• Rolando Nieves

Vitamin K: This vitamin you've never heard of may have saved your life (Transcripts)




GAME CHANGERS IN MEDICINE

EPISODE 1

VITAMIN K: THIS VITAMIN YOU’VE NEVER HEARD OF MAY HAVE SAVED YOUR LIFE

[DR. RUBIN PILLAY]

Forget genius. In many ways the significant advances in modern medicine can be viewed as little more than the product of a happy combination of dumb luck and coincidence. As you are about to hear, some of healthcare’s most significant milestones were the result of fortuitous accidents followed by scientific rigor. But serendipity and science alone don’t improve health and healthcare. It took curious, creative and persistent individuals to bring these accidental discoveries from the lab bench to the patient bedside. This is their story. This is . . . Game Changers in Medicine.

Hello and welcome.

I’m your host, Dr. Rubin Pillay— professor of medicine and professor of business at the University of Alabama Medical Center. I’m also a medical futurist. And by that I mean that I look at how software, hardware, communications, and biomedical technology converge to improve patient care. And while it may seem odd for one focused on the frontier of medicine to host a podcast exploring medical innovations from the past, I can tell you that there is much to be learned from the scientists and clinicians who preceded us.

Our story today is about the discovery of vitamin K. Now, this discovery took place nearly a century ago, so you may wonder why we’re choosing to debut Game Changers in Medicine with it. That’s a lot of pressure to put on one vitamin. We chose it because the story of vitamin K encapsulates so much of what our podcast series is about— monumental discoveries that happened in unexpected ways.

Let’s begin.

There are close to four million babies born each year in the United States[1], and more than 130 million worldwide.[2] By way of greeting, many of those babies are injected with a needle filled with Vitamin K.[3]

[DR. BRUCE FURIE]

Newborns are Vitamin K deficient. They don't have Vitamin K. And breast milk is quite deficient in Vitamin K.

[DR. RUBIN PILLAY]

That was Dr. Bruce Furie, a professor of medicine at Harvard Medical School and a world leader on vitamin K and hemostasis and thrombosis research. He has countless awards and a few ground-breaking medical discoveries of his own.[4]

[DR. BRUCE FURIE]

The risk of becoming of continuing Vitamin K divisions over the first week or so is significant enough that it can lead to bleeding disorders due to the absence of vitamin K and the inability to make the vitamin K dependent blood coagulation proteins. It's the normal physiology.

Vitamin K deficiency is not actually measured. Rather, all babies are assumed to be Vitamin K deficient. This leads to a bleeding disorder. In its modest form (it) could be ecchymosis, black and blue marks on the skin. In its most severe form, and this is what is really it was a problem, is cerebral hemorrhage - brain hemorrhage. There are minimal, if any complications, from giving a half a milligram of vitamin K to a newborn.

[DR. RUBIN PILLAY] For more about this, let’s hear from Catherine Ruhl. Catherine is a nurse-midwife who has delivered thousands of babies. She is also the Director of Patient Education at the Association of Women’s Health, Obstetric and Neonatal Nurses.

[CATHERINE RUHL, NURSE-MIDWIFE] All newborns have lower stores of Vitamin K at birth than what adults would have. It's not because the mothers are deficient. It's really because Vitamin K does not cross the placenta very well at all.

Now for the Vitamin K injection. A really excellent recommendation is to administer the Vitamin K while the baby is still with the mom. You give the baby the Vitamin K injection while the baby is on the mom's chest maybe even while the baby is nursing. That is a strategy to help minimize the pain of the injection for the baby, cuddled up with mom and nice and warm. Obviously, the nurses are very skilled and know how to do it very quickly and minimize any of the procedure for the baby.

[DR. RUBIN PILLAY] While it’s hard to quantify exactly the impact of vitamin K on infant mortality, there was a definitive study done in Sweden in 1944 that estimates that for every 100,000 full-term infants born, vitamin K would save the lives of 160 babies each year.[5]

Since 1961, the American Academy of Pediatrics has recommended that vitamin K be given to all newborns.[6] That one vitamin K injection is really one of these simple and yet very effective therapies that have a history of long standing.

Let’s contrast this with the early days of vitamin K use. Listen to the words written by Dr. William C. Moloney, a pioneering hematologist who set up practice in Boston in the early 1930s. Dr. Moloney was among the first to test patients for vitamin K deficiency. In his memoir, Pioneering Hematology, he recounts the day George Allen, a close physician colleague, called him for an emergency consult of a newborn.

We are fortunate to have with us Sean Moloney, grandson of Dr. Moloney. He’s also the co-founder of Dramatic Health and the producer of this podcast series.

I’m going to ask him to read that particular passage from his grandfather’s memoir.

Sean . . .

[SEAN MOLONEY READING FROM DR. MOLONEY’S MEMOIR]

My colleague George Allen had just delivered a baby who was convulsing and bleeding from the nose, mouth and into the skin. I rushed to George’s practice in Norwood and agreed with his diagnosis of hemorrhagic disease of the newborn. I told George about vitamin K, and he was anxious to give it a try.

