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My name

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is John Gallin and I'm
the director of the Clinical Center

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and a co-organizer of this course.
So, the topic that I'm going to cover

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is an overview
of the history of this business, which is,

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after all, risky business for the patients,
as well as big business

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for the pharmaceutical industry
and the biotechnology industry.

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But we can learn a lot from going back

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to the beginning
and seeing some of the things that happened.

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So, I will try to give you a survey.

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It's sort of a hobby of mine and I enjoy it.

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And I want to just say, right out
front at the beginning,

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that it's impossible to cover everything
and to recognize everyone.

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And if I omitted your favorite

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historical feature, you can tell me,
and next time I'll try to include it.

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But I apologize,
but there's literally thousands of thousands

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of superstars
that make this a wonderful story.

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So, let me start with the definition
of clinical research.

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And this is not a historical definition,
but it sets a perspective for the course.

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This was produced at NIH in 1996
in a special panel that met here and divided

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Clinical Three research into three broad

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categories:
patient-oriented research, epidemiologic

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and behavioral studies, and outcomes
research, and health services research.

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So, patient-oriented research,
which is the one we most frequently

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think about if we're doing clinical research,
is research conducted with human subjects

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or a material of human origin,
such as tissues, specimens,

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and cognitive phenomena
for which an investigator or a colleague

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directly interacts with human subjects, and
includes the development of new technologies,

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mechanisms of human disease, therapeutic
interventions, and clinical trials.

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So, these three categories
-- patient-oriented research, epidemiologic,

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and behavioral studies, and outcomes
research, and health services research

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-- is what you're going to be
thinking about during this course.

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So, I love this quote,

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which comes from Isaac Newton, who, in 1676,
wrote, "If I have seen a little further,

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it is by standing on the shoulders
of giants." And that's applicable to anyone

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who's succeeded in doing clinical research
over the many millennium.

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It's hard to know
when clinical research started.

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But in 2850 B.C., Imhotep,
who was a known scribe,

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a chief lector, and a priest,
an architect, astronomer, and a magician --

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and in those days, medicine
and magic were used together -- he diagnosed

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and treated over 200 diseases, performed
surgery, and practiced some dentistry.

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And he extracted medicine from plants
and knew the position

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and function of the vital organs
and circulation in the blood system.

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So, this was 2850 B.C.

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The Chinese -- here we are
2737 B.C., according to the source

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that I had -- were also exploring medicine.

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Emperor Shen Nung experimented with poisons
and classified medical plants.

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He's reputed to have eaten 365
medicinal plants over the course of his life.

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Supposedly, he turned green and died.

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Now, I'm going to go through some examples
as I go through this talk.

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And, some of them, I will go from the ancient

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to the present,
just to give you a perspective.

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And one of them is malaria,
which is an ancient disease

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first described in China
in ancient medical writings.

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In 2700 BC, several characteristic
symptoms of malaria were described

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in the Nei Ching, and a plant called Qinghao

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or Artemisia annua was described
in some medical treatises,

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and 52 remedies were advocated
as found in the Mawangdui Tomb.

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In 340
AD, the anti-fever properties of this plant,

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Qinghao, was first described by Ge
Hong in the East Yin Dynasty.

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And the active ingredient,
known as artemisinin, was recently

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isolated by a Chinese scientist,
Professor Tu Youyou, in 1971.

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And I had a chance to meet Dr.

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Youyou because she received the Lasker Award
in clinical research in New York,

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the same year that the Clinical Center
received the Lasker Award in public service.

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And she said that

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what she did was she was asked,
apparently by Mao [spelled phonetically],

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earlier, to find some medicines for malaria
because the Chinese Army needed these

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where they were going.

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And she went to this old literature

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and found that this Artemisia plant
was reported to be helpful.

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And she went back to the original readings
and, with her

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colleagues, the biochemical structure,
which is shown here, was identified.

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And she developed this new drug,

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which has literally saved millions of lives
throughout the world.

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And just this month,
she received the Nobel Prize for this work,

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the first Chinese investigator
to ever receive a Nobel Prize.

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I'm also going to tell you
about some of the areas

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of medicine,
and we'll spend a few minutes on surgery.

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Sushruta is the father of Indian surgery

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and, many would say,
was perhaps the father of surgery.

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He lived about 600 BC,
although this was not completely clear,

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and lived with the era of the Gupta kings.

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He wrote medical text about surgery
and is most famous -- Sushruta

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Samhita is literally an encyclopedia
of medical learning from his day.

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He counted the bones in the body,
and he came up with 300.

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Does anybody in the audience know
how many bones people think

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are in the human body today,
or know that are in the human body today?

