Active Biological Evolution: Feedback-Driven, Actively Accelerated, Organismal and Cancer Evolution

By Frank H. Laukien

The underlying active mechanisms of change generation, which enable efficient adaptive evolution, have eluded biologists for decades. Until now...

 

The prevailing scientific view still holds that organismal and cancer evolution is largely a function of accumulated random genetic mutations and natural selection.

While inefficient random mutations were the primary mechanism of evolution during early life on Earth that still play a prominent role in pathobiology...

 

in the modern era of biology, genomic adaptive change generation prior to Darwinian selection is primarily the result of feedback-driven, active cell biology processes.

 

Introducing Active Biological Evolution, by Frank H. Laukien—a groundbreaking book that synthesizes a vast body of empirical observations and recent research, as well as his novel concepts of the evolution of evolutionary processes, and of short-term, fast epigenetic and epiproteomic evolution into the cogent and comprehensive framework of Active Evolution.

 

The takeaway is clear: the Active Evolution concept can explain not only the efficient evolution of advanced molecular, cell, and organismal biology processes, but also finally rationalize the origins of complex traits and new species. In short...

 

the processes of adaptive evolution are, themselves, evolving.

 

In Active Biological Evolution, you will learn that...

• The Modern Synthesis theory and the Central Dogma are insufficient to explain the rapid, active, and more efficient adaptive evolutionary processes of the last billion-plus years.
• While random mutations remain important in monogenic diseases, cancer driver mutations, and viral evolution, they play a negligible role in the modern adaptive evolution of organisms.
• The Active Evolution framework integrates vertically heritable and horizontally transferable genome changes, as well as short-term heritable epigenetic and epiproteomic changes.
• These active evolutionary processes also have a darker side—explaining accelerated evolution of metastatic, treatment-resistant cancers, the adaptability of viruses, and giving us pause on inherent risks of genetic engineering, DNA vaccines, and synthetic biology.

The new paradigm of Active Evolution underscores the fundamental interconnectedness of evolutionary processes—that, in short, "No genome is an island."

 

Active Evolution promises to do nothing less than redefine the fields of modern evolutionary biology and of late-stage cancer evolution.

• Language: English
• Publisher: Frank H. Laukien
• Release date: Apr 18, 2022
• ISBN: 9798985414714

Book preview

RECOMMENDATIONS FOR ACTIVE BIOLOGICAL EVOLUTION

In 1859, Charles Darwin’s seminal book On the Origin of Species brought one of the greatest revolutions in science. From 1918 to 1942, Fisher, Haldane, Wright and Julian Huxley wrote the Modern Synthesis of Darwinism with the then new field of genetics. From 1950 to 2008, Waddington, Gould, Pigliucci, and Müller brought us the Extended Synthesis. From 2005 to 2021, Frank Laukien, the Altenberg-16, and others have been extending the synthesis even further, emphasizing how evolution is not just random mutations, but actively accelerated and driven by feedback. 

Laukien’s two books, Active Biological Evolution and Origins & Evolution, go far above and beyond previous syntheses, covering the evolution of technology, of meaning, of our cosmos, of cancer and neurodegenerative diseases. They do so much more than just bring us up to date on one of the most controversial scientific topics in history. They make us care deeply. We are suddenly in the Age of CRISPR, where apathy and denialism are swept away by the relevance of evolution to our daily lives, with potent medical and economic implications. Carefully researched (with over 600 footnotes), they are also a moving tale, accessible to all.

—GEORGE CHURCH, Professor of Genetics, Harvard Medical School; MIT, Blavatnik Institute, Wyss Institute, Regenesis Institute, SIAT Institute, PersonalGenomes.org; Author, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves

Active Biological Evolution is a well-researched and persuasive argument showing that evolution has been about much more than the gradual point-by-point mutational evolution of genomes. Once evolution reaches the transition to organisms that can protect their vital physiological processes from deleterious mutations without having to wait for natural selection to weed them out, the whole process changes gear. The evidence is incontrovertible.

—DENIS NOBLE CBE FRS Balliol College, Professor in the Department of Physiology, Anatomy and Genetics, Oxford University; Author, Dance to the Tune of Life: Biological Relativity (CUP 2016) and The Music of Life (OUP 2006)

Frank Laukien’s tour de force, comprehensive in scope and insightful in content, is a must-read for anyone interested in the origin, evolution, and meaning of life in the cosmos. There is no other topic in modern science that is more expansive and far reaching. Laukien accurately captures everything we know and do not know. The book is an exceptional resource for scientists and the educated public. Laukien revolutionizes the way we think about evolution by proposing that feedback on genomic and other molecular changes prior to selection accelerates natural evolution, leading to Active Evolution, which is not just the result of random DNA mutations. This new understanding has crucial implications for cancer research and therapy strategies (Active Biological Evolution), as well as for the origin of primitive and intelligent life, the meaning of human history, and what lies ahead in our future (Origins & Evolution).

—AVI LOEB, Frank B. Baird Jr. Professor of Science, Harvard University; Director of the Institute for Theory and Computation; Founding Director of Harvard’s Black Hole Initiative; New York Times bestselling Author, Extraterrestrial (HMH, 2021), and Life in the Cosmos (Harvard University Press, 2021).

