Dan,
This email chain contains some really interesting ideas! Even in teaching the medical science of humans (3-4 billion years later), I think we’ve always underemphasized the importance of thinking about compartments — including microscopic-scale compartments — as being such a key feature of life. The separation of one space from another (compartmentalization) underlies so much physiology, yet (in my opinion) outside of teaching students about membrane potentials and the electron transport chain, this topic kind of gets short shrift in the lecture theater.
Keith F Stringer, MD
Faculty member, Division of Pathology & Laboratory Medicine; Adjunct Professor of Pediatrics
Cincinnati Children’s Hospital Medical Center, and University of Cincinnati College of Medicine (unknown artist for image below) thank you.
From: Jim Adams
Sent: Sunday, July 27, 2025 6:25 PM
Dr Nebert,
I enjoyed your summation of the origin of the chemistry of life, especially the formation of these vesicles and lipid micelles, plus evidence these lipid structures are able to reproduce. This topic (in my mind) reinforces the obvious fact that life and reproduction are inherent in the very nature of the physics and chemistry of Creation — not as an addendum or an afterthought, but one and the same as the very nature of God.
James Adams, MD
Family Practice physician, Cleveland, MS
From: Nebert, Daniel
Sent: Friday, July 25, 2025 5:30 PM
Subject: If lipid micelles can reproduce — this would permit very early Darwinian evolution
From: Doron Lancet
Sent: Wednesday, July 23, 2025 2:18 AM
Dear Dan,
I published my first Origin-of-Life (OOL) paper in 1994 — four years after I had completed an enjoyable sabbatical year in your lab at the NIH. More than 30 years have now passed, and I had to wait this long to see a unique person in the scientific community who is able to write something as succinct, cogent, unbiased, and objective — as your GEITP blog on this OOL topic [written below]. ☹
Almost all people doing research on the origins of Life are completely brainwashed; ~95% of all OOL papers begin with a sentence such as “it is totally clear that life began with RNA.” Once this concept is written at the beginning of any publication, no Reader can be serious about attempting to understand what I have proposed repeatedly over the last three decades. Of course, there are several people, mostly my past students, some currently who are professors, who support what I say. But otherwise, it is totally impossible to find support for my “Lipid First” hypothesis.
I very much hope that you will consider writing an editorial — similar to what you’ve written in this GEITP blog — and getting it published in a high-impact journal. For those not cognizant of all the details in the field of OOL studies, the world of science needs to know there are several viable hypotheses on how Life first began on Earth. And my feeling is that the “RNA First” hypothesis has a substantial number of flaws.
Truly, Doron
Prof. Doron Lancet
Weizmann Institute of Science, Rehovot, Israel
From: Matti Lang
Sent: Tuesday, July 22, 2025 5:51 AM
Hi Dan,
Thanks for sharing this fascinating article as a pdf file — including your excellent summary.
This topic reminds me of a small “discussion” we had at one of your weekly lab seminars, a few weeks after I first joined your group for my postdoc in January 1979. For my first seminar to your lab group, I was discussing the catalytic properties of the “membrane-bound P450 mono-oxygenase complex”, as it was called at that time.
In my thesis work, I had studied the reaction mechanisms of membrane-bound enzymes — in particular, how the activity of enzymes that are integrated in the membrane bilayer can be affected by the lipid composition. As models, I used both the endoplasmic reticulum (ER) as well as artificial lipid vesicles with varying composition of various lipids, to which purified proteins were introduced. Later, some of my experiments were carried out on how membrane lipids supported a multistep-reaction cascade in mitochondria.
At the seminar I explained my results with great enthusiasm, but — to my major disappointment — my theories received a rather “mild,” if not an indifferent, reaction. Then, after a moment of awkward silence, you very politely and patiently explained to me, “Look, Matti, here at the NIH, postdocs are ranked as follows: at the top are the guys who study DNA and genes, followed by the protein people; at the bottom of the list are the lipid and carbohydrate people, …”
The topic was thus settled, but it took me some time to recover, and some effort not to leave the room. Anyway, I finally recovered — and enjoyed the time in your lab enormously — including the secondary social activities. BUT I NEVER AGAIN TOUCHED THAT LIPID-MEMBRANE-VESICLE-ENZYME THEME(!!) ☹
Cheers, Matti
Professor emeritus, Finland
From: Jim Adams
Sent: Tuesday, July 22, 2025 2:44 PM
Sounds like God.
Looks like God.
Walks like God.
Tastes like God.
