Progress in brain research, volume 215

The younger brother, John Lawrence, pioneeredthe use of these particles in the treatment of disease using both radioactive nuclidesand later well-defined narrow particle beams.. Rich Lev

New Haven, Connecticut

USA

Donald G SteinAsa G Candler Professor

Department of Emergency Medicine

Emory UniversityAtlanta, GeorgiaUSA

Dick F SwaabProfessor of Neurobiology

Medical Faculty, University of Amsterdam;Leader Research team Neuropsychiatric DisordersNetherlands Institute for Neuroscience

AmsterdamThe Netherlands

Howard L Fields

Professor of NeurologyEndowed Chair in Pharmacology of AddictionDirector, Wheeler Center for the Neurobiology of Addiction

University of CaliforniaSan Francisco, California

USA

First edition 2014

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ISBN: 978-0-444-63520-4

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No invention or discovery is ever produced in a vacuum First, there must be a

perceived unfulfilled need This will usually be followed by attempts to satisfy that

need which may not always be successful The most familiar example of persistent

lack of success is the alchemists’ failure to transmute base metals into gold One of

the sequences of this kind applied to medicine is the introduction of a new treatment

concept From concept to fruition in the form of a usable new method is painstaking

and time consuming This part of the process may involve useful but suboptimal new

ideas or methods which require repeated adaptation Chance also plays a part

More-over, a treatment perceived imperfectly initially may be improved by totally different

persons from those who first initiated the new notions and the honor may well go to

the discoverer of the successful adapted method rather than to the original creative

thinker who initiated the investigations which ended in success Furthermore, along

the way, a conservative profession, concerned for both the patients under its care and

the standard of living of its members, may well oppose anything new because

unpro-ven novelty may threaten both patients’ safety and practitioners’ domestic luxury

This sequence of partial success, acceptance, and resistance to change and final

success of a truly effective new method should be seen as characteristic of medical

advances which, like it or not, are sought and implemented by human beings with all

our talents, virtues, and weaknesses No better example of the sequences involved

can be found than the series of events which led to the discovery of smallpox

vaccination

Lady Mary Wortley Montagu (1689–1762), daughter of the Earl of Kingston

upon Hull, was a woman of beauty, wit, and independence of spirit unusual at her

time Her father pressed her to marry a man of distinction and property with the

pos-itively Dickensian cognomen of Clotworthy Skeffington, an Irish nobleman whom

she did not fancy So she eloped in 1712 and married Edward Wortley Montagu in

Salisbury In 1715, she contracted smallpox which she survived but with some

scar-ring Her brother died from the disease She had previously been a Court favorite but

her satirical writings about the Princess of Wales, written while she was sick barred

her from Court She thus joined her husband who had been appointed British

ambas-sador to Turkey There she encountered the practice of variolation whereby matter

from an infected person was injected into the vein of someone to induce a mild attack

of the disease, hopefully with minimal scarring and lifelong immunity The

proce-dure was not without risk because some inoculated individuals could suffer a severe

form of smallpox which could prove lethal Nonetheless, its acceptance by the upper

reaches of society led to its increasing use One of those who had survived variolation

but was never as fit afterward as he had been before was Edward Jenner

(1749–1823) While trained by the best in London, he was at heart a country boy

and returned to practice in Berkeley in Gloucestershire where his museum is found

to this day As a country doctor, he had heard of the practice of inoculating milkmaids

with a bovine form of the disease conferring immunity Due to the rarity of cowpox,

v

it was not easy to perform routine inoculations, but those who were inoculated neversuffered smallpox, including Jenner’s little son The success of the procedure needs

no further comment Nonetheless, the method was criticized in the medical sion, not least by those who received substantial fees for performing variolation sothat it was a time before the treatment became universally accepted This sort of re-action following the introduction of a new method in surgery is not unfamiliar Onecould consider Semmelweis and hand washing and Lister and antisepsis, neither ofwhom received rapturous applause for their contributions During the passage of thisbook, it will be seen that the processes which ended up with the discovery of small-pox vaccination would also affect the invention of radiosurgery and the perfection ofinstruments for its satisfactory performance This will be particularly illustrated in

profes-Chapter 11

In the 1930s, the treatments of inaccessible cancers and neurosurgical diseaseswere frustrating and inefficient However, this was a time when understanding ofatomic structure and spontaneous breakdown of unstable radionuclides was expand-ing rapidly The frustration with the poor results of existing treatments was the spur

to develop new methods The first to attempt the use of atomic particles in radiationtreatments were the Lawrence brothers in Berkeley, California, spurred on by no less

a person than Harvey Cushing, who contributed to John Lawrence’s training andclearly had a great respect for him The elder brother Ernest invented the cyclotron

to accelerate subatomic particles The younger brother, John Lawrence, pioneeredthe use of these particles in the treatment of disease using both radioactive nuclidesand later well-defined narrow particle beams It should however be mentioned thatthe Berkeley group, while performing extraordinary creative work, were applying amedical function to a machine designed for a different purpose

In Sweden, a group of scientists developed and expanded the Berkeley technique

to the point where the clinical treatment of a variety of conditions became possible.The Swedish group were in contact with the Berkeley group and express their indebt-edness in a number of their papers However, while the particle beam method waselegant, it was also complex and impractical outside of a laboratory containing acyclotron which could generate the particles This led to the design and production

of the only machine in the world which was specifically constructed to performradiosurgery, the gamma unit subsequently to be called the Gamma Knife.The purpose of this book is to trace the history of the ideas and attempts at ra-diosurgery treatments from the first hesitant steps in California to the production

of the most modern radiosurgery machine the Gamma Knife Perfexion The partplayed by chance is well illustrated in the above account of vaccination MaryMontague was a girl of spirit who opposed her father, married the man of her choice,sustained smallpox, wrote the wrong thing, and had to travel to Turkey where shecame into contact with variolation which she was in a social position to introduceinto London society Jenner was a country lad at heart but during his time in Londonsuffered uncomfortable effects following variolation and was as a country doctor in aposition to be aware of cowpox and the smallpox resistance of milkmaids TheLawrences were both talented but by chance John came into contact with Harvey

Cushing who supported the activities of him and his brother and World War II

in-evitably did no harm to funding the laboratory where the work was carried out In

Sweden, Leksell started a medical career by chance and was possessed of a mindset

which enabled him to design useful instruments, perhaps in part because as a child

he’d had the chance to work under supervision in the machine shop of the factory his

father owned He also had access to a supremely talented physicist B€orje Larsson

20 years his junior without whom the gamma unit would not have been possible

One consequence of Leksell’s social position was his net of personal relationships,

which included Bo Ax:son Johnson one of the owners and directors of the wealthy

Axel Johnson Group which during the relevant period owned the Studsvik nuclear

power plant, the Motala Verkstad engineering workshop, and the Avesta Jernverk

a workshop which also specialized in metal work The Johnson Group thus owned

all the industrial facilities which would be required to manufacture a radiosurgery

machine While there remains evidence of a detailed and comprehensive interest

on the part of the Swedish state to ensure the new machine’s specifications and

patient safety were acceptable, there was no financial assistance from the state

The contribution from national coffers was limited to grants for the research work

in Uppsala during the 1950s and 1960s which would form the basis for proceeding

with a commercially produced machine Thus, Leksell’s relationship with senior

levels of the Axel Johnson concern was a happy chance for the development of

the original gamma unit, leading to the entirely private financing of the machine’s

development and manufacture arising out of respect Bo Ax:son Johnson had for

Leksell’s work

In conclusion, it should be remembered that the nature of scientific advance

means that a day will come when the Gamma Knife Perfexion is not the best

instru-ment for its purpose However, that day has not come yet and there is no sign that it

will come soon

vii Preface

The author would like to thank the following people without whose invaluable advice

and assistance this book could not have been written First, Dr Dan Leksell, the son

