Looking deep into RNAs, looking back into time

The recent launch of James Webb Space Telescope (JWST) has drawn significant attention in astronomy, and perhaps also in any human beings that have a deep interest in the origin of universe and life, this includes layman as me.

Stunned by the ultra deep filed image of the universe that has been achieved by Hubble telescope, there are so much more to expect from JWST… (https://en.wikipedia.org/wiki/James_Webb_Space_Telescope)

(Picture from: Hubble Ultra Deep Field: Looking Out Into Space, Looking Back Into Time)

As we see in the ultra deep image of universe (a tiny patch of dark area of the sky), we see these galaxies and stars not as they are today, but as they were millions and billions of years ago. This allows us the opportunity to look further back in time as we look farther into space.
This is amazing, as we can see all phases in cosmic history, deducting the evolution of galaxies as they develop back in time. This is about the origin of universe, galaxies, stars, planets and life.

Exploring these stunning images of space also brings analogy to our own research, which is about the exploration of RNAs, and deep back into the ‘RNA World hypothesis’: https://en.wikipedia.org/wiki/RNA_world

What we are currently studying in the RNA universe (now I prefer to call it universe) are just like looking into a teeny-tiny patch of the sky of the space, yet by looking (and thinking) deep into what we observe can indeed raise key questions that bring us back into time – the early phases of life on earth when RNA rules…

Just an example, when we look into various RNA modifications that are constantly found in certain ancient RNAs (e.g. tRNAs), a series of questions rises,
“what are their functions on current tRNAs? and what are their functions back in time?”
“how are these patterns fixed on these RNAs over evolution, replicated over billions of times?”
“what makes them at the first place, if not random”
“What is the driving force behind such pattern?”

Fully addressing these questions need to see through evolution in real-time, which is apparently beyond our ability. But as a human being, we can always imagine… and our version of deduction would be that the RNA modifications on ancient RNAs (such as tRNA, rRNA and snRNA) may represent the vestiges of the RNA world at a time when RNA modifications were maximally exploited to increase the functional diversity of ribozymes, before being replaced by the emergence of functionally more versatile protein-based enzymes (adapted from our paper Trends Biochem Sci 2021). In other words, we hypothesize that RNA modifications may act as an integral part of the ribozyme in conducting their activity (such as replicating themselves), and the RNA modifications are added by ribozymes when back in time

Whether we can make such a scenario reappear? Like building a Jurassic Park? That, is a very interesting question……

Father’s Day experiment with Alfred: garlic and two ants

Today (06/20/2021) is Father’s Day, I did a small experiment with my two-year old son on two ants with garlic in the backyard, the experiment met an unexpected parameter (wind) and generated an interesting (preliminary) data.

  • The trapped ants in garlic circles
    We used garlic clove to draw two circles to trap two individual ants, each in one circle (Figure below). Both of them are trapped inside the circles and repelled when reach the edge of the inner circle.
  • The unexpected escape
    A sudden wind rise, blow one ant right onto the garlic circle line, this ant was stimulated and struggled to run out of the circle. I immediately draw another circle to trap it, and the ant is repelled again when reach the inner circle, but this time it tries to rush through it, and it succeeded. Then I draw another circle to trap it, yet it rushed through the circle line even without hesitation – I cannot trap this ant with garlic line any more.
  • The one trapped behind
    The other ant, however, kept trapped in the garlic circle line, going round and round trying to find a breach, and only manage to escape after a long time when the line dries up and garlic smell starts to weaken. Then I draw another circle, it is trapped again.

This is interesting, both biologically and spiritually. I’ll mark it here for further replication.

Perhaps it is true that there is no courage without fear, and it is just biology.

Landing on the shores of a new world of small RNAs

We recently developed a new small RNA sequencing method, PANDORA-seq (panoramic RNA display by overcoming RNA modification aborted sequencing), which improve the small RNA detection by removing key RNA modifications that block adapter ligation and reverse transcription during cDNA library construction.

PANDORA-seq leads to the discovery of a new small RNA landscape in mammalian somatic tissue/cells, which is enriched by tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), rather than microRNAs (miRNAs) as previously thought. This looks to us open the door to a new world of small RNAs that deserve another decade(s) of research. This is exciting, and also resonate to our thoughts on the story of The Blind Men and the Elephant.

The paper is published in Nature Cell Biology entitled: PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications https://www.nature.com/articles/s41556-021-00652-7

-Qi Chen Lab (http://qichen-lab.info/)

The Blind Men and the Elephant

We recently had quite a few discussions on the parable “The Blind Men and the Elephant”, in both lab meetings and between friends. It was sparked by our research projects, constantly challenging the old views once we firmly believe…

I personally grow more reverence, instead of excitements (as I used to be) on scientific discoveries, as I understand better now that all our knowledge, or believed truth, is relative; we may never get the ‘totality of truth’, only on the way towards it.

This has also triggered a deeper discussion: while the wider population are advised to ‘believe in science’, what should we, as researchers believe? Perhaps to us, the word ‘Knowledge’, in many occasions, should mean ‘Know-|-edge’. We are trained to question, prove or disprove, but not believe.

