Yves here. KLG’s latest essay starts out with the history of how biology has been conceived (at least in part) as an engineering exercise, and how some simple real world cases illustrate how that approach has limits. Nevertheless, that line of though has produced some sqillionaire-appealing notions about how to defeat death and preserve (supposedly) functioning brains. So this article includes more of a walk on the wild side than usual.
KLG’s intro:
The engineering ideal in biology is just that, an ideal. Sometimes it works. More often it doesn’t. The theory that living organisms are machines explainable by resorting to simple physics and chemistry goes back to the research of Jacques Loeb in the years surrounding the turn of the twentieth century. This theory of “Mechanism” has been successful at times.
But engineering doesn’t allow for “black boxes.” The physiological functions of human beings, on the other hand, can be effectively indeterminate, that is, full of black boxes. And when the engineering ideal has been applied to human biology in health and disease, the results have often been less than useful.
Still, the imperative remains, and a recent book claims to show how death can be abolished by preserving a functioning brain. This will strike most people as outlandish, because it is. Nevertheless, this engineering ideal is seen as the answer to “eternal life” of a sort and to therapeutic success. It is not. But the idea is congenial to those who would command our scientific research establishments. They will make a lot of noise, do a lot of damage, but eventually retreat. The damage caused by the disutility of the engineering ideal in biomedical research, both in the lab and the institution, will remain. For a very long time, perhaps forever.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
The indispensable historian of science Philip J. Pauly (1950-2008) published a remarkable book in 1987: Controlling Life: Jacques Loeb and the Engineering Ideal in Biology (Oxford University Press) in which he described the approach to biology developed by Jacques Loeb (1859-1924) more than a hundred years ago at the Rockefeller Institute for Medical Research (later Rockefeller University) and the Marine Biological Laboratory (MBL) in Woods Hole. [1] Loeb is largely forgotten except for the building named for him at MBL, but he was the scientific superstar during the first decades of the twentieth century, when he was the model for the scientist Max Gottlieb in the novel Arrowsmith(2025) by Sinclair Lewis.
As explained by H.M. Fangerau (2006; lightly edited):
Loeb embodied the archetype of a ‘radically reductionist mechanist’ who also served as a model of the research scientist for Sinclair Lewis, Theodore Dreiser, and Walker Percy…For Loeb, every form of life, all creatures were physicochemical machines; hence, his primary research objective was to explore the physics and chemistry of all life processes. His greatest research success, granting him international fame, was the discovery that by manipulating their liquid environment, sea urchin eggs could be stimulated to divide as if they had been fertilized. He called this phenomenon ‘‘artificial parthenogenesis.” (emphasis added) [2]
Through the 1930s “mechanism” and a more holistic approach to explaining biology vied for authority, as described in The Life Organic: The Theoretical Biology Club and the Roots of Epigenetics by Erik Peterson. Few scientists since the late-nineteenth century have denied that biological mechanisms are based in chemistry and physics, but not reducible to either chemistry or physics, are responsible for all biological phenomena. But “Mechanism” won the epistemological argument, primarily because of its frequent utility in modern biomedical research.
For example, using red bread mold as their experimental model, George Beadle and Edward Tatum developed the “one gene-one enzyme theory” to explain the connection between the genes and biological function. Francois Jacob and Jacob Monod and Salvador Luria used the bacterium Escherichia coli and bacterial viruses to develop a model of gene regulation that is extensible to all organisms, and it is now a commonplace that dysregulated gene expression contributes to disease.
The Central Dogma of Molecular Biology (DNA makes RNA makes Protein) enunciated by Francis Crick of Watson & Crick in the late 1950s led directly to the modern molecular biology of recombinant DNA and gene cloning, which is often called “genetic engineering.” As a result, Big Pharma can now produce human insulin and other bioactive proteins in the laboratory. Drugs (imatinib/Gleevec) target specific proteins that cause certain cancers when dysregulated. CAR T-cell therapy can now treat a specific individual’s cancer on demand, sometimes.