Two nicely written books that will delight expert scientists and science fans alike. Laukien uses his expansive view of developments in research and technology to deliver deep insights in unexpected places. From medicine to philosophy, he weaves a common thread and urges you to adopt an expanded view of biological evolution, as one inherently biased to select the most flexible and efficient molecular and cellular processes. Natural biological evolution evolves! From his unique place, Laukien masterfully connects all that to our daily lives and to medicine in particular. A must-read!

—DIMITAR SASSELOV, Professor of Astronomy at Harvard University; Director of the Harvard Origins of Life Initiative; Author, The Life of Super-Earths: How the Hunt for Alien Worlds and Artificial Cells Will Revolutionize Life on Our Planet

Synthesizing three waves of evolutionary thinking spanning two centuries, Active Biological Evolution combines powerful writing, compelling arguments, and erudite references to make an electrifying case for feedback-driven, actively accelerated biologic evolution. This book will change how we think about cancer, and it may revolutionize the translational medical applications of evolutionary principles. Using the conceptual framework of adaptive evolution, Laukien also attempts to demystify other disciplines extending from cosmology, extraterrestrial life, the emergence of meaning, all the way to climate evolution in Origins & Evolution.

—AZRA RAZA, M.D., Professor of Medicine, Director — MDS Center, Columbia University Medical Center; Author, The First Cell: And the Human Costs of Pursuing Cancer to the Last

There is no doubt that all textbooks dealing with the paradigms of evolution now need to be rewritten. Active Biological Evolution and Origins & Evolution represent the next-generation books on evolution, not only in biology, but with consequences in philosophy and our culture. The general naive belief that organismal evolution is caused just by genetic trial-and-error processes has been falsified. It turns out that Einstein’s famous quote God does not play dice is also applicable to biological evolution! Rather, we have to assume a directed underlying feedback concept that raises questions not only in biology, but also in moral philosophy. Frank Laukien’s two volumes, Active Biological Evolution and Origins & Evolution, offer answers as far as they can be formulated, and they touch on questions at the limits of meaning and interpretation. The parallel world of epistemology and knowledge recognition is not unaffected by this.

—DR. HERMANN REQUARDT: Vice Chairman of Fraunhofer-Gesellschaft; Member of Executive Board of acatech, the German National Academy of Science and Engineering; Former CEO of Siemens Medical Division; Former CTO and managing board member of Siemens AG; Honorary professor of physics at University of Frankfurt

In these wide-ranging books, Frank Laukien fundamentally challenges the consensus in the modern synthesis in evolution. His original and provocative insights are sure to start a wide-ranging discussion. Well worth reading for the background information and bold hypotheses alone.

—PROFESSOR MATTHIAS MANN, Director at the Max Planck Institute of Biochemistry, Martinsried; Director, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen

In Active Biological Evolution, Frank Laukien provocatively challenges the scientific community to develop an altered framework on how to interpret biological evolution. Simply put, the insights laid out in this delightful book could impact how the scientific and biomedical world views, and therefore, treats disease. This is not only a must-read for scientists but for the lay public as well, as Laukien presents his views in a masterful way that weaves back and forth between both worlds. You will not regret reading this book!

—NEVAN KROGAN, PH.D., Professor of Cellular and Molecular Pharmacology, Senior Investigator at the Gladstone Institutes, Founding Director of the Quantitative Biosciences Institute (QBI), University of California San Francisco

In Active Biological Evolution and Origins & Evolution, Laukien takes the reader on a comprehensive journey to understand humanity’s place on earth and in the universe. They synthesize, put into context, and simplify the many nuances of evolutionary theory and how we evolved to get here. More important, through his EDITA (Externally Driven, Irreversible, Transferable Adaptation) hypothesis, he proposes evolution can occur more rapidly in unicellular life and cancer evolution, and even in multicellular life and in humans. This gives us additional insights into how, when, and why we will continue to evolve through adaptive evolutionary changes. These books are a must-read for anyone interested in the future of Homo Sapiens.

—KENNETH J. PIENTA, MD, Professor, Johns Hopkins University School of Medicine Director of Research, The James Buchanan Brady Urological Institute

I am not a biologist, but I find compelling Dr. Laukien’s argument that evolution itself has selected for mechanisms that accelerate mutations to rates much higher than those attributable to chance events. This is a novel view and its applications to many processes, like cancers for example, could be very valuable.

—MARC KASTNER, Donner Professor of Physics, Emeritus, Massachusetts Institute of Technology, and former Dean of the School of Science at MIT

Frank Laukien has written two daring books. He applies modern 21st-century evolutionary biology thinking to subjects as diverse as how the cosmos came to be and how we humans developed the social institutions we have today — and where we may go in the future with ever-increasing technological capabilities. The readers of Active Biological Evolution and Origins & Evolution are in for a stimulating voyage across a remarkably wide range of topical and important questions.

—PROFESSOR JAMES A. SHAPIRO, University of Chicago; Author, Evolution: A View from the 21st Century

Active Biological Evolution is truly remarkable. By re-examining the traditional principles of evolutionary biology from the perspective of modern biology, Frank Laukien proposes wholly new ideas for how species, and even cancer cells, evolve in a non-random manner. This lucid and well-written book will prove to be provocative, controversial, and ultimately prescient as the 21st century unfolds with mankind taking control of the future of life.

