INSIGHTS

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PERSPECTIVES

PHYSIOLOGY

Challenges of human nutrition research

Facilities to house and feed subjects could increase rigor and advance nutrition science

By Kevin D. Hall regarding important aspects of healthy diets. between diet and health outcomes in large

PHOTO: WALLACE KIRKLAND/THE LIFE PICTURE COLLECTION VIA GETTY IMAGES

For example, it is widely agreed that Western numbers of people. Although nutritional

N
utrition is fundamentally important diets high in ultra-processed food are delete- epidemiology has ardent defenders (5, 6),
for human health (1), but there is rious and that considerable health improve- its critics suggest that it is plagued by mea-
widespread public confusion about ments would likely result from shifting the surement error, reverse causality, selection
what constitutes a healthy diet. Flip- population toward eating mostly minimally bias, weak effects, analytical flexibility, and
flopping headlines report conflicting processed foods (2). But expert consensus unmeasured or residual confounders that
information about whether individual erodes when discussing detailed questions of can result in spurious relationships be-
foods (e.g., butter, eggs, meat), nutrients (e.g., optimal human nutrition or the physiological tween diet variables and health outcomes
saturated fat, cholesterol, sodium), or eating mechanisms underlying the body’s response (7). Increased funding for large, long-term
patterns (e.g., Mediterranean versus keto- to diet changes. Rigorous controlled feeding randomized diet intervention trials has
genic diets) result in improved, worsened, or studies would help to address such questions been suggested as a way to mitigate reliance
unchanged health. However, public confu- and advance human nutrition science, a field on nutritional epidemiology and improve
sion about nutrition belies expert consensus whose overall veracity has recently been causal inference about the effects of diet on
questioned (3, 4). human health (8). However, such trials have
Much of the criticism of nutrition science their own challenges, including the imprac-
National Institute of Diabetes and Digestive
and Kidney Diseases, Bethesda, MD 20892, USA. has been directed at nutritional epidemiol- ticality of randomizing large numbers of
Email: [email protected] ogy, a field that investigates associations people to eat different diets for months or

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In 1945, a domiciled feeding study carried out studies are required to stay at the research vidual physiological variability in response
at the University of Minnesota involved participants facility for periods of days, weeks, or months to controlled diets. Nutrient requirements
being fed a semistarvation diet. without leaving to ensure that they consume and their dependence on overall dietary
the provided food under observation while and physical activity patterns could be as-
years while ensuring high levels of adher- avoiding exposure to off-study food. sessed in a variety of populations of men and
ence throughout. Domiciled feeding studies have a long his- women of different ethnicities and ages. The
Indeed, most randomized diet interven- tory of yielding important discoveries about effects of diet on physical and cognitive per-
tion trials do not actually study the effects of human nutrition and metabolism. For ex- formance could also be carefully evaluated.
different diets; rather, they investigate the ef- ample, many of the physiological responses Comprehensive assessment of the effects of
fects of differing diet advice. In other words, to starvation and nutritional rehabilitation diet interventions on common health condi-
subjects are randomized to receive education were revealed in a controlled feeding study tions such as obesity, metabolic syndrome,
and support to consume diets that are as- of 32 male volunteers who simultaneously and type 2 diabetes, as well as rare diseases
signed by the investigators. Although diet- resided at the University of Minnesota for such as those that result from inborn errors
advice trials assess real-world effectiveness, a continuous 48-week period during the of metabolism, could also be rigorously deter-
their results conflate adherence to a given Second World War (12) (see the photo). The mined in domiciled subjects.
diet with the effects of that diet. subjects were fed a baseline diet for 12 weeks Although domiciled feeding studies can
Knowledge about the effects of diet per se followed by a 24-week semistarvation diet, provide important mechanistic insights,
is required for advancement of fundamental after which they were fed several rehabilita- their artificial environment may limit gen-
nutrition science. However, studies in free- tion diets for the final 12 weeks. The result- eralizability and application to free-living
living people have a limited ability to provide ing detailed physiological and psychological populations. Furthermore, domiciled feeding