But sometimes the engineering approach fails, and this is because engineering proper does not admit of unknown or unexpected “black boxes.” There were no black boxes in construction of the Pantheon almost two thousand years ago, only great knowledge the use of concrete and the engineering physics of static forces. Biological “engineering” is not the same. For example, more than thirty years ago a yeast strain was tweaked to produce the amino acid tryptophan as a dietary supplement/sleep aid. Manipulating the tryptophan biosynthetic pathway in this yeast strain, which is very well understood at the molecular level, also produced a vanishingly small amount of byproduct that was missed as a contaminant of the supplement. This led to an outbreak of hairy cell leukemia, which has a 5-year survival rate of 95% now but did not during 30+ years ago and people died after using these lots of the supplement. [3]
The one gene-one enzyme principle often led to an inchoate expectation of a “one gene – one disease theory” to explain many human diseases. When the first genes responsible for human disease were first identified and cloned (e.g., CFTR in cystic fibrosis), the immediate expectation was that gene therapy would follow. This has not been a regular occurrence despite the initial hype. Gene replacement in a cultured cell in the laboratory is one thing. Gene therapy in a human being is usually another thing even though the underlying technology is identical, because targeted delivery and expression of the therapeutic gene is a “large body” problem no matter how simple the concept.
More recently, mutant gene correction using CRISPR technology has been developed but it also has black box characteristics because it is also a “large body” problem. [4] Big Pharma and Small Pharma are also having second thoughts about CRISPR, although the current technical obstacles will probably be surmountable at the margin that includes diseases where the target tissue can be hit accurately with therapy (e.g., blood cell progenitors – stem cells – in the bone marrow).
So, engineering approaches have shown that life is generally not controllable at the level required in engineering. But that does not stifle the urge. Nor should it, necessarily. But expectations should be informed by a deep appreciation that genetic engineering and biological engineering are only useful expressions and that the underlying biology of a multicellular organism is effectively indeterminate and therefore incompletely understood.
In June 2023 my essay here was entitled Artificial Intelligence and Your Health – Thoughts on Virtual You: How Building Your Digital Twin Will Revolutionize Medicine and Change Your Life. The authors of that remarkable book were certain the prospect of personalized medicine informed by the construction of a so-called “digital twin” based on the “data” of one particular individual –You! – would make illness a (virtual) thing of the past. Thus, my digital twin [5] or yours would: “Harness computers to put the ‘spark of life’ into mathematical understanding of the human body…and…Stitch together different mathematical models of different physical processes that operate across different domains of space and time within the body.”
In an effort to go way past a personal medicine that banishes disease one person at a time, an unintentional sequel to Virtual You was published in late-November 2024 by the Australian neuroscientist Ariel Zeleznikow-Johnston. AZ-J explains how we can use the “engineering ideal of biology” to abolish death. Yes, you read that correctly: The Future Loves You: How and Why We Should Abolish Death.
AJ-Z begins with this lament, “The brutal reality is that, out of those who die from disease each day, a disquieting number felt they still had more time to live…(and)…These innumerable personal tragedies unfold because, even though medicine has developed greatly between the 1920s and the 2020s, it is still far from maturity.” In this book:
- Neuroscientists will see how their work clearly points to the conclusion that a person can be preserved.
- Doctors will be provided with a showcase of this astounding progress and the impact int can have on their practice.
- Everyone will come away feeling we should be setting our own expectations higher before giving up on dying.
Because there are indeed scientists and entrepreneurs seeking out ways to dull death’s scythe, which would seem to make death worse, but I digress.
Part One asks the question “Why Don’t We Get More Time?” and immediately proceeds to state: (1) the purpose of life is to stay alive, at least from an evolutionary perspective; (2) “natural selection mandates that creatures better suited than others to their environment will become more common over time, no exceptions;” and (3) “natural selection operates at the levels of traits and genes, not at the level of individual animals. AZ-J then proceeds to list examples illustrating his assertions. This is the common trope of The Future Loves You: The statement of a biological or philosophical proposition followed by an explanation/example such as: “Since whales live a lot longer than humans, there is no reason in principle that humans cannot increase their lifespans to match them.” One could also ask “Why not the Greenland shark?” that may live 500 years. This argument ignores three billion years of biological evolution. But who’s counting? AZ-J does imagine a time machine on occasion. So there is that.
