J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
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The philosophy of science: a history
of radioiodine and nuclear medicine
J.W. (Hans) van Isselt
correspondence: [email protected]
Cite this article as: Van Isselt JW. The philosophy of science: a history of
radioactive radioiodine and nuclear medicine. Tijdschr Nucl Geneeskd 2010.
http//www.nvng.nl/tijdschrift/vanisselt.history.html
Abstract
The history of nuclear medicine is formed by a long sequence of events from the earliest
traditions of medicine into the evidence-based research of the present day. Although through
the ages many prominent figures have pioneered new territories, only a few are well remembered: Henri Becquerel, Marie Curie, George de Hevesy, Bernard Cassen, Hal Anger. The
contributions of so many others – philosophers who had the courage to go against prevailing
opinions, scientists whose insights shaped a different world – have largely been forgotten.
This journey into the philosophy of science is mostly about their inspiration and dedication,
about will power and perseverance, about paradigm shifts and serendipity. It also honours
the role of radioiodine as a link between thyroid research and the origin of nuclear medicine.
May it serve to sustain the collective memory of all who work in this field.
To read the article, click HERE
accepted: March 21, 2010
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
Contents
1
1.1 1.2 2
2.1 2.2
2.3 2.4
2.5 2.6 2.7 2.8 2.9 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Paradigm shifts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Information transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Building the structures of science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Earliest history: Eastern and Mediterranean roots . . . . . . . . . . . . . . . . . . . . . . . . 3
The Middle Ages and Islamic medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
The Middle Ages in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Humanism and the Renaissance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
The Scientific Revolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Advances in algebra, calculators, and physics . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The Enlightenment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
The Scientific Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Advances in chemistry, and the concept of atoms . . . . . . . . . . . . . . . . . . . . . . . . 9
3
Science in the 19th century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.1 A different view on atoms and elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.2 Medicine in the 19th century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4
4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10
The discovery of X-rays and radioactivity . . . . . . . . . . . . . . . . . . . . . . . . . 12
A new age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Wilhelm Röntgen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Henri Becquerel and Silvanus Thompson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Marie Curie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Biological effects of ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
First medical applications of radioactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Early advances in radiophysics: Lord Ernest Rutherford . . . . . . . . . . . . . . . . . . . 15
First tracerkinetic studies with radionuclides: George de Hevesy . . . . . . . . . . . . 16
First diagnostic nuclear medicine procedures . . . . . . . . . . . . . . . . . . . . . . . . . . 16
First therapeutic use of artificial radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . 17
5
5.1 5.2 5.3 5.4
Thyroidology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Medical developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Surgical developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
The pivotal role of radioiodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Nuclear warfare and ‘Atoms for Peace’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
6
6.1 6.2
6.3 6.4 6.5 6.6 6.7 6.8 7
7.1
7.2
7.3
The dawn of molecular imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Laboratory practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
In vitro nuclear medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Geiger-Müller tubes and scintillation detectors . . . . . . . . . . . . . . . . . . . . . . . . . 21
Rectilinear scanner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Anger camera, gamma camera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
PET scanner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Radionuclide and radiopharmaceutical production . . . . . . . . . . . . . . . . . . . . . . . 23
Radionuclide therapy coming of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
8
Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Technological and societal developments . . . . . . . . . . . . . . . . . . . . . . . . 24
Information technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
How nuclear medicine got organized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
The changing nature of commercial interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2
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J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
1 Introduction
Someone who visits a nuclear medicine department for the first time might think that radio­
pharmaceuticals have always been on the shelf,
ready made, waiting to be picked by some clever
doctor. Similarly, gamma cameras and PET/CT
scanners may seem to have been construed in a
single instant, with a knowledgeable purpose to
make the best possible use of such tracer compounds. A look at the history of medicine will
show that the state-of-the-art practice of nuclear
medicine is the result of a persistent stream of
ideas and inventions – some millennia old, others
just decades. Numerous scientists and clinicians
paved the way, not seldom through tough battles
with tradition, other scientists, religion, and society. Several clinical areas have had a considerable
impact on the inception of our young discipline; the
first and foremost was thyroidology, which in turn
has immensely benefited from nuclear medicine
research.
1.1 Paradigm shifts
In the history of science and medicine there have
been only a few distinct ground-breaking epochs,
characterized by so-called paradigm shifts, when
ideas of scientists from different disciplines converged to create a new frame of mind, to become
the new standard afterwards. Thomas Kuhn used
an optical illusion (fig.1) to demonstrate how the
same information can be interpreted in entirely
different ways.1 From a historical per­spective, the
three most important eras were one around 3000
BC in Mesopotamia and the Far East; another
(named the Scientific Revolution) during the Enlightenment in 16th and 17th century Europe; and
a third, again primarily in Europe, around the turn
of the 20th century.
be stored and communicated across generations
with much greater accuracy. The invention of the
printing press around 1440, generally accredited
to Johannes Gutenberg but to Laurens Janszoon
Coster by most Dutchmen, made a rapid and ubiquitous dissemination of knowledge feasible. The
publication of books and scholarly journals advanced the democratization of science. Centuries later,
the communication between scientists was facilitated by the advent of steam engines (the first public
railway was set up in 1825 by George Stephenson),
internal combustion engines (first automobile
by Karl Benz, 1888) and the wireless telegraph
(Nikola Tesla, 1893). Scientific manu­scripts have
become instantly accessible world-wide through
the invention of the binary computer in 1937 and
the introduction of the internet in 1988.
2 Building the structures of science
2.1 Earliest history: Eastern and
Mediterranean roots
As early as 3000 BC written documents emerged in
the form of clay tablets and papyrus rolls. During
this same period advanced medical and surgical
knowledge had accumulated in China, India, Persia,
and Egypt. For instance, in the field of thyroidology
there is evidence that the Chinese used burnt sea
weed, rich in iodine, to treat thyroid conditions. The
Western medical tradition started more than three
millennia later. In Ancient Greece, Hippo­crates (ca
460–377 BC) developed a metho­dological approach
towards health care and medical practice (fig.2). He
founded an institution, the Asklepion, that would
nowadays be called a hospital. Hippocrates also
had well-formulated ideas about medical ethics;
based on these ideas he formulated an oath that
to our day and age represents the ethical standard
for physicians around the globe.
Fig.1. Thomas Kuhn’s duck-rabbit optical illusion,
illustrating the concept of paradigm shift.
1.2 Information transfer
In prehistoric times knowledge was transmitted
from generation to generation in an oral tradition.
The development of writing enabled knowledge to
Fig.2. Hippocrates
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
Hippocrates’ work was translated into Latin by
Galenus (129–217 AD), a Greek physician and
philosopher who spent his career in Rome. Galenus’
authority on the practice of medicine in Europe
remained unchallenged for centuries.
The following slightly ironic quote (invariably reminding me of radioiodine treatment for thyroid
cancer) is attributed to Galenus: “All those who
drink from this remedy recover in a short time,
except those whom it does not help and who all
die. Therefore, it is obvious that it fails only in
incurable cases.”
Herophilos (335–280 BC), a Greek physician working most of his life in Alexandria, was the first to
perform systematic scientific dissections of human
cadavers, and as such is deemed to be the first
anatomist. By founding knowledge on empiry,
Herophilos introduced the experimental method to
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medicine. Aulus Cornelius Celsus (ca 25 BC–ca 50
AD) wrote De Medicina, a book on diet, pharmacy,
and surgery, but there is doubt whether he himself
ever practiced as a physician. De Medicina survived the times, and is now one of the best sources
concerning medical knowledge in the Roman world.
2.2The Middle Ages and Islamic medicine
Medicine had a central position in medieval Islamic culture. It was first based on the traditional
Arabian medicine of Muhammad’s time. Influences
from pre-eminent authorities such as Galenus
and Hippocrates, Indian physicians Ayurveda, Sushruta and Charaka, and the Hellenistic scholars
of Alexandria were later incorporated. None of the
original old Greek texts have survived the perils of
time. The West learned of them only through Latin
translations of Arabic copies.
Fig.3. Surgical instruments (page from a 1531 Latin translation of the
Kitab al-Tasrif).
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
Muslim physicians made their own significant advances in, and contributions to, medicine. Around
1000 AD, Abu al-Qasim al-Zahrawi (known in the
West as Albucasis) developed several surgical techniques and instruments such as the scalpel, catgut,
surgical needles, adhesive plaster, bandage, and
cotton dressing (fig.3), and described these in the
Kitab al-Tasrif (The Method of Medicine). For six
centuries this work served as the paramount practical guide for doctors and surgeons in medieval
Europe. Of near equal influence was Al-Quanun
fi’l-tibb (The Canon of Medicine), a systematic and
comprehensive volume by Persian physician Abu
Ali al-Husayn ibn Abd Allah ibn Sina, also known as
Avicenna. In a Latin translation more than thirtyfive printed editions of this work have been studied
by 15th and 16th century European physicians.
Muslim physicians set up the earliest hospitals in
the modern sense. In these so-called Bimaristans
the ill were welcomed and cared for by qualified
staff; at the same time, these institutions func­
tioned as medical schools. By comparison, the
ancient healing temples, lazarets and leper-houses
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had been primarily concerned with isolating the
sick and the insane from society. And in medieval
Europe the few available hospitals were more concerned with prayer than with anything else.
2.3The Middle Ages in Europe
During the early Middle Ages in Europe (350–1150)
the development of the arts, science, and medicine had come to a virtual standstill. Alchemy
blos­somed, and medical practice was based on
the works of Albucasis, Avicenna, Galenus, and
Hippocrates. In the late Middle Ages (1150–1500)
the so-called Scholasticists introduced a renewal
of learning through dialectic (Aristoteleian) reasoning. Their most prominent representative was
Thomas Aquinas (ca 1225–1274), whose Summa
Theologica summarized the reasoning for most
points of Christian doctrine. Among the scholars’
greatest achievements were the institutionalisation
of education and the building of schools. Universities were founded in most large cities of Europe
(fig.4) during the 13th and 14th centuries, i.e.,
after the Crusades.
