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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
The combined effects of population growth and aging have led to an increase in the number of cancers. Preventing, diagnosing, treating and curing cancer are therefore, more than ever, imperatives facing medicine especially to continue the decrease in cancers mortality rates and to improve the quality of survival. Over time, the classic modes of treatment (surgery, external beam radiotherapy, chemotherapy) have become more refined and efficient. From the beginning of this century, new therapeutic options have been developed: targeted cancer therapy, targeted radionuclide therapy and immunologic therapies based on monoclonal antibodies, cellular therapy and vaccinations. Artificial intelligence and machine learning are also being introduced to the field of oncology. Starting with the basic scientific principles relevant to oncology, this book explains and makes these concepts and innovations accessible to a wide audience especially in the interest of patients. It also contributes to the oncological field of 4P medicine with 4P standing for predictive, preventive, personalized and participative.
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Table of Contents
Cover
Preface
Acknowledgments
Introduction
1 Genomics and Epigenetics
1.1. DNA, RNA and genetic code
1.2. Sequencing and genomics
1.3. Transcriptome and proteome
1.4. Epigenetics, the missing link
2 Overview of Cancer Chemotherapy
2.1. The introduction of an innovative method
2.2. Nitrogen mustards, the first revival
2.3. Anti-metabolites, the potential for chemotherapy finally revealed
2.4. Natural products in the first line
2.5. Cisplatin and organoplatin derivatives
2.6. An evolving therapeutic approach
2.7. Targeted therapies
3 Immunology and the Immune System
3.1. From variolation to vaccination
3.2. The hegemony of the humoral theory
3.3. Towards a conciliation between cell theory and humoral theory
3.4. A complex and specific mode of action of a so-called adaptive immunity in collaboration with an innate immunity
3.5. Summary of innate and adaptive immune responses
4 The Development of Immunotherapy
4.1. Immunosuppressive treatments for graft tolerance
4.2. Hybridoma techniques for the production of monoclonal antibodies
4.3. Towards an understanding of the immune response (anti- and pro-tumor)
4.4. Antitumor immunotherapy
4.5. A promising path tending towards improvement
5 The Maturation of Artificial Intelligence
5.1. From Babbage machines to the universal Turing machine
5.2. Cybernetics, for an association between machine and physiology: towards the development of the first neural network
5.3. Cognitivism and the true emergence of artificial intelligence
5.4. From optimism to the first crisis
5.5. Expert systems, a renewed interest in AI
5.6. The return of neural networks: an optimal method of automatic learning?
5.7. A new crisis before a decisive rebound
5.8. Deep learning, an association between Big Data and neural networks: AI in another dimension
6 The Evolution of Cancer Therapy
6.1. Cancer surgery
6.2. External beam radiotherapy (or external beam radiation therapy)
6.3. Great innovations in one formula
6.4. Genomics and epigenetics
6.5. The new therapies of the 21st Century
6.6. Theranostics
6.7. Artificial intelligence (AI) and Big Data
6.8. “
In fine
”
Conclusion
List of Abbreviations
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1. Classification of cytotoxic anticancer agents
List of Illustrations
Chapter 1
Figure 1.1. DNA double helix (© MesserWoland, DNA structure and bases PL.svg, Wi...
Figure 1.2. The nitrogenous bases (A, G, C, T) are linked together by a phosphat...
Figure 1.3. Transcription and translation (© E. Jaspard, University of Angers)
Figure 1.4. Chromosomes, components of the genome present in cells, contain DNA....
Figure 1.5. Genome/transcriptome/proteome relationship
Figure 1.6. Epigenetic mechanisms (© public domain)
11
Chapter 2
Figure 2.1. DNA replication. The separation of the two DNA strands precedes the ...
Figure 2.2. Main mode of action of nitrogen mustards. The deterioration of nitro...
Figure 2.3. Molecular structure of the main nitrogen mustards used in chemothera...
Figure 2.4. Cellular mitosis. Through DNA replication, the same genetic material...
Figure 2.5. Influence of topoisomerases on DNA replication. Topoisomerases are u...
Figure 2.6. Action of different chemotherapy products according to ell cycle [AV...
Chapter 3
Figure 3.1. Representation of Paul Ehrlich’s theory (from Ehrlich’s reading to t...