The Future Loves You is replete with equivalent arguments. All well and good, scientific and all that, except: (1) the purpose of life from an evolutionary perspective, if evolution can be said to have purpose and perspective, it is not to stay alive – the evolutionary “purpose” of life is to leave progeny in the next generation, some of which on rare occasion will be more “fit for their environment” than others and leave even more progeny in the future; (2) evolution by means of natural selection is at the core of the Modern Synthesis of Evolutionary Biology, but natural selection is not the only mechanism of evolution and this has been well understood since the 1960s; (3) the level of selection in evolution is a continuing source of argument and experimentation. As with most books these days, the index of The Future Loves You is only borderline useful, but I did not see reference to The Selfish Gene (1976) by Richard Dawkins. This is the locus classicus of the theory that “traits and genes” are the unit(s) of selection in evolution. This is not the place to reenter this sometimes contentious argument, but the “unit of selection” is much more complicated that AZ-J presents. [6]
Part Two asks What are death, personal identity, consciousness, and memories? Big questions, all, and they are covered well enough from a neuro-scientistic perspective, provided AZ-J has “succeeding in convincing you (the reader) that death is an evil to be fought.” As might be expected, AZ-J has little sympathy for “palliative” philosophers who disagree and for scientists and physicians who refuse to consider death as a disease to be cured. To summarize the middle third of the book: Mind emerges from the brain and when the brain ceases to function, mind with its personal identity, consciousness, and memories soon disappear forever and are not retrievable by any means.
For our purposes here, AZ-J’s timeline of death is useful:
The goal of The Future Loves You is to explain how brain-with-mind can be preserved in its “connectome,” with the connectome being the sum total of all the stable and dynamic connections between and among neurons and their axons, dendrites, and dendritic spines, astrocytes, glia and other components of the gray and white matter of the brain.
In Part Three, “if we are to abolish death, we need to put the knowledge gained in Part II to work.” The key insight of The Future Loves You is that no one is dead until his or her connectome is dead. But: “Luckily, we already have a technique to preserve everything down to the molecular level, which is probably a level of detail above what is actually required. The trick is just to stop time.” (emphasis added)
The way to “stop time” described in the book is to basically kill the person, concentrating on the brain first. AZ-J proposes to do this with fixation using glutaraldehyde followed by perfusion with a cryoprotectant and freezing the sample at minus-135 degrees Celsius (minus-211 degrees Fahrenheit), where all molecular motion will cease (not really, but grant this wish for now). I must admit, when I read this I was confused. Glutaraldehyde is a very effective tissue fixation agent (and thus also a very effective disinfectant/biocide). It is also permanent. The molecule is reactive at both ends and crosslinks proteins and other cellular components absolutely irreversibly. Nevertheless, once you have done this:
Congratulations, you have performed aldehyde-stabilized cryopreservation and removed the neural tissue from the ravages of time. At this point feel free to leave the brain in the freezer for a year, ten years, a thousand years, however long you may need – no changes will occur and no information will be lost.
A frozen dead person, or the person’s brain since the body seems to have been dispensed with, seems like a serious problem if preservation is the goal, even with the hypothetical time machine to the future. But, according to AZ-J not so long as one assumes that functionalism is a valid theory of consciousness (details of which do not really matter here). All one has to do to retrieve the mind of the person, with her memories, personal identity, and consciousness intact is to digitize her connectome through the use of technologies not yet developed to within several “orders of magnitude” [7] using tissue sectioning, scanning, and computer imaging that results in something called “whole brain emulation.”
Whatever the quantitative requirements, which are ridiculously large, it is assumed throughout that the structural integrity of the fixed brain down to the sub-molecular detail required retains the information present in the connectome before the entropic consequences of death have had their sting. In my view, this is completely unwarranted. That the brain, with it neurons, astrocytes, and glial cells, is the same when imaged in a transmission electron microscope (with does not take a picture) as before it was killed by the fixative cannot be assumed. But it is throughout The Future Loves You. This is profoundly abiological. It is also probably in violation of the Second Law of Thermodynamics.