Fig.4. Foundation of universities across Europe in the 12th–15th centuries.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
In the 12th and 13th centuries Christian knights
and soldiers engaged in nine Crusades, launched
primarily against the Ottoman Empire. Their aim
was to recapture Jerusalem and the Holy Land from
muslim rule, which had began in the 7th century.
After the decline of the Byzantine Empire and the
fall of Constantinople in 1453, the Ottoman Empire
occupied large parts of the Balkan until the end of
the 2nd Balkan War in 1913.
In the 14th century Europe was severely hit by a
series of catastrophs. In 1315–1317 North-West
Europe was struck by the Great Famine, caused by
excessively cold and wet winters and aggravated
by a substantial population growth in the previous
centuries. Then in 1318 sheep and cattle were
decimated by Bacillus anthrax epidemics. To aggravate matters further, the Great Pestilence (‘Black
Death’) caused a pandemic in Europe be­tween
1348 and 1400 with devastating conse­quences.
This highly contageous disease killed more than
half of all European citizens, and severely damaged
social structures. Many people questioned the authority of the Catholic Church, and most lived by
the moment. No plans were made for the fu­ture,
let alone for a career in science or medicine.
2.4 Humanism and the Renaissance
Late 15th century Europe witnessed some important historic events: the fall of Constantinople
(1453), Christopher Columbus’ discovery of America (1492), the Protestant Revolution initiated by
Martin Luther’s 95 theses nailed to the Wittenberg
church door (1517), and the Catholic CounterReformation thereafter. After the fall of the Byzantine Empire many Greeks fled their homes; most
Fig.5. The Vitruvian Man (Leonardo da Vinci).
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of them migrated to Italy. This probably helped
fuel the Renaissance. At the dawn of the Renaissance (14th–17th century), Scholas­ticism had been
overturned by Humanism with Desiderius Erasmus
(1466–1536) as its most outspoken representative.
Humanists proclaimed that God created the universe, but man had developed and industrialized
it. Emphasis was placed on the study of primary
sources rather than the study of interpretations by
others. Consequently, large parts of the 15th and
16th centuries were devoted to the translation of
Greek texts into Latin, the lingua franca of European intellectuals at the time. Leonardo da Vinci’s
Vitruvian Man (fig.5) is a fair example of humanistic
art and science. In 1492 Leonardo made this drawing to illustrate a treatise, De Architectura, about
geometry and human proportions. This book, written by Roman engineer Marcus Vitruvius in the 1st
century BC, had been rediscovered and reprinted
in the late 15th century.
During the Renaissance a general interest in all
things human led to an intensified study of the
functions of the human body. Almost 1800 years
after Herophilos, the dissection of human corpses
was again taken up by Da Vinci. In 1543, Brussels­
born Andreas Vesalius published De Humani Cor­
poris Fabrica (On the Fabric of the Human Body),
one of the most influential books on human anatomy ever (fig.6). Vesalius had performed sur­geries
Fig.6. From Vesalius’ De Humani Corporis Fabrica.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
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as well as autopsies during his years as imperial
physician to the court of Charles V. Among many
other discoveries he established that the circulation
of blood issued from pumping of the heart. He was
the first to assemble a human skeleton with the
knowledge he had gathered from the autopsies,
and presented an accurate macro-anatomical
description of several organs, including the thyroid
gland.
experimental techniques, Harvey concluded that
the heart was a muscular pump and that arterial
and venous valves prevented the regurgitation of
blood. In 1628 he described the circulatory system
in his book Exercitatio Anatomica de Motu Cordis
et Sanguinis in Animalibus (On the Motion of the
Heart and Blood in Animals) (fig.7). His position
was equally unexpected and disputed in a world
where Aristotelian ‘vitalism’ was still law.
2.5 The Scientific Revolution
In 1543 the Scientific Revolution incepted with the
publication of two works that changed the course
of science: Nicolaus Copernicus’ De Revolutionibus
Orbium Coelestium (On the Revolutions of the
Heavenly Spheres) which advanced the heliocentric theory of cosmology, and Andreas Vesalius’
De Humani Corporis Fabrica which discredited
Galenus’ views. The Scientific Revolution radically
changed the way in which scientists worked, and
laid the foundations of modern science. This was
the second era of paradigm shifts – changes in
basic assump­tions within the ruling theory of science. The Aristotelian belief of natural and artificial
circum­stances was abandoned, and slowly a research tradition of systematic experimentation became accepted by the scientific community. In the
16th century, under the influence of scientists and
philosophers such as Alhacen and Francis Bacon,
an empirical tradition developed. Almost a century
after Vesalius, English physician William Harvey
applied a combination of close observations and
careful experiments to learn about the functions
of the body. Partly based on the works of Italian
surgeon and anatomist Matteo Realdo Colombo
(ca 1516–1559), and using dissections and other
2.6 Advances in algebra, calculators, and
physics
The 16th century greeted the rapid development
of algebra and geometry. Scipione dal Ferro (1520)
and Niccolò Tartaglia (1535) independently devel­
oped a method for solving cubic equations. The
symbol of equality (=) was probably first used
by Robert Recorde in 1557, and around 1590 the
notation of modern algebra was introduced by Simon Stevin and Franciscus Vieta. Vieta’s In Artem
Analyticem Isagoge of 1591 (Introduction to the
Art of Analysis) gave the first symbolic notation
of parameters in literal algebra. Advancement
con­tinued through the 17th century. John Napier
invented logarithms in 1614. William Oughtred
invented the logarithmic slide rule in 1622, after
Edmund Gunter had created the logarithmic scales. Around 1660 Gottfried Leibniz invented the
binary system – the backbone of all modern computer architecture – and in 1623 Wilhelm Schickard of Tübingen, Germany, built one of the first
calculating machines. The realisation of the first
computer using binary addition for its calculations
by George Stibitz in 1937 would have to await the
many fruits born by a second scientific revolution
and the industrial revolution. Christiaan Huygens
Fig.7. From Harvey’s Exercitatio Anatomica.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
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(1629–1695) argued that light propagated in the
form of waves. This concept, now known as the
Huygens-Fresnel principle, contributed to the understanding of wave-particle duality. Huygens was
also the first to use formulae in physics.
2.7 The Enlightenment
Around 1650 a political and philosophical move­
ment emerged throughout Europe, which ended
with the French Revolution in 1789. This move­
ment, called the Enlightenment, overturned the
almost dogmatic belief in authority which had
prevailed during the Renaissance. Observation,
experimentation, and criticism characterized this
period. In 1687 Sir Isaac Newton published his
Philosophiae Naturalis Principia Mathematica (The
Mathematical Principal of Natural Philosophy),
which layed the foundations for classical mechanics. Newton described universal gravitation, and
the three laws of motion which thereafter have
domi­nated physics science for over three centuries.
Newton taught that scientific theory should be coupled with rigorous experimentation, the key­stone
of modern science.
French surgeon Ambroise Paré (1510–1590) was a
leader in surgical techniques, especially the treat­
ment of wounds. Although he is considered to be
one of the fathers of surgery, it seems unlikely
that Paré was unaware of Al-Qasir’s 11th century
work in the same field. In 1546 Valerius Cordus
authored one of the greatest pharmacopeias and
one of the most celebrated herbals in history, the
Dispensatorium.
Microscopic anatomy came within grasp after
Antoni van Leeuwenhoek’s invention of a 200x
magnifying single lens microscope (fig.8). Until
then, magnification had been achieved in the order
of about 8x.
Fig.8. Antoni van Leeuwenhoek’s 200x magnifying
microscope (one of few remaining originals).
In 1674 Van Leeuwenhoek was the first to witness a living cell under a microscope.2 His main
dis­coveries include the erythrocyte, the bacteria
(fig.9), the spermatozoa, and the banded pattern of
Fig.9. Drawing by Antoni van Leeuwenhoek of bacteria
taken from the plaque of his teeth (reproduced from a
letter to the Royal Society.3
muscular fibres. His findings eventually over­turned
the traditional belief in the spontaneous generation
of small organisms.
After Robert Hooke had confirmed Van Leeuwenhoek’s 1677 claim of myriad life forms in a drop
of water, Antoni was elected a Fellow of the Royal
Society (FRS). Van Leeuwenhoek much valued
his FRS status, and in 1723 on his death bed he
bequeethed 27 of his microscopes to the Royal
Society.
Cornelis Drebbel and Zacharias Janssen developed
compound microscopes with multiple lenses for
oculars and objectives. The scientific potential of
the microscope was demonstrated by Jan Swammerdam, who described the microscopic anatomy
of the human brain, spinal chord, and lungs. Marcello Malpighi, regarded as the founder of microscopic anatomy and the first histologist, published the
discovery of capillaries (the link between arteries
and veins that had eluded William Harvey) in 1661.
In 1708 Boerhaave wrote Institutiones Medicae,
a textbook which soon became a reference work.
He also introduced the concept of clinical teaching.
Boerhaave, Rector of the Leiden University, occupied three faculty chairs (in practical medicine,
botany, and chemistry) and enjoyed enormous
fame as a teacher. By the end of the 17th century
Boerhaave, Spinoza, van Leeuwenhoek and Malpighi were among the most famous men in all of
Europe.
The experimental and source-finding nature of medicine of this time is illustrated in Rembrandt’s painting Anatomy Lesson of Dr. Nicolaes Tulp (fig.10).
Such achievements, a small handful amongst
numerous products from the Dutch Golden Age,
marked the transition from the Renaissance to the
Enlightenment.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
9
Fig.10. Anatomy Lesson of Dr. Nicolaes Tulp (by Rembrandt Harmenszoon Van Rijn, 1632).
Fig.10. Anatomy Lesson of Dr. Nicolaes Tulp (by Rembrandt Harmenszoon Van Rijn, 1632).
