I will begin by connecting to what Giuseppe Longo said in the introduction. I work in the center of the debate about genetic engineering, ecology and agro-ecological transformation. I would like to take you along a little discovery journey of how it was for me to get my head around some of the issues that Giuseppe alluded to. You could consider my journey of discovery as a case example of how what Giuseppe just explained manifests itself in practical terms. I am a research practitioner, not a theoretician. I stepped into this field completely naively 30 years ago, being a young scientist trying to make a career in science. For me, in the end, it was the unholy convergence of scientific dogmas with politics and economic interests. In my field, it even has that name; it is called the ‘central dogma’, which is converging with scientific reductionism, private profits, and power interests. Proponents of these different stakes got together and hijacked the whole field. It fell on fertile grounds when it came to academic institutions at a time when they were being reorganized to focus on productivity measured with quantitative statistics and indicators like the h-factor to evaluate a scientists’ success in a cut-throat competitive environment for money and patents. That is the field I survived in over the last 30 years, we all did who speak here today.

In genetic engineering, however, it was less science than a belief system right from the beginning. And it could sustain itself only by creating what I term bubble science. The proponents stay in a bubble, they have their science narratives, they reaffirm themselves, are self-referential, and escape external scrutiny by shielding themselves from any critical influence. This situation leads partly to the misery we have today and that Giuseppe deplores, that we do not have proper theories or constructive dialogues about the underlying science. Dialogue or debate was shut down basically right from the beginning - no external exchange and critique allowed. There was this one narrative only perpetuated vigorously by boasting proponents from academia in concert with those from industry. Whoever deviated from this dogma was met with vicious discreditation that had a massively chilling effect on anybody else who agreed with the critical analysis.

It all started well over half a century ago, with the discovery of the material substance of genes, DNA, and its structure that came along with a defining, albeit scientifically unsupported, narrative regarding its function and its form. It created what we call the DNA-centered world. Giuseppe calls it ‘geno-centrism’. The defining narrative of this belief system has been officially termed by one of the early protagonists of the field, Francis Crick, a dogma. So, this is not my invention and I will find this forever interesting. This dogma centers around the role of DNA or genes as the sole unit of information passed to the next generation, in essence, serving as the atom of biology, the smallest unit and the blueprint instruction for how to assemble organisms. It comes with a very strong reductionist understanding of how an organism comes about. Later on, the nucleotides, of which DNA is composed, could be easily equated to a digital code. This reductionist dogma lent itself as the ideal foundation for easy capture when digital codes came along. (1)

Francis Crick coined this the ‘Doctrine of the Triad’ in a conference in the late 50's when he explained how he saw information flow from one generation to the next. (2). Using the term ‘triad’ is somewhat reminiscent of the trinity and its religious connotations. Anyway, from this unidirectional and rather simplistic understanding of gene functioning, one could start doing calculations. For example, one could start counting of how many proteins humans, and other organisms, are composed in order to subsequently extrapolate how many genes they should, therefore, have. This happened long before we could actually sequence DNA and count genes in reality.

The largest number I have read was something like one hundred and twenty thousand genes that we should have to explain our complexity (3), and it would only go below that for other organisms, as human beings would be, of course, the most complex organism of all. Today, the debate is about whether or not Crick meant information, whether or not he meant material. However, nobody questions that those nucleotides would hold, and later ‘code’, the information for the orchestration of how organisms come about. Crick reiterated roughly 20 years later again his understanding of the role of DNA and genes as a dogma. (4) That should be enough time to reconsider if you really mean your theory, notably still without much scientific evidence at that time, to serve as a ‘dogma’ or not.

