My name
is John Gallin and I'm the director of the Clinical Center
and a co-organizer of this course. So, the topic that I'm going to cover
is an overview of the history of this business, which is,
after all, risky business for the patients, as well as big business
for the pharmaceutical industry and the biotechnology industry.
But we can learn a lot from going back
to the beginning and seeing some of the things that happened.
So, I will try to give you a survey.
It's sort of a hobby of mine and I enjoy it.
And I want to just say, right out front at the beginning,
that it's impossible to cover everything and to recognize everyone.
And if I omitted your favorite
historical feature, you can tell me, and next time I'll try to include it.
But I apologize, but there's literally thousands of thousands
of superstars that make this a wonderful story.
So, let me start with the definition of clinical research.
And this is not a historical definition, but it sets a perspective for the course.
This was produced at NIH in 1996 in a special panel that met here and divided
Clinical Three research into three broad
categories: patient-oriented research, epidemiologic
and behavioral studies, and outcomes research, and health services research.
So, patient-oriented research, which is the one we most frequently
think about if we're doing clinical research, is research conducted with human subjects
or a material of human origin, such as tissues, specimens,
and cognitive phenomena for which an investigator or a colleague
directly interacts with human subjects, and includes the development of new technologies,
mechanisms of human disease, therapeutic interventions, and clinical trials.
So, these three categories -- patient-oriented research, epidemiologic,
and behavioral studies, and outcomes research, and health services research
-- is what you're going to be thinking about during this course.
So, I love this quote,
which comes from Isaac Newton, who, in 1676, wrote, "If I have seen a little further,
it is by standing on the shoulders of giants." And that's applicable to anyone
who's succeeded in doing clinical research over the many millennium.
It's hard to know when clinical research started.
But in 2850 B.C., Imhotep, who was a known scribe,
a chief lector, and a priest, an architect, astronomer, and a magician --
and in those days, medicine and magic were used together -- he diagnosed
and treated over 200 diseases, performed surgery, and practiced some dentistry.
And he extracted medicine from plants and knew the position
and function of the vital organs and circulation in the blood system.
So, this was 2850 B.C.
The Chinese -- here we are 2737 B.C., according to the source
that I had -- were also exploring medicine.
Emperor Shen Nung experimented with poisons and classified medical plants.
He's reputed to have eaten 365 medicinal plants over the course of his life.
Supposedly, he turned green and died.
Now, I'm going to go through some examples as I go through this talk.
And, some of them, I will go from the ancient
to the present, just to give you a perspective.
And one of them is malaria, which is an ancient disease
first described in China in ancient medical writings.
In 2700 BC, several characteristic symptoms of malaria were described
in the Nei Ching, and a plant called Qinghao
or Artemisia annua was described in some medical treatises,
and 52 remedies were advocated as found in the Mawangdui Tomb.
In 340 AD, the anti-fever properties of this plant,
Qinghao, was first described by Ge Hong in the East Yin Dynasty.
And the active ingredient, known as artemisinin, was recently
isolated by a Chinese scientist, Professor Tu Youyou, in 1971.
And I had a chance to meet Dr.
Youyou because she received the Lasker Award in clinical research in New York,
the same year that the Clinical Center received the Lasker Award in public service.
And she said that
what she did was she was asked, apparently by Mao [spelled phonetically],
earlier, to find some medicines for malaria because the Chinese Army needed these
where they were going.
And she went to this old literature
and found that this Artemisia plant was reported to be helpful.
And she went back to the original readings and, with her
colleagues, the biochemical structure, which is shown here, was identified.
And she developed this new drug,
which has literally saved millions of lives throughout the world.
And just this month, she received the Nobel Prize for this work,
the first Chinese investigator to ever receive a Nobel Prize.
I'm also going to tell you about some of the areas
of medicine, and we'll spend a few minutes on surgery.
Sushruta is the father of Indian surgery
and, many would say, was perhaps the father of surgery.
He lived about 600 BC, although this was not completely clear,
and lived with the era of the Gupta kings.
He wrote medical text about surgery and is most famous -- Sushruta
Samhita is literally an encyclopedia of medical learning from his day.
He counted the bones in the body, and he came up with 300.