Figure 3.2. Diagram of the structure of a type G immunoglobulin. Light chains (g...
Chapter 4
Figure 4.1. Diagram of the hybridoma technique invented by Kohler and Milstein f...
Figure 4.2. Antitumor immunotherapy with immune checkpoint inhibitor. Anti-CTLA-...
Chapter 5
Figure 5.1. Schematic architecture of the original perceptron: an artificial neu...
Figure 5.2. Schematic architecture of the multilayer perceptron. The so-called h...
Figure 5.3. Architecture of a convolution neural network. The term convolution c...
Figure 5.4. Internal structure of a convolution neural network
Guide
Cover
Table of Contents
Begin Reading
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Health and Patients Set
coordinated by
Bruno Salgues
Volume 2
Therapeutic Progress in Oncology
Towards a Revolution in Cancer Therapy?
Jacques Barbet
Adrien Foucquier
Yves Thomas
First published 2020 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.
Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:
ISTE Ltd
27-37 St George’s Road
London SW19 4EU
UK
www.iste.co.uk
John Wiley & Sons, Inc. 111 River Street Hoboken, NJ 07030 USA
www.wiley.com
© ISTE Ltd 2020
The rights of Jacques Barbet, Adrien Foucquier and Yves Thomas to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.
Library of Congress Control Number: 2019954831
British Library Cataloguing-in-Publication Data
A CIP record for this book is available from the British Library
ISBN 978-1-78630-493-3
Preface
As contributors to a research and development organization (Arronax GIP) that designs and manufactures radiopharmaceuticals for PET (positron emission tomography) medical imaging and cancer therapy, we felt the need and motivation to write a synthesis of a possible future of oncology approaches, to facilitate dialogue both internally and with our multiple partners from diverse backgrounds.
More generally, this book is intended to popularize new concepts and corresponding scientific and technological innovations in order to shed light on the cancer dimension of P4 medicine that is coming: predictive, preventive, personalized and participatory. It can only be participatory if patients and their families have a sufficient understanding of the new logics, issues, therapeutic strategies and machines that are emerging or will emerge in this field.
Despite our desire to make this book as accessible as possible for readers, it cannot be devoid of essential technical words that can be found, if necessary, on hospital websites or on the websites of major organizations dedicated to medicine and oncology such as the World Health Organization (WHO), the American Society of Clinical Oncology (ASCO), the National Cancer Institute (NCI), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the Institut national de la santé et de la recherche médicale (Inserm), the Institut national du cancer (INCa), the European Association of Nuclear Medicine (EANM), the Radiological Society of North America (RSNA), the European Society of Radiology (ESR), etc. In addition, we thought it would be a good idea to add, in some places, web links to videos of good pedagogical quality, to enhance the readers understanding.
In addition, the list of abbreviations can be consulted at the end of the book, and all abbreviated terms are explained in the text when they first appear.
In order not to be discouraged by the details and possible difficulties of the initial chapters, impatient readers can go directly to Chapter 6, returning to the previous chapters if a better understanding is required.
We finish with a warning. In this book we highlight and suggest probable futures with, of course, the risk of error. Finally, we must draw attention to this strong rule: we do not provide any advice to patients and have no legitimacy to suggest medical prescriptions. This is especially the case as some of the medicines mentioned in Chapter 6 may still be in clinical trials or may cause more or less controllable side effects at this stage.
Jacques BARBETAdrien FOUCQUIERYves THOMASNovember 2019
Acknowledgments
This book was developed as part of our missions within the Arronax GIP. We would like to thank the GIP management for the encouragement and assistance provided to us through projects ANR-11-EQPX-0004, ANR-11-LABX-18-01, ANR-16-IDEX-0007, SIRIC ILIAD and Horizon 2020 RIA-ENSAR2 (654 002).
Several of our distinguished colleagues have kindly contributed to this work through the exchange of knowledge and expertise. We would like to thank them warmly for this. We are thinking in particular of Gilles Blancho, Marc Bonneville, Jean-François Chatal, Michel Closset, Brigitte Dréno, Steven Le Gouill, Férid Haddad, Françoise Kraeber-Bodéré, Albert Lisbona, Eric Mirallié and Dimitris Visvikis.