Based on this decidedly dogmatic understanding of how inheritance should work came along ideas like: wouldn't it be nice if we knew how to manipulate genes, and if we could create organisms at our will, that is, redesign them, or create them completely anew? In the early 70's, the next step in this enterprise was taken. Scientists discovered methods to manipulate DNA (5): how to cut DNA strands and how to exchange and transfer DNA from one organism to another, building on the fundamental assumption that DNA or the information ‘coded’ in DNA taken out of an organism A will do the exact same thing in any other organism B that receives it, and that it will do only that and nothing else.

This discovery and invention immediately inspired what I call promissory science. There was free reign in using any terminology you liked to describe the envisioned possibilities; there was no limit to the semantic grandeur of what was before us - ‘revolutionize’, ‘promise’, one could be as affirmative as wished, about promising to meet the most fundamental needs in medicine and agriculture and what have you. Two key papers that took this limitless enthusiasm up were published in 1981 in the New York Times Magazine (6) and the New York Times. (7) They make very interesting reading. The Second Green Revolution was predicted, and the ‘Gene Machine’ was going ‘to hit the farm’ and produce all the custom-tailored organisms a farmer may dream of, redesign farming operations and create the types of farming plants and animals that humans would need. This promissory hype continued in fairly aggressive ways, already at that time. If you dared to doubt this narrative, you were in for some abuse, and that was long before Twitter and Facebook were invented and becoming instrumental to this kind of abuse. For example, in a paper by late Norman Borlaug who, notably, got the Nobel Prize of Peace for developing the first-generation crop plants of what became called the green revolution (using hybrid technology) quite aggressively attacked dissenters of his enthusiasm for genetic engineering. This is the title of his paper, "Ending the World Hunger. The Promise of Biotechnology" and the second part states: “and the threat of anti-science zealotry.” (8) Quite personal aggressive language for a piece in a scientific journal and for a Noble laureate of Peace, too. I do not think anybody would have been allowed to publish a dissenting view in a similarly aggressive and emotional way.

Life as a product of a construction kit orchestrated by nucleotides-becoming-code happened in parallel to the developments in the Information Technology (IT) industry and was gaining traction and speed from the 70's and 80's on. Hence, we had both the DNA-based, genocentric (mis)understanding of how organisms work developing in parallel throughout the 80's and 90's with the digitalization and the IT industries. Since the foundation of the understanding of genetic processes and gene functioning as a kind of unidirectional, linear instruction/coding process had been laid in the 50's by Crick and others, it was easily framed as analog to IT programing using IT language. Terms like ‘coding’, ‘cutting’, ‘pasting’, ‘editing’ et cetera became en vogue for describing genetic engineering processes. Papers were published in high-ranking journals that conveyed the message of nucleotide sequences functioning like digital messages or information. They spoke of the grand unification of biological sciences in the emerging information-based view of biology1, meaning the coming together of genetic engineering, IT and nanotechnology. Imaginaries of ‘intentional biology’ emerged, terms like ‘digital biology’ were invented and scientists started to dream of molecular computers that could be using the quaternary code of genetics instead of the binary code of IT. If that would be possible, it would indeed be a huge a leap in the programming of computational machines.

However, hardly any of this materialized. Decades later, today, hardly anything of this is even on the horizon to materialize in marketable forms in the near future. But what was the problem? Why did it not work? Now, I would have thought that if you claim you can produce a machine or something, and you try and try and try with all the money and support in the world and you weren't able to deliver that product after decades, at some point, somebody would take a step back and at least wonder about why that was? Maybe start critically thinking and asking some questions, like: “Did I get something wrong?”. But that is not how it went. It has been recognized that the products did not materialize and that there was a problem. But that problem was not the technology and the presumptions underlying it; the problem was the environment. Not the predictable part of the environment like the deterministic information that could be predicted, such as gravity and the fact that the sun would go up and down every day. Those things are predictable, and engineers could sort of adjust to it. But there was this stochastic information or events, where chance dictates the outcome, and that just ruins all the engineering ideas of any biological ‘machinery’, i.e., living organisms. The funny thing to me was how they termed it: as “noise.” (9) So, in their perception, there is all this noise in this messy environment, and this noise ruins the designing and the construction of what they had hoped to be ‘intentional biology’. And of course, you had to frame it in a way that an engineer can understand or perceive it along the parameters they are familiar with and that was ‘noise’. And this gave rise to the question of how can you identify the origins and how can you attenuate that noise?