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such knowledge because it is not currently measurements in response to known diets studies alone are insufficient for determin-
possible to accurately and objectively quan- would have been impossible had the subjects ing what constitutes a healthy diet because
tify their food intake. Indeed, most human not been domiciled during this classic study. it is impossible to continuously house for sev-
nutrition studies rely on self-reported diet Unfortunately, domiciled feeding studies eral years the large numbers of subjects that
measures that are known to have systematic have become prohibitively expensive in the would be required to objectively measure
biases, such as underestimation of energy United States since the National Institutes both food intake and clinical endpoints, such
intake. Furthermore, errors in self-reported of Health ceased directly funding Clinical as cardiovascular events or diabetes progres-
diet measurements may be associated with Research Centers (13). Very few centers sion. Therefore, long-term nutrition studies
other variables (e.g., socioeconomic status) or around the world currently conduct domi- in free-living people will always be required.
health outcomes (e.g., obesity) that can result ciled feeding studies, and their study popu- Nonetheless, domiciled feeding studies
in biased associations (9). lations often comprise students, staff, and can help to improve long-term human nutri-
Rather than relying on self-reported diet faculty, which limits their generalizability. tion studies. For example, the development
assessments, some diet intervention trials Furthermore, the few facilities conducting and validation of objective diet assessment
provide food to their free-living subjects, domiciled feeding studies are typically lim- technologies requires domiciled feeding
but these studies seldom verify whether all ited to housing and feeding only a handful of studies because the only way to objectively
the food is eaten. Even when subjects are subjects at a time, which restricts their power know what people eat is to house them con-
instructed to eat only the food provided by and duration. tinuously in a research facility and directly
the study, substantial quantities of off-study Such limitations are surmountable. measure their food intake. Advancement of
food may be consumed amounting to several Investment in research facilities for domiciled objective diet assessment technologies has
hundred kilocalories per day that can con- feeding studies could provide the infrastruc- been identified as a top priority for human
found study results (10, 11). To understand ture and staff required to simultaneously nutrition science (14) and promising new
how these challenges impede the progress of house and feed dozens of subjects comfort- technologies are emerging, such as sen-
human nutrition science, imagine trying to ably and safely. One possibility would be to sors and cameras that detect food intake.
develop a new drug without being confident create centralized domiciled feeding facilities Biomarkers of diet are also being developed,
that researchers could administer known that could enable teams of researchers from such as plasma concentrations of vitamin C
quantities of the drug or measure its phar- around the world to recruit a wide range of and carotenoids as indicators of fruit and
macokinetics, pharmacodynamics, or dose subjects and efficiently conduct rigorous hu- vegetable intake. Domiciled feeding studies
response. Successful pharmaceutical devel- man nutrition studies that currently can only can validate objective diet assessment tech-
opment requires such studies because they be performed on a much smaller scale in a nologies and biomarkers in diverse subject
investigate benefits and risks of the drug un- handful of existing facilities. groups consuming a variety of known diets.
der highly controlled conditions where ques- Well-designed domiciled feeding studies These validated technologies and standard-
tions of patient adherence are minimized can increase the rigor of human nutrition sci- ized biomarkers can then be deployed in
because the researchers administer the drug. ence and elucidate the fundamental mecha- large, long-term nutrition studies to monitor
The inability to conduct such trials would se- nisms by which diet affects human physiol- diet adherence and improve understanding
verely impede the drug development process. ogy. For example, such studies can investigate of the relationships between diet and disease,
Why should human nutrition science be ex- complex interactions among changes in diet, and diet and health.
pected to advance without the benefit of well- the microbiota, and its role in modulating Domiciled feeding studies can also help
controlled diet efficacy studies? host physiology. The effects of meal timing researchers to design and interpret large,
Therefore, it is important to conduct hu- and circadian biology could be advanced by long-term nutrition studies. For example,
man nutrition studies where subjects can enabling precisely controlled periods for eat- surrogate biomarkers of disease risk often
comfortably reside at a research facility, ing and sleeping. Personalized nutrition and change rapidly in response to controlled diet
thereby allowing investigators to control nutrient-genomic interaction studies could interventions. When surrogate markers are
and objectively measure their food intake. be facilitated by reducing the usual noise of causally related to disease risk, then it may
Subjects enrolled in such domiciled feeding unknown diet variability to focus on indi- be possible to cautiously extrapolate the re-

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INS IGHTS | P E R S P E C T I V E S

sults of domiciled feeding studies, especially NEUROSCIENCE

those that test dose responses, and to esti-
mate the effects of diet changes on long-term
disease risk. Such information can be useful
for planning long-term randomized diet tri-
Is it worth the effort?
als by helping to avoid underpowered stud- Individual variation in dopamine affects the weighting
ies whose null statistical results might be
misinterpreted to conclude that the diet had
of benefits relative to costs
no real effect when even a small undetected
effect might be important, especially on the By Amy C. Janes gions affects nuanced elements of cogni-
population scale. tion and behavior. For example, Westbrook

B
For example, prior to devoting many mil- efore undertaking any task, hu- et al. expand on the finding that a blunted
lions of dollars to a large, long-term random- mans implicitly determine whether dopamine signal can result in cognitive
ized trial of a Westernized Mediterranean reaching the goal is worth the ef- dysfunction (4). Specifically, they show
diet intended to prevent cardiovascular fort. Weighing costs and benefits is that the willingness to expend cognitive ef-
disease, domiciled feeding studies could be a fundamental brain function that fort is diminished in those with lower do-
used to help develop and validate biomark- often occurs unconsciously, allowing pamine function in the caudate nucleus, a
ers of varying degrees of adherence to the di- for the adaptive use of resources to attain portion of the brain involved in goal-moti-
etary pattern while also evaluating surrogate goals. The neurotransmitter dopamine is a vated behavior (5). This finding blends two
markers of disease risk in response to known key player in this process (1). On page 1362 known roles of dopamine—motivation and

