The Strange Studies of Calorie Restriction Research – Biosphere 2 and the Minnesota Starvation Study

colinchamp December 23, 2019 6 Comments

“Quantity has a quality of its own.”

-Often attributed to Napoleon, likely incorrectly

On September 26, 1991, eight individuals set foot into Biosphere 2, an enclosed self-contained simulated living environment built in rural Oracle, Arizona. Located not far from a gold mine owned by Buffalo Bill Cody, Biosphere 2 sits at the base of the Catalina Mountains, a short drive from Tucson. With a price tag of $200 million, the structure, eclipsing three football fields in size, completed construction in 1991 through funding from billionaire philanthropist Ed Bass. It remains the largest closed-living system ever constructed and is considered only the second fully livable biosphere (Planet Earth is the first). The project, which Discover Magazine described as “the most exciting scientific project to be undertaken in the U.S. since President John F. Kennedy launched us toward the moon,” was created with the goal of studying the interactions between life systems within a closed system. These interactions and life systems included the eight participants and their interactions with each other, along with those between plants, animals, nature, farming, and technology. The underlying objective, many surmised, was to assess whether a similar enclosed living environment could one day be created on another planet to simulate earth’s living conditions in otherwise inhospitable environments.

Roy Walford was the only physician of the eight study subjects in Biosphere 2, which early on was already being slammed by critical opponents of the experiment who felt that it lacked tangible scientific basis. Others applauded the impressive undertaking, hopeful of what new scientific lessons might be gleaned. A Professor of Pathology at the University of California Los Angeles School of Medicine who received his medical degree from the University of Chicago, Walford was considered by many to be a trailblazer within the world of calorie restriction and aging research. His work was integral in entwining scientific threads into a project that many felt to be more of a cultish fad idea than a scientific experiment – indeed, most of the other participants were part of a controversial group known as Synergia Ranch. The Ranch, a self-described ecovillage, was established by the original inventor and director of Biosphere 2. While it designated itself a private retreat and workshop center for small groups, Synergia Ranch had come under fire for its alternative cult-like nature and its influence on the creation and direction of Biosphere 2. This viewpoint of The Ranch as a radical organization influenced famous novelist Tom Clancy, who in his 1998 thriller Rainbow Six centered the plot around a team of elite soldiers battling a terrorist group aiming to exterminate the human race via bioterrorism while themselves surviving in a closed-off biosphere.

Like his predecessor Tannenbaum, Walford dedicated most of his career to studying the health effects of calorie restriction, but he focused sharply on its potential ability to enhance lifespan. He practiced what he preached, surviving on what is known as the CRON diet, which recommends a 20% calorie restriction or roughly 1,800 calories per day. Along with the seven other Biosphere 2 participants, he would be consuming a similar diet within the biosphere, one resembling the calorie-restricted diet that he often utilized in his research studies and touted in several of his books. This diet included beans, wheat, rice, bananas, and root vegetables like sweet potatoes and beets, all grown in an environment without toxic chemicals or pesticides (the use of these chemicals in a sealed environment would have disastrous consequences). The diet was also described as nutrient-dense, containing a proportionally significant number of vitamins and nutrients compared to calories. While overall their diet was a low-fat one, domesticated animals were also present for consumption in Biosphere 2, and goats provided milk as well.

However, as the Biosphere 2 experiment unfolded, unforeseen difficulties were encountered almost immediately, fueling the arguments of the many critics of the innovative project. Microbial life within the soil seemed to have been unaccounted for by the scientists, and also ignored was the thick layer of concrete curing beneath the biosphere dome. The soil microbes extracted valuable environmental oxygen from the crew and animals, slowly suffocating them and leaving them lethargic and functionally impaired. The concrete layer produced unexpected carbon dioxide, which further hampered the breathing situation. Eventually, oxygen had to be pumped into the enclosed structure to ensure the crew and living organisms’ survival.