—From James Adams, MD [semi-retired]
Family Medicine Practice, Cleveland, Mississippi
From: Nebert, Daniel
Sent: Monday, July 21, 2025 2:39 PM
Periodically, our GEITP blogs have touched on the topics of “Origin of Life on Earth” and “at what time in our planet’s history did the Last Universal Common Ancestor (LUCA) exist?”
These questions are fundamentally related to gene-environment interactions, the most prominent theme of these GEITP essays. How did a chaotic mix of non-living chemicals spontaneously give rise to the first entities capable of reproducing and evolving? From the earliest “attempts to create from the primordial soup on planet Earth”, there seems to have been an inexplicable “Force” to generate “reproducing and evolving protocells” — which would become the prebiotic precursors of living cells. Whatever that Force was, its internal regulatory machinery was being created and modified by external signals in the environmental milieu surrounding this entity; this would be among the earliest gene-environment interactions. Subsequently, whatever and whenever the LUCA came into existence, this was followed by “speciation” [formation of new and distinct species from a previous species during evolution] — and gene-environment interactions certainly played a pivotal role in the process of speciation. And it still does, today.
To get everyone on the same page, let’s begin with some History. Our planet first formed ~4.54 billion years ago; this happened during early stages of the solar system formation — due to accretion of dust and gas particles circling the Sun. A phylogenetic tree of Life would directly portray the idea of evolution by descent from a single ancestor. In 1809 an early tree-of-life was sketched by Jean-Baptiste Lamarck in his “Philosophie zoologique.” In 1859 Charles Darwin famously proposed the theory of universal common descent through an evolutionary process in his book “On the Origin of Species.” The term, last universal common ancestor (LUCA), was not coined until 1990 by Carl Woese as the hypothesized common ancestral cell from which the three domains of Life (Archaea, Bacteria, Eukarya — at that time) originated. Based on a formal statistical test, this theory of a universal common ancestry is supported in preference to competing multiple-ancestry hypotheses.
The hypothetical cell must have had a lipid bilayer — and it must have possessed ribosomes and the genetic code which got transcribed from DNA and RNA, and then the RNA was translated into proteins. The earliest life forms that we know of — were microscopic organisms (microbes) that left signals of their presence in rocks ~3.7 billion years ago. Although the timing of the LUCA cannot be definitively constrained, most studies by 1990 had suggested that the LUCA existed by 3.5 billion years ago (~1 billion years after the planet formed) and the universal ancestor was some form of pre-bacterium [shown in figure]…
Last universal common ancestor – Wikipedia
Was the origin of Life based on DNA? Concatemerization of polymers? Or something else? In the 1960s, scientists — including Woese, Francis Crick, and Leslie Orgel — independently suggested that early life forms might have relied on RNA for both genetic information storage and catalytic functions (i.e., before the evolution of DNA and proteins). In 1962, Alexander Rich proposed that RNA could have had a phenotype beyond its informational role, suggesting RNA’s catalytic capabilities. The discovery of ribozymes (RNA molecules that act as catalysts) in the early 1980s by Tom Cech and Sidney Altman — provided strong experimental support for RNA preceding DNA in the origin of life. In 1986, Walter Gilbert was the first to coin the term “RNA World” in a commentary on the catalytic properties of RNA.
Research over the past several decades has confirmed the useful properties of random RNA sequences (e.g., the production of active RNA ligases from random sequences of RNA); this is not enough, however, to prove the RNA World hypothesis. Based on what is known about organisms before 2015, it was not possible to conclude that a self-replicating molecule was the primary source of catalytic mechanisms fundamental to living systems. Research on the RNA World hypothesis is ongoing, although recent findings threaten to disprove the hypothesis. In a 1996 report, NASA specified that the “significant difficulties” surrounding the RNA World concept include the chemical fragility of RNA and its narrow range of catalytic activities. Some proponents of the RNA World have noted that many viruses are made of RNA, not DNA. Whether the genesis of viruses falls before or after the LUCA — as well as the diversity of extant viruses and their hosts — remains a subject of investigation.
While the prevailing scientific narrative is that of a ‘polymers first’ approach or an ‘RNA world’, Prof Doron Lancet’s group at the Weizmann Institute of Science in Rehovot, Israel, present an alternative, describing a ‘lipid world’ scenario as a plausible origin for life, in which lipid micelles (structures simpler than cell-like vesicles) could have been nanoscopic protocell precursors [see all the pdf attachments]. Core to the theory is that — these micelles could exhibit catalysis and compositional self-reproduction, passing information through the mixture of their lipid components — rather than through a genetic code.
