It was 2004 and I was reading on the futon in my office, when a man in full motorcycle gear with a large brownish orange moustache barged in and sat down. He was coughing up a storm and ranting about phage and CF and the Master's program; for about the first 10 minutes I thought he was a little crazy and was worried that he was giving me some horrible pneumonia. Eventually I caught up. His name was Mike Furlan, a passionate teacher of anatomy, and he wanted to use phage to cure cystic fibrosis (CF) as a Masters student in the lab. Little did I know that this indomitable Texan would redirect the lab's research program and become a world-class CF researcher.
Over the next decade, Mike was a key member of a remarkable team of people that took metagenomics from an academic exercise in phage natural history to personalized medicine. Mike worked in the lab, inventing and refining many of the protocols for quantifying and sequencing viruses and microbes in sputum. He could get things to work when all other methods failed and we called his unorthodox approach "Mike's Magic". As the lab's Praetor Urbanus, Mike pushed through the avalanche of paperwork that is the main inertia of any research effort. And, as the lab safety officer, he kicked everyone's ass into line, delivering a yearly diatribe straight-out of Full Metal Jacket. In total, Mike co-authored thirteen papers, most of them on CF. When not in the lab, Mike continued to teach human physiology, rode his motorcycle, trekked back and forth to Disneyland, attended Comic-Con, built chicken coops (really!) and in general enjoyed life. CF may have killed Mike but it never stopped him from living.
So what happened? Mike was doing well with his CF. Lung function was fine and he was feeling pretty good; maybe a little weak from a couple of surgeries earlier this year. Two weeks before his death, he started an exacerbation. Exacerbations occur when the microbial communities in the lungs cause enough problems that the patient feels sick and has a hard time breathing. The switch from stable to exacerbation is one of the things that Mike and the CF group has been studying. We know that these disease flares are caused by both the invasion of new pathogens and changes in the physiology of the resident microbes. This is what we call the Attack community.
Mike was treated with antibiotics and should have entered the recovery period. During this period, the "normal" microbes of the patient reestablish themselves in an uneasy, semi-quiescent state within the lungs. This is was we call the Climax community. We now know that this happened in Mike's case. However, instead of getting better his lung function continued to decline.
While all this was happening in San Diego, most of the lab's CF group was in Telluride, where we saw data about a small set of patients "crashing". Essentially, a small set of CF patients are going from a relatively stable disease to rapid decline. We didn't even realize this patient group existed until some recent deep statistical analysis by Doug Conrad and Barb Bailey identified this subpopulation. Alarm bells went off when we returned to San Diego and learned of Mike's continual decline in lung function. We got samples and Yanwei Lim worked day and night to sequence the metatranscriptomes. By this time Mike was sick enough that he was sent to the emergency room and then the ICU.
Thanks to Rob Edwards and Rick Stevens (Argonne National Lab), the sequences were put through an amazing number of bioinformatics analyses in record time. The results were initially confusing. There was evidence of both an Attack community, consisting of E. coli STEC F2B1, and a Climax community of Mike's normal microbiota, Pseudomonas aeruginosa and Strenotrophomonas maltophilia. The E. coli STEC was extremely worrying because this is an aggressive pathogen that causes dysentery through the production of the shiga exotoxin. The problem with treating STEC is that antibiotics release the toxin and lead to epithelial failure. This is what we think happened in Mike's case. Sometime in the relatively recent past, Mike was exposed to E. coli STEC F2B1. Because of the lung remodeling from CF, this bacteria colonized the lung and caused the earlier exacerbation. The antibiotic treatment killed this STEC strain, but unfortunately initiated a hemolytic event that continued to wreak havoc. Even as the Climax community re-established itself, Mike's lungs continued to atrophy.
In the ICU, treatment initially slowed down the tissue swelling for about 24 hours. Then there was too much damage and he was sedated and kept comfortable. Mike was slowly with drawn from life support and passed away quickly and quietly.
So what can we take away from this? Yes, we lost a remarkable friend and co-worker. Even those of you that didn't know Mike can appreciate how tough he was and his central role in a CF lab. However, his legacy is about life. He worked like hell, both in the lab and to support the lab, so that we could figure out this horrible disease. The approaches he helped pioneer worked to figure out the cause of Mike's death. For the next patient, let's figure it out before it is too late and give them a chance.