2.8The Scientific Method
During the 16th and 17th centuries a few key ideas
emerged that contributed to the origins of what
came to be known as the scientific method. Sir
Francis Bacon’s Novum Organum (1620) outlined
a new system of logic based on the process of
reduction, which was offered as an improvement
over Aristotle’s philosophical process of syllogism
(inference). René Descartes published the Discours de la Méthode (1637), which helped establish the scientific method further. Galileo Galilei
(1564–1642) improved the telescope, and made
several important discoveries in astronomy. Galileo con­ceived perhaps the most innovative idea
at the core of the scientific method, in relation to
the interpretation of experiments and empirical
data: “The universe stands continually open to our
gaze, but it cannot be understood unless one first
learns to comprehend the language and interpret
the characters in which it is written. It is written
in the language of mathematics, and its characters are triangles, circles, and other geometrical
figures, without which it is humanly impossible to
understand a single word of it; without these, one
is wandering around in a dark labyrinth.” In 1642
Galileo was put on trial by the Catholic Church for
publishing his theory of heliocentricism. More than
anything else this pointed out the contradictions
between traditional religion and humanism.
2.9Advances in chemistry, and the concept
of atoms
The idea that all matter is composed of small units
had been proposed in India in the 6th century BC.
This concept was philosophical rather than scien­
tific. It was introduced to the West by Leucippus,
whose student Democritus coined the term atomos
(Greek for indivisible). Aristotle defined an element
as “one of those bodies into which other bodies can
be decomposed and which itself is not capable of
being divided into other”. Early philosophers used
the four archetypal ele­ments (fire, air, water, earth)
in an attempt to describe the structure of matter. In
Europe the Middle Ages provided an excellent base
for obscure practices. Magical thinking dominated
this era. Medics were in search of the Stone of
Wisdom, and of a panacea – a remedy that would
cure all diseases and prolong life indefinitely. The
unity of matter was symbolized by a snake biting
its tail. Alchemists tried to find ways to transform
common metals into gold (the word alchemy is
derived from the Persian kimia, and later Arabic
al-kimia, meaning gold). None­theless, alchemy
should be seen as the predecessor of chemistry, as
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
it introduced the techniques of analysis and syn­
thesis. During the 17th century alchemy developed
into chemistry, most notably through the works of
Robert Boyle who in 1661 laid the foundations of
modern chemistry in his book The Sceptical Chymist. The book’s subtitle sheds some light on the
mindframe of that time (fig.11).
10
the names of 33 elements. Lavoisier investigated
the com­position of water and air (which were then
still considered elements), and determined that the
components of water were oxygen and hydrogen.
He proved that air was a mixture of gases, primarily
nitrogen and oxygen. Lavoisier had devised a sys­
tematic chemical nomenclature, which he described
in Méthode de Nomenclature Chimique (1787).
This system is still largely in use today. Lavoisier
demonstrated the role of oxygen in the rusting of
metal, and in collaboration with Laplace he also
proved that respiration was essentially feed­ing a
slow combustion of organic material using inhaled
oxygen. Lavoisier outlined the Law of Conservation
of Mass, after similar ideas had previously been put
forward by Nasir al-Din al-Tusi (in the 13th century)
and Mikhail Lomonosov (in 1748).
3 Science in the 19th century
3.1A different view on atoms and elements
In 1803 English natural philosopher John Dalton
used the concept of atoms to explain why elements
invariably react in a ratio of small whole num-
Fig.11. Frontispecies of The Sceptical Chymist (Robert
Boyle).
Boyle argued that matter was composed of com­
binations of different ‘corpuscules’, rather than of
just the four elements that the ancients had assumed. In 1680 he rediscovered Hennig Brand’s
1649 purification of phosphorus. This marks the
first recorded discovery of any element. Late in the
18th century the discovery of hydrogen (1766),
nitrogen (1772), and oxygen (1773) triggered the
quest for the arrangement of the universe. Boyle’s
earlier achievements include experiments with
gases. His finding that the volume of a gas varies
inversely to the pressure of that gas (if the tem­
perature is kept constant within a closed system)
was later called Boyle’s Law.
About a century after Robert Boyle, the term
‘element’ was coined by Antoine Lavoisier in his
Traité Elémentaire de Chimie (1789), the first
modern chemistry textbook. The book contained
Fig.12. John Dalton’s symbols for atoms and molecules.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
bers. This led him to propose the Law of Multiple
Proportions. Dalton published a table of relative
atomic weights for six elements (hydrogen, oxygen, nitrogen, carbon, sulphur, and phosphorus)
and he published the atomic theory in his book A
New System of Chemical Philosophy (1808). In the
process, he devised various symbols for atoms and
molecules to visually represent the structure of
matter (fig.12). The five pillars of Dalton’s atomic
theory were: (1) elements are made up of tiny
particles called atoms; (2) all atoms of a given
element are identical; (3) atoms of a given element
are different from those of another element; (4)
atoms of one element can combine with atoms of
another element to form chemical compounds;
and (5) atoms cannot be created, nor can they be
divided into smaller particles, or destroyed.
Finally ‘atoms’ had evolved from a philosophical
concept into a purely physical entity. At the turn
of the 20th century scientists discovered, through
experiments with electromagnetism and radio­
activity, that the ‘indivisible’ atom was in fact made
up of subatomic particles.
By 1818, Jöns Jakob Berzelius at the Uppsala University in Sweden had determined atomic weights
for 45 of the 49 accepted elements, and in 1869
Dmitri Mendeleev had included 66 elements in
his periodic table (fig.13). Mendeleev intended
the table to illustrate recurring (periodic) trends
in the properties of the elements. In 2010 a total
of 117 elements have been observed. Only 80 of
Fig.13. First publication of Mendeleev’s periodic table of
the elements.
11
these have stable isotopes, viz. all elements with
atomic numbers 1 through 82 with the exception
of elements 43 (technetium) and 61 (promethium).
3.2Medicine in the 19th century
In the 16th century the Scientific Revolution had
established science as the pre-eminent source for
the growth of knowledge. During the 19th century,
the practice of science became professionalized and
institutionalized in ways which continued through
the 20th century. After the French Revolution the
metric system was officially introduced by Napoléon
Bonaparte to replace various traditional measuring systems. The metric system spread swiftly
across Europe over the next fifty years, but the
International System of Units (abbrev.: SI, after
the French Système International d’Unités) was
finally accep­ted internationally almost two centuries later, in 1960.
Physiological knowledge began to accumulate at
a rapid rate with the publication in 1838 of the
cell theory by Matthias Schleiden and Theodor
Schwann, stating that organisms consist of a gathering of units called cells. In 1858 Rudolf Virchow
concluded that all cells stem from pre-existing
cells; this completed the classical cell theory.
Little by little, non-invasive diagnostics and preventive medicine emerged. A 19th century fore-runner
in non-invasive medical diagnostics was French
physician René Laennec, who in 1816 invented the
stethoscope.4 In its original design, the stethoscope
was a wooden cylinder; the present-day binaural
type was developed by Arthur Leared in 1851. In
1847 Hungarian physician Ignác Semmelweis dramatically reduced the incidence of puerperal fever
by requiring physicians to wash their hands before
attending to women in childbirth. His discovery
predated the germ theory of disease. Semmelweis’
findings acquired general acceptance only after
discoveries by British surgeon Joseph Lister, who
proved the principles of antisepsis in 1865. Lister
started from the work by French biologist Louis
Pasteur, who had been able to link micro-organisms
with disease. Pasteur also in­vented the process of
pasteurization, to help prevent the spread of dis­
ease through milk and other nutritients. In 1880
he furthered preventive medicine by producing a
vaccine against rabies.
One of the most prominent and far-reaching theories in science has been the theory of evolution by
natural selection, put forward by British naturalist
Charles Darwin in his book On the Origin of Species
(1859). Darwin proposed that the features of all
living beings, including humans, were shaped by
natural processes over long periods of time. In the
early 20th century the study of heredity became
a major investigation area after the rediscovery
in 1900 of the Laws of Inheritance, developed by
Moravian monk Gregor Mendel in 1866. Mendel’s
laws mark the beginnings of the study of genetics.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
4 The discovery of X-rays and radioactivity
4.1 A new age
At the dawn of the 20th century Europe experienced a third era of paradigm shifts, under less
than stimulating conditions. As stipulated in an
eminent historical article by John M. McCurley,5
“in 1895 there were no automobiles, few telephones, and hardly any electricity. The major form of
commu­nication was mail. Gas lights illuminated the
larger cities of Europe. Science laboratories were
judged by the size of their batteries; some could
reach the outrageously high potential of 1.95 V.
Subjects treated in the leading Annalen der Physik
included the liquefaction of gases, measurements
of specific heats, and attempts to reproduce the
phenomena of optics with electromagnetic waves.
The cor­puscular theory of matter was still being
widely debated.”
12
(fig.15). In the first year after Röntgen’s announ­
cement, over 100 papers were published on the
subject.
4.2 Wilhelm Röntgen
The discovery of cathode rays by Michael Faraday
in 1838 spurred a number of developments, one of
which would cause a revolution in medicine. On 8
November 1895 Wilhelm Conrad Röntgen (fig.14)
discovered what he called ‘X-rays’.6
Fig.15. Radiographs of tropical fish (Eder and Valenta,
1896).7
Fig.14. Wilhelm Conrad Röntgen.
For this achievement, Röntgen in 1901 became
the first Nobel laureate in physics. Soon after his
discovery, applications in radiology opened up an
enormous potential to explore the interior of the
living human body as well as of other creatures
4.3 Henri Becquerel and Silvanus Thompson
The phenomenon of phosphorescence was the
scientific domain of French physicist Henri Antoine
Becquerel. The news of Röntgen’s discovery – the
phosphorescence shown by the walls of the dis­
charge tube and of the barium platinum cyanide
screen under the effect of the X-rays – diverted
Becquerel’s research into a new direction. He found
that sun-excited uranium acted on a photographic
plate which had been shielded from light. He then
devised another experiment in which he interposed a sheet of black paper and a small cross of
thin copper between the plate and the uranium
salt. He could not expose his contraption to direct
sunlight, because the sun was blocked by heavy
clouds. Therefore he put it back into the dark cupboard and left it there for a while. However, the
sun kept behind the clouds for several days. Tired
of waiting, Becquerel developed the plate. Instead
of a blank, as expected, the plate had darkened
under the uranium as strongly as when the uranium
would have been previously exposed to sun­light,
and showed the image of the copper cross white
against the black background (fig.16).
