Harvard Lab Studies Daily Biorhythms

For most Harvard students, earning money while sleeping seems like a dream come true.

At Harvard-affiliated Brigham and Women's Hospital, subjects are doing just that.

Twenty-four hours a day, seven days a week, participants in studies conducted by the hospital's Laboratory for Circadian and Sleep Disorders Medicine are busy contributing to the study of circadian rhythms, the science dealing with the operation of one's "biological clock."

Participating in a study actually involves a considerable amount of tolerance and perseverance. Gerald A. Jayne, chief research technician at the laboratory, estimates that the lab receives about 200 phone calls per week from people interested in becoming subjects. "Around 90 percent of people, after hearing what's involved, don't want to do it," he says.

Subjects must typically stay from four days to six weeks in one of the lab's eight suites, which are spacious, minimally furnished and painted completely white.

Ceilings are completely covered by panels of bright fluorescent lights, which can provide lighting levels ranging from dim to extremely bright.

The lights, for example, can be used to induce an artificial jet lag effect in a subject. Researchers can vary the duration and timing of the light and dark periods, as well as the intensity of each light exposure.

To reset a subject's biological clock according to light exposure, in a process called "entrainment," the lights in the suite can be raised to an intensity of 10,000 lux, which is about the intensity of sunlight at dawn or dusk.

Thien T. Huynh '97, a former summer work-study technician at the lab, says that in one particular 11-day study the subject had to stare at a picture of an eye on the wall for 10 minutes, rest for five to 10 minutes, and then look at the picture again for 10 minutes.

"It's just a place to focus on; they had bright light on the whole time. When they're staring at the eye they get more light, and they get less when looking at the floor. There's a light meter that measures how much light they're getting at each point," Huynh says.

Findings that have emerged from research on the ability of light to reset the internal clock has improved the lives of many shift workers. Monica L. Stemmle '96 was involved in shift work research during the summer of 1994. "I participated in a five-year study on whether properly timed bright light could improve shift workers' performance."

Ironically, according to Jayne, the worst part of the technician's job is a rotating schedule. Since technicians wake patients up and bring them meals, a regular staff schedule would give subjects time cues," or clues about what the actual time is rather than what time they are subjectively experiencing.

To ensure irregular staff rotations, the technicians work according to an eight-week schedule so complex that "technicians can't even figure it out," says Jayne.

Jayne also noted that Dr. Charles A. Czeisler '74, director of the lab, has found that shift workers suffer more from rapid rotations, as opposed to fixed shifts or shifts that rotate every few weeks. Jayne jokes, however, that in the interest of science "[Czeisler] doesn't practice what he preaches. For easier adjusting, the schedule always rotates up--for example, the shifts could run day, day, evening evening, night, followed by one of two days off.

Huynh says, "I felt like I was a subject myself because I was working such weird hours. One week I would be working five-hour nights, another week the day shifts, and another week the night shifts."

When asked if researchers ever considered studying the technicians, Huynh quips, "They should."

Technicians' schedules must be unpredictable because the rooms are completely "time-free environments," without television, radio, clocks or windows. Subjects stay in them for the duration of the study, linked only to the outside world by the technicians.

All staff are carefully trained not to provide inadvertent time cues to the subjects, since any apprehension by a subject of the actual time could ruin a study.

"There could be three different times of day in three different rooms, plus the fourth, which is the outside time for the technicians," says Jayne. "Someone might be eating breakfast, someone else might be having lunch, while another person is getting ready to go to bed."

In the event that a technician inadvertently leaves a document in a subject's room, all paperwork is labelled with a "lab time" that disguises the actual time and does not rely on a.m. and p.m. distinctions.

To illustrate just how precarious the time situation can be, Jayne says that in the past, construction on floors below the lab has caused problems. Since construction work is usually scheduled for the daytime, a subject could easily realize that his "bedtime" is really in the middle of the day.

Huynh says that in one type of procedure used in experiments, called a constant routine, a subject may be required to remain in bed for 40 hours or more while sitting up and staying awake.

According to Huynh, who had to make sure the subjects were always awake, the researchers constantly monitor the performance and metabolic status of the subjects during the study.

"Performance tests are a math arithmetic test, at least once an hour...Most subjects, we collect urine samples from. We tested for blood levels of cortisol and melatonin...during a constant routine we take blood more than once an hour," he says.

Moreover, TV monitors in the control rooms keep track of each subject unless he is in the bathroom. And a rectal temperature probe takes a new temperature reading every second, which allows the subject's core body temperature rhythm to be plotted continuously on a computer screen.

