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Self-experimentation, ethics, and regulation of vaccines



As the coronavirus disease 2019 (COVID-19) pandemic continues to sweep the globe, several groups have been working to develop and self-administer unapproved, unproven interventions that they describe as vaccines for COVID-19 (14). Some of the interest in these do-it-yourself (DIY) approaches apparently stems from a belief that self-experimentation is never subject to time-consuming ethics board review or regulation, such as by the U.S. Food and Drug Administration (FDA). This belief is legally and factually incorrect, and the misunderstanding has potentially important public health implications. Any failure by the FDA to regulate DIY vaccines would permit vaccines of dubious safety and effectiveness to endanger public health and would signal a lowering of standards that—in an age blighted by vaccine skepticism and during a highly politicized pandemic—could undermine public trust in all vaccines, however developed (5). Further, some self-experimentation can qualify as human subjects research that is required to undergo ethics review, by law or institutional policy. Even when ethics review is not required, citizen scientists must take seriously their heightened ethical responsibilities when promoting DIY interventions, especially those with potentially serious public health and societal effects, such as COVID-19 vaccines. Given the proliferation of citizen science efforts to fight COVID-19 and the general confusion (even among sophisticated scientists) that surrounds the regulation of DIY research, regulatory leadership is badly needed.

“The FDA Can’t Stop You”

In July 2020, six months after the first case of COVID-19 was confirmed in the United States, scientists associated with the Rapid Deployment Vaccine Collaborative (RaDVaC) reported administering to themselves a product of their own making that was intended to be a vaccine against the disease. As described in the group’s white paper, the putative intranasal vaccine consists of synthetic peptides that mimic those of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and is designed to elicit only a local immune response (6).

By its own account, RaDVaC is engaged in “citizen science,” which broadly describes activities having a scientific aim that invite public participation. RaDVaC’s chosen research path—which involves a homemade intervention, an evolving protocol, and unclear plans for collecting and analyzing outcomes data—is in contrast to traditional paths to vaccine development, which require randomized controlled trials (RCTs) with well-defined endpoints, such as demonstrated immune responses, and protocols concerning the retention and use of data.

Although some citizen scientists have antiregulatory leanings, RaDVaC has explained that it is not anti-FDA. Rather, its stated mission is a humanitarian one, animated by a belief that open, crowdsourced vaccine efforts will hasten the widespread availability of a potentially life-saving vaccine through development activities that it believes are not subject to FDA regulation (6). To that end, RaDVaC published on the internet instructions on how to self-manufacture and self-administer its DIY vaccine. RaDVaC also has provided materials for those activities, reporting as of several weeks ago the delivery of vaccine materials to 70 individuals (1). RaDVaC has made clear to potential users that its vaccine has not been reviewed or approved by the FDA. It also believes, as one of its leading scientists stated, “If you are just making it and taking it yourself, the FDA can’t stop you” (1).

RaDVaC is not alone. A small group of biohackers known as Project McAfee—after the antiviral software—reconstructed and injected themselves with a vaccine previously tested only in monkeys (2). Other known DIY COVID-19 vaccine efforts in the United States include a biohacker who self-administered a DIY vaccine that has reportedly been taken by at least 10 other people (3) and a microbiologist and founder of a small biotech company who sold and administered an unapproved vaccine to about 30 people (4). Given the global reach of the disease and widespread involvement of citizen scientists in biomedical activities, other efforts are likely under way, both in the United States and elsewhere.

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The FDA and Self-Experimentation

In the United States, it is true that the FDA’s authority does not extend to some instances of self-experimentation, for which there is a long tradition in medicine, including vaccine self-experimentation (7, 8). But self-experimentation, for the FDA’s purposes, is a narrow category. The FDA’s jurisdiction would not extend to a citizen scientist insufflating an experimental vaccine that they created entirely from materials around their house. Nor would it extend to the distribution of only information about a DIY vaccine, such as suggestions for where to acquire materials or instructions for making and self-administering it (9).

However, the FDA does have jurisdiction over other forms of self-experimentation. Under U.S. federal law, the FDA is authorized to regulate vaccines that cross state lines. This includes not only the final product itself but also more mundane intermediate components, such as reagents (9). The FDA’s authority covers such vaccines regardless of whether they are developed by traditional industry players or citizen scientists; administered by a health professional or the patient; or, in many cases, sold for money or freely given away. The FDA’s authority is meant to be broad and national in scope rather than leaving things to a fractured pattern of state regulation or jurisdiction that turns on fine technicalities of how money may or may not have changed hands. This ensures that manufacturers and distributors do not easily escape expert public health oversight. Distributing materials intended for the self-manufacture of any vaccine therefore falls squarely within the FDA’s jurisdiction and its public health mission.