Introduction
Cancer is, first of all, the Latin word for “crab”. The oldest mentions of cancer date back to the 7th Century BC, with the first descriptions of the priests of Aesculapius (or Asclepios), the Greek-Roman god of medicine, referring to abnormal lumps that cannot disappear on their own. With the name carcinoma, the Greek Hippocrates clarified by insisting on the ability of the cancer to spread continuously until the death of the patient, before the Roman Galien introduced the term tumor in the 2nd Century AD.
Today, cancer is often associated with numbers that must be carefully disseminated and interpreted. For France in 2018, INCa estimated the number of new cancer cases at 382,000 (274 per 100,000 women, 330 per 100,000 men, median ages 67 and 68 respectively) and the number of cancer deaths at 157,400 (72.2 per 100,000 women, 123.8 per 100,000 men, median ages 77 and 73 respectively) [INS 19]. All these figures, which are steadily increasing, make cancer the leading cause of death in France ahead of cardiovascular diseases.
The number of people living in metropolitan France in 2017 who were diagnosed with cancer during their lifetime was 3.8 million, for a population of 67 million inhabitants.
The World Health Organization reported for 2018: 18.1 million new cases of cancer worldwide and 9.6 million deaths from cancer. The forecasts for 2030 are 22 and 13 million respectively [ORG 18].
These developments, however worrying they may be, can be explained first of all by two reasons independent of oncology. The world population has increased considerably. From 1950 to 1980, it grew from 2.5 to 4.5 billion people. During this period, this increase was 70 million in the United States and 12 million in France. These increases are obviously correlated with the number of cancers today. When looking at the forecast number of cancer cases we should recall that the world population grew by 5 billion between 1950 and 2015.
Then, populations have aged and continue to age: from 1950 to 2015, the increase in life expectancy was more than 20 years, more than 27 years in developing countries and more than 13 years in rich countries. With the exception of the African region, life expectancy now ranges from 70 to 80 years, depending on the country.
Moreover, while progress can be noted here and there in prevention and early detection, in several countries around the world, there is also a deterioration in lifestyles and the environment that is beginning to provoke reflection and reactions, at least in rich or rapidly developing countries.
To have a realistic view of therapeutic progress in oncology, it is necessary to look at the incidence figures, i.e. the number of new cases of cancer reported annually per 100,000 inhabitants. In the United States, for the period 2011–2015, the NIH/NCI (National Institutes of Health/National Cancer Institute) reported an average of 439 cases with a mortality rate of 196.8 for men and 139.6 for women. These numbers are increasing, but mortality rates have declined significantly over the past 25–30 years, both in the United States and France, by about minus 1% per year. Moreover, these annual mortality rates have declined faster in recent years by, for the United States, minus 1.8% for men and minus 1.4% for women over 2005–2015, and, for France, minus 2% for men and minus 0.7% for women over 2010–2018, which could result in decreases of around 35% between 2005 and 2025 [NAT 18].
After this quantified inventory, we need to briefly examine the cancer development process. In the beginning, there is the cell, from the ancient Greek kutos which gave many terms with the prefix of cyto: cytology, cytoplasm, cytotoxic.
In humans, there are more than 200 types of cells. The number of cells constituting an adult human body is estimated at a few tens of trillions. A large part of these cells, 75%, are red blood cells and platelets found in the blood. Without nuclei, they do not divide. Other cells, including hematopoietic stem cells that are the source of all blood cells, can divide and generate new cells that replace the aging or dead cells (apoptosis) that the body gets rid of every day1.
To date, cancers (nearly 100 today) are mainly named after the organ or tissue they affect. The most frequently diagnosed cancers are breast, prostate, lung, colorectal, liver, bladder, skin (melanoma) and brain cancers. In hematological cancers (leukemias, lymphomas, myelomas), cells proliferate in the blood or invade hematopoietic tissues (bone marrow) or lymphoid organs (thymus, spleen, lymph nodes). Cancers are also classified by the type of original cells2. Then, they are referred to as carcinoma, sarcoma, lymphoma, glioma, etc.
The onset of cancer is the result of a series of complex molecular events that are beginning to be well understood. Six biological modifications can be defined that contribute to the transformation of a cell into a cancerous cell:
– ability to divide;
– escape from growth suppressors;
– resistance to cell death;
– replicative immortality;
– induction of angiogenesis;
– activation of invasion factors [HAN 11].
