Meet Dan Vesely, retired Israeli general and high-tech start-up entrepreneur. Here, he describes his response to his own 2013 Parkinson's disease diagnosis:
This is how I was trained in the service: if there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]
This paper examines the solution that Vesely and his associates developed: CliniCrowd, a digital ‘global community’ adopting an alternative approach to clinical research. The initiative was established after the discovery that a substance called mannitol might improve the condition of Parkinson's patients. This discovery was, essentially, being ignored for lack of significant profit potential. Below, we describe how CliniCrowd adopted mannitol as a treatment for Parkinson’s, and how their efforts evolved over time, employing different tactics to meet their shifting challenges as they sought to turn undone to done science.
Specifically, these key phases have been: (1) identification of and frustration over undone science; (2) the decision to circumvent lengthy, inefficient modes of operation; (3) framing as resistance; and 4) exploitation of ways to avoid direct resistance to established actors, in favour of re-framing themselves as complementing, rather than resisting, the status quo.
Phases and tactics: 1. Frustration over undone science
Mannitol is a powdery, natural substance used in the food industry as a sweetener. Hospitals employ intravenous mannitol to reduce intracranial pressure. Our study examined mannitol’s oral use.
Between 2012 and 2014, several pre-clinical studies conducted by a team of researchers at Tel-Aviv University, headed by Professors Dan Segal and Ehud Gazit, indicated therapeutic potential of mannitol against clumps of alpha-synuclein protein, a known sign of Parkinson's disease. The researchers were seeking a substance that breaks down these protein clumps in vitro; they discovered that mannitol does this very effectively. They next examined mannitol's impact on fruit flies (Drosophila) into which the human Parkinson's gene had been transplanted. This transplant severely impaired these flies’ motor function, disrupting their ability to climb the walls of a test tube. The researchers found that mannitol significantly improved the sick flies’ motor function and climbing ability. Post-mortem analysis of mannitol-treated flies’ brains showed that the amount of alpha-synuclein protein had decreased 70%. Next, they studied mice in whose brains the gene was implanted to produce the protein that causes brain disease in humans. Here, too, mannitol injection markedly decreased formation of Parkinson's disease-related structures. After a few weeks, the mice receiving mannitol showed decreased Parkinson's symptoms, and began to run and climb in their cages. Following these encouraging results, the obvious next stage was human experimentation…but here, things got complicated.
The researchers stated that these studies did not progress to the clinical trial stage. A natural substance found in many plants and algae, mannitol and its products cannot be patented. Moreover, given the ageing population, with concomitant rising rates of Parkinson’s, the global market value of Parkinson’s drugs (the overwhelming majority of which are symptomatic drugs with significant side effects), is enormous. Already worth billions annually, it is projected to experience a compound annual growth rate of about 11.3% from 2020 to 2027 (Accumen Research and Forecasting 2021). All this has rendered mannitol unattractive to pharmaceutical companies (and also to government and academic researchers, according to our informants), who have declined to test its value for treating Parkinson’s.
This is how one researcher involved in the study, Moshe [pseudonym], described his frustration:
It's not easy, knowing there is clear potential, yet the research has been shelved. The frustration is very great. It raises a lot of questions about the implications of scientific research. Whom does research serve: science, patients, or other [interests]? [interview Jan. 26, 2020]
Following several years pursuing funding to test mannitol on Parkinson's patients, the team published an article in a respected chemistry journal (Shaltiel-Karyo et al. 2013), and moved on to the next research project.
