I, Biological Nanobot

In the beginning was the first nanobot. It was, perhaps, made of polymerised nucleotides and could replicate itself. It evolved to become more complex RNA, protein or DNA cellular nanobots that are the most efficient compact machines known to mankind. Nanobots are not discussed in polite conversation yet, their names, ribosome, Mariner, Helitron, are scarcely mentioned, but their time is coming...

Monday, May 15, 2006

Nanobiotechnology Aims Small but Thinks Big.

In 2006 Johns Hopkins established the first nanobiotechnology institute.

It's fascinating to see how they phrased their press release back in those early days.

Nanobiotechnology Team Aims Small but Thinks Big
Johns Hopkins Launches Institute to Apply Emerging Science to Medical Problems

The Johns Hopkins University is preparing to aim enormous research and educational resources at some exceedingly small targets.

Drawing on the expertise of more than 75 faculty members from such diverse disciplines as engineering, biology, medicine and public health, the university today officially launched its ambitious new Institute for NanoBioTechnology.

The institute will strive for major advances in medicine by developing new diagnostic tools and treatments based on interdisciplinary research conducted at the atomic or molecular level. The institute will encourage the movement of these campus breakthroughs into the private sector for further development and marketing. At the same time, institute members will train the next generation of scientists and engineers in this emerging field, offering both graduate-level instruction and a new undergraduate minor in nanobiotechnology.

"Our goal is to establish Johns Hopkins as the world's top research center for nanobiotechnology," said Peter Searson, a professor of materials science and engineering who is director of the institute. "We plan to do this in a way that integrates research, education and technology transfer."

The interface between nanotechnology and biotechnology creates a new frontier for scientific exploration, enabling the development of new technologies at scales unimagined even a few years ago.

Nanotechnology explores the creation of new tools at one to one-hundred nanometers in length. At one-billionth of a meter, working in nanometers offers scientists opportunities for discovery and the development at a scale 1,000 times smaller than microscopic techniques. In the same way, biotechnology, combining the traditional fields of biology, engineering, and medicine has advanced in recent years, with the development of ever-smaller devices and techniques that enable new types of less-invasive medical diagnostics and therapeutics.

The Institute for Nanobiotechnology has been established at Hopkins to bring together expertise from the fields of nanotechnology, biotechnology, biology, medicine, and engineering to enable the creation of new knowledge and new technologies. In partnership with research facilities and universities throughout the country, the INBT will revolutionize health care and medicine by creating groundbreaking technologies based on nanotechnology.

Friday, March 31, 2006

The Very Model of a Modern Major Nanobot.

I am the very model of a modern Major-General
I've information vegetable, animal, and mineral
I know the kings of England, and I quote the fights historical
From Marathon to Waterloo, in order categorical

I'm very well acquainted, too, with matters mathematical
I understand equations, both the simple and quadratical
About binomial theorem I'm teeming with a lot o' news
With many cheerful facts about the square of the hypotenuse

With many cheerful facts about the square of the hypotenuse
With many cheerful facts about the square of the hypotenuse
With many cheerful facts about the square of the hypotepotenuse

I'm very good at integral and differential calculus
I know the scientific names of beings animalculous
In short, in matters vegetable, animal, and mineral
I am the very model of a modern Major-General

In short, in matters vegetable, animal, and mineral
He is the very model of a modern Major-General

If you were the very essence of a modern major nanobot, just how would duplicate yourself?

  1. No nonsense cut and paste perhaps (you know, the control-C, control-V use the clip board game)?
  2. Or a more subtle and evasive retro-chic duel personality deception?
  3. Perhaps, a light hearted, round and round the merry go-round , where we stop knoby knws approach.
  4. All of the above?

Yup, there's the options used by mobile DNA nanobots.

Number one was the first route seen by human biologists, and the first genetic engineers. Bacterial viruses do it, bees do even educated fleas do it.