With the recent progress of research at the molecular level and with the current possibilities of genome sequencing, it is possible to observe genetic anomalies and changes in the expression of the genes responsible for the biological modifications. These genetic anomalies and mutations may be due to failure to repair the many natural genetic events and also to the way of life influenced by smoking, alcohol, bad UV exposure or exposure to carcinogens. These mutations mainly concern proto-oncogenes which positively control cell divisions but which can become oncogenic (cancer cell producers). Cell division is indeed a complex process, finely tuned by a small part of the 25,000 genes found in each cell. When this control is lost, the cell acquires the ability to divide indefinitely. These mutations also concern tumor suppressor genes, which inhibit cell proliferation, genes dedicated to DNA repair, which prevent mutations from accumulating, and genes that control the so-called programmed cell death or apoptosis.
Apoptosis is a mechanism in genes that eliminate cells that the body must get rid of, especially damaged cells. When this process is disrupted, cells continue to proliferate and accumulate to form malignant tumors called cancers. Finally, for cancer cells to invade surrounding tissues and eventually spread into metastases by leaving their original location through the blood or lymphatic networks, they must trick and block the immune system. This is the dreaded metastatic process.
The interest of genomics, immunology, cytological and histological analyses and multiple radiological imaging is becoming obvious. These analyses produce massive databases, and artificial intelligence (AI) must be used to take advantage of data from the patient and his or her type of cancer and to propose personalized treatments.
The diagnosis and treatment of cancer has undergone a major evolution in recent years, with several innovations that seem useful to elucidate and explain, particularly in the context of a new personalized and participatory medicine that should greatly involve the patient. This is especially so since these developments, driven by the now proliferating research, computing power and AI, could lead more or less quickly to a therapeutic revolution in cancer therapy.
Here is a brief overview of the six chapters of this book.
Chapter 1: Genomics and Epigenetics
Let us briefly recall some elements of genetics. In the human body, all cells capable of division contain 23 pairs of chromosomes that carry about 25,000 genes and constitute the individual’s genome. The chromosomes and therefore the genes are constituted by deoxyribonucleic acid (DNA) that contains pairs of nucleotides characterized by nitrogenous base pairs – adenine and thymine (A, T), guanine and cytosine (G, C) – arranged in two complementary strands wound in the shape of a helix.
The transcription of genes into messenger RNA (transcripts or transcriptome) then allows, through the genetic code, their translation into distinct proteins essential for the functioning of body cells. There can be several transcripts for the same gene, hence the existence of about one hundred thousand different proteins in the human body (the proteome).
When examining an individual genome, genetic abnormalities can be found: either they are widespread and inherited and they may cause genetic diseases or they concern only certain cells and they may cause cancer. In the latter case, the mutations are acquired and not transmissible or inherited. In this respect, cancer is also a genetic but so-called somatic disease.
Chapter 2: Overview of Cancer Chemotherapy
For 60 years, chemotherapy has been the first medication to treat cancer by killing cancer cells. A large number of cytotoxic products, synthetic or natural, have been developed and marketed after screening in in vitro studies, preclinical studies in laboratory animals, most often mice transplanted with tumor cells, and in several stages of clinical trials involving cancer patients. Besides proven efficacy, the main difficulty lies in the low specificity of the drugs, which affect all cells, particularly the normal cells that divide the most: the bone marrow cells that produce blood cells. Additionally, chemoresistance appears during treatment. Moreover, the patient often suffers from more or less serious and immediate side effects, such as digestive, renal or neurological disorders, and a weakening of the immune system that favors infections.
The objective of pharmaceutical companies today is to combat these difficulties by offering combinations of chemotherapies and developing functional drugs, such as those that prevent DNA replication, thus affecting rapidly proliferating cells as a priority. Finally, today, inhibitors that more specifically block the proliferation of cancer cells – they are said to be cytostatic – have emerged as targeted therapies that will be discussed in Chapter 6.
Chapter 3: Immunology and the Immune System
The immune system is a complex system of defense against pathogens. It also has a tumor surveillance role that allows it to recognize a cancer cell as foreign and kill it [DUN 04]. This system is not yet fully elucidated, but knowledge has progressed considerably over the past 60 years thanks to various technologies such as electrophoresis, microscopy, cell culture, flow cytometry, PCR (Polymerase Chain Reaction), monoclonal antibodies, sequencing techniques and “omics” that have made it possible to observe and understand many of the cellular activities and interactions to validate or disprove old hypotheses.