Does anybody in the audience know how many bones people think
are in the human body today, or know that are in the human body today?
No respondents.
So, I'll make it easy.
It's -- it depends on when you take the measurement.
At birth, it's said there's about 300 bones.
And then, the bones fuse, so that in the adult there's probably about 206 bones.
So, he was remarkably accurate.
Remember, this is 600 BC.
He also realized the importance of keeping wounds clean.
He did not use the word sterilization, but he talked about clean wounds.
And he discussed options for instruments in surgery and concluded
that the hand was the best instrument available.
So, you can go to all sorts of places to get insights into clinical research.
And, perhaps, the earliest so-called trial,
as I'll call it, comes from the Bible, the Book of Daniel.
And Daniel said, "Test your servants for 10 days
and let
us be given vegetables to eat and water to drink."
Now, "us" is a group of Jews who were captured by the Egyptians.
And they didn't want to have to eat the non-kosher food.
And so, he was clever.
And so, to avoid that, he said, "Conduct this test.
So, give us vegetables to eat and water to drink,
and compare your servants who will get rich foods.
So, then, let our appearance and the appearance of the youths who eats the king's
rich food be observed by you, and according to what you see, deal with your servants.
So, he harkened to them on this matter and tested them for 10 days.
And at the end of 10 days, it was seen that they,
the ones who ate the vegetables and water, were better in appearance and fatter
in flesh than all the youths who ate the king's rich foods.
So, the steward took away their rich food and the wine
and gave them vegetables." So, this is in the Bible.
There's no informed consent.
But, perhaps, the greatest mind in early medicine and clinical research
was Hippocrates, who was born about 460 BC and died about 370 BC.
And you all know about the Hippocratic Method.
And what Hippocrates advocated was observation.
And he said, "A great part of the art is to be able to observe."
And he recorded a whole -- over 100 descriptions of clinical situations.
Let me read you one, his description of pulmonary edema.
He said, "Water accumulates; the patient has fever and cough; the respiration is fast;
the feet become edematous; the nails appear curved; and the patient suffers
as if he has pus inside, only less severe and more protracted.
One can recognize that it is not pus, but water.
If you put your ear against the chest, you can hear it
seethe inside like sour wine." So, this is incredible.
And I've had a chance to read a bunch of his descriptions
and they're remarkable for how accurately he observed and described his patients.
So, he had some amazing accomplishments.
He dissociated medicine from theology and philosophy.
He really established the science of medicine and, of course,
he provided physicians the highest moral inspiration that they have.
Wound management is something he wrote about.
And he said, "If water was used for irrigation, it had to be very pure
and boiled, and the hands and nails of the operator were to be cleansed."
This was long before anybody recognized infection, infectious diseases.
And this was from Hippocrates.
So, you're going to see that we're going to be going around the world
and hearing about investigators or champions of clinical research from everywhere.
And let's focus on Iranian medicine for a moment.
There were two individuals, Al-Rhazi and Ibn Sina.
So, Rhazi lived about 865 to 925.
And he discovered use of alcohol and mercurial compounds as antiseptics.
He made numerous contributions
to medicine, as well as alchemy and philosophy.
But he actually wrote the first treatise on pediatrics
and this was recorded in over 184 books and articles.
Now, Ibn Sina, or Avicenna, as he was called, lived from 973 to 1037 AD.
And he was a leader in pharmacy, philosophy, medicine, and pharmacology.
And he was the principle author of the Canon of Medicine,
which was the main European medical textbook.
It had been modified, obviously, over the centuries, but
it was active particularly from the 14th to the 16th century.
And this book contains the first known treatise on clinical trials
and provided the foundation for systematic approach to drug testing.
And I just want to go over with you what was said back then, around 1000 AD.
So, the seven conditions for experimentation:
first, if
you want to experiment with something, it should be pure; second,
the drug must be tested for only one condition at a time; third,
drugs must be tested in contradictory disease states; fourth, strength of a drug
must be a proportionate to the severity of the disease; fifth,
time of therapeutic effect must be considered;
sixth, drugs must be observed for continued action; and, seven,
a drug must be tested in humans before judgment.
So, this is pretty amazing when you think of when these conditions were defined.
