How to cure a

By Steve Kirsch

In August 2007, I was diagnosed with a rare, incurable blood cancer Waldenstrom's Macroglobulinemia (WM). Statistically, I'm likely to be dead in 6.4 years (from the date of diagnosis), either from the disease or the treatments. So I don't have a lot of time left to find a cure. Some people think I'll live longer than that, but I think it's better to be safe and assume for the moment that I don't have a lot of time left.

The first thing that occurred to me is that I'm toast no matter what I do. Given that the average drug takes 7 years to get to market and there are no promising drugs in the pipeline, this looks like a lost cause for me to try to expend energy to find a cure. Even if I succeed, it will be too late to save my life.

The second thing that occurred to me is that the chance of my coming up with some great idea or strategy to cure this disease is zero. The disease has been around for over 60 years. There are lots of people who are smarter than I am who have been working on a cure for this disease (both in terms of doing the research as well as determining what the research strategy should be) for a lot longer than me. I should just try to learn from them and follow their instructions since they've probably already thought through any of the ideas I am likely to bring up and I'd just be wasting their time.

As I learned more, I discovered, to my surprise, that both of these assumptions were wrong. I now believe there is enough time, and I also believe that I have the potential to make a tremendous difference in what can be accomplished. It will not be easy and there is a high chance of failure, but there is a small chance of success.

This web page summarizes the key things I learned from others and the steps I am taking to find a cure for WM. Most of the things I learned are applicable to other diseases. So this page is a generic "how to cure a disease" page.

OK, I know what you are thinking. You are thinking, "Wow, that seems awfully pretentious. You have no medical background whatsoever and you are writing a "how to" page on how to cure any disease? Give me a break!"

Well, you're right. It is awfully pretentious. And if anyone had pointed me to a web page saying "you should read this for how to approach curing your disease" then I would have read it. Instead, people pointed me to lots of information sources and a few books like "Patient from Hell" and "Chasing Daylight" but no proven "how to" guide for the shortest path to a cure.

In my search for the best success models for finding faster cures, one of the most remarkable people that I talked to is a college student named Josh Sommer. Josh has chordoma which is an extremely rare (only about 300 people per year) slow moving malignant neoplasm. Currently, the average life expectancy from diagnosis  is 7 years. So he's in a situation very similar to me.

Rather than sit around and hope for a cure, Josh and his mother Simone are  making a huge difference. Check out this presentation on how to cure chordoma that Josh shared with me. Or the website on chordoma that they set up. It was eye opening what just 2 people can do in less than 1 year. They even convinced the NIH to hold a workshop on chordoma and pulled it off in just months. Nobody else has done for chordoma anywhere close to what they've accomplished in just months. They've accomplished more in less than one year that larger organizations take years to accomplish.

When Josh told me his story, I told him, "Wow, you've just done an amazing job of all this. But why did you have to learn all this stuff from scratch? How come there isn't a web page somewhere on the net that explains all the steps you should take to cure an orphan disease? You can then just find that page and you can just follow the checklist. It would tell you all about how to use the NIH Chemical Genomics Center, how to convince NIH to host a workshop on your disease, resources such as Gene Logic, CombinatoRx, Genetic Alliance BioBank, and all the other key resources and contacts that you had to discover on your own that are critical to your success." Josh said if I found such a web page he'd love to read it because it would have saved him a lot of time! I told Josh I didn't know of any such page, but if there was, I'm sure he would have found it since he seems to have found just about everything else that might be helpful to his disease. So I suggested that he should write it! It should include the key learnings, the key resources, and the most helpful and knowledgeable people that he's run across (such as Chris Austin of NCGC and Sharon Terry of Genetic Alliance).

One thing I found really fascinating is that Josh told me that the NIH funds this organization called the NIH Chemical Genomics Center (NCGC). This center can test your disease against 2,000 FDA approved drugs and 300,000 other compounds to see which ones are effective against your disease. The cost? Free (since it is government funded). Now you'd think that such a center would be just swamped with work wouldn't you? Amazingly, the opposite is true; they provide their service for free and have to beg people use their service but few people do. Why is that? Well, as Josh is fond of saying, "In medicine, the right hand doesn't know what the left hand is doing." That's not to mean people are not competent. It simply is because there is an awful lot going on in medicine and nobody knows it all because if you spent all your time being informed of what others are doing, you wouldn't get anything done yourself!

There are a number of foundation that are trying some very innovative approaches to finding faster cures. The smartest foundations first study the most successful and then set themselves up to copy the best practices and innovate from there.