Well, this ‘noise’ is nothing else than what ecologists, evolution researchers, and at least some biologists call ‘variability’, or ‘plasticity’ and ‘adaptability’ – or diversity - inherent to and among all organisms. It constitutes the fundamental survival strategy of anything truly living. But for genetic engineers, it is something to get rid of. Consequently, they developed ‘new engineering rules’ on how to increase the predictability and reliability and how to get rid of this noise. (10) The strategy, in essence, is to strip life away, to reduce engineered ‘organisms’ more and more until a biological ‘unit’ starts to behave like one of physics. So, the belief system of bio-engineers is that complexity can be captured by digitalization or computers through gene ‘editing’, which leads to precision in targeted engineering. Noise control had to come about through stripping the complexity and reducing ‘biological units’ to the minimum, to “chassis” of biological artifacts, parts, molecules, devices and so on. Big money programs were launched with big universities involved, like for example the ‘BioBrick’ Foundation (11) and I-GEM at MIT, aiming to develop and register biological artifacts called ‘bricks’ or modules for open access synthetic biology. (12) A ‘hands-on’ approach with ‘learning-by-doing’ is cultured in these circles with very little awareness for safety or risk issues that might arise from their activities. In fact, you will find statements like this from a European Report in 2005: “we need to know how the parts operate together – how genes and proteins modify each other’s behaviour, ... and how they interact to form modules and circuits analogous to those in electronic systems. This understanding ... provides the conceptual tools needed for the rational construction and redesign of such ‘biological circuitry’”. So, the questions are not: ‘Does biology work in modules and parts added up? Or: ‘Are biological circuitries analogous to those in electronic systems?’ These questions are not in the minds of biotechnologists; their questions are only ‘how do they work analogous to those in electronic systems’? The framing of these questions leads, of course, to completely different research paths. What if it turns out that biology does not work analogous to electronic circuits? What if biological parts or bricks or modules, or whatever fancy name you may find for the same thing, do not ‘add up’ like electronic parts in computers? How much money and effort will have to be spent until the realization trickles in that perhaps this research has been following a false trajectory – asking simply the wrong questions? Well, so much I can say – although this report is already 16 years old, that day has not come yet. But neither have the promised products, which is still no cause of concern in these circles. Modesty, skepticism, self-critical reflection of ones’ own scientific assumptions, theories and concepts are no virtue in genetic engineering and so-called ‘synthetic biology’ circles. But as Giuseppe is arguing, there is in fact no coherent scientific theory or concept unpinning their science, and nobody seems to be missing it. The field has developed without it as long as big ‘forward looking’ promises catch the attention of joint venture (risk) capitalists, philanthro-capitalists, and politicians who keep the funding flowing in.

For me, the discovery was the big disconnect between engineering and biotechnology on the one hand and ecology and evolution on the other. We observe the same phenomena: variability, plasticity, adaptability--- of course, I also struggle with it, but it is the essence of my research, understanding variability and investigating whether there is a pattern, a biological or ecological rule beyond chance that will help us to understand organisms and their interactions with the environment. To do so, I have to employ all kinds of statistical tools for calculating the probabilities before I can make any confident statement about what I think I am seeing in my experiments. But for engineers, this is just a problem of noise that needs to be eliminated. For ecology and evolution, variability and diversity are the single most important preconditions for life on Earth and we must protect and foster them for our collective survival. For biotechnologists and genetic engineers, they are a proof of nature's imperfection in need of “repair” and “improvement” by human design – an alternative form of creationism, just not by a godly spirit but by humans, thus, quite akin to a religion and belief system. Nobody captured this more concisely in limpid terms than Noble laureate Jennifer Doudna in her book (written with Samuel Sternberg) with the telling title: ‘A crack in creation’: “…we are already supplanting the deaf, dumb and blind system that has shaped genetic material on our planet for eons (note: she means evolution) and are replacing it with a conscious, intentional system of human-directed evolution.” (13) And further: “CRISPR gives us the power to radically and irreversibly alter the biosphere that we inhabit by providing a way to rewrite the very molecules of life any way we wish”.

