I now have to stop talking about
poop GI matters for a while since Adam is going to give the impression that I have an obsession of some sort with the stuff.
Instead of spending time in the laboratory tonight (for which I’m feeling tremendously guilty), I ambled down to my favorite moviehouse, the Coolidge Corner Theatre, for their latest Science on Screen feature, the terrific So Much | So Fast. This is a remarkable documentary about Stephen Heywood, a man diagnosed with amyotrophic lateral sclerosis in December of 1998, and his family’s remarkable journey.
The film was notable on a number of levels. First, woven in and out of the story was the juxtaposition between Stephen Heywood’s physical deterioration, which one saw progressing over the course of the movie, and his infant son’s development. There were multiple scenes of Stephen at varying stages of the disease, entirely fixated on his child testing out new motor skills. As a physician, especially a pediatrician, it was really a privilege to see these images on the screen. I don’t think that I fully appreciated the profound loss suffered by Stephen Haywood, and by extension, any patient with ALS, until I was able to see it in the context of the motor development of a child. We take for granted the normal development and functioning of our nervous system. During residency I memorized the developmental milestones, their anticipated times of onset, the normal ranges, and the differential diagnoses for delays. But there is something very affecting about seeing it in parallel to the devolution of an individual, and even moreso when that individual is that child’s father. I could only imagine what was in Stephen Haywood’s mind as he watched his child gain the skills that he was now losing.
The movie was also remarkable for the other main theme: the mission undertaken by Stephen’s brother Jamie, to accelerate the search for a cure. Without getting into too much detail, Jamie Haywood built a research group over the course of the past 8 years, and in doing so chose to do so according to an entirely different set of principles than those typically followed by the scientific “establishment”. Where as the paradigm of scientific research in this country has been to let clinical discoveries bubble up from investigator-initiated basic science research, Jamie Haywood chose to attack the problem of ALS with a “top down” approach: apply as many drugs as possible to a mouse model of ALS and use whatever works on patients. As scientists we would call this “empiric therapy” – the application of treatment without understanding the underlying mechanism. There are many, many pitfalls to this approach if you look at it from the point-of-view of a scientist. However, there are probably just as many pitfalls to the conventional approach if you look at it from the point-of-view of a patient with a progressive, fatal disease.
After the film I had a chance to talk to Jamie Haywood for a little while. He was a little different from the way he appeared in the movie. Some of the desparation that came across in the movie has been replaced with what appeared to me to be a broader understanding of the size of the problem. That being said, I think that he is willing to call out science for its flaws and shortcomings (e.g., lack of adequate funding, duplicative research, inadequate publishing of ‘negative’ results, the propriatary nature of modern science vis a vis patents, competition for credit, grants and publication, corporatization of research, etc.). But more than just being a gadfly or naysayer, he has the energy and initiative to bring people from outside of science together to find creative approaches. One of the things that we spoke briefly about was a “Science 2.0” akin to the “Web 2.0″. In addition to the “regular” bottom-up science, why not capitalize of the remarkable technologic infrastructure that we have in place to draw important data out of what is going on out there.
For example, if you’re a pediatric patient with, say, acute lymphoblastic leukemia (ALL), depending on where you are you may get treated according to a Children’s Oncology Group protocol, a BFM (Berlin-Frankfurt-Munster) group protocol, at St. Jude’s protocol, or a Dana-Farber Cancer Institute/ALL Consortium protocol. You’ll get some cocktail of many of the same drugs, but on a different schedule, with different doses at different times. Which one is the best (in terms of outcome) with the fewest side effects? One way to find out would be to do a randomized trial with hundreds (or more) patients, dividing them between each of the four regimens. You’d need to have large enough groups to account for differences in patient populations, and you’d need to run the trials for a long time to figure out which had the best outcomes. You’d need to score all of the side effects for all of the patients in the same way. You’d need the cooperation of dozens, if not hundreds, of investigators. It’d be a long, expensive trial.
But what if you had a computer infrastructure in place for all patients on acute lymphoblastic leukemia therapy. A system that was open to the oncologists and the patients and their families. What if you put in all of the data. You’d enter the patient’s demographics, disease characteristics, treatment regimen, drug doses, schedule, the physician’s assessment of side effects, etc. On the patient side you’d have the patient or parent enter their assessment (timing, severity) of side effects. You’d collect other data: how many missed days of school, assessment of mood, appetite, mouth sores, hair loss, infections, missed doses of medication. Anything that you can think of, as long as you’d make it quantitative. As a result you’d have this large array of leukemia data, not dissimilar to the array data that you get from whole-genome cDNA arrays, or SNP arrays. The task then would be to mine the data. Much like gene chip data, you’d be able to mine it in innumerable ways. You’d find subsets of patients who, for example, got through their therapy without much nausea and vomiting. You could then go back and see how those patients did in terms of outcome. You could find out what cocktails of anti-nausea drugs they took and see if that was different than a group of patients with an average amount of nausea and vomiting, or those with the worst nausea and vomiting. Once we have the ability to quickly and cheaply run gene chips on patients and their disease you could correlate outcome or side effects with different patient or disease genotypes. Ultimately we could end up with a remarkable new “meta science” which would pool all disease data and genomic data, allowing sophisticated multi-dimensional views to replace the traditional two-dimensional Kaplan-Meyer curves (probability of survival versus time).
This seems awfully pie-in-the-sky, but in talking with Jamie Haywood, I was struck by the fact that he “gets it”. And while the part of me that is trained as a traditional scientist is skeptical when he takes on traditional clinical trials and peer-review, I appreciate the fact that he is trying to make us, as a community, take an honest look at the system by which we define scientific reality.
For more information about this movie, you can visit the film’s website here. There’s a preview of the movie available here. Jamie’s organization is the ALS Therapy Development Foundation. Their research page is well worth a look.
Tragically, Jamie’s brother Stephen died on November 27th in a tragic accident, in which is home ventilator became disconnected. The alarm was not heard and as a result he died from anoxia. Despite the fact that ALS is a progressive disease, patients can be maintained on a ventilator for many years. It was clear from the movie that Stephen’s life was cut short of what he wanted.
I would encourage anyone who reads this to try to see this movie, if not now, then when it becomes available on DVD. It is a remarkable and touching story of a man and his family. It is also a story about questioning the status quo. It is a story about the cost of pursuing a goal without limits. And ultimately, it is one man’s story about what is important in life.
[Nota bene: An excellent review from the New England Journal of Medicine can be found here.]