For decades, the prevailing scientific narrative (dubbed the ‘RNA world’ or ‘polymers first’ hypothesis) — suggested that Life began when complex, self-replicating molecules like RNA somehow emerged from the primordial soup. These molecules were thought to have been the crucial starting point — later becoming enclosed within membranes to form rudimentary cells. However, this traditional view faces significant challenges. Prof Doron Lancet and collaborators explain how totally impossible it is that complex polymers, like RNA, could spontaneously form with the necessary specific sequences and structures needed for replication — in the midst of chaos and disorder of the early Earth environment.
Furthermore, no single molecule — not even DNA or RNA — can self-reproduce in isolation, because they rely on the intricate machinery of an entire cell. This raises the question: would it be reasonable to assume that prebiotic chemicals could possess capabilities beyond those of modern biomolecules?
Doron Lancet and collaborators present an alternative perspective (often called the ‘Lipid World’ or ‘lipid first’ hypothesis), that proposes a “more thrifty beginning” for Life [see the attachments]. Instead of starting with complex information-carrying polymers, this hypothesis suggests that life emerged from much simpler, spontaneously self-assembling structures made of lipid-like molecules.
Also known as amphiphiles or surfactants, these lipids are molecules with both a water-attracting head (‘polar’ or hydrophilic) and a water-repelling tail (‘apolar’ or ‘hydrophobic’). These compounds were very abundant on early Earth — as evidenced by analyses of meteorites, as well as chemical reactions known to occur in suboceanic vents [see Fig. 1 of first attachment (“A-219”)].
A key property of lipids is their ability to spontaneously self-assemble in aqueous environments, energetically driven by the tendency of their hydrophobic tails to cluster away from the water. This self-assembly can create various structures — including nanoscopic spheres called micelles, and larger spheres with a watery core called vesicles. Unlike highly constrained biological polymers, lipid self-assembly is promiscuous, meaning that any type of amphiphile (biological or synthetic in the lab) can combine to form these structures.
With their enclosed water-filled core, vesicles have long been considered prime candidates for early protocells, due to their resemblance to modern cells. But research from the Doron Lancet lab highlights the compelling possibility that nanoscopic lipid micelles could have been an early precursor to life. In fact, micelles are simpler than vesicles — typically comprising only a few hundred lipid molecules arranged in a single layer, with the hydrophobic tails facing inwards and the polar heads facing outwards onto the water; they lack the water-containing center of vesicles.
Despite their simplicity, micelles possess several advantageous attributes in the earliest stages of evolution: [a] their nanoscopic size means they contain fewer molecules, making their composition more sensitive to change, and potentially facilitating interactions between components; [b] they have a high surface-to-volume ratio, [c] enhanced reactant concentrations, [d] promote all against all molecular networking, and [e] portray a huge diversity of compositions. Their ability to form from a diverse range of lipids makes them compatible with the chemically heterogeneous disorganized chemistry that we predict must have existed on early Earth.
For any entity to be considered a precursor to Life, it must be able to facilitate chemical reactions through catalysis. Lipid molecules have proven to be simple catalysts (“lipozymes”). Micelles provide a unique milieu for catalysis, significantly enhancing reaction rates — due to their concentration, surface effects, and polarity gradients. These catalytic capabilities mean that micelles effectively harbor mutually catalytic networks. In such a network, molecules within the micelle catalyze the entry, formation, or modification of other molecules, helping to maintain and grow the whole structure.
A critical characteristic of Life is self-reproduction. Micelles can grow by incorporating more lipid molecules from their environment (accretion), or by synthesizing/modifying lipids internally. Subsequently, micelles often split into two or more parts, resulting in offspring assemblies. However, meaningful reproduction requires that new assemblies inherit characteristics from the parent. Since micelles lack a genetic sequence like DNA or RNA, the solution is passing information through composition. Reproduction in this context implies the micelle grows
while maintaining stable internal concentration relations (homeostatic growth), which is then transferred to the ‘progeny’ assemblies upon fission. This compositional information would be similar to non-genetic (epigenetic) inheritance in present-day cells.
To quantitatively explore catalytic networks and reproduction, the Graded Autocatalysis Replication Domain (GARD) Model was developed by the Doron Lancet lab [see the 4th and last attachment for illustrations of models]. This simulation model studies the dynamic behavior of mutually catalytic networks within lipid assemblies. This model is purely based on computational chemistry, allowing simulations of the kinetic behavior of micelles and vesicles. A key finding of this model is that certain rare compositions exhibit self-reproduction. These stable, reproducing entities are termed ‘composomes’.
