Pearl Harbor: A Catalyst for Mayo's Early Physiology Research

Early in 1942, just months after the Japanese attack on Pearl Harbor, Mayo Clinic launched its own contribution to the war effort by building the first human centrifuge in the country. Mayo scientists and engineers constructed it with recycled materials that included two 40-ton wheels from an old brewery, and offered its services to the military for the annual fee of $1. The group, which included a newly recruited Dr. Wood, used it to study the physiology that causes pilots to lose consciousness when pulling out of a dive at high acceleration.

"They were very courageous and dedicated to the cause," muses Dr. Ritman. "They thought nothing of having themselves spun around in the centrifuge to the point of unconsciousness."

Based on the instruments developed for the centrifuge studies, the group quickly gained an international reputation for their pioneering work in heart, lung and blood physiology and cardiac catheterization. Their achievements in the 1940s and 1950s includes:

• The first G suit--a flight suit outfitted with air-filled bladders and a system of valves to protect pilots during high speed maneuvers by encouraging greater blood flow to the brain.
• Modification of an aircraft air pressure gauge into an instrument that became the standard tool for measuring arterial blood pressure.
• The first human diagnostic cardiac catheterization.
• The M-1 maneuver, a voluntary exhaling technique for preventing blackouts, developed by Dr Wood.
• Instrumentation and multi-channel recordings that monitored the amount of oxygen present in the blood throughout a surgical procedure.
• Refinement of the heart-lung machine with which Mayo became the first medical center to perform open-heart surgery as a routine procedure.
• Development of indocyanine green dye by Dr. Wood, which was the favored method for measuring heart pump function and diagnosing congenital heart disease for many years and is still used, in some applications, today.

In 1958, research using the centrifuge got a second boost when the U.S. Air Force and NASA requested that Dr. Wood continue his studies on G forces. The space race was on.

A Strike Against Conventional Angiography

Such was the rich scientific environment that enticed Dr. Ritman to Mayo for a one-year research fellowship in 1968. He felt right at home with Dr. Wood's philosophy of "jumping in where angels fear to tread."

"Dr. Wood championed the concept that, to understand physiology, you have to be minimally invasive," explains Dr. Ritman. "One of his group, Ralph Sturm, had developed an electronic, computer-based angiography analysis system and my project was to show it was more accurate than the traditional manual analysis method."

However, Dr. Ritman's studies showed that conventional angiographic silhouettes were not capable of producing highly detailed images of the circulation and the shape and volume of the heart chambers. His findings sent the lab off in a different direction.

"We realized 3D information was what was needed," says Dr. Ritman, whose work led to a fellowship grant from the Minnesota Heart Association and, in 1973, a doctorate in physiology from Mayo Graduate School of Medicine and the University of Minnesota.

Early CAT Scans

By 1971, the group was considering methods of collecting 3D image information--later called Computed Tomography (CT) or Computed Axial Tomography (CAT). The now widely-used technology produces computer-generated images of structures inside the body by taking x-rays at different angles. The initial development team, including distinguished scientists James Greenleaf, Ph.D., Richard Robb, Ph.D., and Barry Gilbert, Ph.D., and Steven Johnson, Ph.D., who coined the word "voxel," built a scanner from an x-ray fluoroscopy system and, in 1973, performed the first 3D CT scan of an isolated beating heart. Coincidentally, in the same year, Mayo purchased the first EMI CT scanner in North America, for which its developer, Godfrey Hounsfield, later shared the Nobel Prize in Medicine.

At a radiology conference later that year, Dr. Ritman was excited about presenting data from the first CT scan of a heart until he discovered that Mayo neuro-radiologist Hillier (Bud) Baker, M.D., was scheduled to speak about the initial clinical experience with the EMI CT scanner at the same time.

"Hardly anyone came to my talk because everyone wanted to hear about the first clinical scans," laments Dr. Ritman. "The EMI CT scanner was an annoying surprise but at least we knew we were on the right track."

For the next five years, the lab pursued grants to fund the development of a machine with multiple x-ray sources that could produce more accurate and truly dynamic 3D images of the entire moving heart, lungs and blood inside the body. They called it the Dynamic Spatial Reconstructor (DSR).

Developing Dynamic 3D Images

In 1977, an early instrument developed by the lab, called a single source dynamic spatial reconstructor (SSDSR), earned the Association for the Advancement of Medical Instrumentation Medical Instrumentation Award. It used a fluoroscopic system to image the beating heart and breathing lungs in anesthetized animals.

