Eureka! I finally have evidence of something I have long believed: that my family and I have a piece, albeit a small and inconsequential one, of one of the greatest stories of human fortitude and achievement in the history of civilization.
For this evidence, we have science journalist Bijal Trivedi to thank. Her recently published book, Breath from Salt, is the 500 pages I have been yearning to read almost since the day in 2002 that I learned my baby daughter had cystic fibrosis. Spoiler alert: Today that baby daughter is a thriving and ambitious 19-year-old scholar-athlete -- but she still has cystic fibrosis and she is always a step or two away from hospitalization. [The photo on the left is that very kid in 2012, with Bob Beall. If his name is not familiar to you -- well, please read on.]
Breath from Salt tells the story of cystic fibrosis, from the death of three-year-old MD in 1937 (which led to the discovery of what we now know is the second most common life-threatening inherited disorder) to the approval in October 2019 of Trikafta (the breakthrough drug that made a treatment for the root cellular cause of CF available to 90 percent of people with the disease). Even if you have no connection to CF, consider reading Trivedi's book, for two reasons: (1) the story, rife with plenty of heartbreak and moral ambiguity, is nevertheless a template for how humanity might think and struggle its way through other daunting disease-related challenges, and (2) in a time when so many are cynical and dispirited, this is a story of scientific truth attained, hopes realized, and thousands of years of human grief abated.
With the broken human being in the White House preparing to slide into obscurity while a weary nation awaited the end of a miserable pandemic, I was ready for such a story. But, in fact, I've been waiting for this opus since at least 2005. That's when I met, briefly, an affable and elderly gentleman named Carl Doershuk in the exhibit hall of the North American Cystic Fibrosis Conference.
Doershuk was nearing the end of a very distinguished career as a CF doctor and he was in the exhibit hall peddling a book he had edited, titled Cystic Fibrosis in the Twentieth Century. But when I explained that I wanted to buy his book because I was a CF dad, he practically refused to sell it to me. "It isn't very good," he said in an effort to discourage his customer.
Nevertheless, I persisted. But, as I perused my purchase, I discovered that Doershuk was right, sort of. He was a gifted pulmonologist but apparently lacked the talent or perhaps just the time to pull together the cystic fibrosis story as a coherent and well-edited narrative. Cystic Fibrosis in the Twentieth Century is a disembodied collection of essays, many of which were written by the physicians and scientists who were personally responsible for the breakthroughs they were describing. Breath from Salt turns the primary sources into the coherent and moving narrative this epic story so richly deserves.
Dorothy Hansine Andersen shines her lamp at the gateway of this story -- appropriately enough, in her photographs she resembles the Statute of Liberty -- as the Columbia University pathologist who, in 1938, published the article in the American Journal of Diseases of Children that brought cystic fibrosis to the attention of the world. Before Andersen conducted her autopsy of three-year-old MD the preceding year, cystic fibrosis had for centuries been an unexplained reason why babies and little kids whose skin tasted salty never made it beyond toddlerhood. More significantly, victims like MD were falsely assumed to have died of celiac disease, a conclusion that stubborn Dorothy Andersen could not abide given the pancreatic cysts and lung damage her autopsy identified.
Certain key factoids about Andersen have long been in circulation. She had wanted to be a surgeon but the prevailing sexism of her time scotched that idea. She came from North Carolina but graduated from the St. Johnsbury Academy in Vermont, having moved to the Green Mountain state with her ailing mother. A dedicated smoker, this giant of pulmonary medicine died of lung cancer at age 62. I cannot think of a more bitterly ironic turn of events.