At that time, vitamin K was not available commercially, but I knew two investigators at the Thorndike Memorial Laboratory at Boston City Hospital who were working on manufacturing it. I lost no time in telling them about the case. They had just prepared a batch of vitamin K from leafy vegetables and offered to give me some to use on this infant. I dashed down to the Boston City Hospital, procured the material in a home-made vial, and returned to Norwood Hospital. The infant was oozing blood, barely alive. I put the home-made vitamin K into a syringe and injected it into the infant’s buttocks. The baby stopped bleeding and eventually recovered completely.

[DR. RUBIN PILLAY]

Thank you, Sean.

That baby was likely suffering from the hemorrhagic disease Dr. Furie was telling us about. Hemorrhagic disease of the newborn is now more commonly called “vitamin K deficiency bleeding.” Prior to the discovery of vitamin K, vitamin K deficiency bleeding could be fatal.[7] It was fortunate that Dr. Moloney happened to read an article about vitamin K and was willing to take a chance on it as a therapeutic solution. What else could he do? At the time, there were no other alternatives for that baby.

Here’s Dr. Moloney, now in his own words thanks to the oral history he recorded for the American Society of Hematology and the Oral History Archives at Columbia University.

[DR. WILLIAM C. MOLONEY] There was a disease in newborns called hemorrhagic disease of newborn which was found to be due to lack of prothrombin. Then it was discovered the antidote for this disease was to give Vitamin K. This evolved over several years in the early (19)30s. So, Vitamin K was synthesized and isolated. Then you could treat Vitamin K deficiency which was a congenital deficiency due to the lack of the Vitamin K from the mother to the fetus. These children would bleed into the head, and either die or be left crippled.

[SEAN MOLONEY]

That’s my grandpa. By today’s standards its safe to say his practice was unconventional. But then again so was he.

[DR. RUBIN PILLAY] It’s stunning to me to hear your grandfather talk about that bleeding disease in newborns. Imagine the thrill for obstetricians at the time to finally begin to have an understanding of what had been causing it.

[SEAN MOLONEY]

Yes, yes.

[DR. RUBIN PILLAY]

I’d love to hear more about this grampa of yours.

[SEAN MOLONEY] I welcome the opportunity to tell you about him.

Grampa was a well-known and well-loved doctor practicing in Boston from the 1930s through to the end of the century. He started out in general practice and wound up specializing in hematology and leukemia. He was raised in Charlestown, Massachusetts, in what was then a pretty rough-and-tumble part of town. He was Irish Catholic through and through and was not one to run from a battle. He used to tell me the stories of his childhood by pointing to the scars on his face.

Throughout his life, but especially as a youngster, he was an avid sportsman. One intense hockey game brought him to the emergency room of Boston City Hospital with a broken arm. The experience there got him thinking that he might make a better doctor than hockey player. I’m sure his patients—and probably his hockey coaches—agreed with him.

[DR. WILLIAM C. MOLONEY]

My interest developed rather rapidly as I had a bad injury that landed me in Boston City Hospital for some weeks. And subsequently over a long period of time I was back and forth. So, I worked around the hospital (in) summers, as an orderly, in fact and then went to pre-med at Tufts. In those days, you could get into medical school with two years pre-med. You didn't have to have a degree. But you had to cram into those two years all of the scientific subjects. That included physics, chemistry and all the other biologic sciences.

We had a very large class in pre-med, and it was competitive in that only one out of four of us would get into medical school. So we all worked our tails off. I had to develop rather rapidly a competitive spirit about survival, and I did get into medical school. I did fairly well considering the fact that I used to work nights at the Motor Mart Garage in the lobby at the cigar counter and tried to go to medical school at the same time, which is kind of a chore as you might imagine.

[ DR. RUBIN PILLAY]

While Dr. Moloney is toiling away in medical school, there’s a biochemist in Denmark named Henrik Dam who’s started a cholesterol study on baby chicks. He feeds the chicks a cholesterol-free diet in the hopes that it will shed light on how cholesterol is synthesized. Pretty quickly, all the baby chicks start to hemorrhage. He tries everything to stop the bleeding: adding cholesterol back into their diet and then feeding them every known vitamin.

Finally, he hits upon a solution, which turns out to be an extract from leafy vegetables. Dam realizes he’d discovered a new type of vitamin, which he promptly calls vitamin K, taking the initial letter “K” from the Scandinavian spelling of coagulation.[8] Coagulation is just another word for blood clotting—or blood changing from a liquid state to a semi-solid state.[9]

The big “ah ha” moment here is that the body needs vitamin K to create prothrombin and other blood clotting proteins.[10] Prothrombin---a key to blood clotting. If you lack it, it can lead to uncontrolled bleeding.[11] This is true if you’re a baby chick or a baby human.

This was a quite unexpected discovery from a biochemist who was simply pursuing an interest in how cholesterol metabolizes![12]

A few years later, another biochemist named Edward Doisy was able to determine the chemical structure of vitamin K which allowed it to be produced commercially.[13] This was a game changer in its own right, and Dam and Doisy shared the Nobel Prize for it in 1943.

