November 30, 1998

Connecting Points: A Pilot and a Surgeon
Medicine and the Machine
Silk as Life Support
"The Culture of Organs"
A Model T and Biotechnology
Medicine for the Next Millennium

Charles Lindbergh was only 10 years old when Alexis Carrel reported "On the permanent life of tissues of the organism" and the "Ultimate results of aortic transplantation" in the Journal of Experimental Medicine.

The year was 1912. Carrel, the father of vascular surgery and soon-to-be Nobel laureate, was laying the groundwork for tissue culture technology and transplant surgery in his laboratory at the Rockefeller Institute for Medical Research in New York City.

Lindbergh, the future pilot of the "Spirit of St. Louis," was growing up on his family's farm on the banks of the Mississippi River near Little Falls, Minnesota. But during the winter he lived in Washington, D.C. His father, C.A. Lindbergh, was a U.S. Congressman from Minnesota.

One day in 1912, he and his mother went to an air show across the Potomac River at Ft. Myer in Virginia. Lindbergh was so fascinated with the new "flying machines" that he determined then and there "to fly myself."

As the 20th century draws to a close, we look for connecting points to make sense of it.

For me, the Carrel-Lindbergh collaboration is one such point. It appears on the page like a cursor whenever I read from the deluge of articles about where we are going in biomedical research:

• "The Body Shop: Need a new nose? A new heart? Someday doctors may be able to grow you one." Life  magazine, Fall 1998. Special Issue: Medical Miracles for the Next Millennium.
• "Cloning for Medicine." Cloning makes possible "the generation of genetically modified animal organs that are suitable for transplantation into humans." Scientific American, December 1998.
• "L'homme aux sens artificiels." ["Man with artificial senses. From hearing to seeing, from smelling to speaking and touching....researchers are beginning to understand the mechanisms of the senses and translate their findings into new prosthetic devices."] L'Express, Oct. 7, 1998.
• "Study finds use of cord blood as effective as bone marrow transplants....doctors are salvaging hope from a curious sources, one that is normally thrown away: blood left in the umbilical cords and placentas of newborn infants." New York Times, Nov. 26, 1998.

All these stories have a common thread: The understanding, incubation, preservation, and sometimes transfer of cells, tissues and organs, aided and abetted by the machine, their performance and therapeutic value monitored by the machine, their future viability predicted by the machine.

Medicine and the machine.

Lindbergh understood the machine like few people of his time. The stories of his boyhood prowess are legion. No piece of mechanized equipment that occupied the farm, not the tractor, the implements, the new milking machine, the Model T, escaped him. He looked into each as if he had X-ray vision, took it apart and put it back together in his head.

Later he helped design the "Spirit of St. Louis." That design took him to France, the homeland of Alexis Carrel, a man who affected his thinking during his adulthood more than any other according to biographer A. Scott Berg.

"In this day of artificial hearts and organ transplants," begins Lindbergh's biosketch on the Lindbergh Foundation Web site, "it is noteworthy that Charles Lindbergh invented an 'artificial heart' in the 1930s."

The Lindbergh organ perfusion pump "indicates the breadth of Lindbergh's interests, a breadth that led to his philosophy that the survival and progress of mankind depend on a balance between technological advancement and preservation of the environment."

Lindbergh's foray into medicine began in 1929 when his sister-in-law, Elizabeth Morrow, was diagnosed with heart disease. It was a quarter century before surgeon C. Walton Lillehei and his colleagues at the University of Minnesota Medical School combined new surgical techniques, heart-lung bypass technologies, and monumental drive to make open-heart surgery a safe and effective treatment for people like Elizabeth Morrow.

When Lindbergh asked why cardiac surgery couldn't be done, physicians had no answer.

"Knowing nothing about the surgical problems involved," he wrote later, "it seemed to me that it would be quite simple to design a mechanical pump capable of circulating blood through a body during the short period required for an operation."