However, the physical atmosphere might have been the least of the crew’s problems: the social environment between the crew members deteriorated faster than the available oxygen. In a scenario that mimicked Lord of the Flies, the crew began to argue incessantly, tensions rose, and they eventually separated into opposing groups. Walford’s diet only served to worsen things, and issues with crop yields further lowered the eight members’ available food, leaving them with an average 1780 calories each to consume daily. The calorically-restricted diet, combined with the daily work of farming and tending to the animals, left the participants in a constant state of hunger, further worsening their crumbling social order. As one crew member, Jane Poynter, describes in her memoir The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2, tensions came to a head as the crew members began to experience the physical and mental states that often accompany hunger: fatigue, depression, mental fog, and an obsession with food.¹

As relationships among the crew continued to dwindle, the population of insects continued to flourish; by the end of the study, the facility was overrun by ants and cockroaches.  Undaunted, Walford persevered to compile his data on the health effects of calorie restriction. Other proposed and well-intentioned ecological studies on the plant, animal, and human interactions were all but abandoned by a crew desperate for survival. After the two years and twenty minutes of confinement, Roy Walford and the rest of the crew of the Biosphere 2 were ready to leave their temporary accommodations. The return to the normal world was bittersweet for the crew members; overall the project was considered a scientific success, but because tensions had reached such a boiling point, the media chose to have a field day with the mishaps. Superficial criticism of the project was easy – with so many moving parts within the massive undertaking, a few glitches were impossible to avoid. Attempting to get past the glitches was in and of itself part of the project.

While seven of the crew members ranged in age from 27 to 42 years, Walford was the outlier at 67. Yet during his time in the Biosphere and afterward, he paid no mind to his advanced age, spending countless hours dedicated to documenting his experience. He even produced scientific publications on the experience while captive in the dome. While the overarching goals of the Biosphere 2 project remain murky to this day, the main ambition, or so it was reported, was to assess whether humans could survive in a completely enclosed and totally contained environment for several years. Ray Walford’s goal was beyond survival; he wanted to quantify the physiologic effects of life inside the biosphere. As part of the study, the human lab rats agreed to have blood drawn prior to crawling into their cage, multiple times while inside the dome, and four times during the following 30 months when they were living freely outside of the bubble. The participants, it had been calculated, would consume approximately 2,500 calories per day as part of their typical diet. All food was to be produced within the Biosphere through farming and animal husbandry. The members engaged in physical activity through farming, facility repair, and raising livestock, which according to Walford totaled 3-4 hours per day, 6 days per week.² All food generated was, according to Walford, apportioned equally between the members to simplify calculations.

Due to crop failures – perhaps the biggest punching bag target of the media’s criticisms – participants found their diets dwindling to just over 1,700 calories in the first six months and were unable to increase their intake to 2,000 calories for much of the remaining time of the study. The ill-fated set of circumstances for the crew were clearly more fortuitous for Walford, who had already dedicated much of his life to researching calorie restriction. Of course, Walford’s prior studies, much like those of his predecessors, were limited mostly to mice. With Biosphere 2, he had finally gotten the chance to perform his dream experiment on humans who were confined to a mouse-like cage. After his time in the dome, Walford founded the Calorie Restriction Society and personally followed a calorically-restricted diet; needless to say, he was a believer in the potential benefits of calorie restriction. Such studies in humans were limited for many reasons, the most obvious one being that starving humans either willingly or unwillingly was unethical. Furthermore, the inability to ensure that humans adhered to the diet without force brought about both ethical considerations and questions of whether such studies would be testing dietary changes or the participants’ ability to follow the diet.

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Prior to Biosphere 2, the largest documented human calorie restriction study in US history was performed by Ancel Keys during World War II. Keys, a physiologist with a keen interest in diet research, had created a formula for packaged meals for soldiers, branded as K-Rations. His war-based dietary studies would continue with the Minnesota Starvation Study, which was initiated three years after the US entered the war and ran from November 19, 1944 to December 20, 1945.³ Thirty-six conscientious objectors were excused from battle in exchange for their cooperation in the study. Upon entering their temporary “biosphere” at the University of Minnesota, they were sworn to uphold perseverance in the project until completion. The participants resided in dormitories within the stadium at the university athletic building. All meals were consumed at a local hall, and they were free to use the library; study programs were provided as well. The investigation was broken into several phases: a three-month control period; the semi-starvation period lasting six months; three months for restricted rehabilitation; and the final eight weeks for the participants’ unrestricted rehabilitation period, where they could freely eat. A battery of physical and psychological tests during each phase of the study awaited the participants.