Other self-experimentation projects have similarly crossed the line into FDA-regulated product development. For example, in late 2017, in response to concerns about DIY gene-editing kits, the FDA stated that any distribution of gene editing materials intended for use in humans qualifies as gene therapy subject to the FDA’s requirements (10). This reach of the FDA’s authority is justified. When self-experimenters provide interventions or their components to others who might follow in their footsteps, this has a serious potential to injure other experimenters, among other negative externalities.

The Common Rule and Ethics

An FDA-authorized Investigational New Drug (IND) application permits unapproved drugs (and their components) to legally cross states lines and be investigated in humans, subject to certain requirements, including approval by an Institutional Review Board (IRB). Additionally, even with respect to DIY vaccines outside the FDA’s authority, research with human participants is independently regulated in the United States by the Common Rule when the research is federally conducted or funded. Most self-experimentation is neither, but research institutions’ own policies generally subject all human participant research in which the institution is “engaged” to the Common Rule’s requirement of advance review by an IRB. IRBs help ensure that a study’s risks are reasonable in relation to its expected benefits and that participants provide voluntary, informed consent. So long as a self-experiment meets the Common Rule’s definition of “research” and the self-experimenter’s institution is engaged in that research—say, because it occurs on institutional property or uses institutional resources—self-experimentation likely requires IRB review (11). RaDVaC’s early systematic efforts to develop their product clearly meet this definition of research, but there is no evidence that any research institution was engaged in it.

Whether or not required by federal law or institutional policy, the kind of independent, prospective review that IRBs provide is ethically important, especially for public health interventions. Although the harms of some DIY interventions tend to be confined to the researchers themselves, DIY vaccines have the potential to harm others, directly and indirectly.

Those potential harms are evident. Both users and bystanders are harmed by ineffective vaccines when users’ false reassurance that they are immune from infection causes them to take risks that they might not otherwise take, such as traveling in crowds. Users of a DIY vaccine might also be unwilling or ineligible to participate in future clinical trials for traditional vaccines. The COVID-19 pandemic has already seen widespread off-protocol use of unproven interventions frustrate attempts to rigorously evaluate those or other interventions (12). At the same time, polls show that many are reluctant to take any COVID-19 vaccine. If scientists—and especially those with elite training or affiliations—herald a readily available vaccine, those who are not hesitant might refuse to take the risk of enrolling in a trial and being randomized to placebo.

Making an untested DIY vaccine accessible to the general public also runs the risk, as RaDVaC’s white paper acknowledges, that lay users might injure themselves as a result of improper preparation, incorrect administration, or heightened allergic or other reactions. These risks raise questions about whether such users are able to give meaningful consent to a DIY vaccine. As demonstrated by reports of desperate individuals drinking cleaning products in an effort to prevent or treat COVID-19, not all individuals attracted to DIY vaccines will have the technical know-how to safely engage in self-experimentation or will invest the time to learn how to do so. Experts can sometimes suffer from a curse of knowledge that leads them to underestimate the risk that less sophisticated users may flub their instructions.

Last, it is concerning that RaDVaC apparently hopes for its DIY vaccine to be very widely adopted but has not disclosed any plans for systematically establishing its safety or efficacy, such as through RCTs. During a pandemic, it is tempting to believe that an intervention that shows early promise has been “proven enough” to justify widespread use (13). Those who are intellectually invested in an intervention may be especially so tempted, perhaps even deeming RCTs, which randomize some participants to placebo, unethical (14). All scientists must resist the temptation to view the rigorous study of COVID-19 vaccine safety and effectiveness as a bureaucratic step that can be skipped. Research that enables us to confidently conclude that a vaccine is safe and effective will take time, whether or not it is overseen by the FDA. But that research, simply, is critical.

Roles for the FDA and Scientists

Given the risks to public health from unsafe or ineffective vaccines, regulatory leadership is needed. First, the FDA should issue a statement clarifying both its authority over, and its intent to regulate, DIY COVID-19 vaccines, as it did with DIY gene-editing kits. This statement should include, at a minimum, clarification that vaccine research, manufacture, distribution, and administration—by anyone—can be subject to regulation. For those activities within its jurisdiction, the FDA has a range of enforcement tools available to it, including sending Warning Letters and imposing civil and criminal penalties. Indeed, the FDA has already sent a Warning Letter to one company, North Coast Biologics, whose founder sold and administered an unapproved COVID-19 vaccine to friends (4). Explaining how the FDA intends to enforce its authority against citizen science groups can help give fair warning to those who might underestimate the scope of FDA jurisdiction as well as reassure those who are not likely to face enforcement actions.