Although a random composition is unlikely to be a composome — the simulations reveal something crucial: reproducing composome states are dynamic attractors. Attractor dynamics means that a system tends to settle
into stable states. In the GARD model, this means that — from practically all initial random compositions, after a finite number of growth and fission events — the assembly will reach a stable composome. Simulations also indicate that repertoire diminution occurs, as assemblies approach attractors: the number of molecule types decreases, often leaving potent catalysts — in a manner analogous to modern cells that use a relatively small subset of the vast assortment of chemical compounds available.
The capacity for compositional reproduction in micelles, opens the door to compositional mutations. Exponential growth of micellar counts having similar composition with some variation would constitute ‘proto-species’. This in turn, will allow natural selection, providing a foundation for primeval Darwinian evolutionary attributes. If micelles with certain compositions reproduce more successfully than others (e.g., due to more effective catalytic networks), their proto-species would become more prevalent. This scenario allows a departure from the view that Darwinian evolution requires complex biopolymers like DNA or RNA (i.e., it could have begun at a much simpler stage).
This scenario also suggests a plausible path for increasing complexity. Once reproducing micellar entities exist, they can evolve. This evolution could drive the gradual emergence of more complex catalytic networks, the seeds of metabolism. Such micellar catalysis could facilitate the synthesis of more complex molecules (e.g., building of amino acids into peptides or nucleotides to increasingly long RNA molecules). Some lipid modifications could lead to structural changes, potentially triggering the transition from micelles to the more complex vesicular form.
The transition from simple micelles to the more cell-like vesicle protocells would be a necessary step towards modern life. For example, sufficiently endogenously catalytic modification of one-chained lipids into two-chained molecules within a micelle could induce a shift to vesicular structure.
How would larger vesicles acquire the complex catalytic networks needed for reproduction and evolution? This requires the crucial synchrony between membrane growth and growth of the internal aqueous content. The micellar hypothesis offers a solution. Reproducing micelles (already containing functional catalytic networks), could fuse with existing non-reproducing vesicular membranes; this fusion would transfer network components and catalytic capabilities from the micelle to the vesicle and allow its membrane to reproduce. This process of transferring compositional information via fusion — is seen as analogous to horizontal gene transfer or epigenetic inheritance in modern biology.
At this point, any molecule in the watery milieu inside the vesicle will not be coupled to the membranal network. However, gradual mutations in the membrane could lead to increasing control of catalytic molecules in the membrane that will begin to control the composition of the inner volume. This will eventually allow synchronous compositional reproduction that encompasses both membrane and the internal metabolism, a well-known challenge in the field. This stepwise progression (starting with simple, spontaneously forming, reproducing micelles) that gradually builds complexity towards vesicular protocells (membrane and inner content) — presents a much more plausible chemical path from chaotic non-living matter to (seemingly more ordered) Life than scenarios relying on the sudden appearance of complex biopolymers(!!)
Doron Lancet’s lab’s hypothesis portrays the first steps of Life — not as a singular, improbable event involving the perfect assembly of complex machinery — but as an emergent property of dynamic, self-organizing chemical systems. His model suggests that the fundamental attributes of Life (catalysis, reproduction, and containment) could have been integrated from the very beginning within simple micellar structures. The subsequent evolution towards the sophisticated, biopolymer-based Life that we see today — including the central dogma of biology — could then be seen because of this initial, more primitive form of Darwinian evolution, rather than a prerequisite for it. While the journey from these early protocells to complex modern cells is still a vast area of hypothetical research — focusing on the self-reproduction and evolutionary potential of simple, dynamic, supramolecular lipid assemblies — this provides a tangible and scientifically rigorous path forward in deciphering the origins of life.
As mentioned above, the earliest life forms so far proven to exist were microscopic organisms (microbes) that left signals of their presence in rocks ~3.7 billion years ago (~3,700 million years ago). Earth formed ~4,540 million years ago, meaning that Life would have begun within the first 840 million years after formation of the planet. However, the 2024 publication by Moody et al. [to be discussed in the next GEITP email blog] shows data indicating the last universal common ancestor (LUCA) likely existed by 4.2 Billion years ago (i.e. 4,200 million is just 340 million years after Earth was first formed). If Doron Lancet’s “lipid first” hypothesis is correct, these replicating lipid micelles would be great candidates for having populated Earth before 340 million years after Earth first formed…!!
DwN
Nat Rev Chem 2021; 5: 870–878
doi.org/10.33548/SCIENTIA1302 (June 2025)