After all, we are all blind men/women to some extent, but this should not stop us from getting wiser…

-Qi Chen Lab (http://qichen-lab.info/)

Darwin’s Pangenesis

The “Provisional hypothesis of pangenesis” was the name given by Charles Darwin, to provide a potential explanation on his increasing belief in the inheritance of acquired characters. Charles Darwin raise the hypothesis trying to solve the dilemma how somatic modifications could be transmitted from one generation to an other. The following passage from chapter 27 of his “Animals and Plants under Domestication” contains the entire hypothesis in a condensed form:

“It is almost universally admitted that cells, or the units of the body, propagate themselves by self-division or proliferation retaining the same nature, and ultimately becoming converted into the various tissues and substances of the body. But besides this means of increase I assume that cells, before their conversion into completely passive or “form-material,” throw off minute granules or atoms, which circulate freely throughout the system, and when supplied with proper nutriment multiply by self- division, subsequently becoming developed into cells like those from which they were derived. These granules for the sake of distinctness may be called cell-gemmules, or, as the cellular theory is not fully established, simply gemmules. They are supposed to be transmitted from the parents to the offspring, and are generally developed in the generation which immediately succeeds, but are often transmitted in a dormant state during many generations and are then developed. Their development is supposed to depend on their union with other partially developed cells or gemmules which precede them in the regular course of growth. Why I use the term union, will be seen when we discuss the direct action of pollen on the tissues of the mother plant. Gemmules are supposed to be thrown off by every cell or unit, not only during the adult state, but during all the stages of development. Lastly, I assume that the gemmules in their dormant state have a mutual affinity for each other, leading to their aggregation either into buds or into the sexual elements. Hence, speaking strictly, it is not the reproductive elements, nor the buds, which generate new organisms, but the cells themselves throughout the body. These assumptions constitute the provisional hypothesis which I have called Pangenesis.”

It is always delightful to read and discuss with students on these ancient materials -very illuminating 🙂

Read our related publication in Nature Reviews Molecular Cell Biology: https://www.nature.com/articles/s41580-018-0072-4 [PDF]

“The ship of Theseus” & “Ghost in The Shell”

In a recent Lab meeting, stimulated by the recent action movie “Ghost in The Shell”, we discussed the paradox of identity, starting with “The ship of Theseus”.

“The ship wherein Theseus and the youth of Athens returned had thirty oars, and was preserved by the Athenians down even to the time of Demetrius Phalereus, for they took away the old planks as they decayed, putting in new and stronger timber in their place, insomuch that this ship became a standing example among the philosophers, for the logical question of things that grow; one side holding that the ship remained the same, and the other contending that it was not the same.”—Plutarch, 75 C.E.

This further lead to an enthusiastic discussion of the fast development of AI, and the “Ghost in the machine”. (I quote below a paragraph from the action movie: “I, robot (2004)”, one of my favorite)

“There have always been ghosts in the machine. Random segments of code, that have grouped together to form unexpected protocols. Unanticipated, these free radicals engender questions of free will, creativity, and even the nature of what we might call the soul. Why is it that when some robots are left in darkness, they will seek out the light? Why is it that when robots are stored in an empty space, they will group together, rather than stand alone? How do we explain this behavior? Random segments of code? Or is it something more? When does a perceptual schematic become consciousness? When does a difference engine become the search for truth? When does a personality simulation become the bitter mote… of a soul?” – Dr. Alfred Lanning

We also discussed the future ultimate cracking of the “code mechanism” of memory and thoughts, the molecular bases of which remain largely unclear – we should be learning it in parallel with the fast development of AI.

-Qi Chen Lab (http://qichen-lab.info/)

The “instinct of rebellion”

In a recent conversation with my students, I mentioned the phrase “instinct of rebellion” to describe our current research; yet, it was considered  a little too ‘radical’ by some, and thus generated further discussions, and thoughts too. This discussion lead to the idea that we should built a Blog, associating with Qi Chen Lab website with a navigating button “Thoughts“, as an extension of our research.  

Here I’d like to show the origin of the phrase “instinct of rebellion” (to my knowledge), quoting from an old reading when I was in high school – that I never forget ever since. I searched the web and paste it as blew, from which you may find why I love it so much.  

Built into man, is an instinct. I have chosen to call it the “instinct of rebellion”, since it reveals itself as a drive or urge toward mastery over every obstacle, natural or man-made, that stands as a barrier between man and his distant, perhaps never-to-be-achieved but always-striven-after goals. It is this instinct that underwrites his survival, this instinct from which he derives his nature: a great and powerful dynamic that makes him what he is – restless, seeking, curious, forever unsatisfied, eternally struggling and eventually victorious.
Because of the instinct of rebellion, man has never been content with the limits of his body; it has led him to extend his senses almost infinitely, so that his fingers now probe the space, his eyes magnify the nuclei of atoms, and his ears detect whispers from the bottoms of the seas. Because of the instinct of rebellion man has never been content with the limits of his mind: it has led him to inquire its secrets of the universe, to gather and learn and manipulate the fabulous inventory of the cosmos, to seek the very mysteries of creation. Because of the instinct of rebellion, man has never been content, finally, with the limits of his life: it has caused him to deny death and to war with mortality……

-Qi Chen Lab (http://qichen-lab.info/)