It is now accepted that the human body has two types of immunity: innate and adaptive immunity [OWE 14]. The molecules and cells of the first kind pre-exist in our body. They constitute the first line of defense of the human body by destroying pathogens by phagocytosis. The innate immune system can also recognize infected or abnormal cells and kill them.
In adaptive immunity, B and T cells (white blood cells called lymphocytes) recognize the antigen by adapting the receptors on their surface. This leads to the differentiation and proliferation of these cells into plasmocytes and activated T lymphocytes respectively. Plasmocytes secrete antibodies that bind to the infectious agent and initiate its elimination via various immunological processes. Other biological components and mechanisms are involved that allow the different activated T lymphocytes to interact with infected cells, ultimately causing the cells in question to die.
Innate and adaptive immunity cooperate to eliminate intruders. Cancer cells are themselves recognized as foreign and are therefore combated. It is when they take over the immune system through multiple escape strategies that cancer progresses. Understanding these various strategies is the basis for the development of cancer immunotherapy.
Chapter 4: The Development of Immunotherapy
Generally speaking, immunotherapy aims to help our immune system to rid our body of intruders. The first tools were serums and vaccines.
The modern development of immunotherapy began with this opposite problem: how to reduce the activity of the immune system (immunosuppression) in favor of tolerance to organ transplants. Cyclosporine, which acts on T lymphocytes, was a radical breakthrough in the early 1980s with a significant reduction in the rejection rate.
Then, it took about 20 years to better understand the interplay between the immune system and cancer cells. At first, the immune system eliminates them, then some cells resist and undergo genetic modifications that help them escape the antitumor response. Immunotherapy consists of avoiding this escape through various actions on cellular interactivities [VIV 18].
Chapter 5: The Maturation of Artificial Intelligence
It is difficult today not to have heard of artificial intelligence (AI), either in relation to robotics or autonomous cars, or because of the game of Go or voice or facial recognition. This discipline, the term for which appeared in 1956, has experienced several crises over time before experiencing some success with expert systems before soaring, since 2012, with the proof of a good learning capacity (using convolutional neural networks) slightly better than that of humans in several applications including computer vision [MAL 19].
These radical advances are due to the talents of researchers in complementary fields such as mathematical logic, computer science, algorithmics, cognitive sciences and neurobiology. The fuel of this AI is constituted by massive databases (Big Data) whose elaboration has been made possible, in particular, by progress in computing and by the power of the machines that everyone doing a web search can appreciate by noting the numbers of results he or she obtains. In Chapter 6, we will be particularly interested in the medical applications of AI and, in particular, its application to the diagnosis and monitoring of cancers by imaging (radiology images and biopsies) and various analyses of biological and genomic markers.
Chapter 6: The Evolution of Cancer Therapy
This chapter summarizes the current possibilities for anti-cancer strategies, taking into account the new knowledge developed in the previous chapters. The establishment of this text owes much to the in-depth examination of recent actions to recommend and approve new drugs taken by international regulatory bodies such as the FDA (Food and Drug Administration) in the United States and the EMA (European Medicines Agency) in Europe.
The evolution of biological and medical science, combined with significant advances in AI and Big Data, technologies, genomic sequencing and biomedical analysis and imaging tools, make it possible to predict faster and more complete diagnoses, better targeted and personalized therapies, fewer side effects and improved prognoses. This is part of a so-called theranostic approach that involves complementarity between diagnostics and therapies.
During the 20th Century, cancer management was mainly based on surgery, external radiotherapy and chemotherapy. Beyond the progress of these “classic” treatment methods, which are gaining in precision and efficiency, the very end of the 20th Century saw the addition of new approaches [MOR 11]. New techniques and methodologies are emerging, such as targeted therapies, monoclonal antibodies, cellular and gene therapies, targeted radionuclide therapy, vaccination treatments, machine learning diagnosis and prognosis.
Thanks to multiple analyses (anatomopathology, genomics, biomarkers, multimodal imaging), cancer should increasingly be characterized by a type based on cellular phenomena and no longer only by the organ or tissue it affects. The number of patients cured of their cancer will continue to increase, as will the number of patients who will benefit from a good quality of life while living for many years with a perfectly controlled cancer.