But, until Trivedi came along to do her research on the history of CF, little else about Andersen and her accomplishments were available for public consumption. Now we know that Andersen's mother, Mary Louise Mason, came from a prominent New England family. Surely that accounts for their migration to Vermont after Andersen's Danish father, Hans Peter Andersen, died when Dorothy was just 13. Now we also know that other physicians, both prior to and contemporenously with Andersen, were noticing similar phenomena; it was she who connected the dots, had the audacity to claim she had identified a new disease, had the persistence to document her claims, and had the passion to follow up on her discovery -- which is how a pathologist came to have a long list of live pediatric patients with very grateful families. Earth to New York Times: Dorothy Andersen is overdue for one of your "overlooked no more" obituaries. Throw in a posthumous Nobel Prize for Medicine and maybe, as Trivedi amply documents, this great woman gets her due at last.
Andersen, it turns out, was only the first in a long line of scientists who have made remarkable discoveries related to cystic fibrosis. Among them: Paul di Sant'Agnese, who figured out that super-salty sweat was an unmistakable symptom of the disease; the sweat test he developed remains the official diagnostic standard. Paul Quinton -- himself a CF patient -- actually yelled "Eureka!" en route to using skin samples he'd gouged from his own arm to figure out that the defect at the heart of CF is ineffective chloride transport across the membranes of cells in lungs, pancreases, sweat glands, and a few other places.
And then there was, and is, the dynamic duo of Lap-Chee Tsui and Francis Collins. I've long known that what they pulled off in 1989 is well worthy of having the face of each added to Mount Rushmore. What Trivedi adds is sufficient detail to knock even a cranky old cynic like me out of his chair and right onto the floor.
Collins and Tsui discovered what is known in the trade as "F508del" -- a deliciously jargon-obscured label for the genetic mutation that causes most cases of cystic fibrosis. I've had my eye on F508del a long time -- I've also seen it referred at various times as DeltaF508, or 508Fdelta -- but geneticists and pulmonologists don't take the time to do what Trivedi does: lay out, in plain terms, that the designation F508Fdel actually means: that a particular amino acid, phenylalanine, is missing at position 508 of a key cellular protein (known as CFTR, "for cystic fibrosis transmembrane regulator") causing the molecule to fold incorrectly and thus not do its job right.
That minutia obscures the enormity of what Tsui and Collins identified. They were the first to
trace a disease to its precise genetic cause. But here's what really blew me away, as described by Trivedi: The discovery of the F508del mutation is the reason we know about the CFTR protein, whose defective performance is cystic fibrosis. That's right! Though you might have assumed, as I certainly did, that figuring out the basic microbiology of the disease would have led scientists to finding the mutation, the discovery path was in exactly the opposite direction. To me this is the equivalent of figuring out that cars exist, and then successfully designing one, by looking at a highway map. [Photo: Francis Collins addresses the North American CF Conference, November 1, 2019]
If that leaves you unmoved, because you can't grasp how that might shed insights with profound implications well beyond the small world of cystic fibrosis, consider the human dynamics of this achievement. It is common knowledge in the CF community that Tsui, leading a team at the Hospital for Sick Children in Toronto, and Collins, likewise heading up a lab at the University of Michigan in Ann Arbor, were both seeking the same thing: the CF gene. Trivedi has finally explained in accessible and lucid terms why they chose to cooperate rather than compete.
The secret? Collins was into jumping and Tsui was into walking. It's that simple.
Walking and jumping are two ways of looking for specific genes along the vast chains of information we know as chromosomes. Walking is meticulous. Jumping -- literally leaping over hundreds of thousands of letters (each referring to a basic component of DNA) at a time -- was, naturally faster. But it was also riskier because, obviously, one could leap right over the gene that was the answer. Thus, as Trivedi writes, on a sunny day in 1987 Tsui sidled up to Collins outside a conference in San Diego and "suggested they team up: Once Collins took a jump, then Tsui's team could 'walk' from the new start point."