of the inventor of the Gamma Knife, has been free with information about the early

days of radiosurgery and has given access to relevant papers which would otherwise

have been inaccessible He has also been an invaluable adviser on textual purity

Next, there is Dr Bert Sarby a physicist who was intimately involved in the

devel-opment of the early gamma unit and has given freely of his time and his literature to

ensure the accuracy of the text Hans Sundquist, the engineer who turned the ideas of

designers into practical machines, has also listened to the author’s questions and

an-swered promptly and concisely whenever approached I should like also to extend

my gratitude to Dr Rich Levy from Berkeley who was generous with his time

and information about cyclotron radiosurgery Finally, to my old friend Ju¨rgen Arndt

another physicist with whom I have roamed the world teaching the practice of

radio-surgery from Mexico to Tokyo via Beijing He has repeatedly advised on the

evolving text

All of the above persons have not only advised on this project but also have read

through the text to ensure their information is correctly relayed It would be remiss of

me if I did not also thank Professor Erik Olof Backlund, my chief in Bergen and my

mentor in the mysteries of radiosurgery He has been a kind and consistently

enthu-siastic support over the years and has also been helpful in supplying valuable and

otherwise unavailable details from the early days

Finally, I should like to thank my wife, Gao Nan Ping or Annie Gao, as she is

known to her many friends in the radiosurgery milieu The wife of any man writing

a book has to put up with the absences, trips, and changing moods of the author as he

pursues his aims Without Annie this book could not have been written

xv

Background knowledge

Abstract

The purpose of this chapter is to outline the medical facilities that were available to the

inven-tors of radiosurgery at the time when the technique was being developed This is achieved by

describing in brief the timeline of discoveries relevant to clinical neurology and the

investi-gation of neurological diseases This provides a background understanding for the limitations

inherent in the early days when investigations and imaging in particular were fairly primitive

It also helps to explain the choices that were made by the pioneers in those early days The

limitations of operative procedures and institutions designed to treat neurological diseases

are also mentioned

Keywords

clinical neurology, radiology, contrast studies, operating theaters, neurological hospitals

Radiosurgery was first defined by Lars Leksell in the following terms: “Stereotactic

radiosurgery is a technique for the non-invasive destruction of intracranial tissues or

lesions that may be inaccessible to or unsuitable for open surgery”(Leksell, 1983)

As stated in this section, no human activity occurs in a vacuum including the

devel-opment of medical technology Radiosurgery was developed out of the perceptions

and efforts of a small group of men who passionately believed that such a method

was urgently needed in the battle against a large number of contemporaneously

untreatable diseases The possibility of developing radiosurgery was a spin-off of

the developing field of nuclear physics, which was such a characteristic development

of the first half of the twentieth century What was required would not be clear at the

start, but would become so There were five essential elements The first chapters of

this book concern the journey toward understanding and eventually the

implemen-tation of these elements; and it was a long journey:

Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00001-6

1 Images that enable the visualization of the lesion to be treated are an essential part

to determine These tests require tuning forks that had been originally invented byJohn Shure (ca 1662–1752) reaching the advanced age for the time of 90 years

He was distinguished enough that parts were written for him by both Ha¨ndel andPurcell (Shaw, 2004) It was applied to neurological testing first in 1903

(Freeman and Okun, 2002) The ophthalmoscope was invented by Helmholtz in

1851(Pearce, 2009) It was developed and its source of illumination was improvedover succeeding decades During my time at the National Hospital for Nervous Dis-eases, Queen Square, London, I was told that such was the value given to ophthal-moscopy that there was a time when junior doctors at Queen Square were required toexamine the fundus of patients suspected of raised intracranial pressure (ICP) every

15 min In 1841, Friedrich Hofmann invented the otoscope(Feldmann, 1995, 1997)

In the 1930s, the examination of the CNS was becoming fairly precise and thisprecision would improve over the decades to come until the arrival of computerizedimaging in the 1970s and 1980s Until then, clinical examination was the most ac-curate method for localizing pathological processes However, not all clinical symp-toms arise from identifiable foci of diseases Thus, subacute combined degeneration

of the cord gives a complex picture with some tracts affected more than others

Again, in multiple sclerosis, with intermittent lesions varying in time and space, a

simple localization from clinical information would be difficult However, this is

not that important for the performance of a surgical technique of which radiosurgery

is one because surgical conditions are single and focal in the vast majority of cases

The advances described in the previous paragraphs greatly increased the accuracy

with which a skillful clinician could localize the position of a pathological process

within the CNS Even so, the first systematic monograph on clinical neurological

localization was published as late as 1921 by a Norwegian, Georg Herman

Monrad-Krohn (1884–1964), writing in English(Monrad-Krohn, 1954) In 1945,

the more or less definitive text by Sir Gordon Holmes (1876–1975) was published

(McDonald, 2007)

3.1 ELECTRICAL

As far as functional investigations were concerned, electroencephalogram (EEG)

became commercial in 1935 and electromyography (EMG) arrived in 1950

3.2 IMAGING

In terms of further radiological investigations, the first visualization of the CNS came

with the use of contrast-enhanced X-ray studies introduced by Cushing’s student

Walter Dandy (1886–1946), specifically pneumoencephalography (1918)(Dandy,

1918)and pneumocisternography (1919)(Dandy, 1919) While these examinations

were undoubtedly an improvement, yet to modern eyes, they still look primitive

Then, in 1927, came carotid angiography that while a further improvement was still

limited and not without risk Vertebral angiography became routine in the early

1950s A brief description of the way these methods works follows Since the first

radiosurgery information was published in the early 1950s, it is necessary to see how

the necessary imaging for radiosurgery could be achieved at that time If we bear in

mind that the technique was solely used for intracranial targets, there were basically

three imaging techniques

3.2.1 Plain Skull X-Rays

Plain skull X-rays existed but were of little value in showing targets suitable for

ra-diosurgery The right side ofFig 4shows an X-ray of the skull, taken from the side,

and indicates that the only reliable location of an intracranial soft tissue is the

posi-tion of the pituitary gland (see Figure 4)

Following 1918, it became clear that parts of the brain could be demonstrated

using what are called contrast media These are fluid substances (liquid or gas) that

affect the passage of X-rays through the skull Either they let the rays pass more

easily, in which case they will darken the part of the image where they are, or they

will stop them passing so easily, in which case the portion of the image-containing

3

3 Investigations

medium will appear lighter The most frequently used medium in this context was airand how it worked requires some explanation.

3.2.2 Brain and CSF Anatomy

It is necessary to digress a little and explain some facts about intracranial anatomy.The brain sits tightly enclosed within the skull but it is floating in a bath of fluidcalled cerebrospinal fluid (CSF) This is created at roughly 0.32 ml/min Figure 1

is a diagram of the anatomy of the brain and the fluid-filled spaces (called ventricles)that it contains.Figure 2illustrates how the CSF is made in the ventricles and flowsthrough the brain It leaves the ventricles and flows over the brain between two mem-branes, the pia mater and the arachnoid The pia mater means soft mother and iscalled that because it embraces the brain as a mother embraces her child The arach-noid is so called after some imaginative anatomists looking through the microscopeconsidered that the membrane and the space under it looked like a spider’s web InGreek mythology, a skillful but arrogant young lady called Arachne challengedAthena, the goddess of among other things weaving, to a weaving contest The girlinevitably lost and was turned into the world’s first spider Thus, spiders are calledarachnids and this explains the use of the term arachnoid in the current context

It should be remembered that at any one time, there is about 150 ml of CSF inthe system and two-thirds of it is outside the brain in the subarachnoid space.3.2.3 Contrast Studies: CSF Replacement Studies