This serendipitous finding marked the beginning of
a long series of experiments that finally led to the
discovery of radioactivity, four months after Röntgen discovered the ‘X-rays’. Becquerel pub­lished his
discovery in March 1896.8 Later he also discovered
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
13
that this type of radiation induced luminescence
in zinc sulphide and other com­pounds, decades
later leading to the development of scintillation
detectors.
Fig.16. Henri Becquerel’s first autoradiograph.
A remarkable blank exists in the history of radio­
activity. Silvanus P. Thompson, the first president of
the Röntgen Society of London, had observed this
very same phenomenon independently from Becquerel. Thompson performed an experiment with
uranium salts and a photographic plate at the end
of February 1896, and called the observed effect
‘hyperphosphorescence’. Although he had reveiled
this in a personal communication to the Society
about a month prior to Becquerel’s pub­lication,
Thompson didn’t publish his findings until June 6,
1896.9 Publish or perish, indeed...
4.4 Marie Curie
Becquerel’s Polish-born chemistry student Marie
Curie, née Maria Salomea Skłodowska (fig.17),
decided to investigate the mysterious ‘uranium
rays’ systematically. She had an excellent aid: an
electrometer for the measurement of weak elec­
trical currents, constructed by her husband Pierre
Curie. Marie soon discovered that thorium emitted
the same rays as uranium. The strength of the
radiation appeared not to depend on the chemical
compound studied, but only on the amount of uranium or thorium in it. Marie drew the conclusion
that the ability to radiate did not depend on the
arrangement of the atoms in a molecule; it must
be linked to the interior of the atom itself. This was
an absolutely revolutionary thought, and from a
conceptual point of view her most important contribution to the development of physics.
Marie’s next idea was to study the natural ores
that contain uranium and thorium. She obtained
samples from geological museums and found that
pitchblende was four to five times more active than
could be assumed from the amount of uranium
Fig.17. Maria (‘Manya’) Skłodowska Curie
it contained. It was her hypothesis that a new
element, considerably more active than uranium,
was present in the ore in small amounts. Pierre
now joined his wife in the project, and they found
that the strong activity came with the fractions
containing bismuth. Every time they managed to
take away an amount of bismuth, a residue with
greater activity was left. In June 1898 they had
isolated a substance about 300 times more active
than uranium, and named it polonium after Marie’s
beloved native country.10 In their publication they
used the term radioactivité for the first time. Half a
year later the Curies discovered an additional very
active substance, chemically behaving almost like
pure barium, and proposed the name radium for
the new element.11
The first World War reduced the already very limited research funds to virtually zero. Madame Curie
redirected her activities, and set up France’s first
mobile military radiology centres. As Director of the
Red Cross Radiology Service she arranged a fleet of
20 small ‘radiology vans’ and 200 stationary units
equipped with X-ray apparatus to assist surgeons
in localizing bullets, shrapnel, and broken bones.
Soldiers nicknamed these cars ‘petites Curies’.
On several occasions Marie manned one of these
cars (fig.18), and also her elder daughter Irène
served as a nurse-radiographer. Up to that time
the use of X-rays had been rather limited. This
changed radically shortly after the war, as most
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
14
Joseph Muller showed that radiation increased the
mutation rate,16 and for this work he was awarded
the Nobel Prize in 1946.
4.6First medical applications of radioactivity
Within a couple of years after the first discoveries
of the biological effects of radiation, countless
‘medical’ experiments with external applications of
radioactive materials were carried out. Quackery
flourished; beauty creams, tooth­paste, and even
condoms containing radium were freely distributed
until the 1930s (fig.19).
Fig.18. Marie Curie behind the wheel of a ‘petite Curie’.
hospitals in France now had their own departments
of radiology.
Like other researchers and manu­facturers of that
time, Marie Curie was ignorant of the dele­terious
effects of ionizing radiation on people’s health. In
1920 she had contracted a double cataract that
required eye surgery four times. In 1925 she participated in a French Academy of Medicine commission that recommended the use of lead screens and
periodic blood tests of industrial work­ers in laboratories where radioactive materials were prepared.
Radioactivity had been a lifetime commitment
for the first female Nobel laureate (for physics in
1903, a prize she shared with Henri Becquerel and
husband Pierre Curie) and later the first scientist
ever to receive a second Nobel Prize (in 1911, for
chemistry). In 1934 Marie Curie died of leukemia,
at the age of 66. Most likely this was the price she
paid for an excessive ingestion of and exposure
to radium, polonium and X-rays. Vivid accounts
of Madame Curie’s life and scientific career were
given by her younger daughter Eve,12 by George
de Hevesy,13 and by R.F. Mould.14 Richly illustrated
information about her scientific research can also
be consulted on:
http://www.aip.org/history/curie/contents.htm.
4.5Biological effects of ionizing radiation
Acute effects of ionizing radiation were first observed in 1896 when electric engineer Nikola Tesla
intentionally exposed his fingers to X-rays. He pub­
lished his observations concerning the burns that
developed, though he attributed them primarily to
ozone rather than to X-rays.
Becquerel’s accidental finding of similar biological
effects (skin burns) of uranium were experimentally confirmed by Pierre Curie, and together they
published their findings.15 The genetic effects of
radiation and the increased cancer risk weren’t
recognized until much later. In 1927 Hermann
Fig.19. Advertisement for a beauty product containing
radium and thorium.
More seriously intended experiments were also
conducted. Danlos and Bloch applied radium for the
treatment of lupus erythematosus,17 Robert Abbé
successfully handled (external) radium sources
in the treatment of hyperthyroidism, and Henri
Becquerel and Alexander Graham Bell suggested
the use of radium sources to tumours. In 1913
Frederick Proescher published the first results of
intravenous radium application for a number of
diseases.
In a different field, Willem Einthoven at the Leiden
University described and recorded the first electrocardiogram (ECG) in 1903 (fig.20). This was
one of the first function tests of the human body
to be performed externally through registration of
minute electrical currents.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
Fig.20. One of Einthoven’s first ECG recordings.
4.7Early advances in radiophysics: Lord
Ernest Rutherford
In a masterful description of the ups and downs
of late 19th century science Marshall Brucer tells
how the inception of radiophysics took shape.18
Progress in engineering made it possible to create
the deep vacuum required to carry out the sophisticated research of the atom’s structure. Just
before the turn of the century, Joseph J. Thomson
of Cambridge University discovered isotopes, as
well as the electron – disproving the belief that
atoms were indivisible. Only the outlines of the
atom’s structure had been drawn when in 1913
Frederick Soddy proposed that an element’s atomic
number, not its atomic weight, is the fundamental
parameter determining its chemical properties.
He introduced the word isotope for elements that
reside in the same place in the periodic table, and
hence have identical chemical properties, but different mass.19 Soddy was working on radioactivity
in Montreal (Quebec, Canada) together with Lord
Ernest Rutherford, one of Thomson’s students.
They realized that the strange behaviour of radio-
15
active elements resulted from their decay into other
elements. When radioactivity was first discovered,
the source of the energy carried by the radiation
was not understood. Soddy’s and Rutherford’s
work proved that atomic transmutation was what
actually happened, and established that radioactive
decay produced alpha, beta, and gamma radiation.
Soddy also showed that an atom moves lower in
atomic number by two places on alpha emission,
higher by one place on beta emission. This was a
fundamental step towards understanding the relationships among families of radioactive ele­ments.
Rutherford fathered the physico-mathe­matical concepts of ‘decay constant’ and ‘half-life’, and drew up
the formula It = I0.e–λt. In 1909, under the direction
of Rutherford at the University of Manchester’s
Physics Laboratories, the ‘gold foil experiment’
(also named the Rutherford experiment) was undertaken by Hans Geiger and Ernest Marsden to
examine the atom’s structure.20 The unexpected
results of the experiment demon­strated for the first
time the existence of the atomic nucleus. Together
with his assistant Niels Bohr, Rutherford perfected
the atom model as proposed earlier by his former
professor Joseph Thomson.21,22 Over the following
two decades researchers at the Cavendish Laboratory in Cambridge, headed by (again) Rutherford,
found that the nucleus itself was made of neutrons
and protons. The number of protons in the nucleus
determined the element and for each element there
were, potentially, many different isotopes differing
in the number of neutrons in their nucleus.
In 1934 Marie and Pierre Curie’s elder daughter
Irène Joliot-Curie and her husband Frédéric Joliot
demonstrated that unstable radioisotopes existed,
and that their transmutation could be induced.23
Their milestone research had followed up on work
by Rutherford, Soddy, Francis W. Aston, and others.
In the early years of the 20th century many new
radionuclides were discovered, and several more
after the Joliot-Curies demonstrated that radio­
nuclides could be artificially produced. The neu­tron,
discovered by Sir James Chadwick in 1932, proved
to be an enormous source of radionuclides.
Late in the 19th century a certain complacency
about science had developed. This was rudely
shattered by the discovery of radio­activity, and a
short time later again by the publication of Max
Planck’s quantum theory (1900) which described
the physics of the atom and its nucleus (in which
Einstein’s special theory of relativity of 1905 played
an important role). The quantum theory and the
theory of relativity were the major extensions
to classical physics at the beginning of the 20th
century. In the history of science, no equation has
ever been as widely known as E=mc2.
In December 1938, German chemists Otto Hahn
and Fritz Strassmann reported that they had detected the element barium after bombarding uranium
with neutrons.24 Simultaneously they communicated these results to Lise Meitner and Otto Frisch,
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
who correctly interpreted these results as being
nuclear fission.25 When fission was discovered it led
rapidly to the development of nuclear weapons. The
domain of nuclear physics became heavily politicized, while at the same time the scientific questions
of the field made nuclear physics the queen of the
sciences. In 1944, Hahn received the Nobel Prize
for Chemistry for the discovery of nuclear fission.