Blood is drawn intravenously through a tube stretching across the room through an opening in the wall, which can be attached to a subject's arm for up to a week. A technician can therefore draw blood regularly without disturbing the subject, even when he or she is asleep.

Finally, scalp electrodes monitor brain activity through electroencephalograms (EEG's), which can track periods of REM and non-REM sleep.

All of the monitoring and careful control make the circadian rhythm and sleep studies expensive--averaging about $3,500 per day per subject, according to Jayne.

A college student would earn about $1,000 to stay at the lab for 11 days. An elderly person would earn more, and a blind person would earn the most. The lab advertises for males and females of ages 18-30, elderly people of ages 65-85, and blind people.

Before accepting a willing, needy student, however, the lab insists on a rigorous screening process that takes about a month to complete. Among the criteria: the person cannot have crossed more than three time zones in the past six months, and the person must have been drug-free for years and must not have smoked or had an alcoholic drink in the last month.

In addition to psychological and physical exams, the subject must agree to certain conditions, which Jayne admits are daunting--especially for college students. During the three weeks prior to the entering the lab, a subject must refrain from having caffeine and must agree to go to bed and wake up within half an hour of the same time.

Jayne says that the commitment required during the screening process ensures that about 95 percent of subjects assigned to a study complete their stays. Subjects are free to quit anytime.

"I've come across a lot of college students who need the money, and they've convinced their professors to give them school work for a week. They always work it out," says Jayne.

On the other hand, Jayne said that elderly subjects usually participate for the sake of the companionship of the technicians. "They're usually very lonely," he says.

Jayne cites the clinical contact with subjects as one of the benefits of working in the lab. Huynh says he spent a lot of time with subjects. "I played Monopoly with them or just talked to them, to get their life story or something. They [the researchers] told us not to get into political arguments so their [subjects'] temperatures wouldn't be shooting up."

Blind people, says Jayne, are recruited nationally and are often interested more specifically in contributing to research. "They stay on their own time zone and won't have jet lag at all--only what we might induce," says Jayne.

Wan-yin Wu '97 worked with blind subjects during the summer of 1994.

"All the people we chose were retinally blind. Some of them were actually still able to be entrained with exposure to bright light. However, many other blind people have trouble sleeping. People with artificial eyes could not be entrained at all," Wu says.

"We brought them in on five separate visits, for five days each. We wanted to monitor them at different times in their cycle, to monitor the progression of their cycle. The first day was for getting accustomed to the lab and was a regular day. The second day, we started the light therapy. [This meant] turning it up very bright, then turning it off for brief periods of time. We would get blood drawn every hour to see how hormone levels change," Wu says.

Getting Involved

Harvard students can participate in circadian rhythm research in three ways: They can apply for a Nathariel Kleitman Fellowship, work as a work/study lab technician or volunteer as subjects in a study. The Kleitman Fellowship is a summer program founded by Megan E. Jewett '87, a resident tutor at Currier House, to honor the American researcher to first discover REM sleep.

"I wanted to create a program in which students would get the experience of being actual scientists in both the technical side of running experiments and the intellectual and academic side," Jewett says. "This involves understanding how to design protocols to answer specific research questions and critiquing current research available, presenting their finding, and writing a technical, scientific paper."

Sheri K. Green '96, who spent the summer of 1994 as a Kleitman fellow, says, "I would advocate the fellowship as a good experience for pre-meds. It's a great way to spend the summer. You get paid, you get clinical experience, and you get to work with Dr. Czeisler." Green received a $1,500 stipend for her work.

"This year there are people applying from all over the country so it's going to be a lot bigger," she says.

Stemmle, who spent two summers as a Kleitman fellow in 1994 and 1995, echoes Green's recommendation. "It was a really good experience for what research is really like, for what your daily life is if you're a researcher," she says. "I decided in the end that primary care is going to be more for me."

Huynh, who as a technician had less input into the research process, says, "It was interesting at first but after a while everything got very repetitive and menial...I usually had the night shift so I didn't really see anyone."CrimsonMary W. Lu Technicians monitor the subjects in the studies from a high-tech control room.

In the event that a technician inadvertently leaves a document in a subject's room, all paperwork is labelled with a "lab time" that disguises the actual time and does not rely on a.m. and p.m. distinctions.

To illustrate just how precarious the time situation can be, Jayne says that in the past, construction on floors below the lab has caused problems. Since construction work is usually scheduled for the daytime, a subject could easily realize that his "bedtime" is really in the middle of the day.

Huynh says that in one type of procedure used in experiments, called a constant routine, a subject may be required to remain in bed for 40 hours or more while sitting up and staying awake.

