Issue Twelve
“Let’s Hear it for the Pathologist” by Vincent McConeghy
“The formal narrative of Michael Anthony Gimbrone, Jr.’s career reads as a tour de force of scientific achievement...”
The formal narrative of Michael Anthony Gimbrone, Jr.’s career reads as a tour de force of scientific achievement, fundamental discovery and international acclaim. At 28, he developed a technique to culture endothelial cells in vitro and thus established an entirely new field of study - vascular cell biology. This burgeoning field has led to some of the most important discoveries in our understanding of the mechanisms of cardiovascular disease.
“The lining of the entire circulatory system,” Gimbrone explained to a gathering of medical students at Harvard, “from the chambers of the heart to the smallest capillaries in the tips of your toes, is a continuous layer comprised of a single cell type, vascular endothelium. Simply stated: endothelium is nature’s container for blood.“
Gimbrone’s talk was designed to illuminate how a single research question can lead to an entire career pursuit. For Gimbrone, it all started when he posited this question as a second year medical student: “What does endothelium do for a living?”
This was a question many had pondered before but few had actually studied in-depth due to the long-held belief that endothelial cells could not be coaxed out of their natural environment and studied outside the human body. Gimbrone had the providence to recognize that the profundity of his question could initially be answered by his dazzling accomplishment of culturing endothelial, yet he remained sanguine enough to realize that the ultimate answers to his quest would be settled by the next generation of researchers, some of whom he would nurture as mentor and college.
From Plymouth Avenue to Harvard
Gimbrone’s probing nature is traceable to the stoic figure of his father, Michael, Sr.
“I think my father was a very, very dominant influence in my life, “ Gimbrone recalled. “I was an only child. The thing about my dad that was so amazing was that he had imparted to me the inquisitive mind. “
Indeed, Michael Gimbrone Sr. had an astonishing capacity to “figure things out”; from teaching young Michael the various intricacies of the working trades (plumbing, carpentry etc.) to more exotic interests such as photography and film development all within the tight confines of a dark room he erected in their bungalow on Buffalo’s West Side.
Lacking any formal training, Gimbrone Sr. progressed in the Buffalo police department to the head of the Criminology division. He developed many of the first tests for matching gun powder residues, constructed the formal procedures for investigating crime scenes, and became a handwriting expert through the use of chemical analysis. He was sought after as an expert witness in forgery cases after a nearly fatal attack on his life while on duty forced his early retirement. It was this experience that profoundly affected both father and son.
“My father at a very young age, once said to me: “the most important thing you could do for another human being is to help them with their suffering.” Gimbrone recounted. “ And he was a man who experienced physical and emotional suffering in his life. I have always kept what he said to me uppermost in my mind.”
An Early Crossroad
As a teen, Gimbrone interned at Roswell Park Cancer Institute where he learned surgical techniques that would later astound his first year classmates at medical school.
“I think Roswell Park was one of the few places in the world, at that time, where science and the treatment of cancer were coming together in a purposeful way, and where the whole purpose of translational science was really being realized,” Gimbrone said
After graduating Cornell on a full scholarship, Gimbrone matriculated to Harvard with the firm intent of becoming a pediatric surgeon. It was during a second year lecture on atherosclerosis that Gimbrone’s mind began turning in another direction.
“I leaned over to one of my classmates,” he said. “ I remember this as vividly as yesterday. I said to him: “they don’t understand this disease worth a damn. I mean, all this stuff we just heard, there isn’t a single mechanism in it. It’s all phenomenology. This was 1967-68, and we were learning about endothelium, and I was fascinated by it.”
Gimbrone’s confrontation with endothelium led him to a more disquieting notion: perhaps he would not pursue his quest to alleviate human suffering as a surgeon, but rather as a researcher. It was not something Gimbrone could answer definitively within a set calendar year. He had been captivated by the unknown functioning of the endothelium - and the underlying assumption that it held the answers to atherosclerosis- and now Gimbrone turned his voracious intellect to those who could guide him.
This search eventually led Gimbrone to the lab of Judah Folkman who was immersed in other fundamental discoveries regarding solid tumor growth. Gimbrone had heard that Folkman was perfusing organs outside the body and that something was causing harm to their endothelium. Gimbrone offered to be Folkman’s first student research assistant as a means of studying the damaged endothelium in the perfused organs while helping Folkman along in his angiogenesis theory of tumor growth.
The collaboration between Gimbrone and Folkman has continued to this day. While the subject of Folkman’s research remained divergent from Gimbrone’s interest in the endothelium, Gimbrone learned many “take home lessons” from his first year spent in Folkman’s lab.
“I learned how to design experiments, how to interpret data, but most importantly,” Gimbrone said, “ I learned from Judah the importance of asking the right question. It is a question that should consume you and sustain you through all the many failures you are bound to have in the lab.”