The diets were calculated to result in a 25% weight loss in the conscientious objectors, who were of normal weight at the start of the study. The participants initially subsisted on a daily 3,150-calorie diet containing 34% fat and 110 grams of protein. In order to simulate the starving conditions in famine-ravaged Europe during the war, participants entered a state of “semi-starvation” and watched their calories initially drop to 1,850 per day, and eventually to just over 1,700 calories, with fat dropping to 11% of calories and protein to 49 grams. Furthermore, participants engaged in physical activity, leading to further caloric expenditure. Their diet, which remarkably closely resembles the current United States Department of Agriculture’s ChooseMyPlate, contained grains like oatmeal and whole wheat bread; vegetables including onions, garlic, celery, carrots, cabbage, lettuce, turnips; various legumes like beans and peas; and starches. However, to keep the subjects’ diets consistent with those in famished war-torn areas, meat and dairy were limited and most protein came from vegetable sources and legumes. The diets did not, and could not, fully resemble the macabre diets in Europe, which contained 500-800 daily calories – an amount that would have resulted in significant health consequences and death, far beyond the ethical boundaries for a study that already bordered unethical conduct.

Nearly a century after Moreschi and his colleagues’ groundbreaking studies, Keys found himself calorically restricting his subjects like Tannenbaum did – only for Keys, they were humans. The Minnesota Starvation Study diet was remarkably similar to the Walford diet, though it remains unknown if this was by design. In his publications afterward, Walford describes their low-calorie diet ranging from 1,750-2,100 calories per day, comprised of the exact same 11% from fat, small amounts of eggs, dairy, and meat, and large amounts of non-animal foods like fruits, vegetables, nuts, legumes, and grains. Walford does describe a diet containing significantly more fruit, both in number and variety. Additionally, the men in Biosphere lost 21% of their initial weight, quite similar to the 25% weight loss by subjects in Keys’ study. While the Keys study subjects were engaging in physical activity, Walford describes intense physical labor for 3-4 hours per day, 6 days a week, totaling between 18-24 hours. Furthermore, the issue of carbon dioxide accumulating within the Biosphere required the inhabitants to manage this issue via a carbon dioxide scrubber and collection of biomass from the Savannah area of the sphere, requiring even more physical labor.  Keys’ subjects remained active via less intense methods including walking on treadmills and helping with housekeeping and laboratory operations; according to the report, these tasks initially occupied 25 hours per week. By the end of the semi-starvation period, the authors noted that all men were unable to continue this activity level as they succumbed to the weakness and fatigue that accompanies starvation; thus, activity levels at that point were unknown. Yet surprisingly, beyond this similarly painted picture, the reports describe drastically different outcomes between the Walford and Keys’ experiments.

During the Minnesota starvation study, most participants completed the study. Upon initiation of the semi-starvation diet, several had prolonged infections and persistent common colds, and another was removed for a severe urinary tract infection. An additional man was removed for “psychological reasons” and several others experienced “periods of emotional stress.” However, according to the study team these individuals “responded well to simple psychiatric measures.” By the second month of starvation, the physicians noted progressively visible swelling of the men’s faces and lower legs. Some had an accumulation of fluid in their knees, others had decreased reflexes, and some even lost their reflexes. Joints creaked during normal activities. The gradual loss of protein was likely responsible for the fluid accumulation, known as edema from third-spacing.

By the end of the six months, the scientists and examining physicians noted that participants had appeared malnourished and emaciated. Furthermore, facial color was described as “sallow and pallid” with a patchy brownish pigmentation around the mouth and eyes, resembling the shape of glasses. Cyanosis, a purple and bluish discoloration, was seen around their nail beds and lips, indicating low oxygen saturation. Their eyes were eerily white without the hint of blood flow. The physicians even attempted to irritate their eyes with soap to elicit the typical redness and irritation that follows but found none. The men’s tongues had swelled, and an imprint of their teeth had formed around its edges. Their skin became thickened, a condition known as hyperkeratosis, with a tinge of brown throughout.

In the conclusion of their medical report, the physicians mentioned a general lifelessness seen in the men, further embellished by their lack of muscle. Men were described as progressively “silent, apathetic, and immobile.” Their heart rates slowed significantly, and for some as slow as 30 beats per minute or below, a state known as bradycardia. Physiological changes showed a 40% decrease in basal metabolic rate – the men’s bodies were shutting down both physically and psychologically. At the start of the study period, the men could push themselves to exhaustion on a treadmill for 245 seconds. By the end of the semi-starvation period, the average was 51.9 seconds, and the men were frequently collapsing – their hearts were unable to speed up and pump the required blood to the brain, and their muscles were equally unable to bear their weight when fatigued. The physicians described an additional strange phenomenon where the men would gradually lean farther and farther forward, as though expecting their feet to catch them from falling, but due to severe muscle loss and weakness, they would instead eventually tumble face-down.