—STEVE GULLANS, PH.D., Co-author with Juan Enriquez, Evolving Ourselves: How Unnatural Selection and Non-Random Mutation are Changing Life on Earth

It will never be possible for us to correctly diagnose or treat disease so long as we fundamentally misunderstand the feedback system life employs to improve itself. Evolutionary theory has been acutely overdue for a major update for 25+ years. Frank Laukien delivers, synthesizing dozens of new discoveries, from the demolition of the Central Dogma to epigenetics to brand-new cancer insights. If you want a state-of-the art tour of evolution’s mechanisms in detail, Active Biological Evolution condenses hundreds of scientific papers down to a single, no-stone-unturned, readable book. Anyone who cares about how evolution influences practice in medicine and biology must take this very seriously.

—PERRY MARSHALL, Author, Evolution 2.0: Breaking the Deadlock Between Darwin and Design; Founder, Evolution 2.0 Prize

To take pride in what we know prevents us from really knowing. In Active Biological Evolution, Dr. Laukien hastens the death of dogma and pries open the fast track of evolution. This book is a must-read for those of us trying to understand the big picture. We cannot let mural dyslexia get in the way.

—STEPHEN M. BRECHER, PH.D., Director of Microbiology, VA Boston Healthcare System and Associate Professor of Pathology and Laboratory Medicine, Boston University School of Medicine

ACTIVE BIOLOGICAL EVOLUTION

Feedback-Driven, Actively Accelerated Organismal And Cancer Evolution

Frank H. Laukien

Science is above all about visions.

—CARLO ROVELLI

The effect of a concept-driven revolution is to explain old things in new ways.

—FREEMAN DYSON IN IMAGINED WORLDS

All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.

—ARTHUR SCHOPENHAUER

No genome is an island.

—JAMES A. SHAPIRO

Copyright ©2022 Frank H. Laukien

All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the publisher, except in the case of brief quotations embodied in critical reviews and certain other noncommercial uses permitted by copyright law.

Project Management by Marla Markman, MarlaMarkman.com

Book Design by Peri Gabriel Design, PeriGabriel1.wixsite.com/mysite

Publisher’s Cataloging-in-Publication Data

Names: Laukien, Frank H., author.

Title: Active biological evolution : feedback-driven , actively accelerated organismal and cancer evolution / Frank H. Laukien.

Description: Includes bibliographical references and index. | North Hampton, NH: Evolution Press, 2022.

Identifiers: LCCN: 2021924735 | ISBN: 979-8-9854147-0-7 (hardcover) | 979-8-9854147-1-4 (ebook)

Subjects: LCSH Evolution (Biology) | Carcinogenesis. | Cells--Evolution. | Cancer--Etiology. | Cancer--Genetic aspects. | Epigenesis. | Natural selection. | BISAC SCIENCE / Life Sciences / Evolution

Classification: LCC QH365.08 .L38 2022 | DDC 575--dc23

I dedicate this book to my parents, and to my children and their future.

May each of my children be blessed to make their own useful and meaningful contributions to their families, society and humanity. May each be healthy and safe, full of integrity, compassionate, and satisfied with her or his endeavors and journey in life.

TABLE OF CONTENTS

INTRODUCTION AND OVERVIEW: CONCEPT AND IMPLICATIONS OF ACTIVE BIOLOGICAL EVOLUTION

Active Evolution in Biology and Cancer

Active Evolution in Unicellular and Organismal Evolution

Beyond Natural Biological Evolution

No Gene Is an Island – The Inherent Risks of Gene Editing and Synthetic Biology

Potential Cancer and Birth Defect Risks of Viral-Vector DNA Vaccines

Real-time Evolution of Multiclonal Cancer Cells in Patients

Active Evolution in Cancer

Viral Evolution, and the Impact of Viruses on Organismal and Cancer Evolution

Significance and Potential Impact of the Active Evolution Framework

CHAPTER 1: A NEW SCIENTIFIC FRAMEWORK FOR ACTIVE BIOLOGICAL EVOLUTION

The Scientific Questions and Their Implications for Evolution, Biology and Medicine

DNA Record, Transcriptome, Proteome, Microbiome and Virome

Virus Evolution by Mutations, Modular Recombinations and Gene Capture

Major Impact of Viruses on Organismal Evolution via Horizontal Gene Transfer

Why Only 21,000 Human Protein-Coding Genes?