4.8 First tracer kinetic studies with
radionuclides: George de Hevesy
In 1924, under Lord Rutherford’s direction, Hun­
garian chemist George de Hevesy (fig.21) started
experiments with internal applications of unsealed
lead-210 and bismuth-210 sources in animals for
diagnostic purposes. Exemplary is De Hevesy’s
account of the start of his Nobel Prize winning
research: “One day, Rutherford suggested that if
I were worth my salt, I should separate radium-D
from all that nuisance of lead. Being a young man,
I was an optimist and fully convinced that I would
succeed; but even though I worked very hard for a
year, trying a large number of separations, I failed
entirely. To make the best of this depressing situation, I decided to make use of the inse­parability
of radium-D from lead. By adding pure radium-D
of known activity to 1 mg of lead nitrate, the lead
present in that compound could be labeled, and its
path followed through chemical reactions with the
aid of radioactive meas­urements”.26 This describes
16
one of the principles of tracer kinetics, an area of
science that De Hevesy was going to explore over
later years.27
De Hevesy made large contributions to many
branch­­es of science through his radioisotope research. He was among the first to employ 32P-labeled sodium phosphate in animals and humans, to
study the rate of incorporation of phosphorus from
the blood stream into bones and tooth enamel.
This type of research usually involved the study
of ex vivo specimens. Similar experiments were
conducted in plants and animals, with radioactive
sodium, potassium, lead, bismuth, and thallium. Of
all his accomplishments, de Hevesy was proud­est
of his discovery of the element hafnium in 1923
in cooperation with Niels Bohr. First, because the
separation of hafnium from zirconium (where hafnium occurs naturally at 1‑5% abundance) was
extremely difficult. Second, because hafnium was
an important element in organizing the periodic
table of elements.
De Hevesy is now considered one of the founding
fathers of nuclear medicine.
4.9 First diagnostic nuclear medicine
procedures
When in 1925 Herrmann Blumgart and Soma Weiss
used bismuth-214 to measure the circulation time
in a human subject, this was the first diagnostic
nuclear medicine procedure in history.28 The invention of the cyclotron by Ernest O. Lawrence in
1931 (fig.22) made the production of radio­nuclides
in large quantities feasible.
Fig.22. E.O. Lawrence (right) and S. Livingstone with the
4th version of the cyclotron.
Fig.21. George de Hevesy.
This created the facilities for large-scale laboratory
and clinical experiments, first at Berkeley, University of California, where the cyclotron was located.
A new window was opened to the study of human
physiology and pathophysiology.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
4.10 First therapeutic use of artificial
radionuclides
Until the outburst of World War II substantial progress had been made in the therapeutic use of radionuclides. In 1936, one year after Chievitz and De
Hevesy had used 32P-phosphate to demonstrate the
physiological process of mineral bone component
renewal, J.H. Lawrence (Ernest’s brother) applied
32
P-phosphate for the treatment of leukemia and
polycythemia. This marks the first documented
clinical therapeutic use of an artificial radionuclide.
C. Pecher described the uptake of strontium-89
in bone metastases in 1939, and within a year
he used it for the treatment of bone metastases.
In the following years J.J. Livingood and Glenn T.
Seaborg were involved in the discovery of several
radionuclides, among which 131I in 1938. In the
same year Seaborg, now with Emilio Segrè, was
also responsible for the discovery of 99mTc.29 World
War II caused the foreclosure of civil radiophysics
research, as a direct result of the internment of the
most eminent allied radiophysicists at Los Alamos
(see also paragraph 5.3).
5 Thyroidology
5.1 Medical developments
Circa 1500 BC the Chinese used burnt seaweed
(with high iodine content) for the treatment of
goiter. Three millennia later (1811) Bernard Courtois, a manufacturer of gunpowder for the French
Revolution, discovered the element iodine when
he accidentally isolated it from seaweed. Twenty
years after his discovery Courtois was distinguished
by l’Académie Royale des Sciences. Swift use was
made of this new insight by William Prout, a clinical
pathologist of London, who in 1816 administered
iodine in the treatment of goiter. George Murray
in 1891 used a glycerine extract of sheep thyroid
glands to treat a case of myx­oedema.30
It would take almost a hundred years before the
physiological and pharmaceutical principles connecting iodine with the thyroid gland were un­
rav­­elled. In 1895 Eugen Baumann established
that stable iodine is present in the normal thyroid
gland,31 and in 1916 David Marine demonstrated
that iodine is cleared from the blood by the thyroid.32 In 1914 Edward C. Kendall succeeded in
isolating in crystalline form ‘the compound con­
taining iodin, which occurs in the thyroid’, later
to be called thyroxine.33 Almost 80 years before
thyroid hormones were discovered, Irish physician
Robert Graves (fig.23) had published a detailed
description of the clinical condition of the hyper­
functioning thyroid, a condition that was later
named after him.34
Further investigations into the thyroid’s functioning
weren’t feasible without the spectacular potential
of tracer kinetic studies with radioiodine, the exist­
ence of which was yet to be discovered by the
time of Robert Graves’ death. Long thereafter, with
an increased understanding of the physiological
17
mechanisms governing the thyroid gland, medical
treatment came within reach. In 1943 E.B. Astwood
was the first to treat hyperthyroid patients with the
thyroid blocking drugs thiourea and thiouracil.35
Several other effective anti-thyroid drugs were
developed over the following two decades.
Fig.23. Coin commemorating Robert J. Graves.
5.2 Surgical developments
The first successful thyroid surgery was performed
in 1849 by Theodor Billroth in Vienna. Thyroid
surgery was deemed extremely dangerous at that
time. Less than a year after Billroth’s performance,
l’Académie Française de Médecine issued a ban
on all thyroid surgery. Much has changed since
then. Major complications now occur in less than
1% of all cases; nevertheless, even today total
thyroidectomy is considered a complex and difficult procedure.
From the days of Albucasis (1000 AD) to the mid18th century surgeons received their training in a
master-apprentice setting. For a long time surgeons, shoemakers and barbers had been united in a
single guild. In 1552 the city of Amsterdam was one
of the very first in Europe to distinguish surgeons
from barbers.36 Explicit training require­ments were
laid down around 1735. Anatomy les­sons, taught
by the ‘praelector anatomiae’, were deemed very
important. Indeed without a thorough and detailed
understanding of the complex anatomy of the thyroid gland and its surrounding structures, thyroid
surgery would’nt have had a viable future. The
same is true for other types of complex surgery
(fig.24).
Anesthesia posed another very difficult problem.
Throughout history, general anesthesia had been
achieved with natural substances such as opium,
mandrake root, and hemlock. Not seldom patients
died from procedures that were intended just to
relieve pain. Even in small doses, hemlock is a
deadly alkaloid which causes neuromuscular block­
ade (hemlock was used to execute Socrates in 399
BC). The advent of modern anesthesiology greatly
enhanced the chances of survival for those poor
souls in need of surgery. After several experiments
by others, the first documented gene­ral anesthesia
with nitrous oxide was performed by Bostonian
dentist William T.G. Morton in 1844, and with
ether in 1846. Chloroform was first used in 1847
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
18
Fig.24. “Shouldn’t that red thing have been put back in?”
(with kind permission from Hein de Kort)
by James Young Simpson in Edinburgh. Through
the continued progression of anes­the­siology into
a highly sophisticated and technical medical specialty, surgical procedures of longer duration could
safely be performed.
5.3 The pivotal role of radioiodine
During the pre-WW II years in vitro and in vivo
experiments with radioactive iodine isotopes had
been instrumental in the elucidation of the thyroid’s physiology (including the identification of the
thyroid hormones) and pathophysiology. Eminent
thyroidologists of the time had expressed a keen
interest in radioactive isotopes of iodine. In 1934
Enrico Fermi made the first: 128I. Karl Compton,
president of the Massachusetts Institute of Tech­
nology (MIT), was able to produce nanocurie
amounts of 128I with the lowest technological
means possible (i.e., a neutron source composed of
discarded medical radon needles). Physicists from
MIT (Robley Evans and Arthur Roberts) started a
joint thyroid-radioiodine program with physicians
Earle Chapman and Saul Hertz from Massachusetts
General Hospital. Hertz, Roberts and Evans inves­
tigated the rabbit’s thyroid function with 128I, and
in 1938 published the very first paper on thyroidal
radioiodine.37 At Berkeley (California) neurologist
Joe Hamilton studied 128I metabolism in animals.38
He had the advantage of virtually unlimited 128I
supply from Ernest Lawrence’s nearby cyclotron.
Hamilton’s success made the competition at MIT
successfully lobby for money to build their own
cyclotron.
Fig.25. Thyroidal 131I uptake measurement with a Geiger
counter, by Hamilton and Soley.34
Also in 1938, 131I – a nuclear reactor product with
a quite useful half-life of 8.03 days – was isolated
by Livingood and Seaborg. Hamilton and Soley
were among the very first to study the kinetics of
thyroidal iodine with the use of 131I and a Geiger
counter (fig.25).
In 1942 radioiodine entered the clinical arena when
two competing groups (from the same institute, on
the same page of the same medical journal!) independently reported on the successful treatment
of hyperthyroidism with radioiodine, which at that
time was available only in very small quantities.39,40
They pursued their therapeutic goals with 130I. We
now know that the dosages they used would have
been mere diagnostic, were it not for a probable
10% 131I contaminant. That same year A.F. Reid
and A.S. Keston discovered 125I.
5.4Nuclear warfare and ‘Atoms for Peace’
The paucity of clinical and scientific developments
during World War II is explained by the internment
by the US government of many of the allied forces’
radiophysicists at the Atomic Research Laboratory
at Los Alamos, New Mexico, for the development
of a weapon with hitherto unimagi­nable force. The
devastating potential of radiation, demonstrated
by the bombs on Hiroshima and Nagasaki, drove
large parts of society away from nuclear warfare,
nuclear testing, and nuclear power. The adjectives
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
Fig.26. Atom bomb testing in Nevada (USA), 1952
‘atomic’ and ‘nuclear’ acquired a very negative
connotation. The protracted testing of nuclear
weapons in the United States (fig.26) and the
issuing results of fallout measurements (fig.27)
mounted a growing opposition from US citizens to
military nuclear programs.