A physician friend introduced him to Carrel, a maverick of like mind when it came to understanding how things work and taking on the world of the impossible.

It is significant that Carrel's native Lyon honored Lindbergh following his transatlantic flight with a U.S. flag made of silk.

Lyon was granted a royal monopoly during the Renaissance for selling silk and became the heart of France's textile industry. Carrel's grandfather was a linen merchant, and Carrel himself drew upon sewing techniques used in the trade when he pioneered anastomosis, the suturing of vessels.

His knowledge of fabrics came in handy in his cell and tissue culture experiments.

On January 17, 1912 Carrel placed a slice of heart muscle from a chick embryo in a culture medium. The cells lived until 1946, two years after Oswald Avery, one of the country's first molecular biologists working in another laboratory at Rockefeller, discovered that DNA (deoxyribonucleic acid) and not protein is the genetic stuff. They stopped pulsating two years after Carrel himself died of a heart attack after being associated with the collaborationist Vichy government in France.

For many years, Carrel's laboratory hosted a birthday party for the historic heart cells on January 17th, celebrating over the pulsating culture. [Today, alas, the story of the "eternal cells" is regarded by leading authorities as spurious, if not fraudulent.]

In his original paper, Carrel wrote that it was difficult to induce cultured tissues to expand because the protoplasm in the medium invariably retracted, causing the culture to assume a spherical shape. While cells on the periphery next to nutrients would thrive, internal cells with restricted access became necrotic.

Borrowing from his heritage, he used a silk veil to create a three-dimensional culture. The silk veil "acted as a skeleton for the plasmatic jelly, the original [tissue] fragment, and the new tissue cells," he wrote. The silk veil-enhanced culture "could be handled easily without folding and retraction of the medium, and without deformation of the cells."

Silk, the lustrous fiber, the precious material that enriched the merchants of Lyon, transformed into a life support.

Today, three-dimensional cell culture is a key to advances in biomaterials research, bioartificial tissue and organ engineering, and bioprocessing--the large-scale production of valuable cellular products like insulin.

A key to "Medicine for the Next Millennium."

The Lindbergh organ perfusion pump was not actually an "artificial heart," but a way of keeping whole organs alive outside the body, in an artificial environment.

Richard Bing, a physician who worked with Lindbergh in Carrel's laboratory in early 1930s, wrote that Lindbergh's original idea was never referred to as "a system for cardiopulmonary bypass."

Apparently, Carrel persuaded Lindbergh early on that a better chance of success lay in designing a system to culture organs. Of course, this direction also served Carrel's own interests and immediate needs.

Carrel "had always considered the concept of organ culture to be a logical extension of the concept of cell culture," Bing wrote. But previous attempts had failed. Infection and necrosis had set in rapidly.

On September 1, 1935, three months before the Lindbergh family left the U.S. for England to escape the barrage of publicity surrounding the kidnapping and murder of Charles, Jr. and the subsequent "trial of the century," the Journal of Experimental Medicine  published "An apparatus for the culture of whole organs" by C.A. Lindbergh.

"The apparatus described in this paper was designed to maintain a sterile, pulsating circulation of fluid through living organs," the article began. "More than twenty-six experiments, with various organs, have been made up to the time of writing."

A writer for Time   in a cover story three years later described the pump this way:

"Looking like a twist of vitrified bowel oozing out of a clear glass bottle, the Lindbergh perfusion pump consists of three chambers one above the other. The organ to be studied lies on the slanting glass floor of the topmost. Nutritious fluid from the lowest or reservoir chamber is driven up a glass tube connected with the organ's artery, to and through the organ by pulsating gas pressure."

Among the many original features in the overall design was the use of non-absorbent cotton in the filters, which inhibited passage of germs.

The culmination of the Lindbergh-Carrel collaboration occurred with the publication of The Culture of Organs  by Paul B. Hoeber, Inc. in 1938. The book is in many ways typical of books on medical methodology of the time, with many black-and-white plates of cells and tissue sections, schematics, tables and graphs.