Lambda bacteriophage does it. Herb Boyer and Stan Cohen did it. Even bacterial integrons and transposons do it.

Number two is used by retrovirus and retrotransposon mobile nanobots. HIV virus for example slyly converts from RNA forn to DNA form, with a bit of cut and paste in between, before evasively coming out again as RNA to find new places to hide.

Just how deceptive can you get than that?

Number three is the Rolling Circle approach or RC (its not Roman Catholick though). Corn chromosome scramblers (Helitrons) get around by this approach, and it has a tendancy to pick up extra genes on the way. But Rolling Circle replication too has a long history, discovered in bacteria. Gee these little mites get around.

That enough for the moment, as a first taste of how DNA nanobots got to be so pervasive, in fact how half of plant, animal and human genes are made from these mischaevious but helpful little parasites and symbionts, hand-maidens of evolution.

Treasures in the attic: Rolling circle transposons discovered in eukaryotic genomes
Cédric Feschotte and Susan R. Wessler

Since the advent of methodologies to analyze the content of whole genomes (e.g., renaturation kinetics and Cot analysis), it has been known that a large fraction of eukaryotic genomes is highly repetitive. Recent computer-assisted analysis of several sequenced eukaryotic genomes, including Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana, and humans, has demonstrated that most repetitive DNA is composed of or derived from transposable elements (TEs). In the human genome, for example, TEs are the single most abundant component, accounting for over 40% of the total DNA. Although this amount of TEs is viewed as a hindrance to those engaged in the determination and assembly of DNA sequence, the availability of both complete and partial eukaryotic genome sequences is providing TE biologists with a bonanza of raw material that is being used to understand how genomes evolve.

Before the report in PNAS by Kapitonov and Jurka, all eukaryotic TEs were thought to use one of two mechanisms for transposition. Class 1, or retrotransposons, transpose via an RNA intermediate in reactions catalyzed by element-encoded proteins, including reverse transcriptase. In contrast, the transposon itself is the intermediate for class 2 elements where an element-encoded transposase catalyzes reactions, resulting in TE excision from one site and reinsertion elsewhere in the genome (the so-called cut-and-paste mechanism). In addition to these two mechanisms, some prokaryotic TEs (called IS or insertion sequences), move by another mechanism called rolling circle (RC) transposition. This process is similar to the RC replication of some plasmids, single-stranded (ss) bacteriophage, and plant geminiviruses. In a recent issue of PNAS, Kapitonov and Jurka report that RC transposons also occur in eukaryotes where, surprisingly, they comprise about 2% of the genomes of A. thaliana and C. elegans.

PNAS July 31, 2001 vol. 98 no. 16 8923-8924

Friday, March 10, 2006

Hark! Poetic nanobotes are kniving silent in human blood as we bespeak. But nay, neither Frogge Prince nor Sleeping Beauty tarry there today.

One of the most poetical genres of nanobot are certain mobile genes made of DNA that possess ability to insert themseves in new chromosomal locations. They come in several different forms, often have strange names, like Frog Prince or Sleeping Beauty (I'm not kidding), or even uglier scientific jargon.

The correct technical name for a large group of these mobile genes is "transposons".

We'll defy convention here and usually call them nanobots. Remember this blog is about the new territory of nanobiology, and to be understood by ordinary mortals nanobiology cries out for new terms like nanobots .

In terms of structure, transposons are nothing much to write home about, just a stretch of double helix DNA a thousand base-pairs long or so. But in names, they really outdo the rest of the nano-entities. One of my favourites is Mariner.

The Rhyme of the Ancient Mariner

Samuel Taylor Coleridge
Farewell, farewell! but this I tell
To thee, thou Wedding-Guest!
He prayeth well, who loveth well
Both man and bird and beast.

He prayeth best, who loveth best
All things both great and small;
For the dear God who loveth us,
He made and loveth all.