19
The post-war period was characterized by a rapid
expansion of nuclear science into the medical
world. This was caused by a single article on a
single treatment of a single patient: 131I had been
suc­cessfully applied in a thyroid cancer patient.41
In the entire history of nuclear medicine not one
scientific paper has had so much impact as this
publication by Seidlin, Marinelli, and Oshry. The
news of a potential cure for terminally ill patients
fuelled the public imagination immensely, and it
soon reached the political agenda. Effective on
August 1, 1946, the Atomic Energy Act (AEA) made
radionuclides available for medical use in the USA.
This date marks the beginning of atomic medicine,
later renamed nuclear medicine. The ‘Atoms For
Peace’ program had only just started, and within
five years the US Food and Drug Administration
(FDA) approved the use of 131I for the treatment
of benign thyroid diseases.
From 1940 to 1970 countless experiments with
radioiodine revealed the details of the iodine uptake
mechanism, the basis of the therapeutic effect of
radioiodine, the complete identification of thyroid
hormonosynthesis, and the serum transporter of
thyroid hormones. In more recent years, immu­
nological and molecular studies have changed the
understanding of thyroid diseases. Although the
general princple of iodine uptake by thyrocytes
had long been recognized, the molecular basis of
this so-called ‘trapping mechanism’ was unrav­
elled as late as 1996 when Dai, Levy and Carrasco
charac­terized the transmembrane sodium iodide
trans­porter (NIS).42
Fig.27. Per capita thyroid doses for the US population (1955).
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
6 The dawn of molecular imaging
6.1 Laboratory practice
During the 20th century a revolution took place in
the way laboratory science was executed. Whereas
scientists traditionally did virtually everything
single-handed (such as designing, engineering,
crafting, logging and analyzing results, calculating,
publishing), the complexity of science increased so
much that a multi-disciplinary approach devel­oped
as the only efficient way of doing things.
Fig.28. Signatures of Francis Crick and James Watson.
In 1953, James D. Watson, Francis Crick and Rosalind Franklin had clarified the basic structure of
DNA, the genetic material for expressing life in all
its forms (fig.28).43
By 2001 >95% of the entire human genome had
been sequenced,44 and a few years later this task
was completed. Major discoveries followed from
Crick and Watson’s findings (fig.29). The first genetically engineered pharmaceutical was synthetic
human insulin, approved in 1982 by the U.S. Food
and Drug Administration (FDA). Another early
application of genetic engineering was to create
20
human growth hormone as replacement for a compound extracted from pooled (cadaveric) human
pituitary glands. In 1987 the FDA approved the
first genetically engineered vaccine for humans,
against hepatitis B. Genetic modification has gradually expanded, and it has generated a variety of
drugs and vaccines. Recombinant DNA tech­nology
has resulted in the in vitro synthesis of several
compounds, among others recombinant human
thyrotropin (rhTSH) in 1988.45,46 The role of rhTSH
during 131I treatment and follow-up of thyroid
cancer patients is now fully established; approval
for its use as an adjuvant to the 131I treatment for
non-toxic goiter is expected in the near future.
6.2 In vitro nuclear medicine
The radioimmunoassay (RIA), developed in 1959
by Rosalyn Yalow and Solomon Berson, made it
possible to determine minute concentrations of
hormones in human serum.47 With their work
Yalow and Berson laid the foundations for in vitro
nuclear medicine.
Although the RIA technique is extremely sensitive
and extremely specific, biochemists regarded the
use of radioactive substances in their laboratories
(and possibly also the required extra study of
a domain they saw as exotic) as somewhat un­
desirable. Therefore, today RIAs have been largely
replaced by the enzyme-linked immunosorbent assay (ELISA). With this method the antigen-antibody
reaction is measured using colorimetric sig­nals
(fluorescence) instead of radioactivity. In several
Western countries this meant the end of in vitro
nuclear medicine.
Fig.29. Some of the most important genes ever identified in human DNA.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
6.3 Geiger-Müller tubes and scintillation
detectors
Hans Geiger and Werner Müller in 1928 invented a
device for detecting and measuring radioactivity.
Pretty soon it was called Geiger-Müller tube or GMtube. The GM-tube was not a perfect instrument
for this purpose: (a) its sensitivity was very low
(about 1%); (b) there was no correlation between
the amount of radioactivity and the GM-tube’s
response; (c) it gave no spectral information.
Professor H. Kallmann from Berlin realized these
shortcomings, and in 1945 he construed a basic
scintillation detector. Kallmann did the job with
quite simple equipment, as his former laboratory
in post-war Germany had been stripped completely by the Russian army. For his first experiment
Kallmann used radioactive lead from wall-paint, a
scintillation crystal made of naphtaline from moth
balls, and plain photographic film to record the
events. Later he was able to purchase an electronmultiplier phototube on the black market, and the
very first photoelectric scintillation detector was
born. When finally he connected it to an oscillo­
scope, Kallmann could produce energy spectra from
a range of radionuclides. Scientific publication in
Germany in those days was severely restricted, but
Kallmann’s work was picked up by Martin Deutsch
at the Massachusetts Institute of Tech­nology (MIT),
and published by him in 1948.48 Proceeding from
these early experiments, Robert Hofstadter at
Stanford University (California, USA) demonstrated
the importance of higher density materials with
higher proton numbers for improved light yield.
He found that sodium iodide, enriched with a small
amount of thallium halide, gave very satisfactory
results.49 The consequences of his research for
nuclear medicine have been huge, as it induced
the manufacturing of large scintillation crystals.
6.4 Rectilinear scanner
Until five decades after the discovery of radio­
activity, tracer studies could only be done with
Geiger counters and scintillation probes. Although
such equipment allowed measurements of specific
physiologic processes from outside the human
body, imaging potential was lacking. For the present generation of physicians it may be hard to
imagine that once there was a time when patho­
physiology could not be visualized outside the
body. But the invention in 1950 of the rectilinear
scanner by Benedict Cassen (fig.30) was a truly
revo­lutionary breakthrough.50
Cassen connected a collimated NaI/Tl scintillation
crystal and a photomultiplier tube to a scanning
mechanism, and coupled all these to an electronic circuit. In doing so he could produce a signal
containing X, Y, and Z coordinates; this signal
could then be transferred either to paper, film, or
an oscilloscope. Medical imaging, until then solely
anatomical, had acquired a molecular dimension
overnight. Physicians could now perceive visual
21
Fig.30. Benedict Cassen and the rectilinear scanner.
demonstrations of brain tumours, disturbances in
the pulmonary circulation, and thyroid disorders
(fig.31). Pioneer Benedict Cassen co-authored
some of the first publications in functional imaging
of the thyroid gland and of the liver in the early
1950s.51,52
Fig.31. Thyroid adenoma imaged with a rectilinear
scanner after I.V. injection of 3.7 MBq 131I-NaI (early
1970s by Prof.dr. K. Ephraïm, Academic Hospital Utrecht,
the Netherlands).
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
6.5 Anger camera, gamma camera
The development of radiopharmaceuticals was
boosted by Hal Anger’s introduction in 1957 of
the gamma camera with its revolutionary wholebody imaging technique (fig.32).53 The basis for
his device was a large NaI/Tl scintillation crystal,
a collimator, and an array of photomultiplier tubes.
Its images were called scintigrams, and the entire
human body could be scanned within one hour (the
‘whole body’ option, with a moveable table, was
included in later commercial models of the gamma
camera). The relation between a specific organ and
its physiologic surroundings became much more
apparent than with the rectilinear scanner (com­
pare the images of a thyroid adenoma in figs. 31
and 33).
22
Anger also used Na18F and 85SrCl to study bone
metastases with his camera. The former procedure
never really became fashionable, even after the
introduction of PET scanners; the current worldwide 99mTc shortage might turn this around. The
latter eventually led to the introduction of 89Sr as a
therapeutically useful radionuclide (after the earlier
efforts by Pecher in 1939, see paragraph 4.10).54
In later years, although the principle remained
unchanged, several substantial improvements
were invented and included in the concept. The
advent of modern computers facilitated the development of dedicated nuclear medicine software
such as for the generation of time-activity curves,
phase analysis, ECG-triggering, and so on. Most
impor­tantly, it advanced the clinical applicability of
3D-reconstruction algorithms (see paragraph 7.1
Information technology).
Fig.32. Hal Anger.
6.6 PET scanner
The concept of emission and transmission tomog­
raphy was introduced by David Kuhl and Roy
Edwards in the late 1950s. Their work at the University of Pennsylvania later led to the design and
construction of several tomographic instru­ments.
Tomographic imaging techniques were further perfected by Michel Ter-Pogossian, Michael Phelps, and
others at the Washington University School of Medicine. Work by Gordon Brownell, Charles Burnham
and their associates at the Massachusetts General
Hospital beginning in the 1950s contributed significantly to the development of positron emission
tomography (PET) technology and included the first
use of annihilation radiation for medical imaging.
Their innovations and volu­metric analysis have
been important in the deploy­ment of PET imaging.
In 1973 the first full-ring PET scanner was built by
Michael E. Phelps and Edward J. Hoffman (fig.34).55
Fig.33. Thyroid adenoma, imaged with a gamma camera
after I.V. injection of 40 MBq 99mTc-pertechnetate.
Fig.34. The first full-ring PET scanner.
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
6.7 Radionuclide and radiopharmaceutical
production
In 1946 the first production site of radionuclides
for medical use was Oak Ridge National Laboratory
in Tennessee. This lab was established in 1943 as
part of the Manhattan Project at Los Alamos (to
separate and produce uranium and plutonium for
the development of a nuclear weapon), and con­
tained the world’s first production nuclear reactor.
