Approximately twelve months ago, Siobhan and I learned that a close friend we’ll call Captain Noonan had just been diagnosed with a dreaded mankiller disease called Amyotrophic Lateral Sclerosis. This is not news for the weak of heart. ALS busts open the door, stomps across the room, grabs you by the collar and throws you out the window, all before you can blink. The mean time between diagnosis and death is a pitiful three years, most of which is spent watching your body turn into a skin-and-bones version of Raggedy Ann. Muscles twitch, legs fail, waves of weakness assault the body in the early stages. As the disease progresses to the grand finale, virtually all voluntary muscles become paralyzed and it becomes impossible to talk, eat or drink. Finally, there is the closing act, as respiratory failure struts across the stage and tips its hat. Curtain. There will be no encore.
When a man goes to a doctor for lung cancer, rabies or Crimean-Congo Hemorrhagic Fever, he knows he is in deep shit. Nonetheless, not a one of these is an absolute death sentence, there is a treatment plan and Fate allows a fortunate few through Door #2. Amyotrophic Lateral Sclerosis spits at Fate, locks it out of the room, drops a piano on its head. Go to a doctor for ALS and all you get is a wan smile and an offer to be placed in a study which might help some poor candidate down the road---but you, sir, are toast. It’s the last of the ninth, two out, two strikes and your team is down 10-0. In all the history of the game no one has come back from such a deficit. The best you can do for yourself is cut the lead to nine. You’re going to need a lot of help.
There are people in this world, however, who do not take inevitability kindly. Everyone laughed when Edison sat down to play with his lightbulb, but he slogged through the swamp and prevailed. A mere two years after Wilbur Wright muttered “Man will not fly for 50 years,” he had a powered craft in the air. And Richard James was downright peeved when people told him his ridiculous $1 helical spring toy couldn’t possibly walk down a flight of stairs and wasn’t worth a dime. The Slinky inventor promptly went out and sold his entire inventory in 90 minutes. Similarly, inventor/microbiologist/private detective Siobhan P. Ellison thought there might be a tiny gap in the ALS wall, or at least a tunnel under it. She pulled her giant magnifying glass out of a drawer and began looking. Some say she’s persistent, others call her stubborn, but she’s still out there to this day. Good thing, too. She’s the only one with a Plan.
All Around The Mulberry Bush
What does a man do when he has an irresolvable problem, a Gordian knot? Can anyone tell you why a raven is like a writing desk? The ancients went to the gods with their questions, but Frank Lloyd Wright is gone, Red Auerbach is dribbling through the cosmos and Marlon Brando just wants to be left alone. Is there no hope, no succor for the pilgrim lost in the moors?
In May of 2018, Sean Healey, then 57, executive chairman of Affiliated Managers Group, Inc. (AMG) was diagnosed with ALS. He mulled over his plight for a bit, summoned a plane, flew to Boston and gave Massachusetts General Hospital and its chief of neurology Dr. Merit Cudkowicz a spiffy $40 million, hopefully in large bills. Mass. General promptly opened a new ALS center, named it after Healey and started doing ALS studies left and right. We have no idea whether any of them will manifest in time to help Healey but the size of the gift promptly elevated Cudkowicz and Mass. General to the top rung of ALS researchers in the world, at least as far as notoriety is concerned. Captain Noonan thought a trip to The Hub might be in order.
When visiting The Bay State in search of Amyotrophic Lateral Sclerosis information, a stop at the ALS Therapy Development Institute in Cambridge to see CEO Steve Perrin might be in order. Among other things, Perrin’s outfit seeks better ways to measure the progression of the disease by learning from those who live with it, including asking 600 questions on the history of the patient’s life, sequencing their full genomes after quarterly blood drawings and asking for monthly recordings of their voices. “If there were 100 newly diagnosed patients in the room here with us, I couldn’t tell you which ones are going to lose their battle with ALS in two months and which ones could live as long as Stephen Hawking,” Perrin says. “The disease is that unpredictable.”