In the meantime, until Josh (or someone else) writes his page, I'll offer my humble contribution to the "how to cure a disease" page by summarizing for you what I've learned over the past 2 months and the approach I plan to take for curing WM.

The first thing to recognize is that the medical research is done very inefficiently. For example:

  • Researchers in the same field typically don't collaborate; they compete. This is because the researcher who makes the breakthrough gets rewarded. They don't want others even to see their grant proposals because they are afraid of someone else stealing their ideas. There is an "R01 culture:" scientists replicating efforts as a result of competing with each other rather than collaborate.
  • When information is shared, it is shared through publication which can delay the dissemination of important results for months or years. For example, a researcher who did a clinical trial can't tell anyone the results in advance or his paper describing the results will not be published.
  • If you search the NIH database of clinical trials, you'll find lots of trials listed and you'll find ZERO results of any past or on-going trial. So it's easy to find the experiments people are doing, but much harder to find the results.
  • A lot of researchers spend 40% of their time writing grant proposals; over 90% are turned down, even if you are a top researcher. So close to 40% of time is wasted.
  • You are rewarded for publishing papers; curing a disease doesn't give you any "extra points."
  • If you fund research at a university, about 20% of your funds go for "overhead." While this may seem like a lot, this is less than cost for the university; the NIH gives universities approximately 70% indirect costs.
  • There is no standard for tissue banks so it's not easy to combine tissue banks from multiple places. In addition, many samples are collected by individual researchers with no standards in place.
  • Getting tissue samples out of a university can take years. MMRF spent 2 years negotiating with 4 universities to get them to share tissue banks.
  • Intellectual property rights can also take years to negotiate with a university. One prominent foundation spent 2 years negotiating with 4 universities for rights to do a common tissue bank. Of course, it can take a lot less time too. Generally, it takes no longer than would occur between corporate partners (2 to 8 months depending on how complex it is).
  • If you get care at multiple locations, the data isn't tracked between centers so things like survival rates and long-term data on treatments are not tracked well. In fact, I had one heck of a time just getting my own medical records from one place to another (still no records 6 weeks after request)

The main point is that the competitive grant proposal process set up by the NIH scales well in terms of management and suitability to large government bureaucracies, but it is an inefficient way to get results quickly. It does nothing to encourage sharing. In fact, it creates the opposite effect. As Debi Brooks of the Michael J. Foundation has said:

NIH is a big, basic science discovery machine.  It is an enormous and important source of funding for academic research in the country. But the lion’s share of the money is put toward interesting investigator-initiated questions.  This approach favors elegant projects that further basic research at the expense of projects that are more practical, complex or translational.

However, in the last 10 years, the newer NIH grants, such as large, multi-year SPORE grants start to move things in the right direction. SPORE grants support innovative, multidisciplinary translational research approaches that potentially may have an immediate impact on improving cancer care and prevention. But there is still a long way to go.

So the next question you'd ask is, "Surely, there must be somebody out there doing it right!"

Andy Grove is one of the smartest people I know. He has Parkinson's and he did a lot of research on what others were doing so that he could learn from the best. I know that because the most innovative foundations I talked to mentioned that Andy talked to them. So I asked him which foundation's approach to faster cures most impressed him. He said nobody impressed him.

If you want to impress someone like Andy you have to have a consistent track record of breakthroughs or cures, i.e., you'd have to prove your research process has a proven track record of results that matter to patients. So if your foundation is cranking out one miracle drug a year (e.g., one Gleevec a year), you are clearly doing something right that others should emulate. Nobody is doing anything close to that now.

Nor is it clear that there is a "holy grail" model for how to do medical research. I'm in the anti-spam business trying to find a magic filter that filters out just the spam without impacting the good mail. There is no research process you can describe to solve this problem. Hundreds of people have tried to solve it both in companies and universities. Nobody has figured it out. The solution just popped into my head about 4 years after trying different things. I now have a precise and elegant mathematical model for spam. I can describe the algorithm to others who would say, "That is so simple. Why didn't we see that before?" Is medical research any different?

