From the Shadows to Essential

From the Shadows to Essential

you very much, Dave. When you get to
be a certain age, you find that history becomes
actually much more interesting. And so since I’ve
gradually moved my way into administration and gotten
to the point where I really am completely incompetent in the
lab, it’s very difficult for me to talk specifically about my
research, great progress I’m making, and so forth. So I’m going to go and
give you a historical sense for laboratory medicine,
how we arose out of really basic science. And that relationship
continues, but also how closely we are tied and
how the practice of medicine is tied to us– that one of my chief points
is that medicine doesn’t exist without laboratory medicine. Remove us and the
practice of medicine as we know it falls apart. So let’s see. Objectives– these
are objectives. Good luck. You will all be tested
at the end of this hour. My disclosures– this content
is free of any obligations to anyone, but I would like to
thank all the people that I’ve known and worked with
over the past 42 years here in the department. I actually came here
in 1969 as a student to help Dr. [INAUDIBLE]
set up his research lab. So I was here at the beginning. So to begin with, to
paraphrase Rodney Dangerfield, we don’t get no respect. And I think we’re sort
of a hidden specialty that often people don’t
really know who we are, what we’re doing, and
we’re just down in the lab doing something. And I think it’s
very important that I want to make a point
that anytime anyone tries to call you ancillary– I hope at the end of
this lecture you will realize we are not ancillary. We are essential. Don’t let people
get away with that. It’s the one piece of legacy
I want to leave you with. So we’re going to go through
the age of innocence, enlightenment and rapid change,
and today’s tsunami of riches. So I actually began
in internal medicine, and when I started
internal medicine, we had to do the problem
oriented medical record, which was developed by a
fellow named Larry Weed, and all of our notes
had to be in this form where we would have the
subjective impressions, objective data,
assessment, and plan. I think this has sort
of been garbled here at the University of Washington. You’ll look at the
chart, and you’ll find it ASOP, which
I couldn’t figure out what the hell this was. But this is sort of the
way the thinking goes here, where you put the assessment
before you put the subjective, because nobody waits to find
out what the patient is actually complaining about when
you do it that way. But what I always taught–
you first talk to the patient, find out what their
chief complaint was, get some history,
do a physical exam, and start ordering some
labs and other things. You need data. Make an assessment and decide
on what the patient’s– where you’re going to go
with the treatment. And all of our notes were done
in this format and so forth, but I think it is a good
concept to think about where we sit because we sit
in that objective level where we’re trying to give
data to our clinical colleagues and help them move forward. So let’s go back about
2,000, 3,000, 4,000 years and think about the subjective. It was pretty much the
same as it is today. Patient came in. They got chest pain. Objective– well,
pretty primitive. You look at him. Maybe they might
look pale, and/or they might have
trouble standing. You will use your senses. You’d smell them. They smell pretty bad. And your assessment
would be they’re sick, or they’re not sick. Now the plan would be
we could bleed them. We could bore a
hole in their head, do incantations, and
a lot of other things, but there was really
not a lot of connection with what was going on. And the one thing we could
examine was the urine. So urine became a very
important element, and really the first
laboratory examination. Around 400 BC,
Hippocrates writes and has a lot of comments
about the examination of urine, and has all kinds of
things that he writes about and ways to interpret urine. Just look at the bottom
line, but the most deadly of all kinds of urine are
the fetid, watery, black, and thick. And this is a really bad sign. He really took you
through the urines. Galen, considered the founder
of experimental physiology– he actually dissected
animals and humans, and looked at the relationship
between fluid intake and urine output. And he actually
described diarrhea of the urine, so a condition
where actually people were peeing a little bit too much. And the amazing thing
is the findings of Galen from over 2,000 years ago– they remained in
effect and that was pretty much the way medicine
was practiced based on Galen’s findings for 14 centuries. Mostly what they did was
they looked at the urine. So if you can imagine that,
1,400 years looking at urine. Now here in 900 AD,
this Isaac Judaeus writes a book, book