Let’s pause for a quick announcement. When we come back, we’ll look at the critical role vitamin K played in making sure a patient was safe to undergo surgery.

[SEAN MOLONEY]

Thanks for listening to Game Changers in Medicine. Be sure to visit gamechangersinmedicine.com to join the conversation, access show notes, and discover even more content as it relates to this segment and others. Head over to iTunes to subscribe, rate and please leave a review. It’s very much appreciated. And follow us on Facebook and Instagram at Game Changers in Medicine. Thank you.

[ DR. RUBIN PILLAY]

As you can imagine, any type of surgery on a patient who happened to be vitamin K deficient posed a high risk. But there was no way to know about a patient’s vitamin K status in advance of surgery.[14]

A physician-pharmacist named Armand Quick developed a simple test doctors could use to measure a patient’s prothrombin level. Prothrombin is an indirect measure of a patient’s vitamin K status.[15] So the level of prothrombin measured would determine whether or not the patient’s blood had the required clotting factor to make surgery safe. The test was appropriately named the Quick test. Not only was it quick, it was easy to administer. If a patient were found to be vitamin K deficient, a pre-operative dose of vitamin K would bring the levels up and mitigate any excessive bleeding during surgery.[16]

Here’s Dr. Furie again to explain this further.

[DR. BRUCE FURIE] Prothrombin is a protein that circulates in our blood. We know the pro part of prothrombin is the part that makes it a vitamin K dependent protein. And the other side of prothrombin in thrombin. And that's the enzyme that is generated from prothrombin, that goes ahead and activates the blood coagulation.

It is necessary. If you're missing prothrombin you're going to have a bleeding problem.

[DR. RUBIN PILLAY]

Dr. Moloney recognized that the Quick test could be a real game changer for any patient about to undergo surgery. He gathered the few necessary materials, put them in a wooden cigar box, secured the box top with a rubber band, got in his car and set out to administer the test at hospitals throughout Boston and beyond. He was one of the first, if not the first, to administer these tests to preoperative patients.[17]

This is a good place for me to introduce Dr. H. Franklin Bunn. Dr. Bunn worked closely with Bill Moloney and they came to be good friends. We’re fortunate to have Dr. Bunn with us to share some of his recollections.

[DR. FRANK BUNN]

He made do with what he had. In those days there were patients who were thought to have serious blood problems there, couldn't make it into the Boston City Hospital. And so Dr. Moloney was - sometimes spent a fair amount of his time on the road going to see patients. As far away as central New Hampshire or western Massachusetts. And so he had to take a kit with him to enable him to make what would be relatively simple tests compared to what could be done in a hospital. But yet that base sufficed and provided additional information above and beyond what he could gain from talking to and examining a patient.

[DR. PILLAY]

I’d be remiss if I didn’t tell you more about Dr. Bunn, who is affectionately known by his colleagues as “Mister Red Cell.” He is a true hematology heavyweight. He’s a physician, hematologist, and biochemist at Harvard Medical School. He has many discoveries to his name, including the co-discovery of hemoglobin A1c. Each day, millions of people around the globe receive the A1c test to diagnose diabetes and pre-diabetes. Dr. Bunn took over from Dr. Moloney as Chief of Hematology at Boston’s Brigham & Women’s Hospital.[18]

We’ll hear more from Dr. Bunn later. For now, let’s continue with Dr. Moloney, describing how he did those tests.

[DR. WILLIAM C. MOLONEY AUDIO] In this test you took some plasma, the liquid part of the blood, and placed it in a small tube. A small amount of brain tissue extract, called thromboplastin, was added, and with a stopwatch you measured how fast the little fibrin plaque formed. You could see it form as a white film. The test was called the prothrombin time.

I began going around to numerous hospitals, maybe 15 or 20 hospitals, because nobody else in Boston would go out consulting. No one would go out and see the nitty gritty thing, like a bleeding problem. Or anybody like myself who would carry their own lab stuff with them and do it, because these hospital labs didn't have this capacity at the time. So that's how I got involved with coagulation and blood problems.

Now, at many other hospitals -- you start at the bottom of the ladder and you didn't get your head up above the rest or you get it knocked off very promptly. They weren't having some young upstart like me come in there and start doing things like these tests. The chief of my service, who was a nice, kindly gentleman, he was very resentful of the fact that he wasn't getting these consultations and I was. But he couldn't do the test.

[DR. PILLAY] As the demands for Dr. Moloney’s testing services increased, he struggled to procure thromboplastin, which was the key reagent in that Quick test[19].

I’m happy to be able to call upon Dr. Furie again for an explanation of thromboplastin.

[DR. BRUCE FURIE] Thromboplastin is the old name for a well-known protein involved in blood coagulation called Tissue Factor. Tissue Factor is a well-studied protein on the surface of cells. It is a membrane protein, meaning it's attached to the cell membrane. It is the initiator of blood coagulation.