The DSR consisted of multiple X-ray sources and multiple 2D fluoroscopic video cameras on a continuously rotating machine. It could simultaneously scan up to 240 contiguous, 1mm thick cross sections within one one-hundredth of a second and repeat it 60 times per second. That year, Dr. Ritman became chair of Mayo's Biophysical Sciences Unit and Principal Investigator (PI) of the National Institutes of Health (NIH) Program Project grant that funded the DSR project, continually for the next 18 years.

In 1987, the American College of Chest Physicians awarded the Outstanding Film Award to E. Hoffman, Ph.D. and Dr. Ritman. The film, largely put together by Dr. Hoffman from DSR image data, was able to settle a longstanding physiological question regarding heart volume by showing that the normal heart stays at a constant volume during the entire cardiac cycle by emptying the ventricles as the atria fill.

DSR-based studies spanned nearly two decades and included numerous physician scientists from many disciplines as coauthors. However, eventually the technology changed enough to make updates to the machine expensive and impractical and Dr. Ritman decided not to reapply for the grant's renewal and the DSR was dismantled in 1998. Nevertheless, his whole-body CT research continued with use of Mayo's Electron Beam CT scanner and the recently installed Dual Source Fast CT scanner, housed in the new Opus Imaging Research Building. In addition, he began focusing on micro computed tomography to provide 3D analysis of the microcirculation.

Micro CT

In 1993, funded by the National Science Foundation, Dr. Ritman's lab built their first micro CT scanner. The machines that the lab has since designed and built, sit on floating tables because they are extremely sensitive to vibration and temperature change.

"We're talking about spatial resolution of a few micrometers," says Dr. Ritman. "If the doors are left open while scanning, the resulting temperature change can distort the picture by many micrometers."

Although, initially, Dr. Ritman focused on coronary circulation, he has since collaborated on micro CT projects with scientists from at least 10 different disciplines. He also has several ongoing collaborations with University of Minnesota researchers as well as with a number of out-of-state and international scientists. The following three images are examples from Dr. Ritman's work. They illustrate the fine details made available through micro-CT imaging and the ability of the Dual Source CT scanner to image the transit of blood flow in microscopic vessels deep within the body.

Extending the Technology

Aside from research projects that study images produced by micro CT images, Dr. Ritman continues to work on further developing the technology. For example, his lab designed and built a way to make 3D images of frozen specimens.

"Imaging a frozen specimen on the micrometer scale presents the problem of the frozen object accumulating condensation or of it sagging as it thaws, in both cases introducing mathematical inconsistencies," explains Dr. Ritman.

Steven Jorgensen, a technician in the Ritman lab who recently earned Mayo's Associate in Research title--an honor bestowed on Mayo technicians whose work has made a substantial contribution to research--solved the problem. He designed a cryogenic vessel made, in part, of beryllium, which is transparent to x-ray and has two walls that are separated by a vacuum. Inside the vessel, the specimen is continuously flushed with nitrogen gas, which keeps it at liquid nitrogen temperatures. There is a need for examining frozen specimens because other preservation methods destroy some immunohistological processes that are the target of study.

Following Dr. Wood's tradition of pushing the envelope, Dr. Ritman and research fellow, Congwu Cui, Ph.D., are also tackling the difficult but exciting technology that exploits the fact that a significant percentage of an x-ray beam scatters instead of being transmitted through the object. X-ray scatter is measured both by its intensity and the angle at which it scatters.

"Scatter can distinguish between different chemicals that have comparable density," explains Dr. Ritman. "Some airport scanners use scatter to identify explosives by their unique chemical bonds. A potential medical use would be to monitor current treatments that destroy tumors by "cooking" them, a process that changes its chemical bonds. Our goal is to develop technology that can measure scatter accurately enough to identify the critical point when the tumor is completely destroyed so that the procedure can be stopped before harming the healthy tissue that surrounds it."

Much like his mentor, Dr. Wood, who continued his research well beyond the conventional retirement date, Dr. Ritman continues working toward the goal of developing imaging methods that can detect diseases before symptoms appear, thereby increasing the likelihood of stopping their progression or even of reversing them.

"I have grants active for a few more years," he says. "Being a scientist means always having something new to discover. There's still much to be done."

- Yvonne Hubmayr