Abigail [pseudonym] is a veteran researcher who has led clinical trials at several international drug companies:
My research stopped, the money ran out, and I saw, to my regret, that projects are simply stalling and there are still questions. It’s not that the project is inefficient; often, I've seen good projects that have been shelved because of financial considerations. As you go up the ranks it becomes more evident, and I found it myself….in an Israeli pharmaceutical company, and also deep within international companies with tens of thousands of workers. You realize that the patient’s welfare in these places becomes secondary: the money, the investors come first…. I'm not against making money, it's okay to make money, as long as you protect the patient's welfare above all. [But] when the good of the patient is neglected due to financial considerations—I mean, we have a very good project, but we haven’t yet patented it, and [the new project] is a better treatment, but we will not release it to the world until we patent it, and then we will renew the patent [of the old drug], even though we know we already have something better. And my conscience had a hard time accepting this behaviour. [interview June 12, 2018]
These cases led Abigail to leave the pharmaceutical industry. She began working with Vesely on what became CliniCrowd’s project to explore natural substances with clinical potential.
Based on earlier treatment activism, we observe that the orphan is often parent to innovation. Thus, the original AIDS activists were motivated partly by their conviction that AIDS was essentially an orphan disease since, they assumed, mainstream actors would care little about a disease striking mainly marginalized, stigmatized groups (Indyk and Rier 1993). Similarly, French activists for muscular dystrophy (MD), given its comparative rarity, recognized that MD’s ‘orphan’ status confronted them with “being abandoned by the medical and scientific profession” (Callon and Rabeharisoa 2003, p. 197). In both cases, activists concluded that their fates lay in their own hands; orphan status thus helped stimulate significant patient-led innovations in the creation, diffusion, assessment, and application of new knowledge.
Treatments can also be orphans—with similar stimulus to innovation. We normally understand orphan drugs as those aimed at orphan diseases—those so rare that commercial manufacturers would expect little profit, hence do not produce them (Mikami 2017). Yet another type is one which, though useful for a common-enough disease, cannot be patented, hence is not commercially produced (Orphanet 2019).
This describes mannitol—although the real obstacle here is testing, not production. Other entities can produce and distribute mannitol reasonably simply and inexpensively. CliniCrowd’s problem—and key role—lies upstream: getting mannitol properly tested, to demonstrate its efficacy in humans to physicians and patients. Without prospects of corporate profits, the lengthy, costly process of formal trials is nearly impossible. As such, the phenomenon of orphan drugs represents an overlooked type of undone science, posing both an important, painful obstacle in treating disease, and an area ripe for research.
Phases and tactics: 2: circumvention—(A) If you can’t go through the door, go through the window
The fusion of a former commando’s mentality with that of a technology entrepreneur prompted Vesely to deploy his own resources to address his condition. Dissatisfied with his treatment options, he asked acquaintances for help. A small group of entrepreneurs banded together with him to search the published Parkinson’s research. They soon noticed the published—and forgotten—study about the possible effect of mannitol on Parkinson's patients. Vesely and some partners contacted Professor Dan Segal of Tel-Aviv University, who had co-headed the research team, and asked to meet:
It had not yet been tested on humans. So I made an appointment....Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there’s no incentive for the pharmaceutical companies. We looked at each other and said, ’So we’ll take it!’ The professor said, ’Who exactly are you? You brash Israelis, who are you?’ But it was clear to us that if you can’t go through the door, you go through the window. [Vesely interview, Jan. 24, 2018]
The story of the study and the lack of economic feasibility for clinical trials affected the group, comprised of former members of elite military units and high-tech entrepreneurs, coalescing around Vesely. Seeking to apply to himself, as patient, an approach traditionally reserved for researchers (Weisse 2012), Vesely resolved to test mannitol first on himself. However, his partners dissuaded him. Instead, they agreed to test mannitol on some number of Parkinson's patients.
Lacking a pharmaceutical company willing to invest in clinical research, they sought to test mannitol by launching a “circumvention of the entire medical system.” Indeed, when discussing CliniCrowd, they repeatedly used such terms as: “reconnaissance unit”; “commando operation”; and “quick-and-dirty”. These terms portray the mind-set of those accustomed to thinking creatively and acting decisively, specifically outside of existing frameworks and expected patterns.