According to Huynh, who had to make sure the subjects were always awake, the researchers constantly monitor the performance and metabolic status of the subjects during the study.

"Performance tests are a math arithmetic test, at least once an hour...Most subjects, we collect urine samples from. We tested for blood levels of cortisol and melatonin...during a constant routine we take blood more than once an hour," he says.

Moreover, TV monitors in the control rooms keep track of each subject unless he is in the bathroom. And a rectal temperature probe takes a new temperature reading every second, which allows the subject's core body temperature rhythm to be plotted continuously on a computer screen.

Blood is drawn intravenously through a tube stretching across the room through an opening in the wall, which can be attached to a subject's arm for up to a week. A technician can therefore draw blood regularly without disturbing the subject, even when he or she is asleep.

Finally, scalp electrodes monitor brain activity through electroencephalograms (EEG's), which can track periods of REM and non-REM sleep.

All of the monitoring and careful control make the circadian rhythm and sleep studies expensive--averaging about $3,500 per day per subject, according to Jayne.

A college student would earn about $1,000 to stay at the lab for 11 days. An elderly person would earn more, and a blind person would earn the most. The lab advertises for males and females of ages 18-30, elderly people of ages 65-85, and blind people.

Before accepting a willing, needy student, however, the lab insists on a rigorous screening process that takes about a month to complete. Among the criteria: the person cannot have crossed more than three time zones in the past six months, and the person must have been drug-free for years and must not have smoked or had an alcoholic drink in the last month.

In addition to psychological and physical exams, the subject must agree to certain conditions, which Jayne admits are daunting--especially for college students. During the three weeks prior to the entering the lab, a subject must refrain from having caffeine and must agree to go to bed and wake up within half an hour of the same time.

Jayne says that the commitment required during the screening process ensures that about 95 percent of subjects assigned to a study complete their stays. Subjects are free to quit anytime.

"I've come across a lot of college students who need the money, and they've convinced their professors to give them school work for a week. They always work it out," says Jayne.

On the other hand, Jayne said that elderly subjects usually participate for the sake of the companionship of the technicians. "They're usually very lonely," he says.

Jayne cites the clinical contact with subjects as one of the benefits of working in the lab. Huynh says he spent a lot of time with subjects. "I played Monopoly with them or just talked to them, to get their life story or something. They [the researchers] told us not to get into political arguments so their [subjects'] temperatures wouldn't be shooting up."

Blind people, says Jayne, are recruited nationally and are often interested more specifically in contributing to research. "They stay on their own time zone and won't have jet lag at all--only what we might induce," says Jayne.

Wan-yin Wu '97 worked with blind subjects during the summer of 1994.

"All the people we chose were retinally blind. Some of them were actually still able to be entrained with exposure to bright light. However, many other blind people have trouble sleeping. People with artificial eyes could not be entrained at all," Wu says.

"We brought them in on five separate visits, for five days each. We wanted to monitor them at different times in their cycle, to monitor the progression of their cycle. The first day was for getting accustomed to the lab and was a regular day. The second day, we started the light therapy. [This meant] turning it up very bright, then turning it off for brief periods of time. We would get blood drawn every hour to see how hormone levels change," Wu says.

Getting Involved

Harvard students can participate in circadian rhythm research in three ways: They can apply for a Nathariel Kleitman Fellowship, work as a work/study lab technician or volunteer as subjects in a study. The Kleitman Fellowship is a summer program founded by Megan E. Jewett '87, a resident tutor at Currier House, to honor the American researcher to first discover REM sleep.

"I wanted to create a program in which students would get the experience of being actual scientists in both the technical side of running experiments and the intellectual and academic side," Jewett says. "This involves understanding how to design protocols to answer specific research questions and critiquing current research available, presenting their finding, and writing a technical, scientific paper."

Sheri K. Green '96, who spent the summer of 1994 as a Kleitman fellow, says, "I would advocate the fellowship as a good experience for pre-meds. It's a great way to spend the summer. You get paid, you get clinical experience, and you get to work with Dr. Czeisler." Green received a $1,500 stipend for her work.

"This year there are people applying from all over the country so it's going to be a lot bigger," she says.

Stemmle, who spent two summers as a Kleitman fellow in 1994 and 1995, echoes Green's recommendation. "It was a really good experience for what research is really like, for what your daily life is if you're a researcher," she says. "I decided in the end that primary care is going to be more for me."

Huynh, who as a technician had less input into the research process, says, "It was interesting at first but after a while everything got very repetitive and menial...I usually had the night shift so I didn't really see anyone."CrimsonMary W. Lu Technicians monitor the subjects in the studies from a high-tech control room.