of fevers, and he describes the formation
of urine and the value of visual examination
of the urine. Now this became an
important textbook that it lasted into
the 17th century. You can see we’re making
a lot of progress. We’re examining, and then
we got published books on urine examination. And it became such that
the code of Jerusalem– I think this is
from the crusaders. The failure to examine
the urine could result in public beating
of the physician. So this was really
a requirement. Now, the faith in uroscopy
was such that most of time you didn’t even
have to see the doctor. You just had to give a specimen. You give it to the
apothecary or whatever, and they would deliver
it to the physician, and the physician would
make an interpretation and decide what to
do with the patient. Now, it is an interesting story. This Thomas Willis is one of
the first people that says, wait a second, this is craziness. So this is a story
of a shoemaker’s submitting one of these flasks
of urine for interpretation. And he looks at it,
and he dumps it– he says this is coming
from a shoemaker. And he’s reached the
point– this is ridiculous, and I have to see the patient. So he pours urine
back into the boot, and he sends it back
to the shoemaker and says, if you can
tell me what kind of boot I should wear from this
boot filled with urine, then I will interpret
what I receive. And so this is sort
of we’re starting to make a break with this
way of looking at things. The small changes starts
in the introduction of additional devices like
the microscope, thermometer. And now we have some measures
that we can actually rely on. And so I’m going to take
you now through just we’re going to talk a little
bit about chemistry, hematology,
microbiology in terms of how these areas evolved. And I apologize for the other–
immunology, coagulation, transfusion medicine,
and so forth. We just don’t have time
to cover everything, but we’ll start with chemistry. The dawn of clinical
laboratory testing– so way back in the
1600s, Van Helmont introduces gravimetric
analysis, but he doesn’t really apply it to medicine. Dekkers observes that
urine would precipitate when boiled with acetic acid. So we’re doing something
a little different than just looking. We’re actually
taking it, and we’re starting to manipulate it. And Willis notes the sweet
taste of diabetic urine. There is a certain kind
of urine that’s sweet. It’s associated with these
people that are peeing a lot. We don’t have a lot of
things to help them with, but we know that,
and we can actually distinguish this between
another condition where they’re peeing a
lot– diabetes insipidus. So we’re starting to
classify, and this is a major thing that’s starting
to occur in medicine as we start some sort of laboratory
testing in some way to distinguish the one
thing from another, because we’re not going to be
able to treat anything until we start dividing stuff up. Now, phlebotomy is a big
thing for us today, but back in the 14th, 15th centuries,
leading up to that time, phlebotomy primarily
a treatment. Blood wasn’t drawn to
actually analyze it, although people
started basically about in the 14th
century it looks like. People started examining the
blood that was drawn off, and looking how it
clotted, and so forth. But phlebotomy was not done
for diagnostic purposes. It wasn’t until about
the 17th century John Locke, the
father of liberalism, suggests chemical
analysis of the blood might yield information
of medical diagnostic and management value. And he encouraged his friend
Robert Boyle to undertake analysis of normal blood. So Robert Boyle
you can remember. Anybody ever hear
of Boyle’s Law? PV equals nRT, or P
is proportional to 1 over V, the
relationship of pressure of a gas to its volume. So that’s Robert Boyle– so he began experimenting,
and he comes up with the physical
properties of the blood– the specific gravity,
temperature, taste. Does some chemical
analysis of it. And looks, and– thick oil,
clear liquid, phlegmic, liquor, volatile salts, caput mortuum– I love that one. It’s the useless residue after
you dry it or boil everything off and some salts. Then the English
physicist Hewson discovers a coaguable lymph, and this
is really what we will learn is fibrinogen. Matthew Dobson proves the
sweetness of urine in blood in diabetes is caused by sugar. It’s not caused by aspartame. Francis Home developed
the yeast test for sugar in diabetic urine. So we can actually
add a little yeast, and we can measure the sugar. A clinical diagnostic
came into vogue in the 18th century–
heart rate, blood pressure, chest percussion, temperature. I mean, these are all things–
when you go to the clinic today, this is how we
measure meaningful use– is the doctor does these tests. So they were introduced
in the 18th century, and it’s very
reassuring that this is how we measure if the