Although appropriate enforcement of the FDA’s authority is critical, the objective should not be to stop all citizen science research; that would be futile given the popularity and reach of citizen science. But more importantly, such a strategy would imprudently deny society the many benefits of citizen science, including its potential contributions to scientific discovery (9, 15). In recognition of these benefits, the FDA should consider ways to support citizen science research while promoting trust in FDA and research processes, including establishing new channels for engaging with citizen scientists working on COVID-19 solutions. One possibility is to designate FDA staff knowledgeable about citizen science objectives and communities to field questions from citizen scientists, provide feedback on their projects (such as through pre-IND meetings, which are an established way for the FDA to discuss product development plans), and, as necessary, help citizen scientists connect with other staff within the FDA with relevant scientific expertise. More citizen scientists would be encouraged to reach out to the FDA if it were easy for them to identify an office to call with questions. This would require the person speaking with them to be genuinely invested in helping them—even if that ultimately means explaining how a project might violate FDA rules.

By adopting a transparent, collaborative approach to citizen science, the FDA can encourage trust, which is particularly important right now amid concerns about political interference with the FDA’s work. At the same time, the FDA can stay apprised of promising solutions that may emerge from these communities, as well as their failures. During a pandemic, this is precisely the kind of information that regulatory authorities should want to know—and without delay.

Although many citizen scientists appear to take seriously the ethical responsibilities associated with their activities, it is important to recognize that those responsibilities expand when public health is at stake, such as with COVID-19 vaccine development. Characterizing or positioning research as self-experimentation does not eliminate risks to bystanders or the collective good. Given those potential risks, citizen scientists who are involved in open vaccine development and testing efforts outside of traditional scientific institutions should seek review by an independent IRB. The cost is not necessarily prohibitive for all projects and should be prioritized the same as critical safety equipment. Ethical and efficient development of a vaccine shown to be safe and effective against COVID-19, and broad dissemination of such a vaccine, are goals we all share and should be able to work together to achieve.

ACKNOWLEDGMENTS: Funding: C.J.G.’s involvement in development of this manuscript was funded by National Human Genome Research Institute grant K01-HG009355 (C.J.G., principal investigator). All authors contributed to the conceptualization, drafting, and critical revision of the manuscript. Competing interests: M.N.M. reports having had conversations, for a brief period of time in early April 2020, with some members of what would become RaDVaC in which she provided comments consistent with this article. She also reports having served, from 2014 to 2019, on the Board of Directors of PersonalGenomes.org, a 501(c)(3) founded by George Church, a member of RaDVaC. All other authors declare no competing interests. C.J.G. and P.J.Z. report having participated in conversations with citizen scientists interested in establishing oversight mechanisms for citizen science.


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Deep abiotic weathering of pyrite



Getting rid of fool’s gold

Pyrite, also called fool’s gold, is an iron sulfide mineral that is very commonly found in rock but is almost nonexistent in sediments today. Pyrite oxidizes quickly and is a major source of sulfur to the ocean, but it is also a proxy for the oxygen content historically in Earth’s atmosphere. Gu et al. conducted a set of detailed observations of the pyrite oxidation process in a shale unit. The authors found that erosion tied to fracturing is just as important as the oxygen content for the dissolution process. They developed a model that helps determine the conditions in Earth’s past for which pyrite might have been stable and the role of microorganisms in the oxidation process.

Science, this issue p. eabb8092

Structured Abstract


Oxidative weathering of pyrite, the most abundant sulfide mineral in Earth’s crust, is coupled to the biogeochemical cycles of sulfur, oxygen, carbon, and iron. Pyrite oxidation is key to these cycles because of its high reactivity with oxygen. Before the Great Oxidation Event (GOE), atmospheric oxygen concentrations were low on early Earth and pyrite was exposed at Earth’s surface, allowing erosion into sediments that were preserved in river deposits. Today, it oxidizes at depth in most rocks and is often not exposed at the land surface. To understand pyrite weathering through geologic time, researchers extrapolate the reaction kinetics based on studies from the laboratory or in acid mine drainage. Such work has emphasized the important role of microorganisms in catalyzing pyrite oxidation. But to interpret the oxidation rates of pyrite on early Earth requires knowledge of the rate-limiting step of the oxidation as it occurs naturally in rocks.


We investigated the oxidation of pyrite in micrometer-sized grains, in centimeter-sized rock fragments, and in meter-scale boreholes at a small, well-studied catchment in a critical-zone observatory. Our goal was to determine the reaction mechanism of pyrite weathering in rocks as it occurs today. The slow-eroding catchment is underlain by shale, the most common rock type exposed on Earth. We determined weathering profiles of pyrite through chemical and microscopic analysis.