For me, in short, this story has presented itself this way: in the 50's to the 70's it was an exploration, a discovery journey, we – as human society – did not know the material, we did not know the functions, we did not know the structure of genes, but people were happily intentionally breeding quite successfully new crop varieties since at least a hundred years since Mendel discovered the rules for systematic cross-breeding. Therefore, I would be willing to grant any explorer, any researcher of these days and ages the degrees of freedom in getting it wrong that they needed in order to get their heads around it. It was not clear what was coming, what they were going to find and they did the best they could, based on what they could see at that time. But by 2001, it became clear that our accounting and book-keeping of genes and proteins based on our then-understanding of genetics was wrong, that humans actually turned out to have very few genes, by comparison to most plants, for example, and to many other organisms out there, too. But nobody would argue that humans are not among the most complex organisms of planet Earth. At that point, there should have been much more reflection; we should have had to stop and look and come up with at least some attempt of a unifying theory, at least understand and face the fact that what we have thought before about genetics was to a large degree wrong or at least far too incomplete to safely begin to move into the commercial application of genetic engineering. Although I want to recognize that there were indeed a few brilliant scientists who were skeptical and ‘humbled’ by the outcomes of these early sequencing projects. (14) But historically, the opposite happened. What I observed then in the 2000's, was the schism to widen dramatically, the splitting off of two trajectories in the field of basic genetics and genetic engineering. The genetic engineering trajectory narrowed down, largely ignored the significance of the discovered discrepancy between what we had thought about genes and their role until 2000 and what turned out to be the reality. They framed genetic engineering and the encountered ‘noise’ as a narrow technical issue that needed more attenuation, more control, more precision, more targeting. To this day, their focus remains on understanding the target DNA sequences they want to engineer – either within the same or across different genomic contexts or simply eliminating the DNA sequences. This method is pursued to the point of maximal reduction with what they coin as building blocks, chassis, modules or whatever in synthetic biology.

Understanding the context of the genomic and wider environment and its impact on gene functioning or inheritance is not a necessary precondition for the safety – or even success for that matter - of their genetic engineering interventions. The other trajectory became broader, in fact, the gene became a fuzzy concept, with some scientists saying there are no genes as Ignacio Chapela will explain in his presentation. When the old concept/understanding of genetics did not explain and not match with experimental observations and reality, a new concept was born called epigenetics which Giuseppe compares to the time and age of epicycles in astronomy, when the measured movements of the stars did not line up anymore with the geo-centric understanding. In order to maintain the geo-centric worldview and power structures that came along with it in those days, epicycles were invented. Today, the ‘stars’, when metaphorically speaking of genes, do not line up anymore with the genocentric worldview, epigenetics help us out to some degree, although not entirely. (15) (16) However, the two different trajectories and diverging worldviews are really not compatible. But why does the one with the least scientific support, lack of coherent theory, and weaning explanatory power survive so long and remain so powerful? Well, a big role is played by the astronomical amounts of money that flow into this field and have created uncountable numbers of start-ups, enormously lucrative business models for capture by big companies. These interests come along with the belief system that we could re-configurate and re-‘create’ the world as explained earlier, a belief that seems to be so immensely attractive to many people. We have reached today a “too big to fail” state of affairs - too much money has been invested, too many people have bought into it for various reasons and too many institutions have been created.