The Mariner, whose eye is bright,
Whose beard with age is hoar,
Is gone: and now the Wedding-Guest
Turned from the bridegroom's door.

He went like one that hath been stunned,
And is of sense forlorn:
A sadder and a wiser man,
He rose the morrow morn.

Don't forget Sleeping Beauty,
Molecular Reconstruction of Sleeping Beauty, a Tc1-like Transposon from Fish, and Its Transposition in Human Cells Zoltan Ivics Perry B. Hackett, Ronald H. Plasterk, and Zsuzsanna Izsvák Cell, Vol. 91, 501–510, November 14, 1997,
and Frog Prince
The Frog Prince: a reconstructed transposon from Rana pipiens with high transpositional activity in vertebrate cells Csaba Miskey, Zsuzsanna Izsvák, Ronald H. Plasterk, and Zoltán Ivics Nucleic Acids Res. 2003 December 1; 31(23): 6873–6881.
Even the scientists who write about these mobile genetic nanobots have romantic names themselves- Zsuzsanna and Zoltan sound like Sleeping Beauty and the Frog Prince personified.

(For more on mobile genes see here.)

It would seems then, judging a transposon by its name, that Transib is a pretty boring name for a mobile gene. But first impressions are deceptive, as it is named after the Trans-Siberian Express running between Moscow and the Pacific Ocean.

And it turns out that this deceptive nanoengineer Transib has played a crucial role in enabling immunity systems of almost all multicellular living organisms to be super-charged into action many millions of years ago, and it is still crucially important in the success of natural immunity to infection in all animals today. Transib is in fact the parent of RAG1 gene of the humam immune system.

Yes, GMOs may be un-natural entities, but human antibody production relies on antibody diversity that is in fact created every day, by nanobot gentic engineers inside our bodies who randomly scramble our lymphocyte DNA, and they arose in the first place because of natural genetc engineering. And thank goodness for that!

Read on:

Uncovering the Ancient Source of Immune System Variety (July 2005)

Animals with adaptive immunity have a secret for dealing with foreign invaders like viruses and bacteria—variety. Their immune systems generate a diverse array of receptors to detect the enormous number of components (antigens) that make up an invader. But with so many potential antigens, it would be difficult for the immune system to anticipate every one and thereby encode a receptor gene for each of them. Instead, the immune system employs a strategy of combinatorial diversity, recombining a few genes to give an unlimited supply of different receptors.

The portions of immune receptor genes that recombine are called V (variable), D (diversity), and J (joining) segments. The immune system randomly recombines these segments in a process called V(D)J recombination. This extraordinary reorganization is undertaken by two enzymes: RAG1 and RAG2. How this process evolved in animals is a mystery, although it has been theorized that RAG1 and RAG2 might have evolved from an ancient enzyme, called transposase, that could move or transpose gene segments. But proof of this theory for the origin of RAG's activity has remained elusive.

In a new study, Vladimir Kapitonov and Jerzy Jurka have found that RAG1 is similar to transposases encoded by transposons (jumping genes that encode transposases necessary for their mobility) found in both terrestrial and marine organisms: the fruit fly and malaria-carrying African mosquito and the sea urchin and hydra. These potentially ancient relatives of RAG1 are all called Transib transposons. The discovery of their relation to RAG1 supports the decades-old hypothesis that V(D)J recombination sprung from a transposase.

A number of different types (superfamilies) of transposons exist in nature, but no one has been able to show that RAG1 or RAG2 evolved from them. Kapitonov and Jurka took advantage of the recently discovered Transib superfamily of transposons to reexamine this problem. They used seven known Transib transposases from the fruit fly and malaria-carrying African mosquito to search the protein database GenBank, finding that part of one Transib transposase, Transib2_AG, was 35%–38% identical to part of RAG1.