1
See “Cells and the human body”, available at:
https://www.youtube.com/watch?v=JD2DBeUoUG8
.
2
See “What is cancer? What causes cancer and how is it treated”, available at:
https://www.youtube.com/watch?v=SGaQ0WwZ_0I
.
1Genomics and Epigenetics
As early as the second half of the 19th Century, the work of Gregor Mendel followed by that of Hugo de Vries, Carl Correns and Erich von Tscherma led to the first postulate concerning the heredity of specific characteristics: due to the presence of a certain type of “particles” present within each organism and transmitted from one generation to another.
It was only at the beginning of the 20th Century that the term “gene” was introduced to designate the fundamental entity at the origin of heredity. In 1911, Thomas Hunt Morgan succeeded in showing that chromosomes, identified in the 1880s and 1890s, carry genes.
1.1. DNA, RNA and genetic code
Deoxyribonucleic acid (DNA) was isolated in the 1870s. But it was not until the 1940s that Oswald Avery and his team highlighted its role as a carrier of genetic information, hitherto generally attributed to proteins. Research was then increasingly oriented towards the question of its composition. In 1950, Erwin Chargaff discovered, by analyzing the DNA of different organisms, that the quantities of adenine (A) and thymine (T) were equivalent, as were those of guanine (G) and cytosine (C)1. These proportions made sense a few years later, when Rosalind Franklin was able to obtain X-ray diffraction images of DNA. It is from these clichés that in 1953, Francis Crick and James Watson created the famous double helix model in which the nitrogenous bases are oriented towards the inside of the molecule and where the A bases of a single strand are associated with T, and the G with C in what we now call base pairs.
Figure 1.1.DNA double helix (© MesserWoland, DNA structure and bases PL.svg, Wikimedia commons)2
In the 1960s, the principles of the genetic code, correspondence between nucleotide triplets (codons) and amino acids (protein components), and of the genetic program were developed [KLU 12]. The basics of DNA functioning were elucidated. François Jacob and Jacques Monod succeeded in describing the phenomenon of transcription of a gene, and therefore of DNA, into a messenger ribonucleic acid (mRNA), a molecule that moves from the cell nucleus into the cytosol3 before being translated into a protein. Each cell is thus genetically programmed to synthesize proteins with specific functions4.
Figure 1.2.The nitrogenous bases (A, G, C, T) are linked together by a phosphate deoxyribose backbone to form a strand of DNA. The double strand is formed by the hydrogen bonds between corresponding nitrogenous bases: A with T and C with G (© Madprime, Wikimedia commons)5. For a color version of the figures in this book seewww.iste.co.uk/barbet/cancers.zip
NOTE.– Unlike nucleic acids, which consist of chains of ribose or deoxyribose groups and phosphate groups, proteins consist of chains of amino acids linked together by a characteristic bond, called a peptide bond, linking the carboxylate group of one to the amine group of the next. A protein is therefore a large polypeptide. Many smaller compounds, called peptides, also play various roles in biology.
Figure 1.3.Transcription and translation (© E. Jaspard, University of Angers)
NOTE.– mRNA is a single-stranded copy of DNA that allows the transport of genetic information. In mRNA, as in the many other RNAs involved in cell life, the T-base (thymine) is replaced by the U-base (uracil).
The protein translation code is based on triplets of nucleotides. For example: the AUG triplet codes for the amino acid methionine, the GCU, GCC, GCA or GCG triplets, all code for the same amino acid, alanine; the UAG, UAA or UGA triplets mark the end of the coding part of an RNA; they are “stop” codons.
These RNAs are most often single-stranded, but double-stranded RNAs also exist in living organisms, particularly in certain viruses, where they act as carriers of genetic information.
Figure 1.4.Chromosomes, components of the genome present in cells, contain DNA. The coding genes of DNA are converted, via the transcription and translation processes, into proteins that perform a multitude of functions in the body (© PD-USGov-DOE)
NOTE.– As early as 1838, the cell theory, in which “the cell is the structural and functional unit of plants and animals”, was introduced by Matthias Jakob Schleiden. Thereafter, the nucleus is considered as the main organelle of the eukaryotic cell. In 1858, it was shown that every cell comes from a pre-existing cell. And the genetic continuity of the nucleus was established in 1878. DNA was isolated as early as 1869 without, of course, its structure being identified yet.