Overcoming the Weismann Barrier or Threshold

Soma-to-Germline RNA Information Transfer via Spermatozoa

Types of Active Biological Processes Rewriting and Restructuring the Genome

Nature Selects the Most Efficient Molecular Pathways and Cell Biology Processes to Advance Flexible, Adaptive Evolvability

Adaptive Evolutionary Change Processes Have Evolved Themselves

CHAPTER 2: FROM DARWIN TO THE MODERN SYNTHESIS TO ACTIVE EVOLUTION

The Evidence Requires Moving Beyond Modern Synthesis and Central Dogma

The Reticulated Tree of Life, Horizontal Gene Transfer and Inter-species Mating

Darwin’s Foundational Theory of Evolution by Natural Selection Was Flexible

Change by Random Mutations vs. Active Biological Processes Prior to Selection

Random Infinitesimal Mutations Can Cause Cell Death or Disease, But Contribute Little to Adaptative Evolution of Advanced Organisms

The Paradigm Shifters and Natural Genetic Engineering

Evolution at the Molecular Level

Endosymbiosis and Ancient Cell Fusions in Active Evolution

Shapiro’s Natural Genetic Engineering (NGE)

Evolution of the Fittest Evolutionary Processes: A Key Insight in Active Evolution

CHAPTER 3: MAJOR LIMITATIONS OF THE MODERN SYNTHESIS AND OF THE CENTRAL DOGMA

The Extended Evolutionary Synthesis

CHAPTER 4: FEEDBACK-DRIVEN, ACCELERATED ACTIVE EVOLUTION

We Are Not Alone

CHAPTER 5: QUESTIONS ABOUT THE MECHANISMS OF EVOLUTION

Lamarckian vs. Darwinian Evolution Concepts

What Is a Gene? Open Reading Frames vs. Functional Definitions

Non-coding RNA, DNA Regulatory Sites and Transposable Elements (TEs)

Conceptual Evolution of Evolutionary Theories: from Lamarck to Active Evolution

Overview of the EDITA Principle and Its Impact on Evolution

Active Evolution in the Age of CRISPR

Soma-to-Germline and Gonad-to-Germline Transfer of DNA Mutations

Proposed CRISPR Experiments to Penetrate or Circumvent the Weismann Barrier

Are Mouse Gene Knock-out Models Proof of Weismann Threshold Penetration?

Proposed Experiment to Demonstrate Potential Phenome Effects on Germline DNA

Ramifications of CRISPR for Our Future

Nature Agnostically Leverages Efficient Molecular Processes for Evolution

CHAPTER 6: THE EDITA PRINCIPLE AS A GENERATOR OF EVOLUTIONARY CHANGE

The EDITA Postulate in Biological Evolution

CHAPTER 7: THE EDITA PRINCIPLE IS UBIQUITOUS

EDITA in Infectious Disease, Cancer and Prion Diseases

EDITA in Immunology: The Adaptive Immune System Demonstrates the Breakdown of the Central Dogma of Molecular Biology

EDITA in Stem Cell Differentiation

EDITA in Evolutionary Biology

Non-DNA Short-term Heritable Information

CHAPTER 8: THE AGE OF GENOMICS; EPIGENETICS AND EDITA

Genomic Cancer Profiling and Liquid Biopsies for ctDNA Detection

No Gene or Genetic Causation for Every Disease or Syndrome

DNA as Protected Heritable Information for the Building Blocks of Life

Epigenetics

Intergenerational Epigenetics and Genomic Speciation

Human Speciation and Evolution

The Molecular Tools of Epigenetics

Hormones

DNA Methylation, Histone Code, Chromatin Structure and 3D Genome Structure

RNA Interference and Silencing

Various Implications of Epigenetics

On Scientific and Medical Groupthink

Epigenetics and Its Evolutionary Corollary of EDITA

Developmental Plasticity and Evolution

CHAPTER 9: EMERGENCE OF BIOLOGICAL EVOLUTION: EVOLVABILITY AND ORIGINS OF LIFE

Synthetic Biology Origins of Life Approaches with Minimalist Genomes

Role of Viruses in the Origins of Life and in Genomic Evolution

Potential Extraterrestrial Seeding of Evolvability of Life on Earth

Liquid Water, Asteroids, Atmosphere and Extraterrestrial Organic Matter

Life Requires Energetically Driven, Dynamic Non-equilibrium Conditions

Chemistry Research on the Origin of Life

CHAPTER 10: SUCCESSES AND SHORTCOMINGS OF GENE-DOMINATED MEDICINE

The Medical Opportunity Cost of the Central Dogma of Molecular Biology

Progress with Monogenic Diseases and Prenatal Genetic Testing

Inherited Genetic Disorders, NIPT and Genetic Family Planning by IVF and PGS

Cystic Fibrosis

Gene Therapy

Complex Diseases and Active Evolution

Genetic Identification of Infectious Diseases and Resistance Markers

Unsatisfactory Progress with Complex Multigenic or Other Diseases

No Clear Genetic Basis for Sporadic ALS

Primarily Non-genetic Causes of Parkinson’s and Alzheimer’s Diseases

Value of Genetics for Predicting Pharmacological Responses

Is Autism Partially Preventable?