doctors are doing enough. And Dave Chu will
attest to that. Brown Langrish in
his New Practice of Physic talks about the
chemical analysis of blood in various types of fever– lymph, volatile salts,
oil, caput mortuum again, and so forth. Davies writes an
essay to promote the experimental analysis
of blood in 1760. And he comes up sort
of empty handed. He says we can do
some of the analysis, but basically we can gain
no particular information from this method of inquiry. So even though he
analyzed the blood and came up with a
number of components, he wasn’t sure that
it meant anything because the problem is
we can measure things, but if there is no clinical
application, so, very nice. That’s sort of the
question we always ask if somebody
wants something done. What are you going to
do with the results? I’m sure that this
is a common thing. It should be amongst
our residents when they get these
crazy requests. What are you going
to do with it? So there really was no further
advances in blood chemistry until the turn of the century. They really didn’t
have the reason. They could do some analysis. They could do some
chemistries, but they really didn’t have a lot
they could apply. Lavoisier, father
of modern chemistry, moved chemistry from qualitative
and quantitative methods. I think this is a
very important change. I mean, he is the guy
that’s given credit for realizing oxygen is
involved in combustion. He actually names
oxygen and hydrogen– helped develop
the metric system. When you read about these
folks, they did a lot of things. They weren’t focused
on medicine per se, but medicine was just a side. Let’s do a little
bit of that, too, at the same time we’re doing
all these basic chemistries and so forth. By 1800, quantitative
methods of analysis were leading to a rapid
progress in chemistry. Blood chemistry included water,
albumin, muriates of potassium, sodium, sodium carbonate,
potassium sulfate. Albumin could be broken
down into its components, but there was no immediate
application in medicine. Medical diagnosis,
again, we’re limited to the appearance of blood. Did it look dark? Did it clot fast? These were very simple things. So even though we
could do some analysis, it really wasn’t being used. Proteinuria– how many of you
have heard of the term dropsy? About six hands go up. It’s interesting, because
I’m going to mention this, and I’m going to mention
Bright’s disease. I’m so old, when I
was an intern, when I was a medical student, you’d
take a patient’s history, and you’d get family history,
and grandma had dropsy. Grandpa had dropsy. And dropsy is basically edema. Dropsy comes from– I can’t remember what the term
is, but it comes from water. And so this is an
accumulation of water. Anyway, so people started– they would look at
patients with dropsy, and they found some of them
had serum in the urine, or really protein. John Blackwell describes
proteinuria and dropsy, but the problem is they
don’t make the link. They describe what’s there,
but the link hasn’t been made. What does it mean? You got patients that have
basically protein in the urine, and they have this condition. Well, that’s really nice. It took Richard Bright– now, this is another one. I would hear patients-
Bob, did you ever hear a patient had Bright’s
disease, or a grandfather, or something? How many else in the room? Eric I know, yes. We’re a small group now, but
when we’d take histories, you’d have patients whose
family history– there was Bright’s disease. And Bright’s disease goes
back to Richard Bright in 1827 in his reports. He writes a report. He makes the association. He’s looking at
cadavers and so forth– that there actually is kidney
disease in these patients, and he starts measuring
the specific gravity, urea, the salts. And urea normally–
urea is about 4% of urine in his measurements,
and the salts were 2%, but they were reduced
in these patients. And they had albumin
that might be present in enormous quantities. So he’s describing patients
that are losing proteins and are putting out otherwise– they’re having dilute– low
specific gravity and so forth. But he makes the association. These other researchers
didn’t make the association that it’s actually disease of
the kidney that’s happening, that he can find
pathological changes. And this allowed people
then to go and investigate kidney disease and
try to associate it with what’s
appearing in the urine. So here is laboratory tests,
protein, examining the urine, and actually making
a determination that there’s a cause
and effect here. And maybe if we can
figure out treatments– that’s the ultimate goal– doing these
measurements is actually going to make a difference. William Prout, in his Enquiry
Into the Nature and Treatment of Diabetes,
Calculus, and Other– he was the first one in
terms of his overall research to suggest atomic
weights of all elements were multiples of hydrogen.