Perhaps what sets it apart is the grand vision laid out for a three-year-old technology, how it could serve to help identify the specific nutritional requirements for each organ.

Proper nutrition was the secret to revitalizing any diseased organ: "To bring about the regeneration within the pancreas of the Langerhans' islands would be a far more efficient method of treating diabetes than to inject insulin daily into the body of the patient."

"In 1912," Lindbergh wrote in his autobiography, "my father bought a Ford Model T automobile, which my mother christened with the undignified name 'Maria' (pronounced like rye). For me, Maria brought modern science to our farm, and nothing else attracted me as much, or was as challenging or as symbolic of the future."

Toward the end of his life, his confidence in technology and medical science was tempered by the experience of war and by persistent transcendent questions that the study of "biological mechanics" could not answer.

Yet 20 years after Carrel's death, Lindbergh found himself back in biomedical science -- at the Naval Medical Research Institute in Bethesda, Maryland, redesigning its organ perfusion system.

The Navy had established a cryobiological-perfusion research program with the objective of "creating a storage bank of human organs for transplantation," he wrote, another idea dismissed as "impossible" a generation earlier.

Lindbergh died in 1974 just as the world was being introduced to recombinant DNA technology. He missed the "dawn of biotech."

Accepting the limitations of biomedical science or any science to answer ultimate questions, one wonders how he would have wondered about the possibilities of biotechnology -- on the farm as well as in the clinic.

Isn't biotechnology as symbolic of the future as the Model T was nearly a century ago? Isn't it easy to imagine a young Lindbergh today consumed by how it works?

In their book The Culture of Organs, Lindbergh and Carrel concluded boldly that "A new era has opened."

For the first time, medical science "is capable of apprehending bodily structures in the fulness of their reality, of understanding how the organs form the organism, and how the organism grows, ages, heals its wounds, resists disease, and adapts itself with marvelous ease to changing environment."

A quarter century later, remembering the time he watched his own sperm cells, his "life stream" on a glass slide, Lindbergh observed that science "clarifies man's vision beyond his birth and death and links him to universality."

Each generation further clarifies the vision.

Today, the "new era" goes under the term "molecular medicine." Molecular medicine aims to bring discoveries in genetics, cell biology, and bioengineering to the bedside. But there's pleny of hard work ahead.

"That promising new methods are emerging from our laboratories does not necessarily mean they will soon be translatable to clinical usefulness," cautions Yale surgeon Sherwin Nuland in Life  magazine's special issue on "Medical Miracles for the Next Millennium."

Next month, in the heartland of biomedical technology where advances in organ and bone-marrow transplantation were pioneered, the University of Minnesota will dedicate the Center for Molecular and Cellular Therapy.

The Center's mission is to help make the new field of molecular medicine a reality for patients and their families.

One of the Center's projects is pancreatic islet cell transplantation for patients with diabetes. Islet cell replacement has eliminated the need for insulin injections, glucose monitoring, and dietary restrictions in a number of patients in preliminary studies.

The "appropriate nutrient substances" that Carrel and Lindbergh believed held the secret to organ regeneration we know today as cellular growth factors, molecules that regulate cell division and tissue proliferation by binding to receptors on the surface of the cell.

Molecules important for understanding how genes, cells, tissues and organs are built and how life in the organism is orchestrated.

The challenges of molecular medicine are daunting, but so were the challenges a pilot and surgeon faced together some 60 years ago as they pushed back the frontiers of knowledge of their time.

    --William Hoffman    hoffm003@tc.umn.edu

Acknowledgment: Thanks to Elaine Duncan of Paladin Medical, Inc. for bringing the Carrel-Lindbergh collaboration to my attention and providing background materials.

Disclaimer: The opinions expressed herein are the writer's own.