If we go back to the table of brain death events above, absent the case of revival after cold drowning that is described in The Future Loves You, the structure of the brain required for mind begins to disappear within minutes of cardiac arrest. That synapses are clearly visible 4-hours post-heart function is meaningless for brain function that supports the mind, with “memories probably still intact.” The apparent order seen in a fixed and cryopreserved brain is not the same as the stable, highly ordered but dynamic state of a living brain. This leads to the relationship between entropy and information that is not a theoretical concern in The Future Loves You.
Without going into detail while going very far out on a limb, this Shannon entropy [8] posits that a low-entropy, high-order state can produce multiple outcomes while a high-entropy, low-order state cannot produce much of anything at all. The visible superstructure of the brain left over after fixation may look ordered but it is not. It lacks the necessary information to produce multiple outcomes of the previously living brain. An analogy is perhaps the card catalog [9] of a research library, but without the several million volumes in the floors above that are theoretically connected to that card catalog. The authors, titles, and call numbers are incapable of producing any outcome at all other than a list, no matter the sophistication of any emulation based on them. The information is simply not there, as lost as the previously dynamic molecular components of a fixed brain’s now-dead synapses.
The Future Loves You ends with a series of speculations about how nanobots will one day swim through a bloodless brain or body and snip all the glutaraldehyde crosslinks that killed that brain and body. Richard Feynman is used as an authority for this, based on a lecture entitled “There’s Plenty of Room at the Bottom,” along with a book by Eric Drexler [10]. The final chapter explains how we can save everyone, because we already spend a lot of money on health care, or because we can now determine the sequence of an individual’s genome for less than $1000 instead of the $100,000,000 it cost 25 years ago. The former is irrelevant because it is a political instead of a scientific issue. The latter is true for two reasons: (1) the information remains present in virtually every living cell of that person’s body and the DNA is readily accessible, and (2) improvements in DNA sequencing technology were a small-body problem with no “black boxes” between the DNA and its sequence.
So, why is it useful to consider how the “engineering approach to biology” may one day abolish death? Previously in this essay I used the term “neuro-scientistic” when introducing Part Two of The Future Loves You. While cryopreservation of living tissue for subsequent transplantation is a very important component of transplant medicine, that is a thoroughly scientific and fundamentally a small-body problem. Abolishing death is utterly scientistic, however, even more than the creation of a digital twin that will allow doctors to cure your ills in silico before doing so in vivo. There will be no “harnessing computers to put the ‘spark of life’ into mathematical understanding” of a dead and sectioned human brain, no matter how fine the apparent resolution, that leads to the retrieval of the human mind that previously emerged from that human brain.
In summary, two things. First, three billion years of evolution means that biology is not a theoretical science amenable to small-body solutions to its most interesting problems. The amyloid cascade hypothesis (ACH) of Alzheimer’s disease is the result of the mistaken assumption that plaques and tangles cause AD. The implication is the ACH is a small-body problem, so if the plaques are eliminated the disease will be cured. [11]. Similarly, the SARS-CoV-2 mRNA vaccines were not the small-body solution to COVID-19. While it may be true that vaccination lessens the deleterious effects of COVID-19 in some patients, it does not prevent the disease or its transmission. The failure of these vaccines to meet these usual and reasonable expectations of vaccines as a result of faulty politics and misguided science has severely exacerbated vaccine hesitancy and skepticism, all for no good reason. We see these results now, every day in the current political environment. The fact remains that biomedical research and medical practice remain resistant to the preferred reductionist approach in 2025, which was not appreciated in 1925 when Jacques Loeb was lionized then as Elon Musk is lionized now in his rampage through the biomedical research establishment. Contrary to Musk, serious biomedical research remains a large-body problem, while terraforming Mars remains a small-body problem, although one that is nevertheless impossible whatever the overhead rate on government contracts with SpaceX.
Second, death is not a disease in need of a cure. In my view, the science in The Future Loves You is flawed beyond repair and the philosophy is not much better. AZ-J is entitled to choose his own philosophers of mind, but Ian MacGilchrist would have been included by me. Yes, mind is a function of brain. But the scientism in The Future Loves You is similar to the same in Determined: A Science of Life Without Free Will by the Stanford neuroscientist Robert M. Sapolsky. The arguments presented by Sapolsky purport to prove scientifically there is no such thing as free will. This cannot be done any more than a killed, fixed, and frozen brain can be revived, with or without a body.