They adopted a model, marrying patient self-experimentation with crowd-sourcing techniques (Swan 2012), described by Kempner and Bailey (2019, p. 4) as, “collective self-experimentation”. Inspired by similar crowd-sourcing ventures like PatientsLikeMe, the group created a website providing its own platform for Parkinson's patients who agree to take mannitol regularly for an extended period. Applying the 'crowd wisdom' familiar to them from other high-tech ventures, the company asked patients registering on the site to complete a detailed monthly survey about their health, Parkinson’s symptoms, and how they took mannitol. They analysed these data, which constituted an initial and rapid research alternative to formal clinical research.
This alternative is not a true substitute for ‘proper’ clinical trials. The survey platform lacks a control group, and patient surveillance is carried out through the site voluntarily and independently, and not by a physician. Nevertheless, they are generating preliminary data with which to justify the need for more formal clinical research. CliniCrowd’s founders initially considered marketing mannitol directly, but decided against this, to avoid conflicts with their research. In fact, although CliniCrowd’s prospects of ever becoming profitable are relatively limited, they nevertheless chose to register it as a corporation, rather than as a non-profit organization. This reflected their primary motivation of ‘getting the job done’ as quickly and efficiently as possible, via entrepreneurial tactics, rather than adopting the identity and tactics of social activism. As co-founder and CEO Amir Sadeh explained:
We want to fill a slot that deals solely with the welfare of the patient, so we are not concerned with marketing mannitol or its commercial aspects. But the management of a non-profit organization moves very slowly, like an aircraft carrier. They are very slow and cumbersome, with reports right and left. Whereas, the behaviour we're used to is more like a missile boat. If there are profits, they will be directed towards further research, not to our gain. The idea remains the same, to do good for humanity. The question is: how to do it fastest and best? [interview, December 3, 2017]
As elsewhere, Israeli non-profits are strictly regulated. Therefore, despite realizing that their company had no great profit potential, the founders of the venture, all entrepreneurs who had already earned significant wealth from their own companies, registered it as a corporation. It has enabled them to function more nimbly and more in accord with how they operate their other concerns. It is also consonant with their primary identity as entrepreneurs, rather than activists.
They established the corporation in August, 2016, and began recruiting patients with the help of patient forums and media exposure. They recruited trained personnel experienced in planning and conducting clinical trials to create the company's platform. It did not simulate a true clinical trial, but created a valuable database by recruiting patient volunteers on the Internet. According to our informants, by early 2021, 2,480 patients had registered on the platform dedicated to researching mannitol for Parkinson's. Of these, 1,364 (55%) had filled out questionnaires, multiple times. The platform has enabled patients to record and track data related to their illness and (while maintaining anonymity) compare these data with those from other members of the community. It was also possible to share the stored data with the treating physician. As mentioned above, the platform’s primary function has been to examine the effect of mannitol on Parkinson's patients, thereby making the patients active participants in the trial of a treatment that has not hitherto been tested on humans.
CliniCrowd's efforts at getting undone science done have involved several stages. Launching the crowd-sourced study was the main step. As Parkinson's patients on the platform began taking mannitol, and regularly completing questionnaires about their symptoms, an alternative body of research began to emerge. The primary value of this research was in the subsequent step of attracting credentialed scientists to conduct larger trials. CliniCrowd's initial data sparked public pressure, in turn leading to a formal clinical study, launched in 2018 at Hadassah Medical Center in Jerusalem. That study (https://clinicaltrials.gov/ct2/show/NCT03823638), conducted with public funding, examines the effects of mannitol on Parkinson's disease. As of June, 2021, the study was continuing, but had slowed somewhat due to Coronavirus and its severe impact on the medical system. Additional studies, at universities and medical centres in the UK and the US, are expected to begin shortly. As far as we know at time of writing, these are limited studies.
