings for him and new surgeons will be reading his books for decades. Read this book to learn about the incredibly vital worldwide revolution in surgical care that is going on right now.

Work: how hard is hard? (Xconomy part 2)

Part 2 of my Xconomy article is available here.

Xconomista Me

Last month, I was on a panel with Janis Machala, among others, that peripherally addressed the topic of how hard startups really work, and how hard they optimally ought to work. Luke Timmerman of Xconomy reported it, and set off a minor firestorm.

In one of those 6-degree things, Luke, Janice, and I all ended up face:face a few days later. Luke invited me to make some comments on work/life balance. I guess they turned out well enough, because Luke published the first installment today, with a second part to follow shortly.

All Fun and No Work Makes Jack a B-Lister?

On Wednesday, I was on a panel on "How to Find, Fund, Protect and Launch New Technologies" sponsored by WBBA, University of Washington School of Law, and Fenwick & West. The panel was moderated by Fenwick's Stephen Graham and the other panelists besides me were WRF CEO Ron Howell, supernetworker Janis Machala, and UW Law's Sean O'Connor.

Luke Timmerman reported it under the title "Seattle’s Lifestyle Keeps Us Trailing the Bay Area, Says UW Startup Maven Janis Machala." That pretty much sums up Luke's take-away from the meeting. Luke certainly reported the most newsworthy event of the panel: Janis saying that quality of life gets in the way of startup success in Seattle. “There’s a lifestyle element here. People want balance. People in Silicon Valley don’t know what balance means.” Janis specifically faulted Microsoft Millionaires for not starting enough new companies.

My comments on the panel were in a different direction. A big problem Seattle has starting companies is lack of a ready bench of people in all roles who have started companies. Seattle is just barely big enough to really make it, or maybe not quite big enough. Seattle has bobbled just above or below critical mass for decades without really breaking out or really failing. Also, the current crisis is a potential opportunity for Seattle. The current uncertainty gives us a chance to redefine Seattle's role in the nation’s and world’s biotech community.

Mirroring People

Marco Iacoboni, Mirroring People. I found out about this book through Charles Mudede's review of it. Actually, I didn't read the whole review. I read the first sentence. Halfway through the second sentence, I had already ordered the book from Amazon. Yep, it's an interesting book.

Lakoff and Johnson's 1999 book Philosophy in the Flesh persuades that a philosophy of mind should be motivated by our knowledge of cognitive science and neurology. That is, what we believe about minds should be consistent with what we know about brains.

Iacoboni's work on mirror neurons, described in his book, thus provides a new foundation on which to address critical philosophical questions. What does one person really know about another? How do we know that we understand another person, or have been understood? In mirror neurons, Iacoboni and his collaborators have uncovered the specific neurological machinery by which we comprehend and imitate the actions of others, and by which we empathize.

The answer is fascinating and unexpected: when we perceive an action by others, we experience the action as if we had performed it ourselves. In a real and visceral sense, we empathize with others by experiencing what they experince. We are far less trapped in our own brains than was once thought. Specific neurological mechanisms allow us to understand the actions and emotional states of others as if they were our own. Iacoboni shows us a world far less lonely than almost anyone has ever imagined.

P4 Medicine

I maintain a biotech/health blog called P4 Medicine. The name comes from Lee Hood's concept of a new medical practice that is "Predictive, Preventive, Personalized, and Participatory." (Other people use different combinations of words beginning with P to get across the same idea.)

But, there is a new P4 appearing in the Google rankings, and it's strong medicine: the Cervelo P4 bicycle. It's very nice.

Now, I'm not a time trialist, so there's no chance I'd actually buy this bike. But it's a very pretty bike all the same. If I saw one in person, I would stare at it. For a good long while.

This brings up a point that has been bothering me for some time: how strong a concept is P4 Medicine anyway? Really, it's not a coherent concept so much as a laundry list of objectives (or adjectives). We have a bike, a revision control system, and a medical revolution all competing for the top of the same Google search. That's less than ideal.

But what are the alternatives? Prospective Medicine is a different, narrower idea. Likewise, Personalized Medicine seems to me inadequately ambitious. PM is personalized medicine as opposed to what? Impersonal medicine? Bulk medicine? Medicine is already personalized. Yes, I know, PM is about medicine that is more personalized in very specific ways, but again that's really beside the point. I don't want my medical care to be more personalized, I want it to help me feel better and live longer, for the same or less money. "Personalized" isn't a value proposition, and it isn't a recipe for how to achieve value any more than four copies of the letter P.

Hmm, maybe I just need to go on a bike ride....

Burrill Personalized Medicine Meeting 2008

Just got back from the Fourth Burrill Personalized Medicine Meeting. I blogged it on my biotech/health blog here.

The conference wasn't exactly upbeat. But given the economic turmoil, it was certainly optimistic. People see a bright future for Personalized Medicine and diagnostics, which is good news both for America's health and for my day job, so I shouldn't complain.