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No respondents.

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So, I'll make it easy.

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It's -- it depends on
when you take the measurement.

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At birth, it's said there's about 300 bones.

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And then, the bones fuse, so that in
the adult there's probably about 206 bones.

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So, he was remarkably accurate.

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Remember, this is 600 BC.

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He also realized the importance
of keeping wounds clean.

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He did not use the word sterilization,
but he talked about clean wounds.

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And he discussed options
for instruments in surgery and concluded

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that the hand was the best instrument
available.

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So, you can go to all sorts of places
to get insights into clinical research.

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And, perhaps, the earliest so-called trial,

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as I'll call it, comes from the Bible,
the Book of Daniel.

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And Daniel said,
"Test your servants for 10 days

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and let

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us be given vegetables
to eat and water to drink."

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Now, "us" is a group of Jews
who were captured by the Egyptians.

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And they didn't want to have to eat
the non-kosher food.

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And so, he was clever.

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And so, to avoid that,
he said, "Conduct this test.

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So, give us vegetables
to eat and water to drink,

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and compare
your servants who will get rich foods.

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So, then, let our appearance and the
appearance of the youths who eats the king's

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rich food be observed by you, and according
to what you see, deal with your servants.

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So, he harkened to them on this matter
and tested them for 10 days.

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And at the end of 10 days,
it was seen that they,

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the ones who ate the vegetables and water,
were better in appearance and fatter

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in flesh than all the youths
who ate the king's rich foods.

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So, the steward took away their rich food
and the wine

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and gave them vegetables."
So, this is in the Bible.

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There's no informed consent.

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But, perhaps, the greatest
mind in early medicine and clinical research

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was Hippocrates, who was born about 460
BC and died about 370 BC.

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And you all know
about the Hippocratic Method.

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And what Hippocrates
advocated was observation.

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And he said, "A great
part of the art is to be able to observe."

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And he recorded a whole --
over 100 descriptions of clinical situations.

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Let me read
you one, his description of pulmonary edema.

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He said, "Water accumulates; the patient
has fever and cough; the respiration is fast;

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the feet become edematous; the nails
appear curved; and the patient suffers

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as if he has pus inside,
only less severe and more protracted.

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One can recognize that it is not pus,
but water.

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If you put your ear against the chest,
you can hear it

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seethe inside like sour wine."
So, this is incredible.

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And I've had a chance to read
a bunch of his descriptions

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and they're remarkable for how accurately
he observed and described his patients.

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So, he had some amazing accomplishments.

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He dissociated medicine
from theology and philosophy.

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He really established
the science of medicine and, of course,

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he provided physicians
the highest moral inspiration that they have.

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Wound management is something he wrote about.

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And he said, "If water was used
for irrigation, it had to be very pure

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and boiled, and the hands and nails of
the operator were to be cleansed."

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This was long before anybody
recognized infection, infectious diseases.

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And this was from Hippocrates.

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So, you're going to see that
we're going to be going around the world

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and hearing about investigators or champions
of clinical research from everywhere.

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And let's focus on Iranian medicine
for a moment.

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There were two individuals, Al-Rhazi
and Ibn Sina.

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So, Rhazi lived about 865 to 925.

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And he discovered use of alcohol
and mercurial compounds as antiseptics.

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He made numerous contributions

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to medicine,
as well as alchemy and philosophy.

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But he actually wrote
the first treatise on pediatrics

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and this was recorded in over
184 books and articles.

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Now, Ibn Sina, or Avicenna,
as he was called, lived from 973 to 1037 AD.

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And he was a leader in pharmacy,
philosophy, medicine, and pharmacology.

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And he was the principle
author of the Canon of Medicine,

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which was the main European medical textbook.

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It had been modified,
obviously, over the centuries, but

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it was active particularly
from the 14th to the 16th century.

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And this book contains
the first known treatise on clinical trials

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and provided the foundation
for systematic approach to drug testing.

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And I just want to go over with you
what was said back then, around 1000 AD.

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So, the seven conditions for experimentation:

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first, if

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you want to experiment with something,
it should be pure; second,

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the drug must be tested
for only one condition at a time; third,

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drugs must be tested in contradictory disease
states; fourth, strength of a drug

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must be a proportionate
to the severity of the disease; fifth,

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time of therapeutic effect
must be considered;

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sixth, drugs must be observed
for continued action; and, seven,

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a drug must be tested in humans
before judgment.

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So, this is pretty amazing when you think of
when these conditions were defined.

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So, now I'm going to be skipping
a couple of centuries

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and start talking about anatomy and,
to my thinking,

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one of the greatest early
anatomists was Leonardo da Vinci.