In other words, the physicians were describing a horrifying report of individuals who were malnourished and losing their minds, conditions partially attributed to fat-soluble vitamin deficiency from the low amount of fat in their diet. Other vitamins and minerals accompany these foods as well, as the limitation furthered their deficiencies. Perhaps most dreadful to bear by the study physicians was the intense psychological impact that the diet had on the participants. They became obsessed with food, leading some to constantly talk of food and any topic related to food, like farming. Others became deeply resentful, further fueled by the incessant food conversations, and oftentimes these discussions would lead to violent outbursts. Eventually, the Minnesota Starvation Study participants stopped socializing with each other altogether, and like with the later Biosphere 2 experiment, the fabric of their social order unraveled.

Not surprisingly, excessive hunger was described by all men in the Keys study, including “tiredness, fatigue…muscle soreness, apathy, general irritability, inability to concentrate, depression, dizziness, lack of ambition, moodiness, [and] sensitivity to noise.” These complaints progressively increased; according to the observing doctors, by the last two months of the semi-starvation period, muscle cramps became endemic. The men also complained of the constant feeling of chills, even in the midst of a warm July; along these lines, the severe loss of muscle and body mass began to bother the men both emotionally and physically. For many it was painful to sit on unpadded chairs, and for others it was grueling to watch as their own bodies melted away and they began to resemble elderly men. The elderly depiction of the men was more than visual as most of them began to talk of feeling “old”; their listlessness, lack of libido, weakness, and depression simply made them feel decades older than they were. Depression gradually worsened, and eventually hysteria and hypochondriasis set in. Self-mutilation followed, and one participant, using an axe, severed three of his fingers, leading to amputation. When questioned later, he was unsure if the act was intentional or accidental. By the conclusion of the study, several of the men were hospitalized for further psychiatric care.

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Months after the Biosphere 2 experiment ended, Walford published multiple reports describing the health changes he witnessed in himself and the other individuals that resided with him in the synthetic environment.⁴ His scientific take on their own Minnesota Starvation Study paints a vividly different picture. Walford, who described the food mishap within the enclosed living space as a “serendipitous opportunity to study the responses of humans on such a diet and over a prolonged 2-year period under carefully monitored conditions,”² felt that his findings were fascinating.

As expected, all team members lost weight – holding onto fat, or even muscle, was nearly impossible on a 1780 calorie per day diet, especially with the massive levels of daily activity that the crew was performing as they tended the land. Their blood pressures dropped well below the normal value of 120/80, dipping to 89/58. Their ratio of total cholesterol to high density lipoprotein (HDL) remained the same, as both low-density lipoprotein and HDL decreased. HDL cholesterol almost halved, dropping from 62 to 38 mg/dl. Walford was also surprised to find that an unintended consequence of the rapid weight loss was release of chemicals from the breakdown of adipose tissue – significant amounts of toxins, including industrial chemicals and pesticides like DDT and PCBs, had accumulated within their fat after years of exposure and were being released as a byproduct into their blood as the fat was being metabolized for fuel.⁵

Other reports noted that “on a diet of beans, porridge, beets, carrots, and sweet potatoes, their weight plummeted, and their skin began to turn orange because of the excess beta-carotene within their diet.” The diet – barring the large supply of fruit – and skin changes were unnervingly reminiscent of the Keys reports. Observers from the outside peered in through the glass enclosure to encounter a scene that was eerily similar to the one described by the physicians in the Minnesota Starvation experiment decades before: faces were sunk in, leaving the appearance of discolored and tent-like skin resting squarely on bone. Walford reports that all participants were given equal amounts of food, but other reports cite evidence that meals were initially served buffet style, only to be allotted equally after crew members began to go hungry, fueling already rising tensions. Walford was later quoted regarding the food situation: “I think if there had been any other nutritionist or physician, they would have freaked out and said, ‘We’re starving,’ but I knew we were actually on a program of health enhancement.”⁶ This response was intended to rebut the outcry of the rest of the crew, who wanted additional food transported in once the situation worsened. Walford’s multiple scientific papers make little mention of any psychological changes in his subjects, but the memoirs of other crew members seem to diverge drastically from his descriptions. Crew member Jane Poytner, acutely described her own depression, excessive hunger, fatigue, and a preoccupation with food.¹ Her account paralleled that of the Minnesota Starvation Study physicians, and in a strange stroke of coincidence Poytner also amputated part of her finger while in the Biosphere, (though it was accidental during the cleaning of a rice-hulling machine). Always the optimist, Walford responded in a phone interview that the fingertip was reattached “within 15 to 20 minutes.” She eventually had to leave Biosphere briefly for a surgical procedure to repair the finger.