Based on what I learned, the process you should follow if you want to cure a disease quickly looks something like this:

  1. Get a basic understanding of the problems with the current system of medical research
  2. Study the foundations who are doing the best job of finding cures faster and choose the closest success model to emulate that is appropriate for your disease. By "appropriate" I mean that some diseases are not very well understood (e.g., no cell lines, no animal model, etc.) and demand a research focus while other diseases have validated cell lines and well understood targets where a focus on drug development would be the smarter investment. It is definitely not "one size fits all diseases." You have to look carefully at where the research is in your disease and then pick the success model that is the most appropriate for where you are in the research process. For example, for WM, there are only 2 cell lines that exist (1 of which is of questionable value) and 1 in development (2 at Dana Farber, 1 at Mayo in development)
  3. Hire a full-time CEO who skills are consistent with what is needed based on the success model you chose
  4. Form a foundation. The foundation can raise money, monitors progress, and provides strategic direction and helps to set priorities and can force coordination if and when required. Forming a public charity allows you to raise more funds. A private foundation allows you to move faster and greater freedom to make decisions and take risks. There is no clear winner here and you may need both, so pick one and get started now.
  5. Using the success model, create a strategic R&D plan and a budget both for internal staff (if required) as well as the medical research and drug development strategy. This is quite tricky to do right because you're often balancing short term vs. long term benefit. For example, establishing a tissue bank that your foundation controls that can be used by multiple researchers is very important over the long term. But forging the legal agreements with the universities to do that can take 2 years per university. If you have a cancer that is going to kill you in 5 years, you may want to start this project, but your strategic plan shouldn't be gated by it. You don't want to minimize the number of dependencies and rate limiting factors.
  6. Raise funds (see below on a really clever way to raise lots of money)
  7. Hire the people you need. At a minimum, you'll need one really sharp person with a medical background because you are going to have to make some important decisions and you are going to get conflicting advice from the experts you talk to from different institutions so you are going to have to trust someone who is really smart and able evaluate the arguments and make a lot of difficult decisions. There is no perfect person for this job. Any person you pick is going to have a bias. You can then validate those decisions with a few trusted people in academia who aren't on your payroll and resolve conflicts when they arise so it's not like you have to pick the perfect person who always makes the right decisions. So you are going to be the ultimate decision maker.
  8. Execute the plan.
  9. Keep tweaking and improving the plan as you learn more.

Time is your enemy. You'll never get the perfect plan on day one and if you keep researching in step #2 and #5 to optimize, you aren't going to get anything done. There will be some stuff that you can figure out that you need to do no matter what. For WM, for example, it is to get validated cell lines and genomic analysis. Get started with stuff that is not controversial now and you can add other stuff later. And don't try to scale everything now, e.g., getting 3 good cell lines gets you most of the way there; you don't need 50.

Lee Iacocca has said management is no more complicated than people and priorities. It's the same for medical research. Getting truly outstanding people working on the problem is fundamentally important and prioritizing what needs to be done ASAP and making the decision to fund it now (rather than waiting until all pieces of the strategic plan are in place) are critical.

There is benefit to collaboration but there is also benefit to isolation. I never would have solved the spam problem if I wasn't off in a corner and forced to think independently. The solution was completely opposite to the way everyone else had been thinking about the problem. So exposure to other approaches and collaboration would have been, in this case, very detrimental. It would have caused me to think conventionally about the problem and I would never have solved it. Instead, the isolation caused me to think in ways that eluded everyone.

It's also theoretically possible to re-direct an existing foundation to adopt these new approaches rather than having to start your own. I say theoretically because I'm not aware of any cases where this has been done. However, there are some foundations that are slowly moving in this direction.

There are 700 breast-cancer related organizations in this country. If you have to start a new foundation, you want to be sure there is a good reason. If the foundation(s) that already exist for your disease are slow moving and won't change, that can be a good reason for starting a new foundation.

Andy Grove and Michael J. Fox both started new foundations for the same disease. Fox felt there was a need for a more focused, aggressive and efficient research effort to find a cure for Parkinson's Disease (PD) which is why he started a new foundation. One of the first tasks Fox and Debi Brooks (co-founder of the foundation) undertook was to seek out best practices in building an effective foundation.Grove took a similar approach. But they ended up with different answers. Grove and Fox found that while their mission was the same, their strategies and tactics were not which created both challenges and opportunities. Also, another key difference is that MJFF is funded mostly from public money while Grove is the sole funder of Kinetics. This gives Kinetics far more freedom to take risks, focus resources, and move swiftly. Conversely, MJFF has ten times as much money per year to spend on research than Kinetics does.

Here is the philosophy of the Kinetics Foundation:

The management philosophy of the Kinetics Foundation was established at its birth.  The hallmarks of the Kinetics Foundation philosophy were: find the right project scale, use fast decision making, and leverage the foundation’s leaders through their personal involvement in selecting and evaluating projects.  Grove and Taylor decided that the strategy of Kinetics should be to focus on underfunded or “orphan” areas. They defined these as “important areas not fundable through traditional mechanisms.”  Kinetics did this to achieve maximum leverage for its investments.  They wanted their projects to have a good chance of high payoff in terms of influencing the field, attracting funding from different sources, bringing different skills and ideas to solve problems or accelerating translational research—the clinical application of scientific medical research from the lab to patients. The overarching concern of Kinetics was salience. Grove and Taylor wanted the foundation and its research to do the best for patients with PD, which meant to seek opportunities where a small foundation could influence basic scientists to do more translational research in the field.