In a nutshell, Dr. Cudkowicz told Captain Noonan his best hope for recovery might be with new stem cell treatments, either in Israel (cost: a cool million) or in bargain-basement South Korea (a piffling $200,000). Although Mass. General and TDI work together on many ALS projects, Steve Perrin’s advice was dramatically different. He thought stem-cell treatment anywhere was insufficiently advanced, very risky and to be avoided unless all else failed. Two of the country’s foremost experts in contretemps. What do we do now, flip a coin? It’s only your life that hangs in the balance.
Now What?
In her day job, Siobhan Ellison, DVM, PhD, analyses the blood of horses sent to her by veterinarians from the four corners of the Earth, looking for evidence of a neurological troublemaker called Equine Protozoal Myeloencephalitis or one of its tributary diseases. When she finds the culprit, as she always does, she recommends a treatment, which might include a drug she dreamed up herself. Comparing notes one day with Captain Noonan, the two agreed that one of the components of the drug might be worth trying on his own malady. Voila!---it worked like a charm for several weeks. The captain, who had barely been able to hobble around his own house, could now comfortably traverse the distance to his airplane hangar one-third of a mile away. He called Dr. Ellison one day in a merry mood. “Can the answer to my problem really be this easy?” he wondered. “Probably not,” said Siobhan.
A few nights later, we got a phone call just before midnight. This is never a good thing. They don’t call you at 11 p.m. to advise you that you’ve won the Publisher’s Clearing House Award or that your Aunt Nellie just broke the bank at Monte Carlo. It was Captain Noonan on the other end. “I think I’m dying,” he rasped. “I don’t think I’ll make it through the night.” Siobhan is by nature a calm, analytical person who does not spook easily. “You are not dying, Cap, but we’ll be right over.” We jumped into her Ford 150 and strapped in. “Do you ever feel like Batman?” I asked her. She smiled, lurching down the driveway. “Yes, I do!” she said.
We picked up the captain and drove to UF’s Shands Hospital, thirty minutes down the road, suffering the usual emergency room indignities before being allowed onto hallowed ground. Captain Noonan was in the midst of a full-blown allergy attack, grossly swollen tongue and all, which was ultimately subdued by the competent crew at Shands, but not before several days of hit-and-miss therapy. So now we were blessed with the ultimate conundrum: what to do when the cure for your disease might kill you?
What Can You Do In A Case Like That? What Can You Do But Spit In Your Hat?
The obvious answer to the question is to find a similar drug to the one which drastically improved the captain’s condition, but without the allergic properties. But where to look---you can’t just ask Alexa? The persistent Dr. Ellison eventually found one in China. Now all she had to do was determine it was safe, find an acceptable importer and have it converted into a form which would allow Noonan to self-administer. None of this is a quick fix and ALS takes no lunch breaks.
In the meantime, in between time, additional measures were considered. ALS is a tricky customer, a combination of malaises which attack in different ways and from all directions. Like Whack-A-Mole, you knock down one tough hombre with your little mallet and another one immediately pops up nearby. Basically, you need to be solving several problems at approximately the same time. You need a posse with super-powers of deduction, some intellectual Avengers, researchers on the brink of new discoveries whose work will mesh to save the day. Then you have to assemble them into a cohesive, communicating force under the command of Captain America. Or in this case, the auspices of Five-Star General Siobhan P. Ellison.
 |
| The General and the Captain plot a course. |
Saving Captain Noonan/by Siobhan Ellison
Our approach to saving the Captain is to take a non-traditional route to treatment discovery. Traditional treatment involves a single medication given to ALS patients in various stages of disease. The drugs are tested in ALS-afflicted mice to pass the first step toward human use, even though it is well-known that mouse disease does not mimic human disease and effective mouse drugs do not always help people. Different approaches to the problem have been taken in other countries, including Israel, South Korea, China, Italy and India and we are exploring those.