CHAPTER 11: CANCER AS AN EVOLUTIONARY PROCESS

Brief History of Cancer and the Never-ending War on Cancer

Disappointments in Progress Against Late-stage Metastatic Cancers

Early Cancer Detection

The Horrific Plight of Patients with Incurable Cancers

Mouse Models and Reductionism in Cancer Research

Multiclonal Cancer Speciation and Active Evolution

The Elusive Cure for Cancer and the Power of Prevention

Organismal Evolution of Cancer and Cancer Suppression

Cancer and Therapy As a Real-Time Evolutionary Battle

SMBE 2019 Satellite Meeting on ‘Molecular Biology and Evolution of Cancer’

Evolvability as a Trait in Therapy Resistance and Metastatic Invasiveness

Genome Chaos and the Two Phases of Cancer Evolution

Cancer As an Evolutionary Atavism

Organismal Pattern and Morphological Homeostasis May Suppress Cancer

Cancer as a Transmissible and Potentially Contagious Disease

Progress in Cancer Genomics

Cancer Evolution Summary

APPENDIX TO CHAPTER 11

The Evolution of Evolutionary Processes in Organismal and Cancer Evolution

CHAPTER 12: EDITA AND ACTIVE EVOLUTION SUMMARY

Afterword

Acknowledgments

About the Author

INTRODUCTION AND OVERVIEW: CONCEPT AND IMPLICATIONS OF ACTIVE BIOLOGICAL EVOLUTION

Scientists and medical researchers are intrigued by evolutionary biology, because evolution is fundamental to our understanding of biology and life, as well as to a better understanding of infectious diseases and of cancer. However, fundamental scientific questions in genomic, unicellular and organismal evolution, and their implications for real-time evolution in cancer, remain largely misunderstood today.

Here we present the new, substantially updated and corrected framework of natural, feedback-driven and accelerated Active Evolution. After all, how the modern and themselves evolving evolutionary biology processes really work, after some 3.8 billion years of the evolution of life on Earth, has very important ramifications for understanding basic molecular and cell biology. This natural, feedback-driven, actively accelerated biological evolution framework, called Active Evolution for short throughout this book, explains not only the adaptive evolution of molecular interactions and pathways, and of organismal traits and new species with increasing fitness, but also the novel concept of more efficient evolutionary processes¹.

An updated and corrected understanding of biological evolution also has crucial implications for disease research and therapy strategies in infectious diseases, and particularly in cancer, where multiclonal cancer cells can undergo very rapid evolution within a host, e.g., a human cancer patient. These so far mostly overlooked real-time cancer evolution aspects are of enormous importance in our ‘war on cancer,’ both for basic and translational cancer research, as well as for the future practice of oncology, as will be explained in this book. As a result, the American Association for Cancer Research (AACR) in July 2021 announced its newest scientific working group Cancer Evolution, which I have the privilege of co-chairing² with Professor Charles Swanton of the Francis Crick Institute and UCL Cancer Institute in London, UK.

Moreover, many intellectually curious individuals marvel at the remarkably broad applicability of the evolutionary principle in other fields of science, and even in philosophy, linguistics, human history, and in societal and technological innovations. Our corrected Active Evolution framework for biological evolution, with evolution not just the result of random, infinitesimal mutations, but often as the result of natural, feedback-driven genomic and systems biology major changes prior to selection — has profound implications for aspects of our prevalent worldview.

The remarkably fast and flexible adaptations in organismal evolution, which are preserved in the fossil record, have often progressed in large, macroevolutionary steps, rather than gradually and incrementally. These observed, seemingly discontinuous and saltatory adaptations to new ecosystem, environmental threats or new opportunities cannot be readily reconciled with the prevailing notion that evolutionary changes, prior to natural selection, occur via the gradual accumulation of random, infinitesimal mutations.

Even today, we observe major evolutionary steps in SARS-CoV-2 coronavirus variants during the COVID-19 pandemic, which can only partly be explained by an accumulation of random mutations. The emerging new variants, each with numerous mutations in multiple viral genes, are also the result of viral RNA recombinations and gene fusions that generate new variants, some with saltatory changes in their genomes.

In terms of evolutionary processes, viruses are relatively primitive compared to unicellular or multicellular life in terms of biological feedback mechanisms to drive evolutionary changes prior to Darwinian selection. Accordingly, ‘primitive’ random mutation evolutionary processes still retain a significant role in viral evolution.

As this book will explain in detail and with incontrovertible evidence, the prevailing random-mutations theory of how change arises in organismal evolution, is severely flawed. Nature has made it mostly obsolete in contemporary cell biology, after some 3.8 billion years of evolution of life’s increasingly flexible, more efficient and faster active evolutionary processes. The very visible exceptions, of course, are well-understood cases where random mutations have deleterious effects, e.g., by causing deformations, deaths or monogenic diseases, and by triggering cancer driver mutations in oncogenes or in tumor suppressor genes, or in the aforementioned viral mutations.

This book synthesizes the new Active Evolution framework of how natural, feedback-driven, active processes, including intra- and inter-cellular, intra-organismal, and vector-mediated horizontal gene transfer (HGT) and viral transduction processes can generate long-term heritable changes to facilitate Darwinian evolution by natural selection. These active change generation processes even can modify and partially rewrite relatively stable and protected eukaryotic nuclear DNA genomes, and even their germline cells which are further protected by the so-called Weismann barrier.

Moreover, it will be shown that short-term heritable changes in information-carrier molecules other than nuclear DNA, e.g., DNA methylation in the epigenome, protein phosphorylation signaling cascades, or viral or cell surface protein glycosylation in immune evasion, with the latter two as epiproteome³ examples, represent induced, neo-Lamarckian short-term, intergenerational evolution. It turns out that Active Evolution benefits from multiple molecular mechanisms with very different timescales and stability.