In general, the larger the foundation the harder it is to change. For example, an executive at one innovative foundation was invited by a board member of the American Cancer Society to make a presentation and the board member suggested that they do a small pilot project to try out these new concepts. The full board denied the request. I find it strange that they are willing to risk funding hypothesis driven research but are unwilling to experiment with things that might improve the process.

The plan is typically not a "put all your eggs in one basket" type of plan. None of these foundation makes a single strategic bet or adheres to a single approach to research. And even when they do make investments along one strategic direction, they will often make multiple investments. For example, Andy Grove's foundation (Kinetics Foundation) supported six different "moon shot" projects to cure Parkinson's disease but each one failed to land on the moon. In this case, a "moon shot" was a project that could test a set of unproven hypothesis in attempting to reach a given end goal. Grove’s logic was it might save the field time if something were proven to work before the details of how it actually worked were discovered

Along the way, you learn that trying to get extra government funding for your disease is probably a long shot. For example, many years ago, when Geraldine Ferraro was diagnosed with multiple myeloma, she got a $250M authorization from Congress for research into blood cancers. The amount Congress actually appropriated in the budget: zero. So they pass a law, but then block the funds for it.

The other thing I've learned to do is to share what I learn There is no strategic advantage to keeping my diagnosis or anything I learn secret. Someone can benefit from what I wrote and often, people stumble on this page and bring important information to my attention.

For my disease, I found that money could be raised. In just one month, I was able to locate sources that could be tapped for more than $5M per year. In fact, a survey of just 72 people with WM showed that there was the potential to raise over $3M per year from those 72 people alone. Yet there are about 5,000 people living with the disease. So the money is there. The problem is coming up with a strategic plan for the best way to spend the money to maximize the chance of success. A plan that the donors will be excited to fund.

One untapped potentially large source of funds is friends of people who have a disease who make a donations targeted to their friend. Here's a simple example. There are only two existing cell lines for WM. Suppose it costs $50,000 to develop a new cell line for WM. There is a huge advantage towards having your own personal cells be the basis for that cell line. You may not be able make a charitable contribution and specify that your cells be used (this is a gray area). But your friends can! That is because your friends don't personally benefit at all from the contribution. So they can aid the science, and aid you at the same time by specifying that their donation helps the disease as it pertains to you specifically. So it is targeted charitable giving. So as a victim, there can be tremendous motivation for you to help raise funds for the disease since the funds can be targeted more directly to benefit you.

Here's a list of Success models for curing a disease.

On November 30, 2007, at the recommendation of Andy Grove, I talked to Marc Shuman a hematologist at UCSF. I asked him about doing a nerve conduction test to establish a baseline to see if I am getting worse and might be at risk for developing PN and he thought it was a good idea. But the main focus of the conversation was on how to give money away effectively. Marc thinks the NIH is a terrible model and things have actually gotten worse, even with SPORE grants. He thinks there are two basic approaches that a funder should consider:

  1. Create, at an existing institution, a "Bell Labs" for your disease. A set of laboratories of modest size (10 to 12 people), each headed by an outstanding, innovative independent investigator. The labs should be clustered and embedded in a cooperative culture in which techniques and equipment are freely shared. Encourage a random collision of people and ideas. Reward systems must strongly encourage risk taking and originality.
  2. Hire a small, top notch scientific and medical advisory board who are not self-interested in the disease (so they can provide objective advice), who meet at least once a year in person, who communicate regularly and who are very engaged. Set up a focused  2 day workshop at the outset, invite <=5 experts and 20 to 25 leading scientists in other areas that might be related or useful to the problem, and go over what is known, not known, and what are the best approaches that should be taken. First half day the experts educate the non-experts. The remaining time is spent brainstorming and breakout groups. This approach has been used successfully by the NAS. See How can future researchers learn to distinguish a critical biological problem from a mundane one?  If done at a college campus, need to ensure people won't walk in and out during the day.

Marc suggested I talk to former National Academy of Sciences President Bruce Alberts for ideas on who to appoint. Alberts spent 12 years at NAS and returned to UCSF to find not much had changed in terms of process (a lot of inertia in the system). He also suggested talking to Sophia Colamarino for other ideas on how to fund research on curing diseases.

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