He is considered to be the founder of many fields, but none of them more important than his astonishing discoveries in microbiology, and none conveyed with such delight. Leeuwenhoek was captivated by his animalcules. His exhilaration in discovery, combined with a fearless and surefooted interpretation of unknown vistas, is for me Leeuwenhoek's true legacy.

It is a spirit effervescent in many later pioneers of microbiology, indeed in science more generally. And many of the problems that beset Leeuwenhoek troubled them too. Take the ultrastructure of cells, especially protists.

These globuls, which in the bursting of these creatures did flow asunder here and there, were about the bigness of the first very small creatures [bacteria]. Another half-century was to elapse before Lynn Margulis and others demonstrated that mitochondria and chloroplasts do indeed derive from bacterial endosymbionts [ 38 ]; and even then, not without a fight. I doubt that the idea of endosymbiosis would have shocked Leeuwenhoek; nor would he have been much surprised by the contemptuous disbelief of many biologists over decades.

The pioneer of comparative biochemistry, Albert Kluyver, was Professor of Microbiology in the Technical University of Delft from until his death in More than anyone else, Kluyver appreciated that biochemistry unified life [ 39 ]. He realized that different types of respiration he cites sulfate reduction, denitrification and methanogenesis are fundamentally equivalent, all involving the transfer of electrons from a donor to an acceptor.

He appreciated that all forms of respiration and fermentation are united in that they all drive growth by means of phosphorylation. Kluyver's student Cornelis van Niel, together with Roger Stanier, made some headway in the s before despairing of the endeavour altogether. In fact, one can say that no unit of structure smaller than the cell in its entirety is recognizable as the site of either metabolic unit process ' [ 41 ]. This is a beautiful insight, worthy of Leeuwenhoek himself.

In eukaryotes, respiration and photosynthesis are conducted in mitochondria and chloroplasts, respectively, and continue perfectly well in isolation from the rest of the cell, as all the soluble enzymes needed are constrained within the bioenergetic membranes of the organelle.

In bacteria, by contrast, the enzymes required are split between the cell membrane whether invaginated or otherwise and the cytosol, making the bacterium as a whole the indivisible functional unit. This distinction applies as much to cyanobacteria classed as algae, not bacteria, by Ernst Haeckel and later systematists as to other bacteria.

Stanier and van Niel therefore argued that bacteria are a single monophyletic group, all similar in their basic plan, but insisted that any further attempts to define phylogeny were hopeless. The timing was unfortunate. Woese [ 45 ] was soon dismissing Stanier and van Niel as epitomising the dark ages of microbiology, when microbiologists had given up any prospect of a true phylogeny.

Woese's tree was based on ribosomal RNA. He showed that prokaryotes are not monophyletic at all, but subdivide into two great domains, the bacteria and archaea. For the first time, it seemed possible to reconstruct the evolutionary relationships between Leeuwenhoek's animalcules in an evolutionary tree of life.

Woese and his co-workers went so far as to argue that the term prokaryote was obsolete, being an invalid negative definition i. The three domains tree is still the standard text book view.

Even so, for all its revolutionary appeal, Woese's tree is the apotheosis of a reductionist molecular view of evolution, based on constructing trees from a single gene.

It is ironic that, later in life, Woese called for a more holistic biology, while refusing to countenance the limitations of his single-gene tree [ 49 ].

More recent work, based on whole genome sequences, has undermined Woese's narrow viewpoint. While the sisterhood of archaea and eukaryotes is upheld for a core of informational genes—genes involved in DNA replication, transcription and translation—it is not at all true for most other genes in eukaryotes, which are more closely related to bacteria than archaea.

Woese's iconic tree is therefore profoundly misleading, and should be seen strictly as a tree of one gene only: it is not a tree of life. We cannot infer what a cell might have looked like, or how it might have lived in the past, on the basis of its ribosomal genotype.

Eukaryotes are now plainly seen to be genomic chimeras, apparently formed in a singular endosymbiosis between an archaeal host cell and a bacterium around 1. This chimerism cannot be depicted on a normal branching phylogenetic tree, because endosymbiosis involves fusion of branches, not bifurcation, producing instead a striking composite tree, depicted beautifully and presciently, as this is still accurate by Bill Martin in [ 51 ] figure 5.

Bill Martin and I have since argued that the singular endosymbiosis at the origin of eukaryotes, which gave rise to mitochondria, increased the energy available per gene in eukaryotic cells by a breath-taking three to five orders of magnitude [ 52 ].

That overcame the pervasive energetic constraints faced by bacteria, enabling a massive expansion in cell volume and genome size, and permitting the evolution of many eukaryotic traits from the nucleus to sex and phagocytosis all of which were first reported by Leeuwenhoek himself. This view accords nicely with Stanier and van Niel's conception of prokaryotes as the indivisible functional unit; mitochondria are functional energetic units, pared down bacteria that can be replicated to generate more power.

It might be that eukaryotes had to evolve by way of an endosymbiosis, for these bioenergetic reasons. A tree of life drawn by Bill Martin in , reflecting whole genomes. The tree shows the chimeric origin of eukaryotes, in which an archaeal host cell acquired bacterial endosymbionts that evolved into mitochondria; and the later acquisition of chloroplasts in Plantae.

Reproduced with permission from [ 51 ]. Even in the absence of endosymbiosis, the idea of a true phylogenetic tree of life is undermined by the prevalence of lateral gene transfer in both bacteria and archaea. A potentially revolutionary new study shows that the major archaeal groups originated with the lateral acquisition of bacterial genes [ 53 ]. Ironically, the unity of biochemistry—Kluyver's edifying guide to evolution—is the root problem: the universality of the genetic code, intermediary metabolism and energy conservation e.