This initial relationship only suggested that RAG1 might be related to Transib2_AG, since the similarity between the two was only “marginally” statistically significant, leaving the possibility that it occurred by chance. To find more statistical evidence of a relationship, Kapitonov and Jurka searched for more Transib proteins. They found a diverse family of Transib transposases in various animals, including silkworm, red flour beetle, dog hookworm, soybean rust, and hydra. The authors also found that plants and vertebrates appear not to contain Transib proteins.

With the new proteins in tow, Kapitonov and Jurka found that a 600-amino-acid region of RAG1 was statistically similar to Transib transposases. This 600-amino-acid region of RAG1 forms the core region that mediates V(D)J recombination. Three important amino acids, which underlie RAG1's ability to recombine gene segments, are also conserved in Transib transposases. Furthermore, RAG1 and RAG2 are known to recombine V, D, and J segments by binding to specific signals in these genes (called recombination signal sequences), which appear to have been derived from the ends of Transib transposons. It was previously thought that both RAG1 and RAG2 likely evolved from two proteins encoded by the same transposon. However, Kapitonov and Jurka could not find any RAG2-like proteins encoded by Transib transposons. The authors therefore suggest that RAG2 appeared later in jawed vertebrates as a necessary component for the evolution of V(D)J recombination.

With the use of similarity searches (using computer programs to identify comparable parts of proteins and transposons), Kapitonov and Jurka have provided support for the transposon origin of V(D)J recombination. This theory was previously up for debate, as it was possible that RAG1 and RAG2 could have independently evolved to function like transposons. But the authors suggest that “these arguments can now be put to rest,” as it appears RAG1 evolved from a transposon currently found in flies and other organisms. Future experiments on how Transib transposons work may allow further understanding into how RAG1 and RAG2 evolved and how they function in vertebrates.

DOI: 10.1371/journal.pbio.0030212
Published: May 24, 2005
Copyright: © 2005 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: (2005) Uncovering the Ancient Source of Immune System Variety. PLoS Biol 3(6): e212

Friday, February 24, 2006

What did the first Nanobots look like? Well, some were ribozymes.

A Ribozyme nanobot, image from here.

The Continuing Ancient Saga of Nanobiology.

Glimpses of ancient nanobots have been found in detailed examination of the minute catalysts particles found inside all cells that manufacture proteins. These catalysts are made from ribose nucleic acid or RNA polymer, but have a coating of protein. RNA catalysts are called ribozymes.

One of the nicest ribozyme images is Starburst, shown here in an image from a Nobel Prize lecture.

Many people believe these ribozyme nanobots were the precursers of life; certainly they were the precursors of DNA, the more well known polymer in which inheritable genetic information is usually stored. DNA is a much more chemically stable polymer than RNA - it's really tough - and that is probably why DNA evolved, for stable biological information storage.

STRUCTURAL BIOLOGY: The Ribosome Is a Ribozyme

The amino acids we obtain by digestion of steak, salmon, or a lettuce salad are loaded onto transfer RNAs (tRNAs) and rebuilt into proteins in the ribosome, the cell's macromolecular protein-synthesis factory. The bacterial ribosome is composed of three RNA molecules and more than 50 proteins. Its key components are so highly conserved among all of Earth's species that a similar entity must have fueled protein synthesis in the common ancestor of all extant life. Although the chemical reaction catalyzed by the ribosome is simple--the joining of amino acids through amide (peptide) linkages--it performs the remarkable task of choosing the amino acids to be added to the growing polypeptide chain by reading successive messenger RNA (mRNA) codons. On page 905 of this issue, Steitz, Moore, and colleagues now provide the first atomic-resolution view of the larger of the two subunits of the ribosome. From this structure they deduce on page 920 that RNA components of the large subunit accomplish the key peptidyl transferase reaction. Thus, ribosomal RNA (rRNA) does not exist as a framework to organize catalytic proteins. Instead, the proteins are the structural units and they help to organize key ribozyme (catalytic RNA) elements, an idea long championed by Harry Noller, Carl Woese, and others.