Nonetheless, there has already been a significant turnaround regarding how scientists regard mannitol research. As Vesely, CliniCrowd’s patient-founder, remarked:
It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019]
Researchers involved in planning the clinical trial have confirmed to us in interviews that, without the pressure applied by the public, it is unlikely that a trial would have been initiated. Vesely's use of the term, ‘buzz’ referred to public and media activity that placed the issue on the public agenda as a demand for change—in this case, a clinical examination of mannitol. His term ‘indications’ referred to the fruits of the surveys, which did not replace clinical research, but—unlike the initial mannitol study on fruit flies and mice—created a pool of patient data difficult to ignore.
Phases and tactics 3: framing—resistance
CliniCrowd’s efforts to address undone research involved tactics of framing and positioning—both of mannitol, and of themselves. The concept of framing has been heavily used by social movement researchers to describe how movements understand, interpret, and present—to themselves, and to others—what their organizations and movements ‘mean’, their values and goals. It is an important resource in mobilization work, whereby activists try to align their own frames with those of others whose cooperation or support they seek. They might, for instance, adopt frames of patriotism or motherhood, when seeking broad public support, or of resisting inequity, when seeking alliances with other aggrieved actors. But the frames adopted can vary, not only with the specific context and audience for which they are deployed, but also as an organization evolves over time (Snow et al. 1986, 2014; Benford and Snow 2000).
In fact, CliniCrowd’s stance vis-à-vis the biomedical establishment has evolved over its short history. In the first interviews, the founders strongly criticized the pharmaceutical industry. For example, in the first interview with CEO Amir Sadeh, he described the decision to establish the company:
The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such ‘ignored’ compounds] do not generate income, they do not make a profit, so it’s better not to know about them at all. But now we’re exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that’s why it’s the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year—as far as they’re concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T]he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]
Sadeh’s rhetoric framed CliniCrowd’s founding as, at least partly, an act of resistance against the perverse negative incentivisation of the pharmaceutical industry, which—notably, for a businessman—he portrayed as cynical and corrupt.
Similarly, CliniCrowd's initial promotional materials, targeted to the wider public, repeatedly emphasized the pharmaceutical industry's reluctance to examine the effect of mannitol on Parkinson's patients. CliniCrowd portrayed their own efforts as a guerrilla campaign aimed at raising awareness and targeting gigantic, cynical corporations. Indeed, even in mid-2021, CliniCrowd's public website still exhorted: “Get more control over your life and your disease, including exploring natural approaches. You have the right to know about and explore nutriments and treatments that big pharma companies generally won’t investigate” (URL: https://clinicrowd.info/what-we-do/ [accessed June 10, 2021]).
At the outset, CliniCrowd experienced significant difficulties in achieving trust and support from the medical establishment. From interviews we conducted with patients who began taking mannitol between 2016 and 2018, it appears that those who consulted their physicians encountered substantial resistance to mannitol. Physicians' objections included comments such as: “this is a home remedy” and, “you would be better off getting a blessing from a rabbi”. At a neurologists’ conference early in 2017, the CliniCrowd delegates were given only a few minutes to present, and most conference attendees ignored their talk. Such disdain recalls the boundary-work (see below) opposition directed at grassroots AIDS knowledge production over a generation ago (Indyk and Rier 1993, pp. 20–21), and illustrates, at least in mild form, Hess’s (2016) observation that incumbents and elites might first attempt to ignore, and then to suppress or co-opt challengers (pp. 34–35). Recall Hess’s words regarding cancer treatments, cited above, that those advocating for “less expensive… nutritional supplements… may even experience intellectual suppression….” (p. 28).
Phases and tactics 4: re-framing and circumvention—(B) from resistance to complement
However, as the fieldwork progressed, we noticed a shift in the attitude of CliniCrowd employees, in the company’s discourse, and in media attitudes. At this point, we began to track the penetration of the term ‘dietary supplement’ into societal discourse. It appeared in interviews, fieldwork, content analysis, and in media appearances. Interviews made clear that the choice of the terms ‘dietary supplements’ and ‘functional foods’ reflected CliniCrowd’s tactical decision to cease resisting pharmaceutical companies, in favour of creating a channel of influence and complementary action, by re-framing mannitol as a new substance in the food supplement market.