Our approach is several-fold. We are combining drugs in a large matrix--somewhat like an exceptionally vast logic puzzle--to look for synergistic drug effects. Synergism is an effect in which the sum is larger than each individual response. While some combinations of drugs will be bad, some may be good and some will do nothing. We are looking at combinations in mice (we want to weed out the lethal ones) and taking cells from people afflicted with ALS and putting them in a test tube. The human cells can be induced in the test tube to respond to drugs by releasing chemicals. The chemicals' signal (the profile for the drug combination) will be compared to the effects of the drugs in mice to delay disease progression. When taken together, the profiles may identify the Golden Treatment combination. The big word for chemical signals is “cytokine.”
Organisms respond to the immediate environment. You shiver when sleeveless in winter Alaska, but you don’t shiver in Hawaii. If you are underdressed in Alaska, after a few months your body will change by making your body fat turn brown. Brown fat releases more energy for heat and less for cells to use for their normal functions. When you move back to Hawaii, your brown fat will turn back to normal white fat. ALS is a disease in which the neurological cells are stressed and burn up energy. The cells can’t get enough energy for their housekeeping chores, so cells die. As the cells die, nerve tissues send stress signals to the body and change the way fat responds. This puts ALS patients in a death spiral.
Our idea is to examine the state of the patient, the fat cell profile, and take the “normal” ones from the population. We will take the cytokine profile and use that to normalize the signals to the stressed neurological system. It is our hope that these normal cells that are grown in test tubes can be used to repopulate the spinal tissues and salvage neurological function. Stem cells are being used as therapy in ALS patients with mixed results. We hypothesize that the ALS patient has started the process of “browning” and taking samples from browned patients would be detrimental. Early in disease—before browning—the stem cell therapy would be beneficial. By determining the patient’s fat cell profile, we can understand when stem cells would be beneficial or detrimental. We can understand when and which products released from the cultured cells would be a cell-free therapy. This cell-free therapy has proved beneficial in mice. All of this work must be done, of course, under the gun. A critical step is knowing when the cell processes are working in your favor and when they are not. Positive news is that a gauge of treatment success has been validated and the results show the progression of disease has slowed. As in baseball, you never know how long the game is going to last. It could go the regular nine innings, it could be rained out after five. Right now, we’re hoping for extra innings.
Baby Is One
A year has passed since Captain Noonan received the first diagnosis of his sorry plight. He is, on the whole, doing better than most. He grudgingly sold his Citation Jet 3 airplane last week but he’s still cruising around in a spiffy yellow Waco biplane and dive-bombing Marion County neighbors in his Robinson R-66 turbine helicopter. He has a multi-million-dollar business to tend to, but he’s got that mostly on autopilot. Every third day, he sits down and subcutaneously injects his Manchurian Candidate, a drug called thymopoietin, while also partaking of medications with funny names like Riluzole, Ibudilast, and Gabapentin. He does what exercising he can, mainly stretching and step-balance exercises, and uses breathing tubes to practice inhaling and exhaling. Life is not a bowl of cherries but Captain Noonan still has some fun.
“I try to ride my new bicycles a bit. They’re nothing fancy, but they are electric. I was riding one this week in St. Pete and one of those serious bike riders in a Speedo outfit called out that he was passing me on the left. He had a little too much attitude in his voice, especially since I wasn’t weaving hazardously around and there was absolutely no traffic. So after he passed, I used the throttle to keep up with him. About two miles later, he had to turn around to come back in my direction. And there I was, nonchalantly peddling away with not a drop of sweat. Life can occasionally still be sweet.”
It’s June, and the sky a brilliant blue. Somewhere, an aging pilot lifts his flagging body into a glorious golden airplane, scoots down the runway and lifts off. The little plane rises up, circles, and soars higher and higher, twisting, turning, laughing at the wispy clouds, almost out of sight now, plane and pilot just a speck against the sky.
But really, now. Aren't we all?
The battle continues. That’s not all, folks….
bill.killeen094@gmail.com
