The Antibody Molecule: From antitoxins to therapeutic antibodies

385 Pages·2015·9.73 MB·English

by  Antony R. Rees

The Antibody Molecule
Oxford Medical Histories Series
This series of Oxford Medical Histories is designed to bring to a wide readership of
clinical doctors and others from many backgrounds a short but comprehensive text set-
ting out the essentials of differing areas of medicine. Volumes in this series are written
by doctors and with doctors, in particular, in mind as the readership.
History describes the knowledge acquired over time by human beings. It is a form of
storytelling, of organizing knowledge, of sorting and giving impetus to information.
The study of medical history, just like the history of other human endeavours, enables
us to analyse our knowledge of the past in order to plan our journey forward and hence
try to limit repetition of our mistakes — a sort of planned process of Natural Selection,
described as being in the tradition of one of the most famous of medical historians,
William Osler. Medical history also encourages and trains us to use an academic
approach to our studies which thereby should become more precise, more meaningful
and more productive. Medical history should be enjoyable too, since that is a powerful
stimulus to move forward, a fun thing to do both individually and in groups.
The inspiring book that led to this series introduced us to clinical neurology, genetics,
and the history of those with muscular dystrophy. Alan and Marcia Emery explored The
History of a Genetic Disease, now often styled Meryon’s disease rather than Duchenne
Muscular Dystrophy. The first to describe a disease process is not necessarily the owner
of the eponym but the Emerys are helping put that right for their subject, Edward
Meryon. The second book in the series, on radiology, took us on a journey round a
world of images.
Thus future volumes in this series of Oxford Medical Histories will continue the journey
through the history of our bodies, of their relationship to our environment, of the joyful
and the sad situations that envelope us from our individual beginnings to our ends. We
should travel towards other aspects of our humanity, always leaving us with more ques-
tions than answers since each new discovery leads to more questions, exponential sets of
issues for us to study, further thoughts and attempts to solve the big questions that sur-
round our existence. Medicine is about people and so is history; the study of the combina-
tion of the duo can be very powerful. What do you think?
Christopher Gardner-Thorpe, MD, FRCP, FACP
Series Advisor, Oxford Medical Histories
The Antibody
Molecule
From Antitoxins to
Therapeutic Antibodies
by
Anthony R. Rees
Principal
Rees Consulting AB,
Uppsala, Sweden
and
Professor Emeritus,
University of Bath, UK
1
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For my wife Marianne and Melissa, Emma, Charlotte, Madeleine,
Lucy, Bruno, and Margo
And in memory of my dear mother
‘‘ . . .  every effect is a distinct event from its cause . . . In vain, therefore,
should we pretend to determine any single event, or infer any cause and
effect, without the assistance of observation and experience”.
Reproduced from David Hume, Enquiries concerning the human understanding and concerning
the principles of morals., Reprinted from the 1777 edition and edited by L.A. Selby-Bygge,
2nd Edn. 1902, Impression of 1970. Oxford University Press.