Let us return to imaging Plane X-rays were of little help, but in 1918, Cushing’spupil Walter Dandy had discovered that the introduction of air to replace the CSFcould provide demonstration of the ventricles of the brain and any distortions or dis-placements of that system The air could be introduced either into the spinal canal

FIGURE 1

This diagram illustrates the shape of the ventricles within the brain There are two lateralventricles to the side of the midline in each cerebral hemisphere, and the third and fourthventricles in the midline are connected by the aqueduct

using a spinal tap(Compston, 2009)or via a burr hole enabling direct access to the

cerebral ventricles The air replaces the CSF, and since it absorbed X-rays less than

the watery CSF, the ventricles could be outlined The appearance of a

pneumoence-phalogram (as this examination was called) is shown inFig 3 It must be obvious

from these images that the findings would not be easy to see and would require great

experience and expertise to interpret reliably

Attempts were made to use positive contrast media These are fluids that absorb

X-rays more than CSF and thus show as a positive or white shadow It took time to do

this as many of the early fluids were too toxic but eventually a water-soluble medium

was discovered, called metrizamide Even so, the sort of anatomical information that

could be derived inside the brain from these different methods was too imprecise for

radiosurgical work However, there was another examination that could be used This

was the cisternogram (with either air or contrast medium) This placed air or contrast

in the subarachnoid space, over the surface of the brain The beauty of this was that it

could demonstrate the presence of tumors in the pituitary region and in the internal

auditory meatus In these regions, any tumor was closely related to the fixed skull

base so that its position could be reliably determined The two tumor types concerned

were the pituitary adenoma, which naturally enough was in the pituitary region (see

Figs 4 and 5), and the vestibular schwannoma (previously called the acoustic

neu-roma), which arises in the bony canal (internal auditory meatus) containing the

FIGURE 2

This picture illustrates the direction of circulation of the CSF, from production in the ventricles

to absorption in the big venous drainage channel, the sagittal sinus The straight black

arrows connect a label to the point labeled The curved black arrows indicate the flow of CSF

and the white curved arrows indicate the flow of blood

5

3 Investigations

hearing nerve on its way from the brain to the hearing receptors in the inner ear, asshown inFig 6 The superficial fixed location of these tumors made it possible topartially visualize them using cisternograms This is why they became two of theearliest targets for radiosurgical treatment Unfortunately, while there are images

of both pneumocisternograms and metrizamide cisternograms still available in lications from that time, they are not really helpful Their appearance is so unfamiliar

pub-to modern eyes, familiar with computed pub-tomography (CT) and magnetic resonanceimaging (MRI) they would not help to clarify their use and are thus not included inthis text

FIGURE 4

This figure shows that the pituitary fossa is at the base of the skull in the midline and is easy

to visualize even on a plain X-ray Insertion of metrizamide into the subarachnoid spaceenables outlining the contours of a tumor in this region

FIGURE 3

The ventricles can be seen from the front and side However, in view of the limited contrast ofthe air and brain, detailed visualization was difficult A precise technique like radiosurgerywould have little advantage from this method

FIGURE 5

This illustration shows the relationship of the pituitary gland to the undersurface of the

brain and the third ventricle above

FIGURE 6

The skull base anatomical specimen on the left shows the location of the internal auditory

meatus, which contains two balance nerves: the facial nerve and the hearing nerve Vestibular

schwannomas grow out of a balance nerve and compress the hearing nerve within the bony

confines of the canal The CT picture on the right shows these canals in a living patient,

although the luxury of this visualization was not available at the time of the early development

of radiosurgery However, the anatomy shown here illustrates how it would be possible to

reliably demonstrate the position of a tumor extending from the bony canal using contrast in a

cisternogram

7

3 Investigations

3.2.4 Contrast Studies: Contrast in Blood Vessels

Another available imaging technique was the angiogram, whereby the arteries andveins to the brain are shown This had been introduced in 1927 by the Portugueseneurosurgeon and Nobel Prize winner Egas Moniz (1874–1955)(Moniz, 1927) Thismethod is called angiography and consists of injecting a radiation opaque fluid intothe arteries, thereby visualizing them on X-ray film The method may be used toshow two things: abnormal blood vessels and distortion or displacement of bloodvessels Abnormal blood vessels in a tumor are illustrated inFig 7 Vessel distortion

It may be seen that these images are clearer and in many ways easier to interpret

than the air studies As far as tumors are concerned, the angiogram had no place to

play in the radiosurgical management However, there is a dangerous illness where a

defect in the development of blood vessels within the head produces a blood vessel

abnormality called an arteriovenous malformation (AVM) These may be treated not

only by microsurgery but also by radiosurgery An example of a case treated with

microsurgery nearly 40 years ago is shown inFig 9 The term microsurgery is

com-mon usage in the professional literature and has a specific meaning Prior to the

1960s, neurosurgery was carried out using a head light to focus illumination on

the operating field and loupes (spectacles with minor magnification of 2–3 times)

Zeiss had invented the operating microscope (OPMI 1) back in 1953, but it was

not taken up by neurosurgeons until the 1960s An operating microscope looks

noth-ing like a laboratory microscope First, it only magnifies up to about 20 times The

advantages with it however are twofold The surgeon is operating looking through

binocular eyepieces not unlike those used in binoculars The instrument is so made

that fiber-optic light is directed along the axis of the microscope so that the operating

field is magnified and beautifully illuminated The technique using this instrument is

called microsurgery Because it permits the demonstration of the anatomy in the head

far more clearly, it had a dramatic effect on increasing the success of surgery and

reducing complications

FIGURE 9

This figure shows the abnormal blood vessels of the AVM indicated by the black arrowhead

The image on the right taken 2 years after the left image shows the absence of the AVM, its

location indicated by the right arrowhead There are numerous small straight lines in the

image These are blood vessel clips used to close abnormal arteries They were standard

technique at the time this surgery was performed The reason that the second angiogram

was taken so long after the first was patient anxiety He was so scared of his AVM that even

after seeing the second set of images, it was another year before he summed up the

courage to go back to work This entirely rational anxiety needs to be remembered by those

who treat AVMs

9

3 Investigations

4 OPERATING THEATER LIMITATIONS

Over and above the limitations of diagnostic and investigative neurology in the1930s, there were practical difficulties in the operating room Neuroanesthesiawas primitive, with preference given to operating under either local anesthesia orether anesthesia The former permitted contact with the patient, which was for thattime the best indicator of the state of ICP Ether was known to be quite safe and isknown even today to have relatively little effect on the ICP Intravenous drips in-volved glass bottles and red rubber tubes, the use of which was cursed with febrilecomplications The rhesus blood groups had not been discovered so that proper bloodtransfusion was not available Indeed, there is a story concerning blood transfusion-related dangers during neurosurgery, told to this author in 1986 by Tormod Hauge,the then-emeritus professor of neurosurgery from Rikshospitalet in Oslo The sur-geon concerned was none other than Monrad-Krohn, mentioned above, who hadwritten a textbook of neurology in 1921 He had no particular surgical qualification

or experience For undetermined reasons, he decided to perform surgery on the head

of a patient at a time when blood loss was replaced from a suitable third party bydirect transfusion from body to body According to the story, the operation occurred

in one room and the prospective donor lay in the room next door connected by tubes

A time came when blood loss needed to be replaced However, the roof of the room inwhich the donor was lying was adorned with a chandelier, which at the criticalmoment fell from the ceiling inducing an instant incurable cardiac arrest in the donor.(It was also claimed that an attending nurse had a leg fracture.) The bloodless patientwas thus also not able to survive so that the procedure claimed a unique operativemortality of 200%