These short-term, rapid changes in the molecular and morphological phenome are representative of the fast, flexible functional or pathogenic changes that are often observed in nature, prior to their long-term fixation via genomic changes in long-term Darwinian evolution by natural selection, often with ‘genes as followers’.

Finally, our present-day evolved cellular and organismal biology is inherently network-centric systems biology, which leads to highly dynamic, non-linear processing of short-term evolution inter-generational transfers of biological or disease information.

Unfortunately, accelerated and active evolutionary processes also can lead to mitotically heritable evolutionary changes from cancer cell generation to generation within a host, in cancer cell genomes (e.g., total mutation load, copy number variations), in cancer cell epigenomes (e.g., methylation), and in cancer cell molecular phenomes (e.g., modified phosphorylation signaling cascades, cancer cell surface decoration by increasingly complex glycosylation for immune evasion). Therefore, rapid, multiclonal cancer evolution often leads to therapy resistance, further progression and metastasis.

More efficient and hence ‘fitter’ evolutionary processes have dramatically accelerated organismal evolution in the last billion years or so, in a manner that now also can be reconciled with the punctuated fossil record. The rapidly accumulating DNA record⁴ of organismal evolution has by now clearly falsified many prevailing notions of random mutations being the only, or even the primary driver of evolutionary changes, prior to selection. But this crucial recognition has not yet permeated mainstream scientific and medical research, nor standard evolution or cancer textbooks or courses. It also has not yet enhanced our cultural worldview, which still incorporates the erroneous notion that evolutionary change is exclusively or primarily random and infinitesimal.

In long-term Active Evolution, non-random, often major and sometimes even directionally functional genomic changes can be selected for by nature according to their differential fitness⁵, in classical Darwinian manner. As these selected adaptive changes have accumulated, they have generated today’s advanced machinery of cell biology, of more efficient and flexible evolutionary processes, as well as of more advantageous traits and species with improved fitness, which are traditionally associated with evolution. In real-time cancer evolution, these accelerated evolutionary processes can lead to therapy resistance and increased invasiveness of metastatic cancers.

The Active Evolution framework draws on nature’s own evidence in the DNA record to explain the genomic variability that has been generated by now highly evolved, active and efficient cell biology DNA change generation processes. These Active Evolution cell biology processes have been complemented by exogenous horizontal gene transfer (HGT) and viral transduction, and very rare but crucial symbiogenesis events during evolutionary history.

An important recognition is that these active cell biology evolutionary processes themselves first had to evolve during the initial 2-3 billion years of unicellular evolution, after the origin(s) of life occurred on Earth some 3.8-4.0 billion years ago. Subsequently, in the more recent 1-2 billion years of life, evolved, active change generation processes have greatly accelerated adaptive evolution. This enabled the emergence of eukaryotic unicellular life, and later the accelerating evolution of complex, multicellular organisms.

In short, after 3.8-4 billion years of life and evolution on Earth, not only our molecular pathways, traits and species, but importantly also the evolutionary mechanisms themselves now evolve more rapidly and efficiently due to feedback-driven, active processes that require no ‘designer’ or teleology. Nature’s contemporary, evolved feedback processes can actively modify, rewrite and rearrange our genes, chromosomes and three-dimensional chromatin-structure and karyotypes over time, via long-range genomic rearrangements, and via trans-chromosomal intra-nuclear, intra-cellular, or intra-organismal processes. These multiple natural genetic engineering (NGE) processes enhance the vertical, intergenerational inheritance in nature. They are complemented by horizontal gene transfer (HGT) induced by viral or organismal vectors. HGT presumably can even be exosome-mediated, but this latter hypothesis needs to be proven empirically.

Using the nomenclature of this book, evolved, flexible, more efficient and often active genetic change generation processes are an integral part of the new framework of accelerated organismal and cancer evolution that I have termed Active Evolution.

I had previously described the generalized EDITA (Externally Driven, Irreversible and Transferable Adaptation) framework in 2005. The EDITA concept contained certain precursor concepts to the more comprehensive Active Evolution framework of organismal and cancer evolution that is discussed in this book.

With the breakthrough discovery of CRISPR, it has become increasingly urgent and inevitable that the scientific community develop a corrected understanding of how the evolved, feedback-driven and active evolutionary processes have worked so efficiently and rapidly in shaping our genomes, epigenomes and also our molecular phenotypes, including proteins, PTMs, glycosylation, lipids or metabolites, and their multiple interaction networks in the most recent billion-plus years of life on Earth.

Interestingly, protein-protein interactions (PPI), as studied for example by PPI network researcher Nevan Krogan⁶, now begin to unravel and map the complexes, pathways and processes that may help us decode functional gene networks.

---

¹ ‘The Evolution of Evolutionary Processes in Organismal and Cancer Evolution,’ by F.H. Laukien, Special Issue in Progress in Biophysics and Molecular Biology, dedicated to Cancer & Evolution Symposium October 14-16, 2020, DOI: 10.1016/j.pbiomolbio.2021.08.008, in Appendix to Chapter 11.

² https://www.aacr.org/about-the-aacr/newsroom/news-releases/aacr-establishes-new-cancer-evolution-working-group/

³ The epiproteome consists of millions of proteoforms with post-translational modifications (PTMs), truncations, or degradation steps, while only 21,000 protein groups are templated in the human genome.