And he actually purified urea. First one to divide
organic substances into groups of carbohydrates,
fats, and proteins. He discovered HDL
was in gastric juice. And he also defined what you
needed in a clinical litmus paper, wash glass, two
small pieces of plate glass to distinguish mucus from pus,
portable hydrometer, and a blow pipe, a few test tubes, maybe
bottles of ammonia, potash, and nitric acid. So he actually came
up with what you need to have in a
little medical lab, but he was really
a basic chemist. Gabriel Andral was the one who
really introduced let’s start measuring things. Let’s get away from
just urine examination. I want to examine
blood, and he’s looking at fiber and red cells,
solid material in the serum and water. He describes low albumin– associated with the dropsy,
again, in the albumin area, but he also sees the
same thing in famine, in patients that are
starved, that they have low serum, low blood albumin. And he also goes on to
divide febrile diseases into two groups– one where there’s
reduction in fibrin. That includes typhoid,
smallpox, measles, scarlatina, an increase in fibrin, those
with a more substantial buffy coat, and internal
inflammation like pneumonia, rheumatism, abscess,
and erysipelas. So we’re starting to see
medicine by laboratory medicine methods, by clinical
pathology being divided. We’re starting to
categorize different states. This is very important,
because what we assume always has existed– this is 1843, less
than 200 years ago. We hadn’t divided. All the things we know, all the
diseases we talk about today– they’re just starting
in the lab that they’re making these distinctions
that are going to allow the clinicians, the
pathologists, other people to actually come up with
different disease categories. Bence Jones– 1847, described a
peculiar protein in the urine. Precipitated in urine
by alcohol, but not by boiling with nitric acid. As the urine cooled,
the precipitate fell. Precipitate that had fallen
redisolved when he boiled it, and at postmortem– the patient,
of course, ends up dying. In postmortem, the
patient was shown to have softening of the bones. Now, you all know what
[INAUDIBLE] proteins are? Multiple myeloma? And these are your light
chain kappa so forth. So didn’t know what
was actually going on, but started describing something
that was occurring that he could distinguish in the urine. It leads back to let’s go
back and look at these things. And over the course
of time, we end up coming up with a disease entity. Colorimetric methods beginning
in modern clinical chemistry– here’s a colorimeter,
and it was employed for doing hemoglobins in 1894. Otto Folin used it
to do a determination of urine creatinine in 1904. This is in the department. It’s in one of my
boxes at Harborview. I have no idea
which box it’s in, but luckily a long time
ago I took a picture of it. This is a Dunning
colorimeter that somehow made its way to my office. But basically what you had
is a whole series of tubes with colored fluid,
and you could actually make a quantitative
analysis of something, some chemical
reaction or whatever by comparing it,
putting it into one slot and comparing your sample. That was a big breakthrough,
the colorimeter. It was sort of the
early mass spec. But there continued to be rapid
advances in clinical chemistry. Folin and Wu– I have to mention Folin
because he was originally from Minnesota. He came from Sweden,
then immigrated to Stillwater, Minnesota, went
to the University of Minnesota briefly, eventually
became the director of the clinical
research lab at Harvard, but he’s a Minnesota guy. Figured out
precipitating proteins with sodium tungstate
and sulphuric acid to give protein free
filtrates, and in 1920 developed a classic
glucose method. Keep in mind, in
sometime in 20 to 21, Banting and Best were able to
isolate and purify insulin. So the need to actually
analyze and come up with a good method
for doing glucose was just starting to
hit as we’re starting to understand diabetes. And so hand in hand we
went with treatment. Microscopy– so we’ll take
you back a little bit. 1676, Dutch businessmen and
scientist and Antonie van Leeuwenhoek– sort of an umlaut with an– Leeuwenhoek, father
of microbiology. He was the first one to observe
bacteria and microorganisms with a microscope. He examined blood
under a microscope and saw small round
globules driven through crystalline
humidity of water– is how he described it. He made these findings. This was all very well and good. What happened? Do we have a blossoming
of clinical microbiology at this point? No. It’s going to take another
100 years or so before there is any application for this. Kircher sometime in the 1600s
is a Jesuit priest in Germany. Probably the first
to use a microscope to investigate a
cause of disease. He showed that maggots and
other living creatures developed in decaying matter,
observed that blood of patients from the
plague contained worms. And what he was
probably looking at was white cells in his
32 power microscope. I tell you, you look at
Leeuwenhoek’s microscope, and you wonder how the
hell he saw anything. But the clinical lab really
incorporated microscopy between the years of
about 1840 and 1890. And just like when
we started developing the use of molecular
techniques throughout our labs, this was a lab unto
itself, so that anyone who wanted to play microscopy
