People often have a sense that all the low-hanging scientific fruit has been picked, or that all the fruit that’s left can only be picked by huge teams with lots of funding. But in fact, there are still lots of projects that are just the right scale for Indie Science.
Good ideas too — the big labs miss them because they seem low-prestige, because a null result would be embarrassing, or because they’re not a funding priority. Yet the subjects considered “prestigious” are always changing, as are funding priorities. And for the curious, null results can be perfectly interesting. (Science, after all, is all about alternative explanations.) These blind spots are an opportunity.
So there are plenty of projects for people who want to answer questions and solve problems. Here are three of them:
Creatine & PMS
Creatine is a compound synthesized from three amino acids. Popular among gym bros for letting them push harder and build muscle faster, there are anecdotal reports that supplementing creatine has a grab bag of other positive effects. This is fairly plausible — creatine is used to recycle adenosine triphosphate (ATP), the energy currency of your cells, so it could be involved in almost anything.
Creatine is cheap, safe, stable, and effective. Given the huge number of plausible but untested anecdotes, studies could be run on topics like 1) whether taking creatine in the evening vs. morning really disrupts sleep onset, reduces total sleep time, or worsens sleep quality, as is suggested by anecdote and rat data but so far never been confirmed in humans, 2) cognitive benefits of creatine in vegans and vegetarians, a result that is probably real but has not yet been formally confirmed, and 3) studying the 20–30% of people who are creatine non-responders, first building a predictive model to identify likely non-responders upfront, and then testing whether higher doses or different forms can convert them into responders. But the research question to start with is almost certainly female reproductive health / menstrual symptoms.
In many anecdotes and case studies, women report that taking creatine can reduce their painful menstrual symptoms (e.g. cramps, mood swings, bloating, fatigue) and give them more regular cycles (see e.g. page 6 of Issue 1 of THE LOOP). There are epidemiological associations from the NHANES dietary data that support these anecdotes. But so far, there are no studies. Many women have menstrual symptoms they would like to reduce; if creatine helps, people should hear about it.
Running some studies would be easy. It would be affordable. It would take only a few months per study, and would require relatively small sample sizes. (In general, we expect women’s health to be full of low-hanging fruit.) Also, creatine suppliers should maybe fund this because the results could open up entirely new market segments for their product. Creatine monohydrate powder is the most studied form by a large margin, the cheapest, and the most bioavailable per gram, so that’s the form to use.
You can imagine forms of this study at different scales.
Pilot study. Recruit 30-40 women with moderate-to-severe menstrual symptoms, give them all creatine, and have them track symptoms for 2-3 cycles as baseline and 2-3 cycles during supplementation. In the best case, you have results in 8 months. This is cheap and fast, but it has real limitations: there’s no control group, so you can’t rule out placebo or regression to the mean, and the results, while suggestive, wouldn’t be considered conclusive by a skeptic. This is more of a proof-of-concept that might justify future research, but it is unlikely to be compelling by itself unless the effect size is really large. Still, better than anecdote.
Full crossover RCT. Recruit 50-60 women (expecting ~35 to complete), randomly assign half to start on creatine, then swap after 2-3 cycles, with a washout period (no pun intended) in between. Each woman serves as her own control, which makes the result much cleaner and reduces the sample size required. This design would be much more compelling, and the timeline is still only 10-12 months to completion, with preliminary data available earlier.
Full study plus. Same design as above, but even stronger: a larger sample, possibly a study arm with a higher dose or different timing to answer one of those questions. You could get a little more nuanced, e.g. expand recruitment to capture more diverse symptom profiles.
If you observe the expected effects, this could become the first study of a longer research program. Once you know there are real effects, you immediately start wondering things like: What’s the optimal dose? The optimal timing? What symptoms does it help with the most? Does it help some populations more than others, etc. For example, a luteal-specific loading protocol might outperform flat daily dosing, since the luteal phase is when endogenous creatine synthesis is most disrupted by shifts in hormones. It would be a more specific finding than just “creatine helps PMS”. But nobody has tested this.
Nutrition Review
Potassium is an essential nutrient that is necessary for the normal functioning of all cells. To be healthy, a person needs a few thousand milligrams of potassium per day. So it’s quite strange that you can usually only get potassium supplements in doses of 99 mg or less, a tiny fraction of the required daily amount.
When we examined this more closely (search for “Theory Viability” on that page), we found that this limitation probably comes from a misinterpretation of a small number of studies of Hydrosaluric-K (“enteric-coated hydrochlorothiazide with potassium chloride”) from the 1960s. These specific pills may have been dangerous, but only because of their unusual coating, not because of the amount of potassium they contained. People get much more than 99 mg of potassium from their diets every day, and potassium pills containing more than 99 mg are often prescribed in clinical contexts without any concern.
This isn’t the only unusual thing about the recommended dose of potassium. For a long time, the recommended daily value for adults (technically, the “Adequate Intake”) was 4,700 mg of potassium per day. But in 2019, the National Academies of Sciences, Engineering, and Medicine changed the recommended / adequate intake to 2,600 mg/day for women and 3,400 mg/day for men.
They say that the change is “due, in part, to the expansion of the DRI model in which consideration of chronic disease risk reduction was separate from consideration of adequacy,” but we can’t help but wonder if they changed it because it was embarrassing that less than 5% of the population was getting the recommended amount. In every CDC NHANES dataset from 1999 to 2018, median potassium intake hovers around 2,400 mg/day, and mean intake around 2,600 mg/day. And in this report from 2004, the National Academy of Medicine found that “most American women … consume no more than half of the recommended amount of potassium, and men’s intake is only moderately higher.”