⁴ The DNA record is also referred to as the genome record, or as the biological record.

⁵ Charles Darwin’s ‘On the Origin of Species,’ published in November 1859, is the foundational book of biological evolution. The original title of the book was ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. Here, the term ‘Races’ never implied human races, but what we today call ‘sub-species,’ which evolve prior to complete speciation.

⁶ Nevan Krogan is a professor in the Department of Cellular and Molecular Pharmacology, and the Director of the Quantitative Bioscience Institute (QBI) of the University of California, San Francisco (UCSF).

ACTIVE EVOLUTION IN BIOLOGY AND CANCER

The feedback-driven Active Evolution framework also explains how today’s evolutionary change generation processes — prior to Darwinian selection — themselves have evolved, about 3.8 billion years since the origins of life on Earth. After billions of years of evolution of biological processes themselves, in the last few hundred million years, newer feedback-driven, active molecular and cell biology processes have made unicellular, organismal and real-time cancer evolution more flexible, rapid and efficient.

Despite the prominent role of mutations in disease biology and viral evolution, nature’s innovation of active evolutionary processes has relegated random, infinitesimal DNA mutations to a secondary role in the modern adaptive evolution of cellular life. Accordingly, our understanding of biological evolution requires a major departure from the Modern Synthesis theory of evolution that has dominated for over half a century, and which has been falsified, at least in its dogmatic form. At best, the Modern Synthesis is very limited in its ability to explain the DNA record of evolution that has rapidly accumulated with next-generation DNA sequencing in recent decades.

The emergence of life on our planet presumably had multiple parallel, and probably all but inevitable origins, in the presence of complex organic feedstock molecules and the right environmental conditions in terms of a) liquid water, b) moderate temperatures with temperature cycles, c) alternating wet-dry cycles in water ponds, puddles or pores, and d) supportive near-surface solar UV radiation. Moreover, I have posited the further hypothesis of the crucial bridging role of liquid-liquid phase separations (LLPS) by polar molecule-induced membraneless condensates to provide suitable, high-concentration conditions for macromolecular replication and emerging evolvability, prior to the existence of protocells with lipid membrane layers.

During nearly four billion years of biological evolution on this planet, there has been accelerating and in the last billion years often punctuated evolution of the molecular and cellular processes of life, of new traits and species with differential fitness, as well as of the ever more flexible and efficient evolutionary processes that have enabled modern, Active Evolution. This trend towards enhanced evolvability as a beneficial trait is evident in organismal evolution, and also in real-time cancer evolution within a host, or patient.

Within the Active Evolution framework, many short-term evolutionary processes are Lamarckian in nature, i.e., unicellular organisms, cancer cell clonal populations within a host, and even multicellular organisms can experience horizontal gene transfer, as well as multigenerational vertical inheritance of acquired epigenetic or epiproteomic molecular patterns, as well as of acquired physiological states and organismal traits.

Over time, some of the acquired, most beneficial, short-term heritable changes in information-carrying molecules can modify and partially rewrite protected genetic and genomic information via feedback-driven, active cell biology processes.

Many natural genetic engineering (NGE) processes for active genome rearrangement, diversification or even for directionally useful, functional genome modifications will be described in this book. Perhaps the most compelling and efficient way to rewrite mammalian genomes actively today involves viral or mammalian reverse transcriptase enzymes that generate extrachromosomal DNA (ec-DNA) from messenger RNA (mRNA). For example, human pol theta is a low-fidelity DNA repair enzyme, but pol theta turns out to be far more suitable for reverse transcription of mRNA into DNA⁷.

This can be followed by retroviral integrase⁸ or similar enzymes for the subsequent insertion of ec-DNA into chromosomes.

It has turned out that the Central Dogma of Molecular Biology only describes a predominant direction of DNA to mRNA transcription followed by protein translation. It should have never been called or accepted as ‘dogma,’ as that has misled biology and evolutionary concepts for decades. This dogmatic and misleading approach also has obscured disease pathways and therapeutic opportunities for far too long.

In multicellular organisms, rewriting germline genes is difficult as their germline genomes are protected against biological fluctuations by the Weismann barrier. But even the Weismann barrier is not impenetrable, and eukaryotic germline genomes can be destabilized or actively modified by sustained and abundant, acquired somatic cell DNA modifications, or via horizontal incorporation of selected viral or parasite DNA or cDNA, or of engineered CRISPR/Cas9 genome modification.

Long-term genomic evolution then occurs primarily via Darwinian selection according to differential fitness, and evolution can also proceed via neutral drift, particularly in small populations. Whenever there is insufficient time for selection, e.g., in heterogeneous, multiclonal cancer cells, rapid co-evolution can occur for certain periods of time also without differential fitness selection.

The Active Evolution concept has important ramifications for a more complete understanding of basic molecular and cell biology. Its enhanced framework of biological evolution also has crucial implications for disease research and therapy strategies, particularly in cancer, where multiclonal cancer cells and host immune and tissue response undergo rapid cancer cell co-evolution and host adaptation within a patient.