DEPARTMENTS

Early neurological departments were opened in the nineteenth century The first wasthe National Hospital for Diseases of the Nervous System including Paralysis andEpilepsy and later the National Hospital for Nervous Diseases at 24 Queen Square,London, opened in the spring of 1860(Colville) Neurosurgical departments camelater, and indeed, hospital neurosurgical practice comes in many forms, even todayranging from an outpatient clinic, to a section of usually a surgical or neurosciencesdepartment, to a fully independent neurosurgical department Thus, Harvey Cushingwas Moseley Professor of Surgery, not neurosurgery from 1912 to 1932 In Europe,Herbert Olivecrona was appointed professor of neurosurgery in a separate depart-ment located in the Serafimerlasaret hospital in 1935(Ljunggren) Both these giantstrained many of their juniors and also published their clinical and operative experi-ence extensively, thus creating written information and advice that could assist theirsuccessors to advance

6 CONCLUSION

The first steps in the direction toward clinical radiosurgery were not taken before the

early 1950s The need was there with high neurosurgical mortality but nobody had

any idea until after the Second World War as to how to approach the issue The next

chapters outline how appropriate technology came into being

REFERENCES

Colville, D UCL Bloomsbury Project Retrieved from

http://www.ucl.ac.uk/bloomsbury-project/institutions/national_hospital.htm

Compston, A., 2009 A short history of the clinical neurology In: Donaghy, M (Ed.),

Brain’s Diseases of the Nervous System, 12th ed Oxford University Press, Oxford,

Feldmann, H., 1995 From otoscope to ophthalmoscope and back The interwoven history of

their invention and introduction into medical practice Pictures from the history of

otorhi-nolaryngology, illustrated by instruments from the collection of the Ingolstadt German

Medical History Museum Laryngorhinootologie 74 (11), 707–717

Feldmann, H., 1997 History of the tuning fork I: invention of the tuning fork, its course in

music and natural sciences Laryngorhinootologie 76 (2), 116–122

Freeman, C., Okun, M.S., 2002 Origins of the sensory examination in neurology Semin

Neurol 22 (4), 399–408

Koehler, P., 2007 Joseph fe´lix Franc¸ois babinski In: Bynum, W.E., Bynum, H (Eds.),

Dictionary of Medical Biography vol 1 Greenwood press, London, pp 142–143

Lanska, D.J., 1989 The history of reflex hammers Neurology 39 (11), 1542–1549

Leksell, L., 1983 Stereotactic radiosurgery J Neurol Neurosurg Psychiatry 46, 797–803

Ljunggren, B Herbert Olivecrona Retrieved fromhttp://www.nad.riksarkivet.se/sbl/Presenta

tion.aspx?id¼7720

McDonald, I., 2007 Gordon Holmes lecture: Gordon Holmes and the neurological heritage

Brain 1 (Pt 1), 288–298

Moniz, E., 1927 Ence´phalographie arte´rielle, son importance dans la localization des tumeurs

ce´re´brales Rev Neurol 2, 47–61

Monrad-Krohn, G.H., 1954 The Clinical Examination of the Nervous System H.K Lewis,

London

Pearce, J.M., 2009 The ophthalmoscope: Helmholtz’s Augenspiegel Eur Neurol 61 (4),

244–249

Shaw, W., 2004 Shore, John (c.1662–1752), rev Oxford Dictionary of National Biography,

Oxford University Press, Oxford Retrieved from, http://www.oxforddnb.com/view/

article/37955

11 References

Some physics from 550 BC

Abstract

This chapter outlines terminology and its origins It traces the development of physics ideas

from Thales of Miletus, via Isaac Newton, to the nuclear physics investigations at the

begin-ning of the twentieth century It also outlines the evolving technology required to make the

discoveries that would form the basis of radiosurgery Up to the 1920s, all experiments on

atomic structure and radioactivity had involved the use of vacuum tubes and naturally

occur-ring radioactive substances There was a need to make useable subatomic particles to obtain

better understanding of the interior structure of atoms Because of this, machines that could

make atoms move at high speed were invented, known as particle accelerators A new era

had dawned There is a brief mention of the effect of radiation on living tissue and of the units

used to measure it

Keywords

physics history, vacuum tube experiments, accelerators, units

It is a truism that radiosurgery could not be possible without understanding radiation

This chapter concerns the expanding knowledge of atomic structure and the radiation

discovered during the research into this topic This radiation is called electromagnetic

So where and how did this term originate? The importance of this for the current

purpose lies in the way in which subatomic structure came to be understood before

machines existed that were designed to split up the atom into its various components

2.1 ANCIENT WORLD

While modern nuclear physics uses mainly particle accelerators of different kinds in

its research, there was a period prior to the invention of these machines when other

methods had to be used In a sense, knowledge about the relevant phenomena extends

Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00002-8

back to the time of the ancient Greeks, indeed to the first of the pre-Socratic ophers, Thales of Miletus (ca 624–546 BC) This sage is said to have predicted aneclipse He measured the height of the pyramids using a method applied in moderntimes to measure the height of the mountains of the moon (Sagan, 1980) He alsoobserved the attraction that lodestones, or loadstones, exert on iron This stone con-tains Fe3O4(magnetite), which is magnetic in its natural state The namemagnetcomes from Magnesia in Thessaly—on the east side of mainland Greece—the loca-tion of deposits of magnetite (Da Costa Andrade, 1958) Magnesium, manganese,and milk of magnesia, that appalling peppermint-flavored concoction beloved bymothers whose children have indigestion, have the same root The magnesia in thispunishment for ill health is MgO, magnesium oxide, which is also considered to be anecessary component of the philosopher’s stone (Fig 1).

philos-Thales also noted that if amber is rubbed with fur, it acquires the property ofattracting small pieces of paper and other light articles (Semat and Katz, 1958).Theancient Greek word for amber was elektron, hence the name of electricity De-spite his genius, Thales would seem to have been an archetypal absent-minded pro-fessor Writing over 150 years later, Plato put the following words into Socratesmouth: “Why, take the case of Thales, Theodorus While he was studying the starsand looking upwards, he fell into a pit, and a neat, witty Thracian servant girl jeered

at him, they say, because he was so eager to know the things in the sky that he couldnot see what was there before him at his very feet The same jest applies to all who

FIGURE 1

A small map to illustrate the location of Magnesia

14 CHAPTER 2 Some physics from 550 BC to AD 1948

pass their lives in philosophy” (Fowler, 1921) Thus, curiosity about and knowledge

concerning electricity and magnetism have been of interest for millennia After this

early work, little happened until the time of Isaac Newton (1643–1727)

2.2 NEWTON TO THE NINETEENTH CENTURY

Following the time of Newton, there were several threads of research that would over

time combine to give an understanding of the nature of electricity Some of the

re-search was directly related to electricity while some of it related to the nature of light

(Since light is today considered just one range of electromagnetic radiation, this is

not a problem for us, but in the years succeeding the insights of Newton, this

percep-tion was impossible.) So the acquisipercep-tion of understanding will be unavoidably

fragmented

Firstly, let us consider research aimed at better understanding electricity itself

A device called a Leyden jar was invented in 1746 that could store a very

consider-able charge of static electricity Such a device is called a capacitor However, while

this can release its electric charge, that discharge happens virtually instantaneously

A collection of these capacitors could provide a greater charge and Benjamin

Franklin (1706–1790) used this arrangement calling such a collection abattery,

taking a metaphor from a collection of military artillery Other scientists, particularly

Volta in 1800, invented a source of continuous electricity using a chemical cell

Thus, an electric current became available, rather than a discharge All of these

findings broadened the knowledge of some characteristics of electricity but not of

its intrinsic nature

Earlier eighteenth-century work with static electricity had shown that sometimes

electrified objects could either attract or repel each other Various theories were

pro-posed but it was Benjamin Franklin who suggested in 1747 that there was one kind of

electricity that could be added or removed from objects making the objects charged

If there was too much electricity, then the object had a positive charge, and if there

was too little, a negative charge Positively charged objects would repel each other as

would negatively charged objects but positive would attract negative It remained to

decide which kind was which He considered that rubbed glass had an excess of

elec-tricity and was positive He was wrong Elecelec-tricity in fact flows from negative to

positive according to Franklin’s classification, and this convention has been

main-tained to this day Thus, more characteristics have been learned Electricity could

be static or could flow It was positive or negative but still the essence of the

phe-nomenon remained obscure

Contemporary relevant research concerned the nature of light The physicists of

the time were faced with a problem They knew that sound waves vibrated the air and

that waves in water needed the water for their transmission However, the nature of

light was explained by two theories (particles according to Newton) (Newton, 1730)

and waves (according to Huygens) Today, it is known that light has some properties

of particles and some of waves, but that duality could not be known in the

seven-teenth or eighseven-teenth century

The above description is a pre´cis of the development of relevant research aboutelectricity or related topics from Newton to the beginning of the nineteenth century.During that century, further crucial advances were made Michael Faraday(1791–1867) discovered that moving electric fields could induce magnetic fieldsand vice versa Thus, they were seen to be two aspects of the same phenomenon.