Finally, acknowledging death is not the same as “giving up,” scientifically or philosophically, as described by AZ-J. Only a silly nihilist would maintain that life is not worth living. Human beings – citizens and scientists, politicians and philosophers – should be most concerned with making every life worth living, because what makes life special is its finitude, not its imperfectly imaginary infinitude. But we should also remember that Dylan Thomas was on to something:
Do not go gentle into that good night,
Old age should burn and rave at close of day;
Rage, rage against the dying of the light.
There is no engineering ideal in biology that can dispute this.
Notes
[1] Most biologists want to spend time at MBL and I was fortunate to spend much of the summer of 2011 in that special place.
[2] The paper is behind a paywall. Abstract: Shortly after bacteriologist Paul de Kruif had been dismissed from a research position at the Rockefeller Institute for Medical Research, he started contributing to a novel in collaboration with the future Nobel laureate Sinclair Lewis. The novel, Arrowsmith, would become one of the most famous satires on medicine and science. Using de Kruif’s correspondence with his idol Jacques Loeb, this paper describes the many ways in which medical science is depicted in Arrowsmith. This article compares the novel with de Kruif’s and Loeb’s biographies, and (1) focuses on the struggles of the main character, Martin Arrowsmith, as an allegory of the institutionalization of medical research in the US, (2) shows that (influenced by de Kruif) Sinclair’s purpose is to caricaturize scientific work in modern medical research institutions anywhere and (3) shows that the novel depicts a reductionist philosophy of research that seems to contradict the ‘‘messiness’’ of medical practice.
[3] It should be remembered that dietary supplements do not fall under the Pure Food & Drug Act, although it is not clear the Food and Drug Administration has much of a future at the moment.
[4] A “small body” scientific problem is sending a probe to the planet Jupiter. Even though the distance is unimaginably large, the engineering physics and technology required are completely understood, including the need for course corrections. A “large body” scientific problem is replacing or correcting a mutant gene in a single human being sitting before a healthcare team in the treatment room.
[5] A digital twin is a useful simulacrum of an actually existing object or system and can be used to simulate engineering design features and changes in supply chains and factories. As complex as logistics and manufacturing are, there are no “black boxes.” The goal with the human digital twin is to extend this engineering concept to human biology and medicine, or to convert a large-body problem into a small body-problem.
[6] The Wikipedia link is fairly comprehensive on the arguments about the unit(s) of selection in evolution during the past 50 years. My view is that selection is usually visible at the level of the individual, which reproduces or not, and is much more than a collection of replicating DNA elements. But like all good scientific concepts, the “selfish gene” can be useful in evolutionary biology. It is also true that these arguments often revolve around willful misunderstanding of apparently conflicting arguments if not outright polemical intent. A very accessible and argumentative summary is Mary Midgley: Evolution as a Religion.
[7] As an unnecessary reminder, an order of magnitude is a factor of 10. A difference of several (at least three) orders of magnitude can be illustrated by this series from 10 to 100,000,000: $100,000 to an “accuracy” of three orders of magnitude can be $100 or $100,000,000. Pick the one that works best for you.
[8] Low entropy ~ high energy/information; high entropy ~ low energy/information.
[9] I contend that the digitization of library records and remote storage has removed the key element of discovery. Yes, I have spent too much time in research libraries, which remain a wonder of the modern world. But my best discoveries, such as they have been, were made when the book beside the one I went looking for was the one I actually needed! The research library is a depository of high-order, low entropy matter capable of producing an essentially number of outcomes.
[10] Engines of Creation: The Coming Era of Nanotechnology (Anchor, 1987). Nanotechnology is indeed a thing now, here and here, but it is unlikely to include a swarm of magic robots specifically clipping protein crosslinks in a cryofixed brain, the remnants of said crosslinks remaining to interfere with protein structure and function as the brain/body is warmed and reanimated.
[11] Update: Sylvain Lesné, who published the altered images in his research on amyloid A-beta*56 has resigned his position at the University of Minnesota. He was by no means the sole driver of the ACH, but he led researchers down an apparent blind alley with incalculable opportunity costs.