As a result of the Atomic Energy Act of August
1946, radionuclides had been made available for
medical use in the USA – at least in theory. It was
no sinecure to put this theory into practice. Oak
Ridge had to be converted from a military base to
a medical production facility. It was lacking procedures for preparation, packaging, shipping, or even
advertising. The lab’s director, Paul Aebersold, was
quite successful in promoting the new use of radio­
nuclides. During the first five years, a staggering
number of 3,200 scientific articles were published
on the use of radionuclides. Radioiodine contributed
to many early success stories. 131I found its way
not only in the form of iodide, but also as a suitable
radionuclide for tagging to human serum albumin
and other substances.56
99m
Tc brought on a second revolution in radio­
pharmacy. In 1938 Seaborg and Segrè had dis­
covered 99mTc.57 It was rediscovered by Walter
Tucker and Margaret Greene as a by-product
(contamination) during the preparation of 132I from
tellurium-132. Powell Richards (at Brookhaven
National Laboratory in Upton, New York) realized
the potential of 99mTc and promoted it among the
medical community. Richards presented the first
published paper suggesting the use of technetium
as a medical tracer at the 7th International Elec­
tronic and Nuclear Symposium in Rome in June
1960. The simplest technetium-labeled compound,
99m
Tc-pertechnetate, stereometrically mimicking
iodine, was the subject of the first publications on
thyroid and brain tumour imaging. Off-the-shelf kit
preparations with 99mTc came within clinical reach
by the commercial production of the 99mTc-generator in 1964, seven years after Tucker inven­ted
it (fig.35). An instant kit for red blood cell labeling
Fig.35. Walter Tucker and Powell Richards.
23
was patented in 1976. Other 99mTc-labelled radio­
pharmaceuticals soon followed.
PET radiopharmaceuticals took a separate trail,
as they invariably materialized in top university
radiopharmacy institutions. Tatsuo Ido, Joanna
Fowler and Al Wolf at Brookhaven National Labo­
ratory described the synthesis of 18F-FDG.58 This
compound was first administered in August 1976
to two healthy human volunteers, by Abass Alavi
at the University of Pennsylvania. Brain images
obtained with an ordinary gamma camera demon­
strated the concentration of FDG in cerebral tissue.
Later the group in Pennsylvania also developed
kinetic modelling parameters such as the lumped
constant and rate constant for 18F-FDG in cerebral
studies.59 In 1977 Gallagher performed the first
myocardial 18F-FDG-PET-scan for the measurement
of regional glucose metabolism.60 Many elements
with a natural occurrence in the human body also
have positron emitting isotopes: 11C, 13N, 15O, 18F,
124
I. All these short-lived isotopes are cyclotronproduced, which limits their clinical application to
hospitals with an on-site cyclotron. A practical (but
partial) solution for this problem was the manu­
facturing of 68Ge/68Ga and 82Sr/82Rb generators.61,62
To date hundreds of PET tracers have been tested
in clinical research and in medical practice. Over
90% are being applied either in oncology, cardiology, (neuro)psychiatry, or inflammation detection.
6.8Radionuclide therapy coming of age
Shortly after the discovery of radioactivity, thera­
peutical applications rapidly emerged. The expan­
sion thereafter, however, was relatively slow. Not
only there was a growing awareness of adverse
effects, but more importantly there was no radio­
phar­maceutical industry prepared to invest heavily
in the necessary research, development, and marketing of new products. After WW II the success of
radioiodine treatment for thyroid cancer aroused
clinicians’ interest in radionuclide treatment in
general. The main focus was on the ‘magic bullet’
concept, targeted at an indiscriminate number of
malignant diseases. Today six major areas can be
discerned in radionuclide therapy. Dutch clinical
researchers have played a prominent role in most
of these.
Radioimmunotherapy. In the late 1970s the first articles on radioimmuno-imaging and radio­­immuno­­­
therapy were published. Labelled monoclonal antibodies (MoAb) and later also FAb fragments had
been tested for the diagnosis and the treatment
of malignant diseases such as breast cancer, colon
cancer, non-Hodgkin’s lymphoma, prostate cancer,
high-grade brain glioma, melanoma, and others.
Despite encouraging initial results in some case
studies, clinically useful radiopharmaceuticals remained elusive for decades. Only quite recently two
products (90Y-labelled ibritumomab, or Zeva­lin®,
and 131I-labelled tositumomab, or Bexxar®) were
registered by the FDA for radioimmuno­therapy in
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
patients with non-Hodgkin’s lymphoma who are
refractory to conventional chemotherapy and the
MoAb rituximab.
Neuroendocrine tumours. Labelled somatostatin
analogues were first identified by Krenning et al.
in Rotterdam as potentially useful in the diagnosis
of neuroendocrine tumours.63 The importance of
this development was greatly enhanced when the
same group also established effective treatment
options with related radiopharmaceuticals (DOTA­
TOC labelled with 90Y, 111In, or 177Lu).64 Others
devel­oped 68Ga-DOTATOC which opened a window
to PET and PET/CT research in this field.65
Painful bone metastases. Pain from bone metas­
tases is not easily relieved by medical treatment or
external beam radiation therapy. After De Hevesy’s
studies on radiophosphorus, 32P-sodium phosphate
was tested as a treatment option in this challenging
clinical condition. Results from systematic clinical
studies were first published in the early 1960s.66
These were followed by publications about other
candidate drugs. After diagnostic studies with
85
Sr, 89Sr-chloride was applied therapeutically in
1974,67 153Sm-EDTMP in 1989,68 and 186Re-(Sn)
HEDP in 1990.69 Dutch research further enhanced
the applicability of 186Re-HEDP for patients with
metastasized prostate or breast cancer.70
Liver metastases. Liver metastases are the major
cause of death from colorectal cancer. The treat­
ment of choice is surgery or laser surgery. However,
a large percentage of metastases are inaccessible
to surgery. Response to chemotherapy and external
radiotherapy is poor. Radiolabeled particles (such
as 90Y-resin or 90Y-glass beads), administered by
way of transcatheter hepatic arterial embolization, have shown the potential of a more localized
approach. Dutch researchers are attempting to
widen this new window by using holmium-166polylactic acid (166Ho-PLA), a radiopharmaceutical
with appre­ciable advantages in terms of biodegradation, radiation safety, and multi-modal imaging
capa­bilities.71
Radioiodine. The recognition of thyroidal iodine
kinetics as the paramount determinant of success
in 131I treatment of Graves’ disease could further
improve the record of the ‘mother of all radionuclide therapies’.72,73 We must bear in mind that
current phase II studies on Rituximab in relapsing
Graves’ disease may give way to directions other
than radioiodine for these patients.74
Developments are also seen in the treatment of
other benign thyroid orders, such as enhanced
volume reduction of goiters using rhTSH as an
adjuvant to 131I treatment.75
Many Dutch nuclear physicians have committed
themselves to the continuing battle against thyroid cancer. The already impressive results of 131I
therapy in patients with well-differentiated thyroid
cancer have been further improved by updated
treatment guidelines, maturing insights in risk
24
stratification,76,77 the introduction of rhTSH, and
the introduction of 124I PET scanning.78,79
As a result of enhanced expertise with an increas­
ing number of radiopharmaceuticals, and the use
of (very) high dosages, more patients than ever
before became eligible candidates for radionuclide
therapy. The construction of advanced therapy
departments made it possible to accommodate
the increased demand, while complying with the
highest safety standards. Gradually, radionuclide
therapy has turned from a palliative treatment
modality into curative medicine.
7 Technological and societal developments
7.1 Information technology
In the fall of 1937, while being an engineer at Bell
Telephone Laboratories, George R. Stibitz used
surplus relays, tin-can strips, flashlight bulbs and
other low-cost items to construct a digital calculator which could add two bits and display the result
(fig.36). Stibitz’s colleagues at Bell Labs named it
the ‘K-model’, after the place he assembled it: his
kitchen table.
Fig.36. George Stibitz’s K-model digital computer.
Bell Labs recognized a potential solution to the
prob­­lem of high-speed complex-number cal­
culation, which was holding back the development
of wide-area telephone networks. By late 1938 the
laboratory had authorized the development of a
full-scale relay calculator based on the K-model.
Stibitz and his design team began construction in
April 1939. The end product, known as the Complex Number Calculator (CNC), first ran on January
8, 1940. On September 11 of that year, during a
meeting of the American Mathematical Society
at Dartmouth College, Stibitz used a Teletype to
transmit math problems to the CNC and receive the
computed results. This is considered the world’s
first example of remote job entry, a technique to
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
disseminate information through telephone and
computer networks. In 1964 Stibitz was appoint­
ed professor of physiology at Dartmouth Medical
School in Hanover, New Hampshire, where he
pioneered the use of computers to deal with bio­
medical problems.80 Among many other subjects,
he investigated the motion of oxygen in the lungs
and the rate at which drugs and nutrients are
spread throughout the body. He also outlined a
computer program for the calculation of isodose
lines around radioactive implants.
In the 1960s CIA’s intelligence operations and
NASA’s space program necessitated the con­
struction of fast mainframe computers. Industrial
Business Machines Corporation (IBM) were the first
to engage in this challenge, and a market for commercially produced computers quickly devel­oped.
Nuclear medicine physicists rapidly took advantage
of the emerging information technology. Faster and
smaller computers accelerated the development
of sophisticated gamma cameras and dedicated
software.
As early as 1964 David Kuhl described 3D image
reconstruction algorithms, 81 and around the
mid 1970s developments in computer hardware
construction made clinical applications of single
photon emission computer tomography (SPECT)
possible. By that time, astrophysicists had brought
3D reconstruction theorems to practice,82 and in
1979 Cormack and Hounsfield were awarded the
Nobel Prize in medicine and biology for the devel­
opment of computer assisted X-ray transmission
tomography (CT), another spin-off from David
Kuhl’s innovating activities. From 1976 onward
tomographic techniques were further developed by
Michel Ter-Pogossian and Michael E. Phelps. Others
had already in 1953 demonstrated the usefulness
of positron emitters for medical imaging.83 Since
the 1970s, SPECT cameras and PET scanners have
potentiated 5D functional imaging, e.g., phase
analysis of a 3D volume in a time loop.
Fig.37. The original ARPAnet.