It was from this discovery that it was possible for Faraday to develop an electric tor and dynamo and permit the construction of machines that could easily generateelectric current in a circuit over long periods All this research reached a climax withthe work of James Clerk Maxwell (1831–1879) who derived a set of equations thatdescribed all known behavior of electricity and magnetism The radiation thus be-came known as electromagnetic It may be noted that light, electricity, and magne-tism have the common characteristic that they can pass through a vacuum From amore modern point of view, it is understood that light is a form of electromagneticradiation that is different only in that the frequency and energy of that radiation areperceptible to the visual apparatus of living organisms The ability to cross a vacuum

mo-is a property of electromagnetic radiation in general and mo-is not limited to any ular frequency of the radiation It may seem a rather abstruse subject to present herebut it will be seen that vacuum tubes came to be of central significance in terms of theearly examination of subatomic structure (Fig 2)

partic-2.3 THE DEVELOPMENT AND APPLICATION OF VACUUM TUBES WITH ELECTRODES AT EACH END

1 The process started in 1855, when a glass blower Johann Heinrich WilhelmGeissler (1814–1879) contrived a method for producing a much superior vacuumthan had previously been possible

2 At the request of the physicist Julius Plu¨cker, he made vacuum tubes with pieces

of metal sealed into opposite ends These could be connected to an electriccurrent The end considered to be positively charged was called the anode and theend that was considered to be negatively charged was called the cathode, from theancient Greek words cathode meaning lower way and anode meaning upper way

It was Faraday who coined the terms

3 Passage of electricity through a partially evacuated vacuum tube containing some

gas produced light, the color of which depended on the gas concerned This is the

underlying mechanism of the familiar neon lights However, when there was a

virtually total vacuum, Plu¨cker noted that there was a greenish glow at the

cathode A later physicist, Eugen Goldstein (1850–1930), showed that the glow

was not dependent on either the gas evacuated to produce the vacuum or the

substance of which the electrodes were made Thus, he concluded the glow was

associated with the current itself and he called this emission cathode rays The

tubes producing them came to be known as cathode ray tubes

4 William Crookes (1832–1919) developed an even more thoroughly evacuated

vacuum tube and demonstrated cathode rays more clearly They traveled in

straight lines and could even turn a little wheel An object placed in the path

caused a shadow to appear in the glow they produced

5 The argument reemerged concerning whether cathode rays were waves or

particles If they were to be particles, they could carry a charge and would be bent

in an electric field If they were waves, then waves carry no charge and would not

deviate From the early 1880s, various experiments all suggested that they were

waves as they did not deviate in electric fields However, all the experiments

suffered from technical difficulties that were finally overcome by Joseph John

Thomson (1856–1940) who demonstrated that the rays were particles with a

negative charge

6 The degree of deflection of a particle in an electric field was proportional to the

mass of the particle, the velocity of its movement, and the charge it carries

A similar deflection will occur in magnetic fields but in different ways By

comparing the two kinds of deflection, Thomson could calculate the relationship

between charge and particle mass He could thereby work out the mass of a

single cathode ray particle for which he received the Nobel Prize in 1906

The particle came to be called the electron (Thirty-one years later, his son shared

the Nobel Prize in Physics for discoveries related to the diffraction of electrons.)

2.4 SUBATOMIC STRUCTURE

Thomson discovered that the mass of an electron was considerably smaller than that

of the smallest atom This blew a huge crater in the accepted wisdom that the atom

was the smallest possible component of matter It became necessary to accept that

atoms were made up of smaller structures At this stage, nobody had any idea about

the internal architecture of an atom Indeed, Thomson’s own idea was that an atom

was a featureless positively charged sphere into which electrons were embedded like

seeds in a cake Thus, for the time being, the nature of subatomic particles remained

unclear Nonetheless, since the electron has a negative charge and the atom was

known to be electrically neutral, the search was on to discover what part of an atom

contained this charge In this part of the march of ideas, chance played an

important part

2.5 EXPERIMENTS USING SPONTANEOUSLY RADIOACTIVE

Antoine Henri Becquerel (1852–1908) somewhat later was also investigatingfluorescence He used a known fluorescent substance, potassium uranyl sulfate, thatcontains one uranium atom He was wondering if fluorescent substances gave offspontaneous radiation, and to test this, he used an elegant but simple experimentalmodel He wrapped some photographic plates in black paper, which sunlight couldnot penetrate He placed this package in sunlight and placed a crystal of his fluores-cent crystal upon the package Sure enough, there was fogging of the plates suggest-ing radiation emanating from the crystal To confirm the finding, he planned to repeatthe experiments However, as happens in northern Europe quite a bit, there was a run

of cloudy days During this period, a package of film plates with a crystal on top waskept in a drawer It would seem that Becquerel could be impatient so he developedthe film after a few days without exposing it to sunlight and discovered that the plateswere strongly fogged in the absence of sunlight-induced fluorescence He reasonedthat the crystals must be giving off radiation independent of an external light sourceand he set about examining this phenomenon He found that the culprit was the ura-nium atom in the potassium uranyl sulfate Later, Marie Curie demonstrated that tho-rium, polonium, and radium and uranium had similar properties From now on, thenext steps of the research would continue using radioactive substances rather than avacuum tube After all, radioactive breakdown provided a spontaneous splitting ofthe atom into subatomic components

In 1899, the New Zealand physicist Ernest Rutherford (1871–1937) analyzed theradiation observing and quantifying its deflection and penetration and demonstratedtwo of its components as shown inFig 3 They were called alpha and beta particles.The alpha particles had poorer penetration than the beta The beta particles were soonshown to be electrons In the 1900s, Paul Ulrich Villard demonstrated the most pen-etrating of the rays, which were called gamma rays This left a query as to the nature

of the alpha particles They were positively charged and more massive than

18 CHAPTER 2 Some physics from 550 BC to AD 1948

electrons The research details do not matter here Various models of the atoms had

been proposed previously, but Rutherford provided convincing evidence that the

ma-jority of the mass of the atom lay at its center and that the mama-jority of the volume of

the atom was made up by circulating electrons Because he provided quantitative

evidence to underpin his concepts, he received the Nobel Prize in Chemistry in

1908 (Fig 3) The central portion was called the nucleus, which means little nut

in Latin Interestingly, it could be argued that he did some of his best work after

receiving a Nobel Prize, which is unusual He devised a method of separating and

accumulating alpha particles (using a specially adapted vacuum tube) showing them

to be helium nuclei He continued to search for the smallest positively charged

par-ticle to match the electron He found nothing that small but instead found the smallest

positively charged particle to have 1836.11 the mass of an electron This he called the

proton from the Greek word meaning first

The proton and electron had been demonstrated However, it became clear that all

atoms except hydrogen had a mismatch between charge and weight For example,

helium has two electrons and two protons The electrons having a mass of 1/1837

of a hydrogen atom do not contribute to an atom’s mass Yet a helium atom has a

mass of four hydrogen atoms There must be something else to account for that mass