This is how CEO Sadeh described the change, in a follow-up interview:
We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]
It is interesting to examine the change in approach as reflected in interviews with Sadeh over time. This trend supports Hess’s (2016, pp. 46–47) discussion of challengers shifting focus from that of replacing to complementing industrial actors. In this, it also echoes AIDS research, where activists initially profoundly hostile to the scientific and pharmaceutical establishments eventually chose to cooperate with them (Petersen et al. 2019; Harrington 1997; Maguire et al. 2004). Still, Sadeh’s final sentence demonstrates that re-positioning themselves as complements rather than replacements did not necessarily mean that CliniCrowd fully renounced their critique of commercial influence.
CliniCrowd's tactical shift is an example of boundary work (Gieryn 1983; Lamont and Molnar 2002) and boundary framing (Silver 1997; Benford and Snow 2000) in which, via re-framing, they withdrew from the risky drug arena, where they had challenged the pharmaceutical industry and the medical community, and relocated to a new niche in another arena, considered less important and therefore less threatening to powerful incumbents. CliniCrowd's actual operations did not change significantly. What did change was mainly how they chose to define and describe—to frame—their mannitol work.
Re-framing mannitol as a functional food proved a valuable manoeuvre, enabling CliniCrowd to disseminate the knowledge they had collected from patients without encountering significant objections. It appears that changing its orientation from resistance to creating an alternative, or complementary, channel of influence helped promote acceptance of mannitol among doctors and patients. Indeed, in the latter half of 2018, we noted an attitudinal change amongst physicians with whom we discussed mannitol. Three doctors interviewed for the study told us that, once they realized that this was a dietary supplement, they stopped objecting: “It is a dietary supplement. It may not help, but it's not harmful” [from an interview with Alona (pseudonym), a neurologist; April 17, 2019].
Actually, this change was presaged by interviews with patients. For example, 68-year-old Alexander [pseudonym] described how he informed his physician in 2018 of his intention to begin taking mannitol:
I went to my doctor and convinced him. I showed him it was not just something I had found, like a home remedy. I told him I was going to take it, and either he would jump on the bandwagon or I would look for a doctor who would agree to work with me the way I wanted. [interview Feb. 4, 2019]
Such pressure from patients who had been exposed—via forums, articles in the Israeli press, and the clinical survey site—to the possibility of a new treatment option, combined with the description of mannitol as a dietary supplement, softened attitudes of those physicians who formerly had objected. This, ‘if you can’t beat ‘em, join ‘em’ approach arose also with AIDS, where patients’ ‘non-compliant’ drug ‘treatment holidays’ led their physicians to explore the phenomenon more systematically, as ‘structured treatment interruptions’ (Rier and Indyk 2006b).
As Alona explained:
I think no doctor likes it when the patient comes and says, ‘Listen, I’ve found a treatment.’ Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably, in his case it won’t work. This was also my initial response to mannitol, complete resistance, not wanting them to take it....The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn’t come and say this is a magic drug, but rather that it may help with some of the symptoms....I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don’t exclude it, in fact quite the opposite. [emphasis added].
Overall, the company’s tactical shift did promote acceptance of mannitol use among patients and physicians, and it helped launch clinical trials to examine its effect on Parkinson’s patients.
To appreciate how the patients, themselves, experienced this, consider Menachem [pseudonym], 68, diagnosed some four years earlier. When asked about the experience of taking mannitol and participating in filling out the web questionnaire, he responded:
My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! ‘Welcome’, he says, ‘tell me how you are getting on’. There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]
Note the ease that Menachem describes in his relationship with the doctor, his feeling that he is an expert, his delight, and the agency he feels because of his participation. These are all so important to him that he mentions them even before his improved health, which he attributes to taking mannitol regularly.