1.2. Sequencing and genomics
The very first sequence, a sequence of amino acids, of a polypeptide (small protein), insulin, was obtained in the 1950s by Frederick Sanger and his colleagues at Cambridge University. It was quickly followed by many other examples. Since these sequences are necessarily “coded” in DNA, a growing interest developed in determining the sequence of nucleotides, the basic elements of genetic material, within the different DNA or RNA fragments. In 1972, Walter Fiers carried out the first sequencing of a gene. It is a gene of the MS2 bacteriophage6 whose genetic material consists of RNA. In 1977, the genome of the same virus was sequenced in its entirety. A year later, the first sequencing of a DNA genome, that of the bacteriophage ΦX174, was performed through the work of Frederick Sanger and Walter Gilbert, carried out independently of each other. However, ΦX174 DNA is a single-stranded DNA and not a double helix. The Sanger method is based on selective enzymatic synthesis. It uses an enzyme complex called DNA polymerase which has the ability to copy DNA by successively adding nucleotides, in a complementary manner (A with T, C with G), to an already present DNA fragment (the primer). Specific nucleotides, called deoxynucleotides and fluorescently labeled, are added in small quantities. They interrupt the synthesis and produce fluorescent fragments that are separated by electrophoresis according to their size. The DNA sequence can then be read by a sequencer [HEA 16].
These discoveries herald the beginning of the era of genomics, a discipline that tends to study the functioning of an organism from its genome and no longer just on the scale of a single gene. However, it was not until 1995 that the first genome sequence of a living organism, the Haemophilus influenzae bacterium, was obtained. A year later, it was the turn of the first multicellular eukaryotic organism, the Caenorhabditis elegans worm. And in 2000, those of the fruit fly (Drosophila melanogaster) and of the arabette (Arabidopsis thaliana) were sequenced.
NOTE.– Viruses, whose genomes were sequenced earlier, are not strictly speaking “living beings”, because they do not feed and cannot reproduce autonomously, but this is still a matter of debate. Bacteria are living beings in their own right, but they do not have a nucleus: they are prokaryotes. Yeasts and cells that make up multicellular organisms have a nucleus that contains the chromosomes. They are eukaryotes.
For Piotr Slonimski, co-founder of the Centre de génétique moléculaire du CNRS in Gif-sur-Yvette:
“If we consider it [genomics] as the understanding of the meaning of a genome, we will remember that the research was first done using experimental genetic techniques, that is, by identifying observable, phenotypic traits for which we knew a wild type and a mutant type. Conversely, where functional genetics started from a phenotype and went back to the genotype - to a disruption of the phenotype corresponds that of a gene - genomics looks in the genome for the elements that explain the difference between the wild phenotype and that of the mutant” [PIC 02].
The idea that diseases can be caused by genetic abnormalities appears early on. As a result, the possibility of replacing “defective” genes becomes possible. The American geneticist Edward Tatum mentioned this possibility as early as 1958:
“With a more complete understanding of the functioning and regulation of gene activity in development and differentiation, these processes may be more efficiently controlled and regulated, not only to avoid structural or metabolic errors in the developing organism, but also to produce better organisms” [TAT 59].
We can already quite clearly see in this passage the ethical problems that the scientific community will soon be confronted with. From the 1970s onwards, controversies and media debates soon appeared, as the risk of a new eugenics came to arouse fear among the public. But Tatum does not only state possible goals, he also pursues them:
“This might proceed in stages from the in vitro biosynthesis of better and more efficient enzymes, to the biosynthesis of the corresponding nucleic acid molecules, and to the introduction of these molecules into the genome of organisms, […]” [TAT 59].
These projections became reality less than two decades later.
Two other essential discoveries will allow the development of sequencing and genomics from the 1960s onwards. Enzymes capable of cutting the DNA of bacteriophage λ were found in the bacterium Escherichia coli and called restriction enzymes. Later, it was demonstrated that the cleavage of simian virus 40 (SV40) DNA by restriction enzymes affords specific fragments that can be separated by polyacrylamide gel electrophoresis. These discoveries are fundamental because they allow DNA to be manipulated and lead to the development of recombinant DNA technology.
In 1986, Kary Mullis added the second pillar of genomics with the polymerase chain reaction (PCR). This in vitro