A German physicist Walther Wilhelm Georg Bothe (1891–1957) bombarded

beryl-lium with alpha particles from polonium in the hope of splitting this very light atom

thereby releasing protons, which had not been done up to that time Beryllium was

attractive for the purpose being a very light element with very small nuclei Instead,

he produced very penetrating rays following this bombardment and assumed they

were gamma rays, since alpha particles do not penetrate well However, Fre´de´ric

Joliot-Curie (1900–1958) and Ire`ne Joliot-Curie (1897–1956) repeated the Bothe

FIGURE 3

The pattern of spontaneous radioactive decay as perceived by Rutherford The proportion of

the different components varies with different elements

experiment allowing the rays to strike paraffin This caused protons to be ejectedfrom the paraffin, an activity that did not happen with gamma rays The stagewas set for a new interpretation This was undertaken by James Chadwick(1891–1974) He thought that because the radiation ejected a massive proton, it must

be massive itself Yet it had no charge, so it was not a proton He suggested that thiswas the missing particle that accounted for the differences between atomic numberand atomic weight and it was called the neutron He received the Nobel Prize in 1935for this work (Fig 4)

Investigations into subatomic structure as outlined above had used vacuum tubes andnatural spontaneous radioactive processes that impose a limit on what was achiev-able To advance knowledge, more powerful instruments were needed that were spe-cifically designed to examine the internal structure of the atoms of matter Thequestion was how to make such a machine The first successful attempt was carriedout in Cambridge in 1929 by John Douglas Cockroft (1897–1967) and ErnestThomas Sinton Walton (1903–1995)

4 A DIGRESSION

We are now approaching the technology that would form the basis for radiosurgery

Before proceeding, a word or two are necessary on potentially confusing terms or

concepts Energy is a primary property of radiation be it electromagnetic radiation

or streams of particles For electromagnetic radiation, the energy increases as the

fre-quency of the radiation increases and the wavelength decreases Thus, in the visible

spectrum, the energy increases from red to violet No visible radiation can penetrate

the tissue that much Electromagnetic radiation of much higher energy and wave

fquency is required and these rays are called X-rays or g-rays It is important to

re-member that the intensity of radiation is not the same as the energy For example, a

bright red light does not contain radiation with a higher energy than a dim violet light

Intensity merely indicates the number of rays as opposed to their intrinsic energy For

electromagnetic radiation that moves at the constant speed of light, the ability to

pen-etrate the tissue depends on its energy The higher the energy, the more the radiation

can penetrate matter Only rays that penetrate matter can knock electrons off atoms

and produce ionization, which is a damaging process The damage is caused by the

moving free electrons pass through the tissues and in the process bump into and

dam-age large molecules, particularly DNA, which is made up of two long helical strands

held together by bridges If both these strands are damaged, the DNA can no longer

be used to convey genetic information at cell division and the cell is effectively

destroyed For electromagnetic radiation, the degree of ionization is related to the

energy of the rays There are three ways in which rays can ionize tissue, but by

far, the commonest in the context of radiosurgery radiation is called Compton

scat-tering It is illustrated inFig 5

For particles, the situation is different Particles have different masses and move

at different velocities In this context, speed is a more important parameter for

pen-etration than energy Thus, while a particles due to radioactive breakdown have a

high energy, they are slow and can be stopped by a sheet of paper Electrons are much

lighter but move much faster and can penetrate much further, although in terms of

say the human head, not that far Again, this behavior concerns the b particles

pro-duced by spontaneous radioactivity Particles that penetrate matter are always

ion-izing It follows that if a or b particles could be speeded up, they could acquire a

higher energy and then be more penetrating

A note about units is needed Volts (V), kilovolts (kV), or megavolts (MV) are

mea-sures of a potential difference that may be used to obtain various effects Electron

volts (eV), kiloelectron volts (keV), and megaelectron volts (MeV) are measures

of energy They could be converted into SI units of joules, but for the sake of

con-venience, this is not done Having said this, the situation is a little more complicated

For conventional linear accelerators, electrons are excited up to say 200 kV They

FIGURE 5

Compton scattering is the commonest mechanism of ionization in radiosurgery An incident high-energy photon knocks an electron off theouter shell of an atom This converts the atom to an ion (hence the term) The photon continues on its way, though with a lower level of energy.The free electron passes through the tissues and is the agent that damages the DNA producing cell death

then get to strike tungsten releasing X-rays using the mechanism of bremsstrahlung.

This means brake radiation The idea is that by suddenly stopping the electrons

(braking them), energy is released in the form of X-rays The X-rays so produced

will have an energy measured in eV or keV

Fowler, H.N., 1921 Theaetetus Translation of Plato in Twelve Volumes vol 12, Harvard

University Press, Cambridge, MA, Section 174a

Newton, I., 1730 Opticks or, a Treatise of the Reflections, Refractions, Inflections, and

Colours of Light, fourth ed William Innys at the West-End of St Paul’s, London, p 191

Sagan, C., 1980 Cosmos Macdonald Futura Publishers, London, pp 176–177

Semat, H., Katz, R., 1958 Electrostatics Chapter 22 in Physics University of Nebraska,

Lincoln, pp 413–426

Medical physics - particle

Abstract

This chapter outlines the early development of particle accelerators with the redesign from

linear accelerator to cyclotron by Ernest Lawrence with a view to reducing the size of the

ma-chines as the power increased There are minibiographies of Ernest Lawrence and his brother

John The concept of artificial radiation is outlined and the early attempts at patient treatment

are mentioned The reasons for trying and abandoning neutron therapy are discussed, and the

early use of protons is described

Keywords

particle accelerator, linear accelerator, cyclotron, radioisotopes, artificial radiation, neutron

therapy, protons

The events described above depended on radioactive events that occurred naturally

from already radioactive substances Further development in knowledge of atoms

would be facilitated by machines that could split atoms into subatomic components,

thus gaining knowledge of their structure The earliest such machine was designed in

Cambridge in the 1920s and is known as the Cockroft–Walton accelerator after the

inventors (Cockroft and Walton, 1932) They generated a potential of 800 kV and

used it to accelerate protons directed at a lithium target, which disintegrated the

lith-ium nuclei into two alpha particles What Cockroft and Walton had designed was a

linear particle accelerator Its descendants were to stimulate the active curiosity of a

brilliant scientist to use a different way of accelerating particles (Parker)

This is a story in which Scandinavians will play a central role The year is 1930 Far

from northern Europe in distant California, a strange-looking contraption has been

made The contraption was the first cyclotron It was made from bronze and sealing

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wax and was 4 in in diameter but could accelerate hydrogen ions to 80,000 V Itcosts $25 to make (Parker A) It will evolve into machines that will produce profoundchanges to a world, which is largely unaware of its existence The man who made thisfirst cyclotron was Ernest Lawrence, a 27-year-old American physicist (Fig 1) In

1929, he read an article in German (Widerøe, 1928) by the Norwegian physicist RolfWiderøe (1902–1996) who was much involved in the design of early linear particleaccelerators (It is rumored that Lawrence read the article to stave off boredom at ameeting.) He had a limited grasp of German so he could not read the article easily.However, he was fascinated by a diagram, which made him think that increasing thepower of linear particle accelerators would eventually make them too large for con-venient use in a university environment Increasing the power of accelerators wasnecessary to gain a wider choice of beam energies to expand the range of experimentsand the knowledge thus acquired Motivated by this notion, a year later, he had builtthe contraption mentioned above and shown inFig 2 By bending a beam of particlesaround a spiral, it became unnecessary to increase the size of a particle accelerator somuch as to make it unmanageable The resulting machine was called a cyclotron Itwas first produced in 1930 and he received his Nobel Prize for the invention in 1939.Lawrence’s main area of interest was the use of a particle accelerator that could firesmall particles at other atoms producing changes that could help expand the knowl-edge of atomic structure He was intimately involved in the Manhattan Project to