Now thromboplastin in the old days was a rather crude mixture. It could have been called the ground up rabbit brain test because the brain has a lot of thromboplastin in it.

[DR. RUBIN PILLAY] I have to say that “Quick test” is probably a better name than “the ground up rabbit brain test!”

[DR. BRUCE FURIE]

Now recombinant tissue factor is human is fairly standard.

[DR. RUBIN PILLAY]

But in the early days of the Quick test, commercial thromboplastin was tough to come by and expensive to boot. However, Dr. Moloney knew that thromboplastin from animal brains could be used in place of commercial thromboplastin. Fortunately, thanks to the close relationships he maintained with his patients, Dr. Moloney had a source.

[DR. WILLIAM C. MOLONEY] I made my living mainly by the emergency calls from the telephone operators. There was an emergency system in those days where the operator would get a call and then she'd have a list of doctors. There were a lot of older doctors out there, and I was the first new doctor for years in that part of Jamaica Plain. There would be all kinds of emergencies during the night and they'd get you up at any hour.

In the midst of the Depression, I got called down to a family we befriended and did a lot for. The family had 10 children in Roxbury. The father had a job in a meat packing firm in Brighton. They were a good couple, but they just didn't have any money. I remember going in and seeing this woman who had twins – about her ninth pregnancy. The house was cold, and they had practically nothing to eat in the house. Both twins had whooping cough. One baby was having convulsions and was cyanotic. Blue.

Well, I didn't know what to do, but I had read a letter in The Journal of American Medical Society, which said that sometimes in a convulsive state, you can control it with ether, which could be given in oil as a rectal instillation. So, I got some olive oil from them, and I had some ether in the bag, and I made a suspension of oil and ether. Then I took a rectal tube, which I carried also, and a syringe, and I injected it and the kid fell asleep. We got this little one into the hospital, and she recovered.

[DR. RUBIN PILLAY] I can’t help but think back to Dr. Moloney saving that baby in Norwood with the homemade vitamin K injection.

[DR. WILLIAM C. MOLONEY AUDIO] Over the years we became very friendly. Later on this man who was a night watchman at the abattoir …

[DR. RUBIN PILLAY, quick interject]

“Abbattoir isn’t a word we hear much anymore, but it’s just the sort of ten-dollar word Dr. Moloney was always using. It’s a fancy way of saying “slaughterhouse.”

[DR. WILLIAM C. MOLONEY AUDIO, continued] … supplied me with a lot of the tissues I needed to make different things which I used for clotting studies. I'd send some of the fellows from the hospital out there to get brains and other tissues from sheep and cows. The husband was very helpful in things like that, and also used to come and help around the house. It reflects the close relationship you had with people. Of course they never had any money.

Well, what could you do? I suppose if they were out on a farm someplace, they would have brought me a bag of potatoes or something, but these people didn't even have that.

[DR. RUBIN PILLAY, quick interject] Sean, are you familiar with this story?

[SEAN MOLONEY] That night watchman at the slaughterhouse was Tom Brown and I have to say that story became the stuff of legend in our family.

[DR. RUBIN PILLAY] Now let’s remember, Tom Brown is the father of those infant twins in Roxbury, the ones with the whooping cough and convulsions.

[SEAN MOLONEY] I remember Grampa telling me how he’d collect the animal brains from Tom and then work late into the night over the kitchen stove, heating and stirring the brains to make a proper reagent. I have to think this would have annoyed my grandmother no end. She took it all in good stride until the day she opened the refrigerator and a cow stomach exploded in her face.

Grandpa assured me that he tried mightily to justify the situation by explaining that he’d been storing the cow parts in the refrigerator for the important research he was doing. You can imagine the conversation. On that day my grandfather’s makeshift kitchen lab closed for good.

[DR. PILLAY] Your grandmother sounds like a saint!

[SEAN MOLONEY] She most definitely was. Fortunately, right about the time the cow stomach exploded in Grandma’s face, commercial thromboplastin had become more readily available. And the demand for services had increased to the point that grampa was able to move his practice from the Jamaica Plain living room to offices on Bay State Road in Boston’s Back Bay neighborhood. Despite the fancy address, he continued to drive his old blue Dodge throughout the greater Boston area to wherever his patients needed him.

He continued to care for patients throughout his career all over Boston. He had some extraordinary experiences that took him away form general practice. For one, he was appointed director of research for the atomic bomb casualty commission and I believe that was in the early 1950s. He and my grandmother and four kids, including my dad, of course, packed up and moved to Hiroshima for a few years so he could study the effects of the fallout of radiation on the survivors of the World War II atomic bombings. But that’s a story and a podcast for another time.

[DR. RUBIN PILLAY] Right. I marvel at your grandfather’s willingness to just jump in and do what was necessary to help his patients. I’m also struck by the close relationships he developed with them.

Let’s hear more about that from Dr. Bunn.

[DR. H. FRANKLIN BUNN]

Bill Moloney viewed every patient as both a friend and one who needed help and who he regarded with enormous warmth. At the same time, he viewed the patient as a challenge.