Again, the link between the ribosomal genotype of a prokaryotic cell and its phenotype—the way it makes a living—is forever changing. The tree of life promises a hierarchical order, and takes authority from Darwin himself, but in microbes at least it is not sustained by the very genetic sequences that made such phylogeny possible. He was happiest without a compass.

Perhaps that, more than anything else, is the lesson we still need to learn from Leeuwenhoek today. There is a danger of complacency in biology, a feeling that the immense computational power of the modern age will ultimately resolve the questions of biology, and medical research more broadly. But pathophysiology stems from physiology, and physiology is a product of evolution, largely at the level of cells. The eukaryotic cell seems to have arisen in a singular endosymbiosis between prokaryotes, and eukaryotes share a large number of basic traits, few of which are known in anything like the same form in bacteria or archaea.

We know of no surviving evolutionary intermediates between prokaryotes and eukaryotes. We know almost nothing about which factors drove the evolution of many basal eukaryotic traits, from the nucleus to meiosis and sex, to cell death—traits first observed by Leeuwenhoek.

Why did meiosis and sex arise from lateral gene transfer in bacteria? Why did the nucleus evolve in eukaryotes but not in bacteria or archaea? What prevents bacteria from engulfing other cells by phagocytosis?

There is no agreement on the answers to these questions, nor more broadly to a question that might easily have been asked by Leeuwenhoek himself—why is life the way it is? Some of us have argued that eukaryotic evolution is explicable in terms of the detailed mechanisms of energy conservation, with an allied requirement for endosymbiosis leading to conflict and coadaptation between endosymbionts and their host cells [ 56 ].

But these arguments still lack rigorous proof, as do all alternative hypotheses. In the meantime, we have at best an unreliable map of the land that enchanted Leeuwenhoek. We should rejoice and explore. His research is on the role of bioenergetics in the origin of life and the early evolution of cells, focusing on the importance of endosymbiosis and cellular structure in determining the course of evolution.

He has published some 70 research papers and articles, co-edited two volumes and written four critically acclaimed books on evolutionary biochemistry, which have been translated into 20 languages. National Center for Biotechnology Information , U. Nick Lane. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Keywords: Leeuwenhoek, animalcule, protozoa, bacteria, eukaryote, tree of life. Leeuwenhoek, Letter of 12 June Leeuwenhoek is universally acknowledged as the father of microbiology.

Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. References 1. Leewenhoeck A. Observation, communicated to the publisher by Mr. Antony van Leewenhoeck, in a Dutch letter of the 9 Octob.

Antony van Leeuwenhoek and his little animals , p. Hooke R. London, UK: Jo. Martyn and Ja. Allestry, printers to the Royal Society. Antony van Leeuwenhoek and his little animals , pp. Dobell C. Ruestow EG. The microscope in the Dutch Republic. An Abstract of a Letter from Mr. Anthony Leewenhoeck at Delft, dated Sep. Shapin S. A social history of truth. Lectures and collections; Microscopium. Ford BJ. Single lens. Gest H. Notes Rec. Oeuvres Compl de Chr.

Preface to Hooke R. London, UK: Royal Society. Single lens: the story of the simple microscope , p. The discovery of Giardia. The Microscope 53 , — Antony van Leeuwenhoek's microscope and the discovery of Giardia. Microscopy and Analysis 21 , 5—7.

The van Leeuwenhoek specimens. The Leeuwenhoek legacy. Sapp J. Evolution by association: a history of symbiosis. Wilson EB. The Cell in development and heredity. New York, NY: Macmillan. Sagan L. On the origin of mitosing cells. Woods DD. Albert Jan Kluyver. Kluyver AJ. Three decades of progress in microbiology. Antonie van Leeuwenhoek 13 , 1— The concept of a bacterium. Crick FHC. The biological replication of macromolecules. Zuckerkandl E, Pauling L.

Molecular disease, evolution and genetic heterogeneity. Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Natl Acad. USA 74 , — Woese CR. There must be a prokaryote somewhere: microbiology's search for itself.

Evolutionary relationship of archaebacteria, eubacteria, and eukaryotes inferred from phylogenetic trees of duplicated genes. USA 86 , — Towards a natural system of organisms: proposal for the domains Archaea, Bacteria, and Eucarya. Antonie van Leeuwenhoek was born in Delft on 24 October In , van Leeuwenhoek was apprenticed to a textile merchant, which is where he probably first encountered magnifying glasses, which were used in the textile trade to count thread densities for quality control purposes.

Aged 20, he returned to Delft and set himself up as a linen-draper. He prospered and was appointed chamberlain to the sheriffs of Delft in , and becoming a surveyor nine years later. In , van Leeuwenhoek paid his first and only visit to London, where he probably saw a copy of Robert Hooke's 'Micrographia' which included pictures of textiles that would have been of interest to him.

In , he reported his first observations - bee mouthparts and stings, a human louse and a fungus - to the Royal Society. He was elected a member of the society in and continued his association for the rest of his life by correspondence. In , van Leeuwenhoek observed water closely and was surprised to see tiny organisms - the first bacteria observed by man. His letter announcing this discovery caused widespread doubt at the Royal Society but Robert Hooke later repeated the experiment and was able to confirm his discoveries.

As well as being the father of microbiology, van Leeuwenhoek laid the foundations of plant anatomy and became an expert on animal reproduction. He discovered blood cells and microscopic nematodes, and studied the structure of wood and crystals. He also made over microscopes to view specific objects.