did it in the microscope lab. So it really included the
hematologists, parasitologists, bacteriologists, all
these histologists, all these functions– really,
it’s something you do. Here’s the technology. The microscope guy
takes care of it. So Alfred Donne was one of
the people who really started popularizing it in Paris. He was so in– loved the microscope that he
started having little classes in the evening where he would
examine blood and show it to his students. He described what today we
would recognize as leukemia, but his real claim to fame
was looking at breast milk. And there was an ill prince,
and he looked at the breast milk from the– because they were
willing to look at anything in the microscopes. They looked at breast
milk and discovered that there was something
wrong with the breast milk, and he told them, and they
got a different wet nurse, and the prince got better. So he was a miracle maker,
and that was a real help to the development of
clinical microscopy. But this went on. Here’s a case with
John Hughs Bennett, one of Donne’s students. He sees a patient
suffering from syphilis. He examines the urine
and saw spermatazoa, and talks to the patient– history of involuntary
seminal emissions. So of course the
logic of what to do– as I said, it takes
a while for people to adapt the clinical
lab, and we find things, but it doesn’t mean it’s
always the right thing– the treatment is always right. So he gives the patient a
treatment of beefsteak, beer, and tonics. And six months
later, the patient is actually doing better. So again, another
success story and another reason to continue to
pursue this technology. 1845, describes a case
of abnormal increase in white cells in a patient. And together with
Rudolf Virchow, the father modern
pathology, is credited with discovering leukemia. And we’ll go into
that a little later. 19th century brought a lot
of technology– stethoscope, 1816– opthalmoscope,
1847– laryngoscope, sometime in the 1800s. More refinements of
the microscope– it became a much more useful too. X-ray, 1895. EKG, 1872. So all these were
new technologies being adapted for
physical exam, for helping the physicians actually
come up with diagnosis and treat the patients. So we’re really moving along. Clinical microbiology–
we’ll go back to 1840. Jacob Henley was an anatomist,
physiologist, and pathologist. He named a lot of
stuff– when you think of even the
kidneys, Henley’s loop. This is a guy who did
this, but he also– he was thinking. I mean, he had the microscope. He’s trying to decide what to– he’s looking for
causes of disease. And he gets on this
idea of bacteria, and let me just read this quote. “We must hold that the cause of
miasmatic contagious diseases is a material endowed with
independent life which can reproduce itself after the
manner of animals and plants, can increase by assimilation
of organic materials and growing parasitically
on the infected body, can give rise to symptoms
of the special disease.” He looked in his material. He looked in the
material that he had, the autopsy material
and so forth. Couldn’t find anything. He was really trying
to find bacteria. He believed bacteria
caused disease, but he couldn’t
find the evidence. But he talked to one of
his students, Robert Koch, who you may have heard of. He was credited
with the criteria of showing the relationship
between causative microbes and disease– Koch’s postulates. Koch actually came
through and did the work that Henley had suggested,
but it’s a slow progress. We look at it. In 1849, a couple
of researchers, Davaine and Pollender, see
bacteria in cow’s blood infected with anthrax. Leukart, Virchow,
and Zenker work out pathogenesis of trichinosis. In 1862, Pasteur invents
the healing process to kill most bacteria molds. 1867, Joseph Lister
publishes in the Lancet his discovery that carbolic
acid will decrease the incidence of gangrene in his patients. And finally, in
1876, Robert Koch proves Davaine’s bacteria
as the cause of the anthrax. So they made these associations,
but they hadn’t really proven, and it took Koch to do that. And it’s also interesting
to look at the literature. Up until 1865, there
was no reference to bacteria in the Lancet. So we think of all these bugs– and we had a great talk by
Farik a couple weeks ago, and all the things
we know today– 1865, not that long ago. They didn’t have any articles. Nobody had written
anything, let alone viruses. 1875, the Pathologic
Society of London was debating the question
the germ theory of disease. This was still up for debate. Koch had already really proved
that germ theory is real, but back in England, let
alone the United States was– they were just recovering
from a civil war. And back in England,
they are still debating whether the
germ theory is real. There was still a lot of
people who didn’t believe it. Anyway, the folks in Germany–
they just went forward. They just do it by the book, and
they had already proved this, so they just kept moving. Koch develops a gelatin
medium on a glass. Slide First, he observes the
colonies growing on potatoes. You can slice open a
potato, and a couple days later, oh my god, it’s got
these little colonies growing. He ends up developing gelatin
medium for glass slides, does some refining
of that, and one of his students, Julius Petri– he comes up with a modification. He puts it in a
little glass dish. It’s actually much