Gimbrone had still not made his decision on what path to choose after his first year in Folkman’s lab. He interned as a surgical scholar but was drawn back to Folkman’s lab as a post graduate fellow. It was a prodigious year for them both. Folkman established the principle that tumors will remain dormant indefinitely if they do not vascularize. It was a Gimbrone-designed experiment that led to the proof of this principle. But, more importantly for Gimbrone, he finally developed the technique to culture and sustain endothelial cells in vitro, leading to the publication of his most quoted work - Human vascular endothelial cells in culture. Growth and DNA synthesis - in the journal of Cell Biology in 1974.
The Future is Now
Gimbrone sits now at the head of the Brigham and Women’s Hospital and the Dana Farber Cancer Institute’s department of Pathology, some thirty-two years after his landmark discovery in Folkman’s lab. He is now much more of an administrator than a researcher, but this transition has not tamed his unbridled joy of discovery. Only now Gimbrone seeks a more strategic goal: that of the reinvention of the way Pathology departments function as engines of change by bringing laboratory discoveries more effectively and quickly to bedside treatment. It is a buzz phrase now - translational pathology - but Gimbrone seems determined to make it a reality.
Gimbrone predicts that not only will new diagnostic tools be the byproduct of translational pathology, that they will be the fertile ground for some of the most exciting new treatments to the most vexing of diseases.
“ We have built an immense biosciences capability in this nation. We have been given a promissory note by every citizen of the United States that needs to be paid off. It is our responsibility to deliver on the promise that modern science will cure disease. The promissory note was the sequencing of the human genome. Ultimately, that has to be translated and mapped onto our understanding of human disease. What’s upstream, what’s downstream? What can be used as a biomarker, and what can be interfered with as an upstream cause? It is one thing to diagnose, yet another thing to prevent. In pathology, we now can help
with both.”
It is a short distance from Gimbrone’s pathology office to his Center for Excellence in Vascular Research Within that ten block square radius remains the highest concentration of biomedical laboratories in the world. Who says the next century belongs to China? The next century belongs right here, and in the other labs across the world, where basic molecular discoveries are rendered into new therapeutic treatments. Gimbrone seemed as dizzied as a tourist by all the possibilities. His only wish was that he had more time to devote to basic science.
At the laboratory, Gimbrone was greeted warmly by a young man in his thirties who has already achieved major advancements in the understanding of the endothelium in its molecular structure. Guillermo Garcia-Cardena spearheads the bulk of the Centers’ use of bioinformatics and cDNA micro arrays as the next generation of research is carried out.
Garcia-Cardena’s research probes even further back to ask more basic questions: Why is an artery an artery? How does a vein become a vein? He has learned something powerful and enduring from his mentor, Gimbrone - that in asking the unanswerable, we define our humanity, and sometimes are fortunate enough to find a life’s work.
“There are many great scientists” Garcia-Cardena concluded. “But there are fewer great men. Dr. Gimbrone is a great scientist and a great man.”
“The lining of the entire circulatory system,” Gimbrone explained to a gathering of medical students at Harvard, “from the chambers of the heart to the smallest capillaries in the tips of your toes, is a continuous layer comprised of a single cell type, vascular endothelium. Simply stated: endothelium is nature’s container for blood.“
Gimbrone’s talk was designed to illuminate how a single research question can lead to an entire career pursuit. For Gimbrone, it all started when he posited this question as a second year medical student: “What does endothelium do for a living?”
This was a question many had pondered before but few had actually studied in-depth due to the long-held belief that endothelial cells could not be coaxed out of their natural environment and studied outside the human body. Gimbrone had the providence to recognize that the profundity of his question could initially be answered by his dazzling accomplishment of culturing endothelial, yet he remained sanguine enough to realize that the ultimate answers to his quest would be settled by the next generation of researchers, some of whom he would nurture as mentor and college.
From Plymouth Avenue to Harvard
Gimbrone’s probing nature is traceable to the stoic figure of his father, Michael, Sr.
“I think my father was a very, very dominant influence in my life, “ Gimbrone recalled. “I was an only child. The thing about my dad that was so amazing was that he had imparted to me the inquisitive mind. “
Indeed, Michael Gimbrone Sr. had an astonishing capacity to “figure things out”; from teaching young Michael the various intricacies of the working trades (plumbing, carpentry etc.) to more exotic interests such as photography and film development all within the tight confines of a dark room he erected in their bungalow on Buffalo’s West Side.
Lacking any formal training, Gimbrone Sr. progressed in the Buffalo police department to the head of the Criminology division. He developed many of the first tests for matching gun powder residues, constructed the formal procedures for investigating crime scenes, and became a handwriting expert through the use of chemical analysis. He was sought after as an expert witness in forgery cases after a nearly fatal attack on his life while on duty forced his early retirement. It was this experience that profoundly affected both father and son.
“My father at a very young age, once said to me: “the most important thing you could do for another human being is to help them with their suffering.” Gimbrone recounted. “ And he was a man who experienced physical and emotional suffering in his life. I have always kept what he said to me uppermost in my mind.”
An Early Crossroad
As a teen, Gimbrone interned at Roswell Park Cancer Institute where he learned surgical techniques that would later astound his first year classmates at medical school.