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diet changes. For a relatively small fraction of of this issue, Westbrook et al. (2) clarify cognition—by indicating that goal-related
the overall investment, data from such a do- the role of dopamine by showing that in- attention drives the motivation to engage
miciled feeding study could be used to help creasing an otherwise weak dopamine sig- cognitive resources.
plan and interpret the results of the large, nal shifts attention toward the rewarding Westbrook et al. also show that a blunted
long-term randomized trial. outcome, resulting in greater readiness to willingness to expend cognitive effort can
The advancement of human nutrition sci- perform cognitive effort to reach the goal. be increased by pharmacologically enhanc-
ence has enormous benefits for health and As such, increasing dopamine appears to ing the dopamine signal using the dopa-
the economy (15). Knowledge of nutrition re- be beneficial specifically for those indi- mine agonist methylphenidate. This is con-
quires triangulation of evidence from a vari- viduals with relatively lower dopamine sistent with prior findings that dopamine
ety of study designs, including observational function. This finding may explain the ef- enhancement leads to increased willingness
studies and randomized trials in free-living ficacy of dopamine-enhancing medications to expend effort in patient populations who
people. Facilitating more domiciled feeding such as Ritalin (methylphenidate), which have disorders with an underlying dopa-
studies will lead to fundamental new dis- is prescribed to treat attention deficit hy- mine deficit, such as ADHD and Parkinson’s
coveries about the mechanistic physiological peractivity disorder (ADHD) and has been disease (6, 7). Thus, dopamine-enhancing
responses to diet and will improve human used without a prescription by students as medications may not improve cognitive
nutrition research in all its forms. j a “study enhancing drug.” ability per se, but drive the willingness to
Dopamine is found throughout the brain expend cognitive effort (8).
REFERENCES AND NOTES
in several neurobiological pathways that More precisely, this greater willingness
1. GBD 2017 Diet Collaborators, Lancet 393, 1958 (2019).
2. D. L. Katz, S. Meller, Annu. Rev. Public Health 35, 83 mediate processes including movement, to expend effort occurs because dopamine-
(2014). reward, and cognitive functions such as enhancing medications raise the salience of,
3. J. P. Ioannidis, BMJ 347, f6698 (2013). learning and working memory (3). Given and attention to, goal-related stimuli that
4. S. E. Nissen, Ann. Intern. Med. 164, 558 (2016).
5. D. Mozaffarian, N. G. Forouhi, BMJ 360, k822 (2018). the range of functions influenced by dopa- would otherwise evoke a response too weak
6. A. Satija et al., Adv. Nutr. 6, 5 (2015). mine, there is a need to better understand to warrant the expenditure of cognitive ef-
7. J. P. A. Ioannidis, JAMA 320, 969 (2018). how dopamine within distinct brain re- fort (8). Methylphenidate and similar drugs
8. J. P. Ioannidis, Am. J. Clin. Nutr. 103, 1385 (2016).
9. M. Cainzos-Achirica et al., Curr. Cardiovasc. Risk Rep. 12,
4 (2018).
10. S. K. Das et al., Am. J. Clin. Nutr. 85, 1023 (2007).
11. K. D. Hall et al., Int. J. Obes. 43, 2350 (2019).
Caudate dopamine affects the weight of benefits
12. A. Keys et al., The Biology of Human Starvation (Univ. of Individual differences in dopamine function in the caudate nucleus relate to one’s willingness to expend cognitive
Minnesota Press, 1950). effort, which can be influenced both by medications and drugs of abuse that enhance the dopamine signal.
13. A. Vella et al., Diabetes 65, 2821 (2016).
14. Interagency Committee on Human Nutrition Research,
National Nutrition Research Roadmap 2016–2021:
Advancing Nutrition Research to Improve and Sustain
Weak dopamine signal Willingness
Health (2016).
15. A. A. Toole, F. Kuchler, Improving Health Through Caudate nucleus to expend
Nutrition Research: An Overview of the U.S. Nutrition cognitive e)ort
Research System (Economic Research Service, U.S.
Department of Agriculture, 2015).
Strong dopamine signal
GRAPHIC: KELLIE HOLOSKI/SCIENCE

Willingness
ACKNOWLEDGMENTS to expend
Thanks to N. K. Fukagawa, M. B. Katan, K. C. Klatt, P. cognitive e)ort
Ohukainen, M. L. Reitman, and E. J. Weiss for insightful
comments. Supported by the Intramural Research
Program of the National Institute of Diabetes and Digestive Dopamine-enhancing medications (e.g., methylphenidate)
and Kidney Diseases. increase the willingness to expend cognitive e)ort
in those with low dopamine function. Drugs of abuse
also increase the dopamine signal and thus the
10.1126/science.aba3807 willingness to obtain them.

1300 20 MARCH 2020 • VOL 367 ISSUE 6484 sciencemag.org SCIENCE

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Challenges of human nutrition research
Kevin D. Hall

Science 367 (6484), 1298-1300.

DOI: 10.1126/science.aba3807

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ARTICLE TOOLS http://science.sciencemag.org/content/367/6484/1298

REFERENCES This article cites 12 articles, 6 of which you can access for free
http://science.sciencemag.org/content/367/6484/1298#BIBL

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