We live in competitive, even mean-spirited times. The year 1989 is not so removed from where we are now. And yet Tsui and Collins transcended the cultural zeitgeist of theirs and every other profession and used cooperation to make a medical miracle. Though only a lunatic would deem himself fortunate to have a serious disease like cystic fibrosis arise in his family, I read a story like that and think: There is something about cystic fibrosis that summons the best in people, and those who are connected to the story of this disease in any way have had something remarkable thrust upon them -- perhaps not a blessing but surely an opportunity that ought not to be squandered.
In that regard, Trivedi explains why one hardly needs to be a medical professional or a scientific researcher to claim a piece of this action. Specifically, she traces the history of the Cystic Fibrosis Foundation -- which, according to Trivedi, became "the largest disease-focused charity in the United States and the fifth most financially powerful health no-profit in the world" by virtue of a deal sealed in 2014 -- to Dallas socialite and CF mom Wynne "Didi" Sharples, the nonpracticing physician who, in 1955, started what was originally known as the Children's Exocrine Research Foundation.
These days, the CF Foundation's official hagiography tends to focus on a different CF mom of the 1950s, Doris Tulcin of Westchester County, north of New York City. Breath from Salt suggests several reasons for this. Trivedi reports that Sharples was "a tough personality," an "uncompromising" leader who "made enemies." She quit the Foundation in late 1959; Tulcin remained the leader of the Westchester chapter and, indeed, still appears on the CFF letterhead as chair emeritus. Critically, however, Tulcin shared with Sharples the strong opinion that the primary focus of the Foundation should be on medical research -- even, in those early years, at the expense of programs to support patients and families in their struggle to deal with what was then an essentially untreatable fatal disease. Unlike Sharples, Tulcin apparently had the moxie and the diplomatic skill to effectuate her conviction; 65 years later the results speak for themselves.
From the time Tulcin became the dominant figure in the CF Foundation forward, the story of this nonprofit cannot help but wow anyone familiar with the governance of 501(c)(3) organizations -- particularly those operating at a national scale. National disease charities tend to be federations of local and state organizations, and the looser they are the more muddle there is. The CFF went through the difficult process of wresting autonomy from its local chapters, which engendered some bad feelings and bruised egos but which facilitated a coherent and unified campaign against a disease that, after all, is pretty much the same everywhere and does not benefit from local solutions. Moreover, nonprofits are chronically vulnerable to mission muddle as wealthy donors impose their whims on everyone else. The CFF attracted wealthy donors aplenty but still managed to keep its eye on the prize -- a cure -- as well as the path to the prize (research).
How the heck did the CFF do that?
I've got a two-word explanation: Bob Beall. (He is pictured, above, posing with my daughter in 2012 at a CFF advocacy gathering in Washington.) Trivedi is somewhat more circumspect than I am about Beall's role, but she has compiled a prodigious pile of information that supports my hypothesis.
Beall was an up-and-coming biochemist in 1976, focused on diabetes, when his boss at the National Institutes of Health asked if he'd be interested in attending a conference on CF. "Never heard of it, Beall said briskly," Trivedi reports, adding that Beall was even less interested when the boss disclosed that CF is an "orphan" disease that affects just 30,000 people in the U.S. (a tiny fraction of those affected by cancer or diabetes and about a third the number affected by sickle cell disease, the nation's most common inherited life-shortening illness).
Still, Beall did not defy his superior and, so, he duly went to the gathering, a CFF-sponsored conference in San Diego. According to Trivedi, Beall was unexpectedly moved by the desperate CF parents he met there. "This community had no resources, no science, and no hope," she noted. "But Beall saw that as a challenge."
Less than four years later, Beall joined the staff of the CFF, first as its medical director and then, beginning in 1994, serving as the CEO. If you have ever met Bob Beall, as I have, then you know Trivedi has him exactly right: He is precisely the sort of relentlessly driven, mission-focused, skip-the-small-talk-and-get-me-results sort of person you would want to be in charge of curing your daughter's incurable disease. But to have even a casual encounter with the man is to know it must have been scary as hell to work for him. At the same time, Trivedi's portrait is suitably nuanced; Beall, not unlike Dorothy Andersen, brought to his work a love of the people whose lives he was striving to extend. I rather think that to have disappointed Bob Beall as a CFF employee might well have involved a tongue-lashing followed by an earnest "how can we fix this together?" conversation.