Also, many young people have bought into the promissory narratives of these techno-fixes, solving the overwhelming problems we all are facing and the large funding basis and career opportunities – it simply cannot be wrong. So, when you see signs, for example, during those ‘Marches for Science’ where it says ‘We have the solution’, I first want to know: what science do you mean, by whom, for whose needs and based on what philosophy? And what belief system have you been signing up to? In that sense, it was reassuring to read the recent and highly exceptional account of a younger scientist who also reflected on the unfolding of the field of genetics and engineering since the outcomes of the human genome projects and how it affected his views on biology and career ethics and he titled it the ‘Making of a Skeptical Biologist’. (17) So, there is hope that perhaps before the century since Crick’s declaration of his dogma is completed at least some stock taking will happen where it actually led us and that young scientists entering the field of biology will finally begin to ask the right skeptical questions. I stop here. Beware, good luck, and thank you.

NOTES

1. Hood, L., Galas, D. The digital code of DNA. Nature 421, 444–448 (2003). https://doi.org/10.1038/nature01410

2. Crick, F.H.C. 1958. On protein synthesis. Symp. Soc. Exp. Biol XII: 139-163.

3. Liang, F., I. Holt, G. Pertea, S. Karamycheva, Sl.L. Salzberg, J. Quackenbush. 2000. Gene index analysis of the human genome estimates approximately 120,000 genes. Nat Genet 25:239-40; doi: 10.1038/76126.

4. Crick, F. Central Dogma of Molecular Biology. Nature 227, 561–563 (1970). https://doi.org/10.1038/227561a0

5. http://www.genomenewsnetwork.org/resources/timeline/1972_Berg.php

6. Peter Steinhart, Oct. 25, 1981, New York Times Magazine; https://www.nytimes.com/1981/10/25/magazine/the-second-green-revolution.html

7. Ann Crittenden, 28 June, 1981, New York Times; https://www.nytimes.com/1981/06/28/business/the-gene-machine-hits-the-farm-of-their-new-usage.html

8. Norman E. Borlaug. 2000. Ending world hunger. The promise of biotechnology and the threat of anti-science zealotry. Plant Physiology Vol. 124: 487-490; https://www.jstor.org/stable/4279449

9. Raser, J.M. and E.K. O’Shea. Noise in gene expression. Origins, consequences and control. Science 23 Sep 2005: Vol. 309: 2010-2013; DOI: 10.1126/science.1105891

10. Andrianantoandro E, Basu S, Karig DK, Weiss R. 2006. Synthetic biology: new engineering rules for an emerging discipline. Mol Syst Biol https://doi.org/10.1038/msb4100073

11. https://biobricks.org/ - however, it’s latest publication dates almost 4 years ago.

12. https://www.sciencedirect.com/topics/engineering/biobricks

13. Jennifer A. Doudna & Samuel H.Sternberg. 2017. A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution. Houghton Mifflin Harcourt Boston New York, USA

14. Gould, S.J. 2001. Humbled by the Genome’s Mysteries. New York Times https://www.nytimes.com/2001/02/19/opinion/humbled-by-the-genome-s-mysteries.html ; Commoner, B. 2002. Unraveling the DNA myth -The spurious foundation of genetic engineering. Harper’s Magazine (can be downloaded at https://grain.org/article/entries/375-unravelling-the-dna-myth)

15. https://www.genome.gov/genetics-glossary/Epigenetics

16. Jablonka, E. and M.J. Lamb. 2005 (updated edition 2014). Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life - A groundbreaking synthesis of evolutionary theory arguing that induced and acquired changes also play a role in evolution. MIT Press.

17. Ogbunu, C.B. 2021.The Human Genome and the Making of a Skeptical Biologist - Thoughts on scientific ambition and progress, 20 years after the first draft of the genome was completed. Scientific American; https://www.scientificamerican.com/article/the-human-genome-and-the-making-of-a-skeptical-biologist/