FIGURE 1

Ernest Lawrence

build the first atom bomb, and in due course, he became the person to devise an

ef-fective way of separating uranium-235 from uranium-238 (Amaldi, 2008)

Lawrence went on to use cyclotrons of ever-increasing size The first had a 27-in

magnet and the final one a 184-in magnet Clearly, this activity required financial

support which Lawrence was expert at obtaining (Anon The Rad Lab) The support

was spread through private and public funding organizations Lawrence encouraged

the application of accelerators to clinical use as he realized it was easier to get

fund-ing for medicine rather than physics One private individual who allocated funds to

the Berkeley cyclotron was the industrialist William H Donner (1864–1953) He

established the International Cancer Research Foundation in 1932 in honor of his

son who died from cancer This institution gave grants to Berkeley establishing

the Donner Radiation Laboratory under the direction of Ernest Lawrence’s brother

John Lawrence, producing the seeds of what would become nuclear medicine Loss

of a loved one would seem to be a well-established motivation for the allocation of

funds for medical purposes Later on, the Rockefeller Foundation was approached

for support for the building of the 184-in cyclotron There is a report from the

foun-dation indicating how opinions fluctuated between those applying for a grant and

those in a position to grant it The document is a clear record of the importance

of human interaction because the grant was finally accepted on the basis of the

con-viction of certain of the applicants and the personal relationships within the

Rockefeller Foundation Informal meetings were of vital importance in gaining ceptance for the project (Hinokawa).

ac-After the war, the budget and administration of the cyclotron laboratory were cussed forward and backward and ended up under political supervision via the estab-lishment by Congress of the Atomic Energy Commission This indicates an unusualwillingness to allocate public funds for the purpose of scientific research Since therunning of the laboratory remained in the hands of the scientists, this was truly po-litical generosity towards the uncertainties of research on an unparalleled scale(Anon Cold War Science; Anon Lawrencein the cold war)

dis-Since the above paragraphs emphasize how the course of human endeavor ing science is shaped by the talents and personalities of individuals, short biograph-ical notes are included

Ernest Orlando Lawrence (Fig 1) was born in Canton, South Dakota, on August 8,

1901, to Gustavus and Gunda Lawrence, both were the children of Norwegianimmigrants and both were teachers Gustavus was also an inspector of schools.Gustavus’ father Ole Hundale Lawrence was a school teacher who came fromTelemark, the home of Norwegian skiing Gudrun’s father came from Lom inOppland County, in the Central Massif in Norway, between Oslo and Trondheim.Forty-eight percent of all mountains in Norway more than 2000 m high are inLom commune His name was Erik Jacobsen and he was a farmer in both Norwayand the United States Thus, the Scandinavian connection was still very close.Lawrence underwent a conventional education locally According to his mother,

he was “born grown up.” She also described him thus: “Ernest was always of a happydisposition and life to him seemed to be one thrill after another, but he was alsoalways persistent and insistent!” His best friend growing up was Merle Tuve, whowould also go on to become a highly accomplished nuclear physicist The two boysconstructed a very early short-wave radio transmitting station Lawrence would laterapply his short-wave radio experiences to the acceleration of protons (Amaldi, 2008)

In 1922, he started as a medical student at the University of Minnesota butswitched to physics and acquired a master’s degree in that subject in 1923 Hefollowed his mentor William Swann from Minnesota to Chicago and then to Yale.There, he acquired a PhD on the photoelectric effect in 1925 In 1928, he moved tothe University of California (Berkeley) and 2 years later became the university’syoungest full professor He stayed there with wartime intermissions for the rest ofhis life

He married once in 1932 his wife Molly and he had 6 children He was unusuallywell respected by his team of associates One of whom, Luis Alvarez, himself aNobel Prize winner wrote “For those who had the good fortune to be close to himboth personally and scientifically he will always seem a giant among men.”Nonetheless, he suffered from ulcerative colitis that finally killed him and the rigidly

systematic, serious workaholic personality he exhibited was in keeping with that

illness He sacked twice one of his associates for less than optimal routines but then

allowed him back into the fold This was Robert R Wilson of whom more later He

was also rigidly correct with regard to financial rewards arising out of his inventions

He patented the cyclotron but never asked for royalties (Hinokawa) He invented the

calutron isotope separator for separating uranium-235 from uranium-238 for the

manufacture of atom bombs He assigned the patent rights to the US government

for one dollar (Kovarick and Neuzil)

Thus, while he would seem to have been something of a martinet, he generated

much respect and affection Part of this paradox may be the result of his being

intel-lectually generous and always willing to argue and accept that he might be in error

He was an unusual, complex, but exceedingly talented person

Although Ernest Lawrence was the more famous, his younger brother John Hundale

Lawrence (Fig 3) is of more relevance to the matters under advisement here He was

born on 7 January 1904, just 2½ years younger than his elder brother He recounts

how he lived in a secure home where discipline was by example His father Gustavus

was a gifted classicist and, while religious, was not fanatical A drink was permitted

on occasion His father was also mindful of the politics of the day His mother was a

mathematician and was the motivator for John and Lawrence to succeed in life ever, neither parent helped with homework Another influence in his young life wasthe family doctor who was instrumental in getting him interested in medicine, and hemaintained that his interest in a career in medicine arose during childhood and neverleft him.

How-He tells that his first 2 years at the university was not successful, involving ketball and a girlfriend Thereafter, he buckled down and set his sights on HarvardMedical School, which was considered the best This was a fateful decision becausethere he met of all people Harvey Cushing Cushing was the world’s leading neuro-surgeon having virtually founded the specialty (Fig 4) His prestige was based ondrive, intellect, and a formidable surgical technique In any medical activity duringhis lifetime, his support would have been of considerable value Cushing showed apersonal interest in John Lawrence In his fourth year as a student, Cushing per-suaded him to do an internship in his laboratory When he asked Cushing what hewas to do about his MD qualification, Cushing told him “I’ll take care of that.”

bas-So he did not finish his fourth year but he got his MD He wrote a couple of paperswith Cushing, and when the internship was over, he told Cushing he was quite sure hedid not want to do surgery Cushing arranged a medical residency at the University ofRochester without Lawrence having to endure a medical internship After a year,

FIGURE 4

Harvey Cushing, the father of modern neurosurgery

Lawrence found Rochester rather provincial so he moved to Yale Cushing retired

from Harvard at the age of 65 and came to Yale as professor of the history of

med-icine but still had patients including patients with Cushing’s disease Lawrence

be-came deeply involved in their management, thus stimulating an interest in

endocrinology At that time, Cushing’s disease was treated with radiation

Later, when John Lawrence was a senior medical resident, the closeness of his

personal relationship with Cushing was shown by his being allocated to care for

the old man when he was a patient in the hospital, a most unusual arrangement

Around this time, Cushing met Ernest Lawrence and under discussions stated of

ar-tificial radiation “This is going to be as important, if not more important, as Pasteur

and bacteriology.” Cushing was close enough to Ernest Lawrence to help him

pre-pare his first commencement address Cushing advised John Lawrence to become

involved with radiation in Berkeley and was instrumental in persuading him to move

to California He quotes Cushing as saying “You are pioneering in a very exciting

new field, which will have a tremendous impact in medicine Go to it” (Hughes,

1979–1980)

In the early 1930s, there was much anxiety related to radiation because the “radium

girls” case had been settled only a few years earlier in 1928 (Shank) This was the

case that ended with considerable compensation to women who had painted radium

onto the dials of watches and suffered various forms of radiotoxicity as a result The

right of individual employees to sue an employer for labor abuse was established by

this case John Lawrence started using the cyclotron to make radioactive isotopes by

firinga particles at substances This was a continuation of the methodology in use

prior to the invention of accelerators, whena particles produced by spontaneous

ra-dioactive breakdown were the only heavy particles available With the isotopes, he

was usingartificial radiation He was insistent that while a particles were used to

produce the isotopes, these were not themselvesa emitters Since there was no

sub-stance involved that could be permanently deposited in bone or other tissues, there

was no risk He also mentioned later that over 20 years, he saw no such delayed

complications

The first clinical application of the cyclotron was treatment with radioactive

iso-topes The first patient treated with a radioisotope had chronic lymphatic leukemia

and on Christmas Eve 1936 received phosphorus-32 The patient was still alive in

1979 at the age of 74 and Lawrence was immensely proud of this success

(Ouellette) The use of the cyclotron in nuclear medicine in the first few years

31

6 First cyclotron-related patient treatment

was limited to the production of isotopes These were used in physiological studies,diagnostic studies, and, as indicated above, medical therapy Lawrence published amonograph on this topic in 1950 having delivered the material in 1949 as a lecture tothe New York Academy of Medicine (Lawrence, 1950).