Oftentimes, it would be a diagnostic challenge and even more often a therapeutic challenge, because in the early days of cancer and particularly blood, blood cell cancers, the therapeutic options were kind of limited. And he was a leader in particularly treatment for acute leukemia and lymphomas. So, there's this combination of his intellect and curiosity and drive to perfect treatment and diagnostic measures, as well as treatment, along with a never ending affection for and respect for patients that didn't know any divisions of class or money was never an object. And there were many patients who got superb care from Moloney without paying a bill.

I first got to know him at the Boston City Hospital, I was in training at a Harvard medical unit. And we had very good research and our group, but very few patients. And we had a very limited clinic where as Dr. Moloney had a very large clinic that covered not only inner-city folks, but referrals from all over the inner and outer suburbs of Boston. So, he had a big influx of patients in both outpatients and inpatients.

So, we went to spend time rounding with Dr. Moloney and seeing his patients to to get additional experience. He was very generous about that because it could it cost him time. And of course, he didn't get any remuneration for the teaching that he did in the unit at the Boston city.

[DR. RUBIN PILLAY]

Let’s continue listening as Dr. Bunn shares memories of Dr. Moloney’s legendary bone marrow course.

[ DR. FRANK BUNN]

Bill Moloney fellow is very important for his trainees to be an expert not only at the bedside with patients, but also to be able to read and interpret the microscopic examination of their blood and bone marrow. And he prepared a course to review this material. But equally important, he shared time with us to look at the specimens of patients that had just been admitted and who were newly diagnosed with usually a bone marrow malignancy. It was it was known affectionately as a Bone Marrow Course, for at least 30 years.

And he was a master at it. He loved sitting at a six headed microscope with five people, usually trainees like residents or fellows, and he would review new patient specimens. But then he had a collection that was amazing. That went back 30 or 40 years of slides from patients who were very instructive with various kinds of disorders. And so then he'd prepare quizzes where he'd eat, ask us to take time and look at these tough slides, diagnostic problems.

And then we would do our best and then he would give us some chances to go wrong. And then he'd tell us what was really going on.

[DR. RUBIN PILLAY]

Dr. David Rosenthal, Professor of Medicine at Harvard Medical School, trained as a fellow under Dr. Moloney at the Peter Bent Brigham Hospital, now Brigham & Women’s Hospital. He has some interesting recollections of his own.

[DR. DAVID ROSENTHAL] I'll always remember when we were at the Holy Ghost Hospital in Cambridge. That's where he had his lab and his mice that he studied the Sprague Dawley rats. We would go over there, help the rats, feed them, take care of them, study them, draw their bloods, cut their tails so we could get their blood to do studies.

[DR. WILLIAM C. MOLONEY]

We all worked together and we did some rather crazy things in the way of investigation. We didn't have computers, and we didn't have a lot of the facilities we have today, but we were curious and we investigated these things the best way we could.

[DR. DAVID ROSENTHAL, continues] You’ve got to understand the times. There's lots of things that we did in those days that didn't go through institutional review boards . . .

[DR. RUBIN PILLAY, quick interjection]

An Institutional Review Board reviews medical studies to ensure the safety of volunteers in human research. It typically goes by the abbreviation IRB.[20]

[DR. ROSENTHAL] We did lots of things that you would never have heard of to be able to be doing them at this time. When we came up with the new therapy, we didn't have to go to an IRB to get it approved.

I see a number of studies coming through now and we have to look very carefully at efficacy. But most importantly, obviously, safety. And I'll tell you, the informed consent process is a tedious one. If you look at some of the informed consent that people have to sign, they're close to 30 to 40 pages long. So now they're doing summaries. And so that's going to help a little bit for subjects to be able to approve them.

[DR. RUBIN PILLAY] Today, a new drug coming on the market will have been through years of formalized testing for safety and efficacy.[21] But that type of formalized testing didn’t come into practice in earnest until the early 1960s.[22]

While there’s no question that Dr. Moloney was dedicated to his patients, I think it’s safe to say that much of the research he did on their behalf wouldn’t be possible today.

This curiosity and interest in experimenting was a through line throughout Dr. Moloney’s career. I can visualize Dr. Moloney driving all around Boston, with that improvised cigar box lab by his side.

[ SEAN MOLONEY] Grampa went the extra mile, literally.

[DR. RUBIN PILLAY] As we near the end of our episode, you’ve probably figured out that it is less the story of the discovery of a vitamin as it is a story of researchers, doctors, and clinicians who gave themselves the freedom to follow their curiosity and explore areas that no one else was investigating, or, for that matter, even knew needed to be investigated.

[DR. BRUCE FURIE]

I'm a great believer in serendipity. You can publish papers and do all kinds of scientific research. And I published over 300 papers. But the number of really significant contributions (can) probably be counted on one hand. And they were all serendipitous. We had you probably heard the expression, the prepared mind.

One of the exciting things of doing medical scientific research is that you don't know where it’s going to go. You follow your nose.

[DR. RUBIN PILLAY] That was Dr. Bruce Furie again. And his thoughts are closely echoed by Dr. Bunn.