25
In an attempt to regain technological advantage
after the USSR’s launching of the Sputnik, the
US Defense Department sponsored yet another
high-tech project through its Advanced Research
Projects Agency (ARPA). By 1969 a system called
the ARPAnet (fig.37) connected computer systems
located at four university institutions, a number
that two years later had grown to fifteen. Vinton
Cerf and Robert Kahn created the essential network
architecture and the TCP networking protocols.84
The ARPAnet first evolved into NSFNET; after it
was opened to commercial interest in 1988, it
effec­tively became the internet. The internet has
provided unequalled dissemination of information. It radically changed the scientific world and
every­thing outside it, much like the invention of
the printing press more than 500 years earlier. In
2010 the estimated population of internet users
has grown to more than 2 billion.
7.2How nuclear medicine got organized
For about 20 years ‘atomic medicine’ had been the
domain of physicists, chemists, and pharmacists,
who assisted internists, nephrologists, endocrinologists and cardiologists in their experimental
studies of the (patho)physiology of various organ
systems. Now the time had come for medical
pioneers such as William Beierwaltes, Rosalyn S.
Yalow, Abass Alavi, and Henry N. Wagner, Jr. to
engage fully in this exciting subject. On 19 January
1954 twelve internists, radiologists, and physicists
established the first Society of Nuclear Medicine.
The growth of the new discipline was so rapid that
in 1971 nuclear medicine was recognized as a medical specialty in the USA. In the Netherlands this
goal was finally achieved in January 1984, mostly
by the efforts of the Dutch Society of Nuclear Medicine (NVNG) which had been founded in 1968.85
In Europe two separate societies had coexisted for
a number of years: the Society of Nuclear Medicine
Europe (founded as a primarily German society in
1963) and the European Nuclear Medicine Society
(with a more ‘pan-European’ orientation, founded
in 1974) until in 1986 the European Association of
Nuclear Medicine (EANM) resulted from a merger
of the two.
7.3 The changing nature of commercial
interest
In the late 1960s and early 1970s the development
of large-field-of-view gamma cameras and the
growing number of 99mTc-labelled compounds was
associated with increasing enterprise in nuclear
medicine. Nuclear Consultants (of St. Louis, Missouri) and Union Carbide Nuclear Corp. (of New
York, New York) engaged in the commercial production of 99mTc-generators in 1964, seven years
after its invention. Off-the-shelf kit preparations
with 99mTc became an area of commercial interest.
Abbott Laboratories were the first to commercialize
radiopharmaceuticals (131I-labelled human serum
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
albumin). Over the next twenty years a number
of radiopharmaceutical companies developed and
marketed dozens of different 99mTc-labelled kit preparations for the study of the brain, myocar­dium,
lungs, liver, gallbladder, kidneys, skeleton, and
tumours. Manufacturers of gamma cameras with
dedicated computer systems (Chicago Indus­tries
as one of the first) followed the initiative of the
radiopharmaceutical companies. For many years
nuclear medicine provided a healthy business environment. In the 1980s and 1990s, in line with
the globalization of major industries, large international companies acquired most of the smaller
firms. Mergers continued, until around the year
2000 only a handful remained in each of the two
branches (i.e., radiopharmaceuticals and camera
equipment), serving the three largest markets: the
USA, Europe, and Japan.
Industrial companies have indeed contributed a
great deal to the development of nuclear medicine. The Association of Imaging Producers and
Imaging Suppliers (AIPES), a European Economic
Interest Group, have been the sponsoring partners of nuclear medicine societies, associations,
and congresses across Europe. They have worked
with these societies on numerous political and
regulatory issues.
Over the past decades the compulsory (and very
costly) registration of radiopharmaceuticals as
pharmaceuticals by the FDA and other regulatory
bodies has become a serious impediment for the
natural growth of potential. Markets in the so-called
third world have remained acutely underdevel­oped.
Because of the relatively small sales market worldwide, shareholders aren’t eager to invest in the
research and development (R&D) required for the
commercial development and marketing of new
radiopharmaceuticals. Moreover, the high-end PET
market uses very short-lived radiopharmaceuticals
which must be produced on-site. As a consequence,
radiopharmaceutical R&D (a pivotal provision for
any future development) seems to have become
the unique responsibility of large academic insti­
tutions.
The development of hybrid camera systems (PET/
CT, SPECT/CT, and PET/MRI) was a strategic choice
made by medical equipment manufacturers, in an
attempt to advance nuclear medicine within the
much larger market of radiology. This strategy
seems to be succesful, as it is being amply adopted
by professionals from both disciplines.
8 Epilogue
In general terms the first decade of the 21st century hasn’t issued much progress. Seven billion
inhabitants are consuming the earth’s resources
at an unprecedented rate, and plant and animal
species become extinct every year. Global warming,
natural disasters, war on terror, banking scandals,
and economic recession dictate political agendas.
Just as much as other segments of society, science
26
and health care suffer from severe financial and
moral restraints. Governments tend to be conservative, and regulatory bodies over-regulating.
Hospitals and universities are being run by business
managers, investors, and insurance companies
rather than by professionals. Health care reforms
are aimed at cost reduction rather than costeffectiveness or cost-utility. Such cir­cumstances
aren’t favourable for a small specialty. In fact, the
very nature of nuclear medicine may be at stake.
Several lines of action should be considered. Priority must be given to a concerted action vis-à-vis
the deplorable state of a number of production
reactors around the globe which has already resulted in acute shortages of 99mTc, 131I, and other
radio­pharmaceuticals in recent times.
Initiatives such as the NIH Roadmap for Medical
Research (launched in September, 2004, to address
roadblocks to research and to transform the way
biomedical research is conducted by overcoming
specific hurdles or filling defined knowledge gaps)
and the CTSA (Clinical & Translational Science
Awards, towards the promotion of translational
research in medicine and elsewhere) should be
embraced by nuclear medicine.
Furthermore we must enhance our public relations, and make the general public and politicians
aware of the fact that nuclear medicine isn’t about
science fiction or a play-ground for Utopian scientists. Over the past 70 years we have brought
forth an impressive range of powerful diagnostic
and thera­peutic interventions. Throughout its history nuclear medicine has often pointed the way
for new directions in radiology (CT, MRI, and US
alike), which has resulted in a healthy competitive
rela­tionship between the two and in a permanent
urge for nuclear medicine to explore new horizons.
After a vigorous promotion in the 1990s of ‘mole­
cular imaging’, which is actually what nuclear
medicine is all about (and has been from day
one) we are now living the marketeers’ dream of
multi-modality imaging. Although this will create
a momentary emphasis on diagnostic procedures,
radio­nuclide therapy will always be a mainstay of
nuclear medicine. Aren’t therapeutic applications
the ultimate goal in all medical disciplines? The
essence of modern nuclear medicine may be defined by the triad: quantitative emission tomog­
raphy–dosimetry–radionuclide therapy. Each of the
three elements in this definition will benefit from
the use of integrated multi-modality cameras. In
the near future such integrated equipment may
also include particle accelerators for external beam
radiation therapy.
With the advent of integrated medical imaging departments, further development of PET and SPECT
will become dependent from an appropriate level
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
of specialist training. Initiatives to reach integrated
multimodality training programs raise concerns
because of the severely limited time available for
specific training in nuclear medicine.
At present the most relevant aspect of multimodality imaging is its application in radiation oncology. The latest generation of radiation delivery
techniques relies heavily on multimodal imaging
for a proper diagnosis, staging, and delineation
of target volumes. The development of integrated
PET/MRI systems and the availabillity of PET tracers other than 18F-FDG will have a major impact
on the ‘war on cancer’.
One potential growth area has thus far been largely
neglected. PET and SPECT have the capabilities
to reduce the cost of pharmaceutical research
dra­stically. If only a small percentage of pharma­
ceutical companies’ multi-billion-dollar R&D budgets were to be reverted to institutional nuclear
medicine-oriented research, most departments
would need to expand their facilities twice their
present size, and many new medical cyclotrons
would be needed. In this domain small animal PET
and SPECT with submillimeter (!) spatial resolution
27
(fig.38) are indispensible tools which can easily be
combined with CT or MRI. However, imaging is not
the industry’s only option to fulfil this goal. New,
competing techniques for pharmaceutical R&D include the accelerator mass spectrometer (AMS), a
tool designed to do micro­dosing studies in humans.
This technology will generate human kinetic data
on drug candidates and innovative food ingredients
earlier than is currently possible. It will significantly
reduce the need for animal testing prior to clinical
phases, and will reduce the cost and duration of
drug development.
New developments in the treatment of differen­
tiated thyroid carcinoma (including 124I PET dosi­
metry, and the introduction of rhTSH) have ensured
a continued interest in clinical thyroid research.
The intensive commitment to thyroid carcinoma
by the majority of university medical centers in
the Netherlands is heralded by well over a dozen
disser­tations over the past decade.
Without exaggerating we can postulate that radioiodine therapy, once instrumental in the birth
of nuclear medicine, is still very much part of its
future.
Fig.38. Mouse thyroid: 125I-NaI micro-SPECT image (left) and corresponding microscopic histology (right); parathyroid
glands are indicated by arrows. Each thyroid lobe is approx. 1 mm in length. (Courtesy Prof.dr.ir. F.J. Beekman.)
J.W. van Isselt - The philosophy of science - Tijdschr Nucl Geneeskd 2010
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Suggested further reading
•
•
•
•
•
Adloff P, Lieser K, Stöcklin G, editors. One Hundred
Years after the Discovery of Radioactivity. München:
R. Oldenbourg Verlag, 1996:412 pp
Brucer M, editor. Marshall Brucer’s A Chronology of
Nuclear Medicine. St. Louis: Heritage Publications,
1990:496 pp
Feld M, De Roo M. History of Nuclear Medicine in Europe.
Schicha H, Bergdolt K, Ell PJ, Editors. Stuttgart/New
York: Schattauer, 2003:166 pp
Fragu P. Le regard de l’histoire des sciences sur la
glande thyroïde (1800-1960). Ann Endocrinol (Paris)
1999;60:10–22
Means JH. Historical background of radioiodine in medicine. N Engl J Med 1955;252:936–940