So, now I'm going to be skipping a couple of centuries
and start talking about anatomy and, to my thinking,
one of the greatest early anatomists was Leonardo da Vinci.
This is the only self-portrait of him that's known to be available.
He did this near the end of his life.
And if you go through his works
and you look at his descriptions, drawings of the human anatomy, it's really quite
phenomenal, and here are a couple of pictures.
The microscope was an important addition to medicine in clinical research.
So, let me tell you, in a slide, a little about the microscope.
In the 1st century AD, glass was tested by the Romans,
who recognized when thick in the middle and thin at the edges, you got magnification.
Ibn al-Haytham, who lived in Egypt, was the father of optics.
He was also a great astronomer.
The 13th century eyeglasses were invented.
The first eyeglasses were made in Germany in 1286.
In 1590, Zacharias Janssen and his son, who were Dutch,
invented the compound microscope with two lenses in a cylinder.
And in 1609, Galileo added a focusing device.
And that was the beginning of the microscope.
But it was Antonie van Leeuwenhoek who first used a microscope in clinical research.
He lived in the 1600s to the 1700s.
And he worked in a dry goods store
and he needed to count the number of threads
in a inch or in a certain amount of space
to judge the quality of the linens that were being produced.
And so, he made special small lenses, which could magnify up to 270 power.
And in the bottom of the slide is his first microscope.
And I got a facsimile of that that I found in a small store in Maine, of all places.
And you can see, this is the lens, and you can put an object on it,
and you look through the other side, and position your object with this screw.
In using this, he described the first bacteria, yeast,
sperm, striated muscle, crystalline lens of the eye, and red cells, among others.
And you can imagine sitting there
and looking at a light, and then making drawings of this.
It's really quite phenomenal.
So, having described red cells,
it makes me want to bring to your attention
William Harvey, who lived in England from 1578 to 1657.
And he was the one who really defined
the circulatory system in great detail and accuracy.
In the same period, a little later, Sir Christopher Wren,
who you probably know for his architecture, he also invented the intravenous needle.
It was made out of sterling silver.
And he connected the bleeder, the needle to the urethra, and infused dogs with opiates,
and was the first to describe the effects
of intravenous opiates in a mammal.
He also gave the needle to a friend of his,
who's shown on the bottom of this slide, Richard Lower,
who in 1667, did the first transfusion into man using sheep's blood.
And the man survived, probably because he only gave about 10 cc's of blood.
And a few months earlier, Jean-Baptiste Denys, in France, gave about the same,
or 12 ounces of sheep blood into a 15-year-old boy who survived.
But the first use of man-to-man,
or man-to-women, or -- transfusion was by James Blundell, who,
in 1828, did a number of transfusions without any typing and cross-matching.
And about half of the 12 subjects he described survived.
And he was able to show in this etching, which appeared in Lancet
in 1828, that he could save a person who was exsanguinating after
-- a woman -- after a uterine operation that wasn't going well.
He saved her life.
Of course, the advent of blood types was not until 1900, when Karl Landsteiner,
who was working at The Rockefeller University, defined the A, B, O,
and AB blood types.
And that was the beginning of really the modem transfusion
medicine approached that we have.
Now, in terms of modern terminology or thinking,
maybe the first clinical trial was done by James Lind.
And he worked in England in the 1700s.
And at that time, scurvy was a major health problem in the British Navy.
And William Harvey, who I had mentioned earlier,
had recommended lemons to treat scurvy, but had argued that
the therapeutic effect was the result of the acid in the fruit.
And it was Lind, who was a Naval surgeon, conducted a clinical trial in 1747
to assess the utility of three therapies on scurvy.
So, he took 12 sailors with classical scurvy, divided into six groups of 2 each,
and all were given identical diets and the various groups were supplemented
with either vinegar; dilute sulfuric acid; cider; sea water; nutmeg,
garlic, and horseradish mixture; or two oranges and one lemon daily.
And here are the results of all his studies.
The only thing that worked was citric fruit and it was not significant.
But, of course, they didn't have statistics in those days.
So, he wrote a paper, which
is shown on this slide, and became famous because, based on
these data, scurvy was prevented in the Navy by giving people citrus fruit.