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This is the only self-portrait of him
that's known to be available.

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He did this near the end of his life.

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And if you go through his works

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and you look at his descriptions, drawings
of the human anatomy, it's really quite

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phenomenal,
and here are a couple of pictures.

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The microscope was an important addition
to medicine in clinical research.

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So, let me tell you, in a slide,
a little about the microscope.

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In the 1st century
AD, glass was tested by the Romans,

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who recognized when thick in the middle
and thin at the edges, you got magnification.

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Ibn al-Haytham,
who lived in Egypt, was the father of optics.

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He was also a great astronomer.

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The 13th century eyeglasses were invented.

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The first eyeglasses were made in Germany
in 1286.

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In 1590, Zacharias
Janssen and his son, who were Dutch,

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invented the compound microscope
with two lenses in a cylinder.

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And in 1609, Galileo added a focusing device.

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And that was the beginning of the microscope.

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But it was Antonie van Leeuwenhoek who
first used a microscope in clinical research.

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He lived in the 1600s to the 1700s.

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And he worked in a dry goods store

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and he needed to count the number of threads

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in a inch or in a certain amount of space

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to judge the quality of the linens
that were being produced.

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And so, he made special small lenses,
which could magnify up to 270 power.

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And in the bottom of the slide
is his first microscope.

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And I got a facsimile of that that I found
in a small store in Maine, of all places.

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And you can see, this is the lens,
and you can put an object on it,

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and you look through the other side,
and position your object with this screw.

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In using this,
he described the first bacteria, yeast,

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sperm, striated muscle, crystalline
lens of the eye, and red cells, among others.

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And you can imagine sitting there

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and looking at a light,
and then making drawings of this.

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It's really quite phenomenal.

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So, having described red cells,

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it makes me want to bring to your attention

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William Harvey,
who lived in England from 1578 to 1657.

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And he was the one who really defined

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the circulatory system
in great detail and accuracy.

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In the same period, a little later, Sir
Christopher Wren,

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who you probably know for his architecture,
he also invented the intravenous needle.

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It was made out of sterling silver.

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And he connected the bleeder, the needle to
the urethra, and infused dogs with opiates,

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and was the first to describe the effects

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of intravenous opiates in a mammal.

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He also gave the needle to a friend of his,

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who's shown on the bottom of this slide,
Richard Lower,

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who in 1667, did the first transfusion
into man using sheep's blood.

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And the man survived, probably
because he only gave about 10 cc's of blood.

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And a few months earlier, Jean-Baptiste
Denys, in France, gave about the same,

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or 12 ounces of sheep blood
into a 15-year-old boy who survived.

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But the first use of man-to-man,

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or man-to-women, or --
transfusion was by James Blundell, who,

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in 1828, did a number of transfusions
without any typing and cross-matching.

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And about half of the 12 subjects
he described survived.

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And he was able to show in this etching,
which appeared in Lancet

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in 1828, that he could save a person
who was exsanguinating after

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-- a woman -- after a uterine operation
that wasn't going well.

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He saved her life.

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Of course, the advent of blood types
was not until 1900, when Karl Landsteiner,

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who was working at The Rockefeller
University, defined the A, B, O,

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and AB blood types.

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And that was the beginning
of really the modem transfusion

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medicine approached that we have.

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Now, in terms of modern terminology
or thinking,

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maybe the first clinical trial
was done by James Lind.

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And he worked in England in the 1700s.

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And at that time, scurvy was a major health
problem in the British Navy.

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00:20:14,913 --> 00:20:18,617
And William Harvey,
who I had mentioned earlier,

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had recommended lemons to treat scurvy,
but had argued that

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the therapeutic effect
was the result of the acid in the fruit.

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00:20:28,827 --> 00:20:35,767
And it was Lind, who was a Naval
surgeon, conducted a clinical trial in 1747

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to assess the utility
of three therapies on scurvy.

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00:20:40,172 --> 00:20:47,346
So, he took 12 sailors with classical scurvy,
divided into six groups of 2 each,

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and all were given identical diets
and the various groups were supplemented

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00:20:52,918 --> 00:20:57,522
with either vinegar; dilute sulfuric acid;
cider; sea water; nutmeg,

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garlic, and horseradish
mixture; or two oranges and one lemon daily.

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And here are the results of all his studies.

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The only thing that worked was citric fruit
and it was not significant.

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00:21:12,537 --> 00:21:16,642
But, of course,
they didn't have statistics in those days.

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00:21:18,810 --> 00:21:21,980
So, he wrote a paper, which

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is shown on this slide, and became famous
because, based on

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these data, scurvy was prevented in the Navy
by giving people citrus fruit.