Somehow Trivedi managed to extract the best Bob Beall story I have ever heard. Since I first became acquainted with the organization in 2002, the chieftans of the CFF have been paragons of discipline and not the least bit inclined to share idle bits of inside baseball. In no aspect of the CFF's work is this more apparent than its relations with Vertex Pharmaceuticals, the Boston-based Big Pharma powerhouse that produces the breakthrough CF drug Trikafta and its related predecessors (Kalydeco, Orkambi and Symdeko). As amply documented in Breath from Salt, these drugs exist because of the "venture philanthropy" model Beall pioneered -- i.e., the CFF paid Aurora Biosciences Corporation, later bought out by Vertex, to conduct the early ultra-experimental stages of developing these so-called "modulator" drugs in exchange for a share of any revenue stream the medications ultimately produced.
Such a relationship is fraught with moral ambiguity and ethical hazard -- as Trivedi, to her credit, makes plain even as she lays out the glorious story of these drugs' successful development (totally made possible, do not forget, by the work of Collins and Tsui previously described). Which brings me around to what is now my favorite Bob Beall story.
The year was 2005. Vertex had identified a promising molecule -- the one that was eventually marketed as Kalydeco, the first of the modulator drugs. But the Big Pharma company had, to date, taken precisely no financial risk; the CFF had funded everything, to the tune of tens of millions of dollars. Vertex was keen on speeding the development of Kalydeco by scaling up manufacturing capability even though the drug was still in its Phase II trials (much as Pfizer and Moderna have more recently done to fast-track the deployment of their COVID-19 vaccines). Usually, a drug company awaits success at Phase II before investing in the production capacity required for the bigger Phase III trials that are a necessary precursor to FDA approval. But in 2005 Vertex was a publicly traded corporation that was still years away from producing a dime of profit for shareholders.
So, Eric Olson and Phil Tinmouth of Vertex headed for CFF headquarters in Bethesda, Maryland for a meeting with Beall and his leadership team. They asked Beall for an additional $20 million.
"Beall was furious," Trivedi reports. Specifically:
"His face was bright pink, a color that was accentuated by his ring of white hair, and he was pacing next to the conference table like an aggravated rhinoceros. The foundation's original model, Beall's model, was that they would fund the discovery phase, creating a zero-risk project for Vertex. But then, once a promising molecule was discovered, Vertex was supposed to pay for its development: large scale manufacturing, drug formulation, animal testing and toxicology, and the phase I, II, and III clinical trials. . . .
"Beall felt the request was a shakedown, a violation of their understanding, and tore into Olson about trust and betrayal."
There are three things to keep in mind about this incident as reported in Breath and Salt. First, Olson -- who left Vertex in 2013 -- has served on the CFF Board of Trustees since 2016. Second, Beall forked over the $20 million that Olson requested. According to Trivedi, as Beall and Olson wrapped up their tense meeting a lunch was delivered by caterers. "Beall looked at the food, then at Olson. 'I've got to get you guys $20 million and I have to feed you too?'" Like I said, you probably never want to cross Bob Beall but, if you do, the meeting might ultimately end reasonably well.
Third, to my knowledge, this story and a smattering of related details in Trivedi's book represent the first public acknowledgement by any of the key figures at the CFF that Vertex has ever done anything other than walk a purely virtuous venture philanthropy path in its dealings with the Foundation. The only possible sources for this story are people who ordinarily would never be caught speaking an unflattering word about the Big Pharma behemoth in question.