[DR. FRANK BUNN]

I think serendipity is huge in medical research in so many different ways. You know, you can be lucky in identifying and encouraging and training an amazingly talented young person who could end up doing really wonderful things in, say, lab research or clinical research. Or you could be have great luck in learning about a technique just because your lab happens to be next door to an unrelated lab doing unrelated work. And yet there they have a technology that just fits perfectly with what you want to do as a research project. And then you have serendipity in terms of international relations that when you go to meetings, sometimes you are lucky and pick up things that you never would have learned if you had stayed in the United States.

So there's all sorts of networking and the drug industry is also plays a role in this. So, yeah, there's a lot of good luck this. That's very handy in making progress in medical research.

[DR. RUBIN PILLAY]

It feels fitting to close this episode on those ringing endorsements for what can happen when serendipity meets science and, as Dr. Furie says, the prepared mind.

Let’s conclude with a salute to the spirit of discovery and those who came before us. The marquee names like Dam and Doisy, to be sure, but also the lesser known inventive and enterprising doctors and scientists who, by accident or fate, changed the way patients are treated today.

My hope is that their stories will inspire medical and non-medical professionals alike to take the time to explore the side paths, to follow where their curiosity leads—to do the modern-day equivalent of packing up lab equipment in a wooden cigar box and driving to patients’ bedsides.

With that, I want to thank all our listeners for spending time with us today. Thank you also to our special and esteemed guests: Sean Moloney, Dr. H. Franklin Bunn, Dr. Bruce Furie, Dr. David Rosenthal, and nurse-midwife Catherine Ruhl. And yes, from the great beyond, Dr. William C. Moloney.

I hope you’ll join us for our next episode, where we explore the discovery of the smallpox vaccine. It has a colorful “creation story,” and is considered to be the first medical vaccine developed against a contagious disease. Despite the vaccine being discovered more than 200 years ago, it was only in 1980 that the World Health Organization deemed the entire planet free of smallpox. May we soon be able to make a similar claim about the coronavirus—though hopefully in a lot less time.

Thank you for listening to Game Changers in Medicine. Please leave feedback, comments, and ideas for medical discoveries you’d like to learn more about at GameChangersInMedicine.com.

Game Changers in Medicine is a Dramatic Health production. Sean Moloney is the executive producer. Rolando Nieves is the showrunner and editor. Sharon Johnson is our researcher and writer. Tom Sliwakowski and Lauren Wiegand are producers. Ryan Liatsis is our audio engineer.