2 MeV, compared with the 10 MeV used today

Neutrons are transiently important in this account as they were the first particles to

be used for therapy This followed some experiments on mice with tumors in the1930s Using whole-body neutron radiation, it was shown that cancer cells werekilled at a lower dose than that that killed the mice This is the reverse of what would

be expected, since the tumor cells are hypoxic and would be expected to be sistant However, nobody was aware at that time that for densely ionizing radiationslike neutrons, oxygenation has either no or a much reduced effect on radiosensitivity.Indeed, there was not yet general awareness of the oxygen effect While it had beenrecorded in the German literature from the early 1920s, it did not permeate to theEnglish language literature until a decade or so later (Hall and Giaccia, 2012).The neutron therapy was managed by a colleague of John Lawrence, a distin-guished radiotherapist called Robert Stone The therapy was carried out for awhile but it had a high complication rate Then, the war came and the treatmentswere stopped In retrospect, it was considered that the dose had been far toohigh, based on ignorance of the associated phenomena at the time (Asimov,1991; Hughes, 1979–1980) The relative biological effect of neutrons was notablyhigher than that of photons, which was positive However, there were many prob-lems with neutron therapy since the particles cannot be directed and collimatedlike charged particles and spread in every direction Thus, a differential dose be-tween tumor and tissue based on selective geometry would be nigh on impossible

radiore-to achieve, and therapeutic success would be based on differential radiosensitivitybetween the tissues and the tumor After the war in 1948, in a Janeway lecture,

Dr Stone recommended that neutron therapy should be discontinued and notrestarted (Hughes, 1979–1980)

8 PRINCIPLES OF EARLY MEDICAL APPLICATIONS

OF THE CYCLOTRON: PROTONS

In 1946, 2 years before Stone’s Janeway lecture, a different approach had been

suggested by Robert Wilson (1914–2000) In 1946, he published a paper on

the advantages of using high-energy (fast) protons as a radiation therapy tool

(Wilson, 1946) He used the phrase narrow beams in his paper, maybe for the first

time He also described the very important way in which a proton beam continued

without spreading until it reached the end of its path (Ouellette)

Robert Wilson was a high profile figure who had a difficult time at the Berkeley

Laboratory He was twice sacked by Ernest Lawrence for errors arising from a

cav-alier attitude (Weart) He twice returned He was a genuine horse riding cowboy It is

reasonable to assume his very American rather physical attitude to life was at odds

with the introspective, obsessional martinet that Lawrence was However, he also

wrote that Lawrence had a big heart After working in Berkeley, he was chosen

to head up the new Fermilab to which he contributed sculptures When being

con-sidered for the appointment, he said he wanted to do research not administration, and

when Fermi tried to persuade him otherwise, he responded that Fermi would not have

accepted the job and he was following in the master’s footsteps Fermi replied “It’s

something you have to earn, and you’re not Fermi yet.” During a senate hearing

where there was an attempt to reduce government spending on large physics

facil-ities, he was asked if a cyclotron had any value with respect to the security of the

country He replied no The senator asked him “It has no value in this respect?”

to which he replied “It has only to do with the respect with which we regard one

an-other, the dignity of man, our love of culture It has to do with: Are we good painters,

good sculptors, great poets? I mean all the things we really venerate in our country

and are patriotic about It has nothing to do directly with defending our country

except to make it worth defending” (Lawrence, 1950) A talented, articulate but

opin-ionated man!

Wilson was interested in a special property of particle beams, which differs

from photon beams Photon beams have no actual mass and move at the speed

of light never slowing down, though they can disappear on absorption Particle

ra-diation consists of particles with mass Thus, they can and do slow down With

charged particles, the beam traverses the tissue with relatively little transmission

of energy to the tissues (a low linear energy transfer), but at a given distance

depending on the speed and nature of the particle, they decelerate over a limited

very clearly defined region, depositing most of their contained energy This

phe-nomenon is called the Bragg peak after its discoverers William Henry Bragg

(1862–1942) and his son William Lawrence Bragg (1880–1971) (Figs 5 and 6)

Wilson’s work stimulated the Berkeley team to use protons to treat diseases within

the head but not initially in the way he suggested How the beams were used is

con-sidered in the next chapter

33

8 Principles of early medical applications of the cyclotron: protons

Amaldi, U., Amaldi, U., 2008 History of hadrontherapy in the world and Italian

develop-ments Riv Med 14 (1), 7–22

Anon Cold War Science AIP Center for History of Physics Retrievedhttp://www.aip.org/

Cockroft, J.D., Walton, E.T.S., Cockroft, J.D., Walton, E.T.S., 1932 Artificial production of

fast protons Nature 129, 242

Hall, E.J., Giaccia, A.J., 2012 Chapter 6 ‘Oxygen Effect and Reoxygenation’ in Radiobiology

for the Radiologist Lippincott Williams & Wilkins, New York, pp 86–103

Hinokawa, S The Rockefeller Foundation’s decision-making process in funding the 184-inch

cyclotron (translated Sugihara B) Retrieved fromhttp://www.rockarch.org/publications/

Ouellette, J Cocktail Party Physics: Robert Wilson, the gun-toting physicist who helped

give us the particle accelerator Retrieved from

Weart, S Oral history transcript—Dr Robert R Wilson Niels Bohr Library & Archives

Retrieved fromhttp://www.aip.org/history/ohilist/4972.html

Widerøe, R., 1928 U¨ber Ein Neues Prinzip Zur Herstellung Hoher Spannungen” Arch

Elektron U¨ bertrag 21 (4), 387–405

Wilson, R.R., 1946 Radiological use of fast protons Radiology 47 (5), 487–491

35 References

From particle accelerator

Abstract

This chapter outlines the requirements for machines that could perform radiosurgery It also

outlines the characteristics of the narrow beams used for this method The reasons for limiting

human treatments to the pituitary fossa are justified The experiments, the results of which

determined what was possible clinically, are outlined The two methods of delivery of focused

radiation are discussed: Bragg peak and beam crossover

Keywords

radiosurgery technical requirements, beam characteristics, animal experiments, clinical

indi-cations, techniques of radiosurgery

At the beginning of the 1950s, the Berkeley group had been using cyclotrons of

increasing size and power up to a 184-in machine In the development of this

new technology, five properties of radiation needed to be considered:

1 Images that enable the visualization of the lesion to be treated are an essential

part of the method

2 A three-dimensional reference system common for imaging, treatment

planning, and treatment

3 A treatment planning system by means of which the irradiation of each case

can be optimized

4 A means of producing well-defined narrow beams of radiation that selectively

and safely deliver the dose under clinical conditions

5 Adequate radiation protection

Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00004-1