Fast forward about seven years to the FDA's approval of Kalydeco It is what Trivedi refers to as the "doorman" drug, which fixes the situation in which the CFTR protein reaches the surface of the cell, implants itself appropriately, but is unable to open and thus function as an effective chloride channel. Taken by itself, Kalydeco helps only about four percent of CF patients, but its approval was a huge milestone nonetheless. "While the success of this drug was the pride of the foundation, Beall was less happy about the price that Vertex had slapped on it: $294,000 a year," Trivedi reports.
According to Breath from Salt, Beall was peeved because he knew that Vertex's ability to roll out Kalydeco was the result not just of (or even primarily because of) shareholders taking a risk. Rather, as Beall knew, the taxpayers had funded a lot of the basic science research and CFF donors -- largely families, of varying degrees of wealth, with a connection to the disease -- had put Vertex over the top when it came to moving forward. There is no word on what Beall makes of the list price for Trikafta: $312,000 a year.
Trivedi is obviously very careful about how she characterizes all of this. Scattered in various places, hiding in plain sight, are references to the fact that through most of the time the modulators were under development neither Aurora nor its successor Vertex had capital at risk; the CFF took care of that. (Indeed, according to Trivedi the senior management and board of Vertex were indifferent to the fate of the company's CF project until it started to look like the endeavor would hit paydirt.) My career in utility regulation has taught me that return on investment should follow risk, which is why investors in Big Pharma firms can reasonably demand a better payout then they'd get by parking their money in shares of a big electric company or some other outfit that is unlikely ever to lose money. But as organizations like the Institute for Clinical and Economic Review have argued persuasively that Vertex is charging too much for its CF drugs, the CFF has not publicly complained.
Much of the criticism Trivedi describes is fairly attributed to Paul Quinton, who is unabashedly critical of both Vertex and the CFF for what he considers "exploiting the goodwill of donors and gouging the patients." Further, according to Trivedi: "The foundation wasn't blameless in this, Quinton believed. By earning royalties from the sales of the Vertex drugs, they had created a conflict of interest: they were making a profit from a drug that helped the people they were dedicated to assisting."
Quinton, alive and well and still working in his lab at U.C. San Diego, has been known to go even further than that with his criticism. He thinks the CFF has sold its soul entirely. That's been widely reported, unlike any hit of unease within the Foundation itself. In that regard, take a breeze through the acknowledgements in Breath from Salt; it is clear that Trivedi had the full cooperation of CFF leadership both past and present.
To the extent venture philanthropy has indeed comprised a Faustian bargain for the CF Foundation, I'm implicated too. So far, the Foundation has pocketed $3.8 billion by monetizing its share of the royalties from Trikafta and its siblings via deals with Royalty Pharma (which is in business to conduct precisely this sort of high-flying arbitrage). I'm almost as far as you can get from that conference room in Bethesda where Beall nearly gored Eric Olson and still be affiliated with the CFF. (I am currently the annual giving chair, and an advocacy volunteer, for the CFF's Northern New England Chapter.) But my daughter has so-called "rare and nonsense" mutations -- little or no CFTR protein is produced in the cells of her body where it is needed. I know, just as Bob Beall knows, and just as current CEO Mike Boyle knows, that those billions of dollars are what will deliver the goods for all cystic fibrosis patients and make CF truly stand for "cured forever."
Between Beall and Boyle as CEO of the Foundation was Preston Campbell. He too had a distinguished career at the helm of the CFF, retiring at the end of last year. I once had the nerve to stand up at a CFF meeting and ask Campbell about the high price of those Vertex drugs. All he would say in response was that it's better to have these drugs, and have the opportunity to argue about their price, than not to have them. Given that Preston Campbell is a kindly gentleman, and given that my daughter would be many years dead, but for the work of the organization he led, his non-answer was fair enough. But I am grateful to Trivedi for finding a way to confirm that the CFF's public adoration of Vertex is not without its misgivings behind the scenes. [Photo = Preston Campbell at the North American CF Conference, November 2019]
This is not to say that Breath from Salt is flawless. Trivedi's focus is more narrow than the CF story deserves. For example, though there is a smattering of references to Warren Warwick and the national CF patient registry he started for the CFF in 1966 and maintained for many years thereafter, his starring role in the CF story is not acknowledged. Warwick, the pulmonologist who for years directed the CF center at the University of Minnesota, was also the inventor of the physical therapy machine known as "The Vest," used by my daughter and (along with its knock-offs) virtually every other person with CF. The advent of this device freed every CF household from the drudgery of administering hours of manual chest physical therapy each day.