easier to use, and so that’s where we
get the Petri dish from. And finally, in 1882,
Koch’s clinical bacteriology becomes legitimate
by Koch’s discovery of tubercle bacillus, TB. 1882, also at the
same time, Ehrlich works on improving the
staining methods for TB. And this was really
an important event in the development
of microbiology, because now we had
the symptomatology. People are trying to
make the diagnosis, but now if we really
can hone it down, this is the bug
that’s causing it. We can stain for it. We can show it exists. This was a real breakthrough
in terms of microbiology, because before it was all
conjecture and so forth. But here was we can
show it in the tissue. We can actually show it existed. 1884, Christian Gram introduces
another staining method for bacteria so that you can
separate the little balls from the little rods,
the ones that are red, the ones that are blue. But he didn’t appreciate, for
years, the ability to do this, because he was looking for a
way to stain tissue and make the bacteria show. So it wasn’t so much
looking at it on a slide and really differentiating
the little balls from the little
rods, but this is– again, today we’re using the
gram stain, 140 years later. Richard Pfeiffer– he
added blood to agar, and now we can grow some
other things, like H flu. So we continue to
do these things. Eddie MacConkey’s media–
there was a whole series of these started happening. And we can see that
now we’ve really got something to work with. Antibiotics– the
exploitation of clinical micro was really dependent
on treatment. Until we had something to treat
with, you make the diagnosis, and this is really interesting,
but unless we could really eliminate these, that was
the key to going forward. So Paul Ehrlich developed the
first antibiotic chemotherapy. So his idea was,
if I’m figuring out all these stains that actually
stain different cells, maybe I can figure
out something that– maybe mix something,
make something thaw would kill bacteria,
like arsenic. Let’s see what I can concoct
and see if they can actually go after these cells– trying to use what he’s
learned from staining to develop an antibiotic, and he
comes up with an organoarsenic that was called
Salvarsan, and that itself was a big breakthrough. Alfred Bertheim went on to
discover a series of arsenic derived synthetic antibiotics. In 1910, Ehrlich and one of
his associates, Sachahiro Hata, really announced the discovery
of Salvarasan and its utility in treating syphilis. So now we had an antibiotic. So this is really
the first antibiotic, and it really made
all this work– identifying these
bacteria, isolating them, figuring out how to culture
them, and so forth– now, same guys, Paul
Ehrlich and company– they develop the
first antibiotic. Then we’ve got a series. We’ve got the
sulfonamides, penicillin. And actually there’s
a whole series of researchers that
noticed that there’s different kinds of penicillins. William Roberts notes that the
mold penicillium glaucum, used in some types of blue
cheese, prevented bacterial contamination. So they’re seeing
the fact that there seems to be a war going on
between bacteria and fungi, but it wasn’t until
Fleming observes the real breakthrough
is penicillin chrysogenum inhibiting the
growth of bacteria in one of his culture plates. And this is pure later
purified in the 1940s, and we end up with
penicillin– again, another drug that can
actually treat the bugs. So this is the
evolution of medicine. Without laboratory medicine,
without clinical pathology, nobody is going anyplace. Remember that. Now, I just threw this
one in because this is the University of Washington. This is from an article
by Bauer, Kirby, Sherris, and Turck. This is the antibiotic
susceptibility testing by the disk method. The Kirby-Bauer test
was developed here at the University of Washington,
and those are the four people that were on the paper. And Dr. Sherris was
actually the first director of our microbiology lab when the
department became a department. Hematology–
Leeuwenhoek, as I said, described some small
round globules. And it took a while to progress
and figure out anything. In 1840, they looked and
they said, look, this shape– nuclear red cells– and there’s
some other things in the urine. There is red cell
nuclei floating around, lymph corpuscles,
albuminous particles. In 1842, Addison
identified pus cells were the white cells of blood. So the cells you
could see in the pus– actually he was the
one who successfully made the connection. These are the same cells
I’m seeing in the blood. So these are big– to you, this doesn’t seem like
a big deal, but this was big. Anemia– again, another
avenue to travel down. This was in the 18th century. We’re now able to
say, look at this. Some of the patients,
when they bleed, the amount of red cells
in the blood is less. On the other hand,
sometimes it’s associated with malabsorption. There are other diseases– cancers and so
forth– they actually started honing in on as they
were able to look at the blood and determine the
number of red cells that was actually making
a difference in terms of diagnosis. The counting, the actual
estimation of this took the development of cell
counting chambers and methods. And so the first one was 1852. Karl Vierordt published
the first method for counting red cells
using the capillary. And then here is a number