Science 11 August 2000: 878-879
DOI: 10.1126/science.289.5481.878
T R Cech

Original annotation to image at top, from Science:
A ribosome's true colors. (Top) The large subunit of the ribosome seen from the viewpoint of the small subunit, with proteins in purple, 23S rRNA in orange and white, 5S rRNA (at the top) in burgundy and white, and A-site tRNA (green) and P-site tRNA (red) docked. (Bottom) The peptidyl transfer mechanism catalyzed by RNA. The general base (adenine 2451 in Escherichia coli 23S rRNA) is rendered unusually basic by its environment within the folded structure; it could abstract the proton at any of several steps, one of which is shown here.

Saturday, February 18, 2006

The Three Domains of Bio- nanobots.

Three main phylogenetic domains of nanobots are known.

The Archaeo-nanobotia (common term ancient nanobots)

The Proto-nanobotia (Simple replicating biological nanobots)

The Cellulo-nanobotia (cellular biological nanobots, or cells)

Definite representatives of the ancient nanobots are hard to detect, but one is found in all cells. It is known as the ribosome.

The Proto-nanobots are the most numerous organisms on the planet, but few people realise this. They are a diverse crowd, including viruses, plasmids, and mobile genes, such as Mariner and Helitron.

Cellular nanobots are very complex and obvious in the natural world. They represent all the more visible organisms on the planet. Lurking within them though, are numerous Proto-nanobotia and Cellulo-nanobotia.

The rich story of these bio- nanobots will follow in subsequent posts.

In the beginning, the Biological Nanobot emerged.

Three Laws of Bio-nanobiotics.

This cover of I, Robot illustrates the story "Runaround", the first to list all Three Laws of Robotics.

In scientific non-fiction, the Three Laws of Bio- nanobotics are a set of three laws first derived by Nanobot Pundit, which all nanobots surviving on this planet have to obey. First introduced in his short post "In the beginning the Biological Nanobot emerged" (2006), they state the following:

  1. A nanobot may harm another nanobot being, or, through a tolerating a different strategy, allow another nanobot to proliferate sucessfully.
  2. A nanobot must obey the orders given to it by the laws of the real universe, including the First Second and Third Laws of Thermodynamics.
  3. A nanobot must protect its own existence, and can thereby keep selective advantages that it gains through errors in replication for play in the competitive game called "Natural Selection", as long as such protection does not conflict with the First or Second Law. Ability to explore the fruits of error prone processes is intrinsic to the discovers of more sophisticated nanobot life styles. This third Law, was first announced by the discoverer of nanobots, Charles Darwin, and extended by his major disciple Saint Richard of Dawkins in "The Extended Phenotype", a macrobiologist who also wrote " The Selfish Nanobot", "The Blind Replicating Nanobot Maker", "The Ancestral Nanobot's Tail" and other celebrated works.

According to the Oxford English Dictionary of Nanobiology, a passage in Nanobot Pundit's thesis dissertation on rule improvement by trial with error, Conjectures and Refutations- Canterbury University, 1945, provides the first known mention of the First Law and also the earliest recorded use of the word bio-nanobiotics in the English language.

At the time Nanobot Pundit was not initially aware of this; he assumed the word already existed in analogy with mechanics, hydraulics, and other similar terms denoting branches of applied knowledge. (Being relatively shy, Pundit wrote this monumental and inspiring work under the pseudonym K. Popper. )

The Three Laws are an organizing principle and unifying theme for Nanobot Pundit's search for elusive truths, eventually appearing in fully developed form in the prestigious Proceedings of the National Academy of Nanosciences of the USA and numerous other articles linked that followed.

Other authors working in Pundit's empirical universe have adopted them, and references (often parodic) now appear throughout science fiction and in other genres. Technologists in the field of artificial intelligence, nanobiotics and biotechnology working to create real machines with some of the properties of the Great Pundit's nanobots, have exploited the Three Laws most successfully in such research.