FOOTNOTES

[1]Births and Natality:Number of births: 3,791,712” https://www.cdc.gov/nchs/fastats/births.htm 2Worldwide Births: The Guardian: “More than 130 million in a year.” https://www.theguardian.com/global-development/2018/apr/23/population-how-many-people-can-the-earth-sustain-lucy-lamble World Health Organization: “There are currently 136 million births per year, including 3.3 million stillbirths. Worldwide, the number of live births will peak at 137 million per year towards 2015.” https://www.who.int/whr/2005/media_centre/facts_en.pdf Our World in Data: “In 2015, there were approximately 141 million births – 44 million more than back in 1950” https://ourworldindata.org/births-and-deaths [3] World Health Organization: “All newborns should be given 1 mg of vitamin K intramuscularly after birth.” WHO recommendation on haemorrhagic disease prophylaxis using vitamin K https://extranet.who.int/rhl/topics/newborn-health/care-newborn-infant/who-recommendation-haemorrhagic-disease-prophylaxis-using-vitamin-k New York Times: “Since the early 1960s, it has been standard of care for newborns to receive an intramuscular injection of vitamin K shortly after delivery.” Vitamin K for Newborns is a No-Brainer. Why are So Many Parents Worried? https://www.nytimes.com/2020/02/19/opinion/vitamin-k-shot-newborn.html [4] “Bruce Furie, M.D. honored as distinguished scientist by the American Heart Association” https://www.eurekalert.org/pub_releases/2014-11/bidm-bbf110714.php [5] Evidence-based birth website: “In 1944, a definitive Swedish study was published including more than 13,000 infants who were given 0.5 mg of Vitamin K (either oral or injection) on the first day of life. The researcher found that infants who received Vitamin K experienced a 5-fold reduction in the risk of bleeding to death during the first week of life. It was estimated that for every 100,000 full-term infants who were born, Vitamin K would save the lives of 160 infants per year (Lehmann 1944).” https://evidencebasedbirth.com/evidence-for-the-vitamin-k-shot-in-newborns/. The Lehmann article referenced is behind the Lancet firewall, but is a reference used by Mayo clinic and other .gov and .org websites. Lehmann J. Vitamin K as a prophylactic in 13,000 infants. Lancet. 1944;243(6294): 493-494. [6] Position Statement: Guidelines for vitamin K prophylaxis in newborns: “Since 1961, the American Academy of Pediatrics (AAP) has recommended that a single 0.5 mg to 1.0 mg dose of vitamin K be administered intramuscularly (IM) to all newborns shortly after birth to prevent VKDB.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6184976/ [7]What is Vitamin K Deficiency Bleeding? “Vitamin K deficiency bleeding or VKDB, occurs when babies cannot stop bleeding because their blood does not have enough Vitamin K to form a clot. The bleeding can occur anywhere on the inside or outside of the body. When the bleeding occurs inside the body, it can be difficult to notice. Commonly, a baby with VKDB will bleed into his or her intestines, or into the brain, which can lead to brain damage and even death.” https://www.cdc.gov/ncbddd/vitamink/facts.html [8] Some Important Milestones in the Field of Blood Clotting: “Meanwhile, in the late 1920s Henrik Dam was feeding a cholesterol-free synthetic diet to chicks as part of a study on the synthesis of cholesterol, and he soon recognized that the chicks were becoming hemorrhagic. Adding cholesterol to the synthetic diet did not help, and Dam realized that something else must be missing from the bland mixture of starch, yeast extract and salts that he was using. Thinking that the symptoms were similar to scurvy, he added in vitamin C but found no benefit. Convinced the missing ingredient was vitamin-like, he tried all known vitamins, water-soluble and fat-soluble alike, to no avail. What did work were ether-extracts of leafy vegetables, leading him to proclaim the substance was a fat-soluble vitamin. He named it vitamin K, in line with the Scandinavian spelling of Koagulation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738807/ [9] blood coagulation: Also called blood clotting. A process in which blood changes from a free-flowing liquid to a semi-solid gel. https://www.radiologyinfo.org/en/glossary/glossary1.cfm?gid=512 [10] The Discovery of Vitamin K, its Biological Functions and Therapeutic Application, Nobel Prize Lecture, by Henrik Dam, 1946: As matters stand at present it is safe to say that vitamin K therapy is relevant against diseases which incur bleeding tendency due to low prothrombin whereas its use against other hemorrhagic diseases is lacking a secure foundation.” https://www.nobelprize.org/uploads/2018/06/dam-lecture.pdf [11] Vitamin K: “Prothrombin is a vitamin K-dependent protein directly involved with blood clotting.” https://www.hsph.harvard.edu/nutritionsource/vitamin-k/ And Prothrombin Deficiency: “Prothrombin deficiency is a bleeding disorder that slows the blood clotting process. People with this condition often experience prolonged bleeding following an injury, surgery, or having a tooth pulled. In severe cases of prothrombin deficiency, heavy bleeding occurs after minor trauma or even in the absence of injury (spontaneous bleeding). Women with prothrombin deficiency can have prolonged and sometimes abnormally heavy menstrual bleeding. Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. Milder forms of prothrombin deficiency do not involve spontaneous bleeding, and the condition may only become apparent following surgery or a serious injury.” https://ghr.nlm.nih.gov/condition/prothrombin-deficiency And The Missing Link: The Story of Karl Paul Link:Vitamin K is necessary in the body to activate prothrombin.” https://academic.oup.com/toxsci/article/66/1/4/1634258 [12] Henrik Dam: Discoverer of Vitamin K. “His interest in steroids (or sterols) prompted Dam to study the metabolism of cholesteroland fat-soluble vitamins” https://www.mayoclinicproceedings.org/article/S0025-6196(11)63617-3/pdf [13] Edward A. Doisy: “In 1939 he succeeded in isolating vitamin K . . . Vitamin K was synthesized in 1939 by Louis Frederick Fieser and by Almquist and Klose, and by Doisy and his collaborators. For their work on vitamin K, Doisy and Dam were jointly awarded the Nobel Prize in Physiology or Medicine for 1943. https://www.nobelprize.org/prizes/medicine/1943/doisy/biographical/ [14] Pioneering Hematology, page 27: “This “Quick test” was a simple, life-saving method for determining, preoperatively, whether or not a patient was lacking vitamin K.” [15] Vitamin K Deficiency Rina E. Eden; Jean M. Coviello.https://www.ncbi.nlm.nih.gov/books/NBK536983/ Ref 11: Suttie JW. Vitamin K and human nutrition. J Am Diet Assoc. 1992 May;92(5):585-90. [PubMed] [16] Armand J. Quick: Pioneer and Prophet: “In 1935 he reported the technique most closely associated with his name, the prothrombin time test, which was used by other investigators in the isolation of vitamin K and the identification of the coumarin anticoagulants. Later the test came into wide use for the control of anticoagulant therapy.” https://annals.org/aim/article-abstract/693891/armand-j-quick-pioneer-prophet-coagulation-research [17] Recollections of colleagues Dr. H. Franklin Bunn and William C. Moloney oral history. [18] H. Franklin Bunn Receives 2009 Wallace H. Coulter Award for Lifetime Achievement in Hematology https://www.youtube.com/watch?v=uz3i2rpm5gY [19] Armand J. Quick: Pioneer and Prophet of Coagulation Research: “After many experiments Quick found that a suitable reagent could be prepared from acetone-dehydrated rabbit brain.” https://www.acpjournals.org/doi/pdf/10.7326/0003-4819-92-4-553 [20] What is the Institutional Review Board? https://research.oregonstate.edu/irb/frequently-asked-questions/what-institutional-review-board-irb [21] Phases of Clinical Trials https://www.nccn.org/patients/resources/clinical_trials/phases.aspx [22] FDA and Clinical Drug Trials: A Short History , Suzanne White Junod, Ph.D By the 1960s, following another drug crisis in 1962, there was a growing recognition of the importance of clinical trials in new drug development as well as in clinical medicine.” https://www.fda.gov/media/110437/download REFERENCES:

Pioneering Hematology: Research and Treatment of Malignant Blood Disorders. Reflections on a life’s work, by Dr. William C. Moloney

Births and Natality https://www.cdc.gov/nchs/fastats/births.htm

“Henrik Van Dam, Discoverer of Vitamin K,” https://www.mayoclinicproceedings.org/article/S0025-6196(11)63617-3/pdf

Edward A. Doisy https://www.nobelprize.org/prizes/medicine/1943/doisy/biographical/

“The Discovery of Vitamin K, its Biological Functions and Therapeutic Application,” Nobel Prize Lecture, by Henrik Dam, 1946 https://www.nobelprize.org/uploads/2018/06/dam-lecture.pdf

“Prothrombin Test Time” https://www.mayoclinic.org/tests-procedures/prothrombin-time/about/pac-20384661

Prothrombin Deficiency: https://ghr.nlm.nih.gov/condition/prothrombin-deficiency

“Vitamin K” https://www.hsph.harvard.edu/nutritionsource/vitamin-k/

Position Statement: Guidelines for vitamin K prophylaxis in newborns

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6184976/

Thrombosis and Bleeding: an Era of Discovery, by Cecil Hougie

The Discovery of Dicumarol and Its Sequels, by Karl Paul Link, Ph.D. https://www.ahajournals.org/doi/pdf/10.1161/01.cir.19.1.97

The Missing Link: The Story of Karl Paul Link https://academic.oup.com/toxsci/article/66/1/4/1634258

This month in 1939: How Dead Cattle Led to the Discovery of Warfarin http://www.pmlive.com/pharma_news/how_dead_cattle_led_to_the_discovery_of_warfarin_485464

Vitamin K in Neonates: facts and myths https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021393/

Some Important Milestones in the Field of Blood Clotting https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738807/

A Brief History of Medical Practitioners . . .

https://www.jstor.org/stable/40111358?read-now=1&seq=1#page_scan_tab_contents

“Acquired Coagulation Disorders,” by H. Franklin Bunn and Bruce Furie

The Countway Library History of Medicine

American Association of the History of Medicine:

https://www.histmed.org/

Armand J. Quick: Pioneer and Prophet https://annals.org/aim/article-abstract/693891/armand-j-quick-pioneer-prophet-coagulation-research

Armand J. Quick: Pioneer and Prophet of Coagulation Research: https://www.acpjournals.org/doi/pdf/10.7326/0003-4819-92-4-553

What is the Institutional Review Board? https://research.oregonstate.edu/irb/frequently-asked-questions/what-institutional-review-board-irb

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

https://www.ncbi.nlm.nih.gov/pubmed/26201483

Warfarin: Almost 60 years old and still causing problems

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885167/

Warfarin: From rat poison to clinical use https://www.nature.com/articles/nrcardio.2017.172

H. Franklin Bunn Receives 2009 Wallace H. Coulter Award for Lifetime Achievement in Hematology https://www.youtube.com/watch?v=uz3i2rpm5gY

Vitamin K: Health Sheet for Professionals https://ods.od.nih.gov/factsheets/vitaminK-HealthProfessional/

Warfarin and Vitamin K https://www.healthlinkbc.ca/health-topics/abo1632

Phases of Clinical Trials https://www.nccn.org/patients/resources/clinical_trials/phases.aspx

FDA and Clinical Drug Trials—A Short History https://www.fda.gov/media/110437/download

Vitamin K for Newborns is a No-Brainer. Why are So Many Parents Worried? https://www.nytimes.com/2020/02/19/opinion/vitamin-k-shot-newborn.html

Vitamin K at Birth: https://www.pregnancybirthbaby.org.au/vitamin-k-at-birth

What is Vitamin K Deficiency Bleeding? https://www.cdc.gov/ncbddd/vitamink/facts.html

WHO recommendation on haemorrhagic disease prophylaxis using vitamin K https://extranet.who.int/rhl/topics/newborn-health/care-newborn-infant/who-recommendation-haemorrhagic-disease-prophylaxis-using-vitamin-k

Worldwide Births: “more than 130 million in a year.” https://www.theguardian.com/global-development/2018/apr/23/population-how-many-people-can-the-earth-sustain-lucy-lamble “There are currently 136 million births per year, including 3.3 million stillbirths. Worldwide, the number of live births will peak at 137 million per year towards 2015.” https://www.who.int/whr/2005/media_centre/facts_en.pdf “In 2015, there were approximately 141 million births – 44 million more than back in 1950” https://ourworldindata.org/births-and-deaths

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