Here’s our point: there are recommended dietary allowances, adequate intake values, estimated average requirements, tolerable upper intake levels, and various limits or warnings, for all kinds of nutrients. Government agencies are happy to provide these numbers. But the history of each number is often obscure, and some of these recommendations are unjustified or entirely mistaken, based on limited data or misinterpretations of studies that by now are several decades old.
We propose a series of in-depth literature reviews, to be written in plain language and released publicly, documenting the history of each of these recommendations and offering analysis as to whether each recommendation is justified. While nutrition is complicated, the foundations can be made simple, or can at least be mapped out clearly. We can enumerate the most important pieces one by one and lay out the available information for each. We could start with an extension of the analysis for potassium RDA and tolerable upper limit, and continue from there.
There are a finite number of amino acids — only 22 α-amino acids make up all proteins, and we can compile the research on each. How much does a person need of each to have a baseline of health? How much variation is there in how much of each amino acid each person needs? How much of each is too much? Can you take 10 mg of glycine per day, or is that dangerous? If we can’t provide definitive answers to these questions, we can at least outline what is known.
There are a finite number of dietary minerals, some subset of the 118 elements. Some of these, like sodium and mercury, have known good and bad nutritional properties. Some of them (like carbon) are not considered minerals per se because they are CHON. Other minerals, like chromium, are in a gray area where it’s still not clear if they are essential micronutrients or not.
For all of these minerals, we can for starters:
- Document the current RDA, tolerable upper intake, etc.
- Document the history of these numbers, if they have changed since they were introduced, and if so what justification (if any) was given for the change.
- Document the reasoning and evidence behind each number, if any is given.
Let’s take a specific case as an example: it’s recommended that people get at least 150 mcg of iodine per day. This certainly seems like it is enough to keep you from developing goiter, and that target may be the source of this specific number — we think health agencies may have chosen 150 mcg because that was the minimum needed to keep Swiss people from getting this disease.
But we wonder if the optimal level of iodine for general health (actually thriving, not just the minimum amount to keep you from getting goiter) might be much higher, and suspect the tolerable limit for iodine might be even higher still. These are questions that you might be able to answer with a detailed analysis of the literature. And if a detailed review doesn’t answer this question, then we’ll have discovered an important gap in the literature.
European Wheat
There are lots of stories where an American goes on vacation for a few weeks, to Europe or Asia, and loses a significant amount of weight without any special effort. Sometimes it’s not weight, it’s something else, like their acne breakouts or digestive issues suddenly disappear.
There are also some stories that are exactly the opposite: someone from Europe or Asia goes on vacation to America for a few weeks, and gains a significant amount of weight without any obvious changes to their diet or lifestyle.
These anecdotes are interesting, at times even compelling. But so far there hasn’t been any systematic study. If people really do rapidly gain and lose weight when they briefly visit other countries, or if other health issues really switch off and on, that would be good to know and easy to document. We should run some studies and find out.
We imagine two different kinds of designs: one for smaller incremental effects like weight change, and another for large binary results like digestive issues.
Incremental outcomes. The incremental effects studies can be relatively simple. One design is: Send obese people from the United States to Vietnam (or some other lean country) for a few weeks, and see if they lose weight. Or: Send lean people from Vietnam (or some other lean country) to the United States for a few weeks, and see if they gain weight.
Obesity is a good choice for these incremental methods because weight is easy to measure, and there are already plenty of anecdotes claiming that people have gained/lost weight this way. You could use this same method to study any other health issue, but there’s less initial support for the hypothesis and most other outcomes will be harder to measure.
Binary outcomes. Studies on large binary issues will demand more complex methods, but they tend to require fewer participants. A small number of people, sometimes even just a single participant, can produce compelling results.
Here’s an example. Find a small number of people with gluten, wheat, or dairy intolerance who report that their intolerance went away when they spent a few weeks in Europe. Recruit them to your study. First, confirm that they have this dietary sensitivity in the US, and find a way to measure it. Have them consume some gluten / wheat / dairy in the US so you can observe and confirm their symptoms.
Then, send these people to Europe for a few weeks, and confirm that they don’t have this same issue in Europe. If so, congratulations, you have an interesting finding.
From here the next question becomes, does this difference come from something about the food in Europe, or some other difference about the environment? Well, you can find out more.
As one possibility, have these people stay in Europe, but ship them American food, exactly what they ate at home, and have them eat the American food while staying in Europe. Does their issue return? If so, then the problem is something in the American food. If not, it suggests that the problem is something else about the American environment, something missing in Europe.
Or, have these people stay in America, but ship them European food, exactly what they ate in Europe, and have them eat the European food while staying in America. Does their issue go away? If so, then the problem is something in American food, something they don’t consume when they eat food shipped from Europe. If not, it suggests that the problem is something else about the American environment, that can’t be fixed by eating carefully imported European foods.
If you can confirm this pattern, you can go deeper. For example, imagine you have an American who thought he had a gluten problem. But when you feed him bread made from flour you ship over from Europe, he has no problem at all. Obviously it can’t be the gluten, because European flour contains gluten just like the US does.
So find out more, you can consider each ingredient and additive in American flour, but not in your European flour, and add them back in one at a time. When you add an ingredient that brings back his “gluten problem”, you’ve found the real cause. If it’s not one of the ingredients, then you test the two flours for contaminants, and you add the contaminants from the American flour to the European flour one by one, again until you discover the true problem.