of different capillary– different counting setups
that were developed. And we go on and on, and of
course Paul Ehrlich pops up again staining blood films. And he actually
starts developing more classification of
the cells– anisocytes, nucleated red cells,
neuroblasts, as well as the recognition of leukocytes
as really distinct cells, which leads us into leukemia. For this one, we have to go
back to 1839, and where Donne noted an increased
proportion of white cells, but didn’t pursue it very
much further in one case. And then we get Craigie, who
describes a 30 year old man admitted with general
feebleness and enlarged spleen, and who dies. A couple of months later,
he’s got a very large spleen. It’s pale, semi-fluid
pinkish blood, and notices the globules
of purulent matter in lymph when looking at the blood. There’s another case
that comes in in 1845. JH Bennett performs the
autopsy on that one, and it’s from this that Virchow,
along with his own case, the 50 year old woman who died
with what he termed white blood and leukocytemia,
that we really start getting into the period
where we’re starting to see a lot of white cells. And it’s Virchow who coined
the term which we call leukemia today. And so in 1847, Virchow
devotes a long article to the discussion
of this new disease, and he was able to distinguish
lymphatic from myeloid cells. And it took a few
years to be accepted. So it wasn’t he comes
up with this idea, but it’s not that right
away people agree with it. Leukocytosis, likewise. He actually discovers that you
can have high white counts, but it doesn’t always mean
that you have leukemia. It is not that something
that’s going to kill him. We have different
reasons for it, and so that, again, is Virchow. And Paula Ehrlich, as
I said, he comes up with a clear distinction
between he’s working on stains and really comes up with
there’s a difference between the lymphocytes,
large mononuclear white cells, transitional forms, polynuclear
leukocytes, eosinophils, and mass cells. 1879– not that long ago. So we can go through stories
like this in coagulation, in immunology, in transfusion,
a lot of other places. I think the bottom
line comes down to what old Doc Evans from
Minnesota had to say– that in laboratory medicine
we look a little bit. It’s microbiology
in urines, and we’ve seen a lot of the looking,
but that led us in to we grow some stuff,
mostly in microbiology, and the rest is
chemistry, whether we call it coagulation, immunology,
transfusion, whatever. So I’ve sort of
touched on your areas. Sorry, I guess that’s
the cheap shot. Getting into the 20th century,
big break in the 20th century is the Flexner Report,
where really he criticized the way we’re getting educated. We’ve got to bring science
into the education. So we’ve got to reduce the
number of medical schools. It’s just catch as catch can
in terms of medical schools. Train people in
scientific manner. Give medical schools control
over the instruction that occurs in the hospitals,
and strengthen regulation. It was the application
of this report that really changed medicine. It changed at the
turn of the century. What was going on
in this country? Who was the real leader in
terms of internal medicine? It was William Osler. Have you all heard of Osler? He’s described as the
father of modern medicine. And at the turn
of the century, he went on a tour he
was out in Europe studying what they’re doing. That’s where all the
advancements were being made in the clinical lab. He comes back. He’s so excited about this. He talks this hospital– some donor or whatever–
into giving $10,000 bequest to build a
lab at Johns Hopkins. He’s got to have a lab. And after that point, as he went
around and would visit places, he would always look. Let me see your lab. This became very,
very important to him. So in a way, if we look at
it, William Osler may be– and in fact, I’ve seen
a couple of authors that have said that
he really should be considered the father
of clinical pathology. He was really the guy pushing. I mean, he’s so
famous for what he did in terms of organized
internal medicine, but he was the guy
who really wanted to– he saw, if you’re
going to do medicine, you have to have a modern lab. So in his Principles and
Practice of Medicine– I’m going to go through– in the 1892 edition,
he said you had to have a clinical lab
that could do a hemoglobin estimate, RBCs, white
cells, parasites of malaria, simple UAs, microscopy
of sputum for tuberculi. By the 1912 addition– I mean, he keeps adding things. By the 1912 edition– and this
is because of the advances that are going on in
medicine– spirochetes in syphilitic lesions, Wasserman
reaction, osmotic fragility, and accrued glucose
tolerance test. So we see an evolution of
laboratory medicine occurring just in his books in
terms of what he’s making a point of these
are the things you should have in your clinical lab. So the organization of
laboratory medicine beginning of the 20th century– we have the American Society
of Clinical Pathology. Early in the 1920s,
CP was in its infancy and generally practiced by
internists and some PhDs, but barely recognized by other
physicians as a specialty. In 1922, Ward
Burdick from Denver gathers his colleagues at
the AMA meeting in St. Louis. May 22, 39 physicians meet at
the Missouri Baptist sanatorium to achieve greater
scientific proficiency in clinical pathology