“I think Roswell Park was one of the few places in the world, at that time, where science and the treatment of cancer were coming together in a purposeful way, and where the whole purpose of translational science was really being realized,” Gimbrone said
After graduating Cornell on a full scholarship, Gimbrone matriculated to Harvard with the firm intent of becoming a pediatric surgeon. It was during a second year lecture on atherosclerosis that Gimbrone’s mind began turning in another direction.
“I leaned over to one of my classmates,” he said. “ I remember this as vividly as yesterday. I said to him: “they don’t understand this disease worth a damn. I mean, all this stuff we just heard, there isn’t a single mechanism in it. It’s all phenomenology. This was 1967-68, and we were learning about endothelium, and I was fascinated by it.”
Gimbrone’s confrontation with endothelium led him to a more disquieting notion: perhaps he would not pursue his quest to alleviate human suffering as a surgeon, but rather as a researcher. It was not something Gimbrone could answer definitively within a set calendar year. He had been captivated by the unknown functioning of the endothelium - and the underlying assumption that it held the answers to atherosclerosis- and now Gimbrone turned his voracious intellect to those who could guide him.
This search eventually led Gimbrone to the lab of Judah Folkman who was immersed in other fundamental discoveries regarding solid tumor growth. Gimbrone had heard that Folkman was perfusing organs outside the body and that something was causing harm to their endothelium. Gimbrone offered to be Folkman’s first student research assistant as a means of studying the damaged endothelium in the perfused organs while helping Folkman along in his angiogenesis theory of tumor growth.
The collaboration between Gimbrone and Folkman has continued to this day. While the subject of Folkman’s research remained divergent from Gimbrone’s interest in the endothelium, Gimbrone learned many “take home lessons” from his first year spent in Folkman’s lab.
“I learned how to design experiments, how to interpret data, but most importantly,” Gimbrone said, “ I learned from Judah the importance of asking the right question. It is a question that should consume you and sustain you through all the many failures you are bound to have in the lab.”
Gimbrone had still not made his decision on what path to choose after his first year in Folkman’s lab. He interned as a surgical scholar but was drawn back to Folkman’s lab as a post graduate fellow. It was a prodigious year for them both. Folkman established the principle that tumors will remain dormant indefinitely if they do not vascularize. It was a Gimbrone-designed experiment that led to the proof of this principle. But, more importantly for Gimbrone, he finally developed the technique to culture and sustain endothelial cells in vitro, leading to the publication of his most quoted work - Human vascular endothelial cells in culture. Growth and DNA synthesis - in the journal of Cell Biology in 1974.
The Future is Now
Gimbrone sits now at the head of the Brigham and Women’s Hospital and the Dana Farber Cancer Institute’s department of Pathology, some thirty-two years after his landmark discovery in Folkman’s lab. He is now much more of an administrator than a researcher, but this transition has not tamed his unbridled joy of discovery. Only now Gimbrone seeks a more strategic goal: that of the reinvention of the way Pathology departments function as engines of change by bringing laboratory discoveries more effectively and quickly to bedside treatment. It is a buzz phrase now - translational pathology - but Gimbrone seems determined to make it a reality.
Gimbrone predicts that not only will new diagnostic tools be the byproduct of translational pathology, that they will be the fertile ground for some of the most exciting new treatments to the most vexing of diseases.
“ We have built an immense biosciences capability in this nation. We have been given a promissory note by every citizen of the United States that needs to be paid off. It is our responsibility to deliver on the promise that modern science will cure disease. The promissory note was the sequencing of the human genome. Ultimately, that has to be translated and mapped onto our understanding of human disease. What’s upstream, what’s downstream? What can be used as a biomarker, and what can be interfered with as an upstream cause? It is one thing to diagnose, yet another thing to prevent. In pathology, we now can help
with both.”
It is a short distance from Gimbrone’s pathology office to his Center for Excellence in Vascular Research Within that ten block square radius remains the highest concentration of biomedical laboratories in the world. Who says the next century belongs to China? The next century belongs right here, and in the other labs across the world, where basic molecular discoveries are rendered into new therapeutic treatments. Gimbrone seemed as dizzied as a tourist by all the possibilities. His only wish was that he had more time to devote to basic science.
At the laboratory, Gimbrone was greeted warmly by a young man in his thirties who has already achieved major advancements in the understanding of the endothelium in its molecular structure. Guillermo Garcia-Cardena spearheads the bulk of the Centers’ use of bioinformatics and cDNA micro arrays as the next generation of research is carried out.
Garcia-Cardena’s research probes even further back to ask more basic questions: Why is an artery an artery? How does a vein become a vein? He has learned something powerful and enduring from his mentor, Gimbrone - that in asking the unanswerable, we define our humanity, and sometimes are fortunate enough to find a life’s work.
“There are many great scientists” Garcia-Cardena concluded. “But there are fewer great men. Dr. Gimbrone is a great scientist and a great man.”