Yeah, venture philanthropy is great. But data is the other secret sauce of the CF Foundation and Warren Warwick did more than anyone to make sure that the medical progress of virtually every person in the United States with cystic fibrosis is tracked and accounted for. Today we live in an era of big data, but the value of developing this raw data and then crunching it aggressively -- well, that too is part of what the world owes to the quest to overcome cystic fibrosis. At the same 2005 conference at which I met Carl Doershuk, my daughter's pulmonologist introduced me to Warwick. We were at a loud party where (since it was Baltimore) crab had been served. When I told Warwick that my daughter was a devoted user of a particular model of his machine, he grabbed a paper crab bib from a nearby table and scribbled out a graph of recommended settings for the device, explaining everything as he went.
I couldn't hear a word he said. But I know that Warren Warwick was a giant figure in CF history. Fortunately, he figures prominently in a memorable article about cystic fibrosis in the New Yorker from 2004 by surgeon/journalist Atul Gawande. Read it if you haven't (but keep in mind that the science is out of date, thanks to all the breakthroughs described in Breath from Salt.)
Alas, Warwick doesn't quite fit into the arc of the story Trivedi had so clearly resolved to tell, whose climax was the approval of Trikafta. Neither does Frank Deford, the literary lion of CF luminaries who chaired the CFF's for many years. The saga Trivedi decided to spin out has but three kinds of characters in it: Visionary nonprofit leaders of the sort epitomized by Bob Beall, scientific strivers in the for-profit sector employed by Aurora and Vertex, and wealthy people who could not bring themselves to stand down when cystic fibrosis touched them personally. There are some pretty compelling stories in Trivedi's report of the latter group. That wealthy Boston-area confidant of George W. Bush and Mitt Romney who is still leading capital campaigns for the CFF, decades after the death of his 12-year-old son from CF? He's probably out there right now, scaring up the donation that will put this quest over the top.
I just wish there were more room in the story of CF for the everyday struggles of regular people who have coped, and continue to cope, with this disease -- perhaps without ever having raised a dime for the CF Foundation. I'm talking about people who sometimes have to skip medications because their coverage has lapsed -- or people like undercover cop Marco DiFranco, one of only three people with cystic fibrosis who have died of COVID-19 in the U.S. (at least so far). The Chicago PD had refused to grant the medical leave DiFranco requested when the pandemic first struck. I like the idea proposed by CF author Jay Gironimi, that every person who steps forward to brag about their courageous struggle with the disease should be obliged to disclose where their health insurance comes from, how much it costs, and how much it covers. Another idea would be to find common cause with the (mostly African American) people who are striving to overcome sickle cell disease, since the contrasting demographics of that disease and our disease might explain why we are much closer to curing cystic fibrosis than sickle cell.
You may say I'm a dreamer. And you will surely say I am an egomaniac when I tell you that I pawed through the index in Breath from Salt and highlighted the names of all 12 people there whom I've met or interacted with over the years. That a nobody like me can have all the access he wants to the leaders of the struggle to overcome cystic fibrosis -- well, it tells you something about the character of the intense and tight-knit CF community. The story of that community is the best tale I have read all year.
[You can buy the book directly from the publisher, BenBella Books, here. And if you are reading this before the end of 2020 you can donate to my Cystic Fibrosis Foundation Annual Fund campaign here.]