and maintain the status of
clinical pathologists on an equal plane with
other specialists. May 23, over 100 physicians
meet to approve the constitution and bylaws of the ASCP. This is basically
an organization that was formed out
of internal medicine. It came on the heels
of an AMA meeting. So this is where
the impetus was, and it really follows,
because of our relationship that we’ve had with the
clinical practice of medicine, that this is where the big
push to have organizations within our specialty. Grand proposal, jumping
way up to Jerry Evans. I have to mention this
because I came from Minnesota. He presented the Dean of
the University of Minnesota with an 80 page proposal,
which I actually have a copy of, to
create what became the first Department
of Laboratory Medicine in the United States. Our growth is our own specialty. The techniques
and basic sciences applied to the enlightened
service and research has lagged compared
with the rate of innovation and development
in other departments. A laboratory that
is standing still is the laboratory that
is going backwards. This would apply at any time. This is not any time, but
a period of logarithmically increasing volume and importance
of technical procedures. We are living in the golden
age of medical discovery. Medicine has advanced
more in the first 50 years of the 20th century
than in all preceding time. The pace is still accelerating. Great discoveries in
fundamental fields have stirred the imagination
of clinical investigators and basic scientists. Medicine has been made over. It is from the
fundamental fields that new things will come. Progress in clinical
medicine will be achieved in large
measure through the use of increasingly complex
laboratory equipment and procedures. So that was his proposal. Then in 1965 was the development
of the Academy of Clinical Laboratory Physicians. Ellis Benson, Ernie Cotlove,
Frank Queen, David Seligson, Jon Straumfjord,
and George Williams meet at the ASCP annual
meeting to discuss the problems of
teaching laboratory medicine to medical students,
and residents, and physicians. And in 1966, they found
ACLPS with the central idea to promote the
education and training in laboratory medicine. Here at the University
in Washington, in 1968 clinical labs were
shared by four departments. It was clinical chemistry and
biochemistry with Alex Kaplan. Microbiology with John
Sherris in the Department of Microbiology. Hematology was shared– Dr. Clem Finch in the
heme division of medicine, and Cecil Hougie in pathology. The King County Hospital, which
is now called Harborview– the clinical laboratories
were two faculty members in pathology. And hematology– Robert Hillman,
heme division of medicine. And so it was these folks
that Paul gathered together when he came to advise the
University of Washington on the formation
of our department. And the clinical
microbiology lab at UH represented a national
standard of excellence. However, the remainder
of the laboratory service had major problems. For example, surgery was
canceled, and in July, 1969, its equipment failures made
it impossible to obtain electrolyte determinations. Many instruments
provided by the hospital were outmoded and in disrepair. Staffing on the evening and
midnight shifts and on weekends was particularly weak. At the university
hospital, for example, there was only one technologist
available for evening and midnight shifts
for all laboratories. She routinely worked
a double shift, and when she was taking
a shower in the hospital, no laboratory service
was available. So he developed a paper for
what he was going to do, and this was his design
of the functional design of the department
with the two hospitals. Specimen receiving and
transportation, very important. But his concept was the baseball
field, baseball diamond. So you’d have the
processing at home plate. All the rapid testing was
gathered in the infield. And in the outfield, with
those tests and procedures that could be done at
a more leisurely pace. And this is an example of
the 1971 virology orders. This was the complete charge
schedule for virology. Kind of modest by
today’s comparison. Here’s an SMA-12 failure. It’s done it again. Our SMA-12 has completely quit. Well, anyway, it quit, and
she sent out this note. This was posted in the wards. Here’s our really multi-channel
analyzer in chemistry. Residency program in 1969– clinical path residency
was struggling as coordination of training
and using laboratories under the direction of
several different departments was difficult. Most
of the residents in anatomical pathology
went elsewhere to obtain training in
clinical pathology, and only one resident
decided to sign up with the new department. We inherited a med tech
program that was actually in pretty good
shape, and it’s now one of the oldest
medical technology, or MLS, programs in the country. And with that, I better quit
because I’m beyond my time. And so there is very little
time to ask questions. So I do have more. I skipped a lot,
but I’ll tell you, it was a lot of fun
putting this together. So, any questions? [APPLAUSE]

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  1. I'm glad I saw this, it puts a few things in perspective. Thank you for a coherent and entertaining presentation.
    And I finally found out what dropsy is 🙂

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