Foreword
‘Another antibody book’ was the subject line of the email I received from Tony Rees
almost a year ago with a request that I consider writing the foreword. From his self-
deprecating email one would have thought that Tony was adding to the ponderous
pile of texts that have focused on this well-studied and even better documented mol-
ecule, texts that range from those purely methodological to those purely didactic. Was
there a need for yet another treatise on the antibody? Probably not. However, knowing
Tony’s work on antibody modelling and engineering as I did, and his intimate associa-
tion with antibody-based technologies, I suspected something more interesting must
have been brewing. Indeed it was. Tony set out to record an historical account of the
antibody molecule, from its first description in the late-nineteenth century to our cur-
rent infatuation with it as a therapeutic entity. What Tony succeeded in doing was to
capture a snapshot of the world of immunology and of the personalities that drove the
field, moving it from one purely descriptive to one based on molecular principles. His
account reads like a mystery novel, with all the drama that can be found with personal-
ity clashes, false starts and, at the end, resolution and clarity.
Several themes emerge from this historical perspective of immunology as glimpsed
through the antibody molecule. Immunology is, at its heart, a discipline inseparable
from the physiology of the organism. It interacts in a dynamic way with every organ
system, balancing its protective features with the unavoidable collateral damage that
accompanies the inflammatory response. Maintaining this equilibrium is key to sur-
vival of the organism; perturbations inexorably lead to pathology. To understand the
immune response one needed a holistic approach, a fact widely appreciated by its
early practitioners, but eclipsed during periods of reductionist fervour. The pendulum
swung up and back throughout the history of the antibody molecule, from in vitro
dissection to in vivo biology, coming to rest in this century at a synthesis of the two
approaches, with the advent of methods that permitted reductionism at the whole ani-
mal level through the use of recombinant DNA technology and the use of genetically
modified organisms. Detailed molecular dissection of the antibody molecule, the path-
ways that generate its remarkable diversity, and the systems that are recruited to medi-
ate its in vivo responses could be manipulated, engineered, and re-introduced into the
organism to interrogate the outcome. And with these tools came insights into genetics,
cell biology, and structural biology that continue to captivate not only immunologists
but also the wider community of scientists.
I was witness to this sea change in antibody research that began in the mid-1970s as
molecular biologists began to wield their formidable tools to approach the problem of
antibody diversity. The problem was clearly recognized-how could the organism encode
the required diversity of antibody molecules, on the order of trillions of different pro-
teins, if one accepts the prevailing viewpoint that each gene encodes only one protein.
viii foREwoRd
The genome is far too small to accommodate this genetic diversity. Remarkably clever
ideas were put forward to resolve this paradox by formidable intellects unaccustomed
to being challenged, yet which remained untestable and thus equally tenable. Enter
the gene cloners. They managed, in a few frenetic years, to bury elegant theories while
elevating others, revealing the power of combinatorial diversity inherent in the unique
organization of the antibody genes. As a young postdoctoral fellow in Phil Leder’s lab
at the NIH I had a front row seat to the spectacle, working at a time where each new
sequencing gel contained a result worth publishing, revealing V regions, J and D seg-
ments, recombination signal sequences, switch regions, and alternative splice sites. The
novelty of the genetic mechanisms that had evolved to generate the antibody repertoire
was breathtaking. The competition was fierce and the atmosphere charged, with each
new journal article, conference report, or casual discussion revealing one group now
pulling ahead, now falling behind. Tony’s book took me back to those remarkable days,
capturing the excitement of discovery and the eureka moments that can still bring a
chill to my spine. It’s fair to say that your never forget your first eureka.
Fortunately for those of us who have never gotten over our infatuation with this
remarkable molecule, its final history has not been written. Tony’s book has shown us
where we started and taken us to the point where we can glimpse where we might be
headed, but the inevitable twists and turns are certain to reveal new and unexpected
landscapes in biology.
Jeffrey Ravetch
The Rockefeller University
New York, NY
Preface
Immunology is one of the oldest of the medical sciences with a history that has seen
chemists, physicists, biologists, and clinicians alike seeking to unravel the most com-
plex system in the human body outside the brain. In this book I have not been so bold
as to try to replicate the erudition and breadth of immunology history in classics such
as those of Arthur Silverstein or Pauline Mazumdar. My objective was to take a chrono-
logical approach since for an amateur historian this was the easiest path along which
I could explore the byways of research in different fields that impacted our understand-
ing of this family of molecules. In doing so, I have uncovered what for me were many
surprises, having been raised on the traditional science history found in most standard
textbooks and scientific reviews. Where I express that ‘surprise’ in the text I have tried
to be as objective as possible but also not shy away from stating my personal interpreta-
tion where I believed it was justified.
While this has been a long journey of discovery it has also been one that has pro-
duced dilemmas. With a limit on the size of the book I decided to exclude areas that
may be considered by some to be of equal historical importance. For example, I do not
discuss in any great depth the tolerance debate, nor do I include to any great extent
the development of antibody control mechanisms. The T-cell receptor and major his-
tocompatibility antigens and their roles in antigen processing have barely a mention
except en passant. The fledgling field of epigenetics is perhaps too young to be able to
draw any meaningful conclusions as yet. To have expanded the story to include these
and other subjects would have opened a Pandora’s Box of quasi-relevant topics that are
best addressed in another place. I hope the reader will understand my rationale but at
the same time be excited and sometimes surprised by the beauty of antibody history,
created in its early years by giants of scientific endeavour and now exploited by a mul-
titude of scientists for the good of human health.
ARR
Uppsala 2014