At the ridgelines of the shale watershed, most pyrite oxidation occurs within a 1-m-thick reaction zone ∼16 m below land surface, just above the depth of water table fluctuation. This is the reaction front at the borehole scale. Only limited oxidation occurs in halos around a few fractures at deeper depths. Above the depth where pyrite is 100% oxidized in all boreholes, rock fracture density and porosity are generally higher than below. However, the narrow parts of pore openings called pore throats remain small enough in oxidizing shale to limit access of microorganisms to the pyrite surface. During oxidation, iron oxides pseudomorphically replace the pyrite grains. High-resolution transmission electron microscopy (TEM) reveals that the oxidation front at grain scale is defined by a sharp interface between pyrite and an iron (oxyhydr)oxide (Fh) that is either ferrihydrite or feroxyhyte. This Fh then transforms into a banded structure of iron oxides that ultimately alter to goethite in outer layers. This complex oxidative transformation progresses inward from fractures when observed at clast scale.


Under today’s atmosphere, pyrite oxidation, rate-limited by diffusion of oxygen at the grain scale, is regulated by fracturing at clast scale. As pyrite is oxidized at borehole scale before reaching the land surface in most landscapes today, the oxidation rate is controlled by the movement of pyrite upward, which is in turn limited by the rate of erosion. Comparisons of shale landscapes with different erosion rates reveal that fracture spacing varies with erosion rate, so this suggests that fracture spacing may couple the landscape-scale to grain-scale rates. Microbial acceleration of oxidation globally today is unlikely in low-porosity rocks because pyrite oxidation usually occurs at depth, where pore throats limit access, as observed here for shales. Before the GOE, the rate of pyrite oxidation was instead controlled by the slower reaction kinetics in the presence of lower atmospheric oxygen concentrations. At that time, therefore, pyrite was exposed at the land surface, where microbial interaction could have accelerated the oxidation and acidified the landscape, as suggested by others. Our work highlights the importance of fracturing and erosion in addition to atmospheric oxygen as a control on the reactivity of this ubiquitous iron sulfide.

Schematic depiction of oxidative weathering of pyrite in rocks buried at meters depth.

Pyrite oxidation was studied from the molecular (TEM) scale of the pyrite―Fe oxide interface through clast and borehole scales to extrapolate to landscapes. The rate of oxidation of pyrite, limited at grain scale by oxygen diffusion through the shale matrix, is regulated at larger scales by fracturing and erosion.


Pyrite is a ubiquitous iron sulfide mineral that is oxidized by trace oxygen. The mineral has been largely absent from global sediments since the rise in oxygen concentration in Earth’s early atmosphere. We analyzed weathering in shale, the most common rock exposed at Earth’s surface, with chemical and microscopic analysis. By looking across scales from 10−9 to 102 meters, we determined the factors that control pyrite oxidation. Under the atmosphere today, pyrite oxidation is rate-limited by diffusion of oxygen to the grain surface and regulated by large-scale erosion and clast-scale fracturing. We determined that neither iron- nor sulfur-oxidizing microorganisms control global pyrite weathering fluxes despite their ability to catalyze the reaction. This multiscale picture emphasizes that fracturing and erosion are as important as atmospheric oxygen in limiting pyrite reactivity over Earth’s history.


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Moving heart elements and cells



Transposable elements comprise a large percentage of the human genome, with the endogenous retrovirus (ERV) subclass representing more than 8%. Using human pluripotent stem cell–derived cardiomyocytes and bioengineered micropatterning to recapitulate cardiogenesis, Wilson et al. found evidence that the primate-specific ERV MER41 is involved in primate heart development. A MER41-derived long noncoding RNA called BANCR is exclusively expressed in the fetal heart. When BANCR is eliminated, cardiomyocyte migration is disrupted. The cardiogenic transcription factor TBX5 and Hippo signaling factors TEAD4/YAP1 bind to a BANCR enhancer during fetal development. A related analysis in mouse shows that heart size increases with embryo BANCR knock-in.

Dev. Cell 54, 694 (2020).


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Obesity and inflammation



Accumulation of fat cells (shown in yellow in this micrograph) may be promoted by gene variants linked to inflammation.


Obesity is associated with chronic inflammation, which can trigger other diseases such as atherosclerosis, type 2 diabetes, and even cancer. There appears to be a genetic component to excess fat accumulation, and studies suggest that inflammatory gene variants may contribute. Karunakaran et al. found that single-nucleotide polymorphisms in the human receptor-interacting serine/threonine-protein kinase 1 gene (RIPK1) increase its expression and are causally associated with obesity. RIPK1 is a key regulator of inflammatory responses and cell death. Silencing of Ripk1 in mice on a high-fat diet reduced fat mass, body weight, and inflammatory responses in adipose tissue. This suggests that RIPK1-mediated inflammation (and possibly other functions) contribute to obesity and that RIPK1 could be a therapeutic target.

Nat. Metab. 10.1038/s42255-020-00279-2 (2020).


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