Similar to the subjects in the Keys’ report, the Biosphere participants began to obsess over food, and “their memoirs of the two-year project are filled with references to their recurring dreams of McDonald’s hamburgers, lobster, sushi, Snickers-bar cheesecake, lox and bagels, croissants, and whiskey. They bartered most of their possessions, but food was too precious to trade. They became sluggish and irritable from lack of it and were driven by hunger to acts of sabotage. Bananas were stolen from the basement storeroom; the freezer had to be locked.”¹ One member wrote a song, titled “Ode to Bananas,” paying tribute to the sweetest fruit available within the Biosphere.

Time magazine judged Biosphere 2 as one of the 100 worst ideas of the twentieth century. Walford published his medical findings throughout his two years and twenty days in Biosphere 2, but otherwise we were left with little other results from the undertaking except the foregone conclusion that it is difficult for humans to cooperate when in close isolation. The strangeness of the project was so comedic that it actually inspired the 1996 comedy film Bio-Dome starring Pauly Shore and Stephen Baldwin. (Much like the real Biosphere 2, Bio-Dome fell below expectations, losing $1.5 million at the box office.) While both the Keys and the Biosphere starvation experiments revealed the psychological issues with calorie restriction, they are two of our only scenarios where this dietary alteration – the same one that Tannenbaum and his colleagues found could decrease the emergence of cancer – was studied in humans. Does either study provide indications that the participants may have a lower risk of cancer? Did Walford’s results, including laboratory and serum blood values, indicate that markers may have been altered in a way that would indicate a lower risk of cancer? Unfortunately, neither questions can be answered from the studies.

Pauly Shore in Bio-Dome

Signaling the end of a strange series of experiments and in an unfortunate twist of fate, Walford passed away in 2004 at the age of 79, nearly a decade after exiting Biosphere 2. He would succumb to Lou Gehrig’s disease, which he felt was precipitated by the elevated levels of carbon dioxide and nitrous oxide that he was exposed to during his time within Biosphere 2.⁷ Adding a bizarre ending to a strange chapter in the history of calorie restriction research, his calorie-restricted diet may have hastened his demise, as mouse studies reveal that it can accelerate the progression of Lou Gehrig’s disease.⁸

The Strange Studies of Calorie Restriction Research References:

1. Poynter, J. The human experiment : two years and twenty minutes inside Biosphere 2. (Thunder’s Mouth Press, 2006).
2. Walford, R. L., Mock, D., Verdery, R. & MacCallum, T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J. Gerontol. A. Biol. Sci. Med. Sci. 57, B211-24 (2002).
3. Keys, A. et al. Experimental Starvation in Man. (1945).
4. Walford, R. L., Harris, S. B. & Gunion, M. W. The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc. Natl. Acad. Sci. 89, 11533–11537 (1992).
5. Reider, R. Dreaming the Biosphere: The Theater of All Possibilities – Rebecca Reider – Google Books. (University of New Mexico Press, 2009).
6. Turner, C. Cabinet // Ingestion / Planet in a Bottle. Cabinet Magazine (2011). http://www.cabinetmagazine.org/issues/41/turner.php.
7. Lassinger, B. K., Kwak, C., Walford, R. L. & Jankovic, J. Atypical parkinsonism and motor neuron syndrome in a Biosphere 2 participant: A possible complication of chronic hypoxia and carbon monoxide toxicity? Mov. Disord. 19, 465–469 (2004).
8. Patel, B. P., Safdar, A., Raha, S., Tarnopolsky, M. A. & Hamadeh, M. J. Caloric Restriction Shortens Lifespan through an Increase in Lipid Peroxidation, Inflammation and Apoptosis in the G93A Mouse, an Animal Model of ALS. PLoS One 5, e9386 (2010).

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