Importantly, feedback-driven and actively accelerated natural evolution, or Active Evolution for short, is not just due to random and infinitesimal DNA mutations, but it is often the result of natural, feedback-driven genomic and other molecular changes prior to selection. This important recognition has profound implications for non-biological evolution, and even for aspects of our world view.

For example, a profound insight is that both organismal and cancer evolution favor accelerated evolvability and an enhanced capacity for adaptive evolution per se — as a superior fitness trait for survival and proliferation. Evolvability is crucial for avoiding threats or extinction by natural selection pressures, and evolvability also can enable the exploitation of unanticipated opportunities that have not been previously experienced.

The pervasive pattern in the biological evolution of both organisms and of cancer cell multiclonal populations, which favors and selects for adaptive evolvability, has analogies in human, societal and technological history. From the rise and fall of empires and nations, to ‘fitness’ differences in the achievements and prosperity of different ideologies or cultures, to scientific, technological, military or organizational innovation, it has been demonstrated over and over again that typically enhanced evolvability wins. Flexible learning structures, with the ability to experiment, succeed or fail rapidly, tend to outperform more rigid, planned, centralized or ‘harmonized’ structures or approaches.

In biology, the Active Evolution framework explains the remarkably fast and flexible adaptations in organismal evolution that are preserved in the fossil record, as well as in the recently accessible DNA record of evolution. Evolution often has progressed in punctuated, macroevolutionary steps, rather than just gradually and incrementally.

This type of punctuated biological evolution, i.e., the often discontinuous and saltatory adaptations to new ecosystem, environmental threats or new opportunities could never be satisfactorily reconciled with the still prevailing, but substantially incorrect notion that evolutionary changes, prior to natural selection, occur only or primarily via the gradual accumulation of random, infinitesimal genetic mutations.

Moreover, the rapid phenomic and functional changes that are observed in short-term biological development, prior to their fixation via genomic long-term evolution, often have the ‘genes as followers’⁹.

Present-day evolved genomes, as well as all cell and organismal biology, are inherently network-centric systems biology, driven by genomic, transcriptomic, protein-protein and metabolic interactions. This insight makes our excessive focus on reductionism in genetic, molecular and cellular research, as well as in disease biology, questionable. A better balance and greater focus on molecular systems, spatial and tissue biology will be far more productive and beneficial in terms of fundamental disease insights, and actionable diagnostic biomarkers and therapeutic strategies.

Interaction network biology leads to highly dynamic, non-linear functionality, and to complex, sometimes mosaic diseases, like cancer, autoimmune diseases or psychiatric, neurodevelopmental or neurodegenerative disorders or diseases.

In Active Evolution, mostly non-random, often major and sometimes already directionally functional changes can be selected for by nature according to their differential fitness, in a fundamentally neo-Darwinian manner. The implications of Active Evolution have an impact on aspects of basic molecular, cell biology and intra-cellular signal transduction research. Corrected evolutionary mechanisms will, directly and indirectly, advance medical and translational research in cancer, neurodegenerative, and infectious diseases, as well as in chronic, psychiatric and other diseases.

In many non-monogenic diseases, new insights into the pathobiological mechanisms have been obscured by the prevailing incorrect Modern Synthesis theory of evolution. The overdue correction should particularly benefit the many areas of medicine where progress has not been satisfactory in recent decades, due to an excessive focus on presumed underlying genetic causes or correlations.

Hopefully, some of the biological evolution mechanisms and concepts that I have elucidated in the Active Evolution framework are relevant also for society-at-large, as many, by analogy, may well have implications on our culture and prevailing world view. Beyond the scientific and medical consequences, the insights of non-random, feedback-driven, actively accelerated organismal evolution have philosophical ramifications. As the concept of evolution is so central, the cultural implications of recognizing that evolution is not random, but feedback-driven and actively accelerated by nature to survive threats and to benefit from opportunities rapidly, are only beginning to emerge.

For many decades now, the implicit but incorrect consensus of how evolutionary change works, prior to Darwinian selection, has had very different scientific, medical and philosophical implications, compared to the concept of active evolution that is in part directed by nature towards enhanced evolvability or even towards already functional and directionally adaptive changes.

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⁷ New discovery shows human cells can write RNA sequences into DNA – Scienmag: Latest Science and Health News: "Pol theta reverse transcribes RNA and promotes RNA-templated DNA repair," Science Advances, DOI: 10.1126/sciadv.abf1771, 2021.

⁸ https://en.wikipedia.org/wiki/Integrase

⁹ In societies and cultures, we can similarly observe new patterns that may be transitory, or, if they are successful and adaptive, they eventually are embedded in culture and norms, or codified in laws or rules.

ACTIVE EVOLUTION IN UNICELLULAR AND ORGANISMAL EVOLUTION

In the nomenclature of this book, the early Lamarckian concept of evolution by acquired traits is considered the Evolution 1.0 hypothesis, whereas Darwin’s classical, 160-year-old concept of gradual change followed by natural selection, is referred to as Evolution 2.0¹⁰. The still prevalent, but insufficient and in many ways falsified Modern Synthesis Theory of evolution is referred to as Evolution 3.0, while Active Evolution represents the new, expanded and substantially corrected Evolution 4.0 framework.

While the Active Evolution concepts remain primarily Darwinian, it has become very clear