Sometimes it feels as though the answer is right there, you can’t see it but it’s just beyond your grasp. So elusive, and yet obviously out there…somewhere.

I wonder how many scientists have felt this way.
(I lost track of how many times i’ve felt like that, anyways).

I recently read an old review (from 2002, heh) on how a string of seemingly unconnected discoveries led to one mammoth discovery in plant RNAi, a mother of si/miRNA processing proteins: DICER-LIKE1 (DCL1)

The reviewer likened the circumstances leading up to it as how six blind men standing at different locations would describe an elephant, if it was before them. Eventually, someone realized they were all describing the characteristics of one huge beast.

(It was six men of Indostan,
To learning much inclined,
Who went to see the Elephant
(Though all of them were blind),
that each by observation
Might satisfy his mind…

‘God bless me! but the Elephant
Is very like a wall!’ ‘…a spear!’
‘…a snake!’ ‘…a tree!’
‘…a fan!’ ‘…a rope!’

And so these men of Indostan
Disputed loud and long…
Though each was partly in the right,
And all were in the wrong!"
(Schauer et al., 2002) )

But, going back to the point…
Months ago a visiting tech gave us a tutorial on some supersonic mindblowing machine high tech phenotyping machine. He likened the lot of us grad students and postdocs to pioneers at the forefront of the field. We go where no one has gone before, to make discoveries built on past discoveries. Really though, it feels like we’re the antennae of some huge slow moving, blind snail, reaching out into space.

It’s daunting sometimes, especialy with “high risk” experiments where the outcome could be anything (nothing even). You can expect certain outcomes…but there are always unforetold results that could mean anything, and could open a can of worms (too many leads in too many different directions and too many possible explanations). Or it could be something altogether paranormal.

And there are the small strokes of unexpected genius.
In 1993 one C. elegans knock out group thought they found some small genetic anomaly that was specific only to the species of C. elegans. Then the same “anomaly” or genetic phenomenon began appearing in other organisms and kingdoms. More and more labs began to notice there was something intriguing about these 21-22 nucleotide long genes, with the ability to regulate specific proteins based on their antisense complementarity to sequences on the protein’s mRNA strands. Eventually Fire & Mello observed that double stranded RNAs were the products of the transcription of the unusual genes, and was subsequently the trigger of RNAi gene silencing. One huge can of worms that turned into a gold mine. That aberrant form of gene regulation by miRNAs/siRNAs helped Fire & Mello win the nobel in 2006 and it’s now on the forefront of genetic, stem cell and cancer research.

But, there’s still so much to RNAi we don’t know.
And they’re rather huge questions people have been trying to find the answers to for years, like what exactly is the mechanisms behind a small 19-22 nucleotide long RNA strand inhibiting the synthesis of specific proteins in translational repression?

Still though, like the 6 blind men of Indostan, together I suppose we use our other senses and tools (*ahem, our biological and biochemical experiments) and call out to other, in our jargon filled articles, conferences and seminars.

(I really do think it would be so much cooler, if we could actually see things happening at the molecular level..eg. if we can see the Taq polymerase tack on the dNTPs to new strands of DNA in during PCR in the thermocycler…)

Schauer, S. E., Jacobsen, S. E., Meinke, D. W. and A. Ray. (2002). DICER-LIKE1:blind men and elephants in Arabidopsis development. Trends in Plant Science 7(11): 487-490.

The review summarizes a series of genetic studies on 6 seemingly unrelated loss-of-function mutant alleles in Arabidopsis. Then it turned out they were all the null alleles of one DCL1 gene. One was EMB76, that suffered through growth arrest at the embryo’s ‘heart stage’. Another was sin1-1, that had abnormal ovules (yes, plants have female parts), and related sin1-2 that lead to embryos with loss of radial or apical symmetry, and loss of differentiation in the meristem. Additionally, sin1 tended to promote the conversion of the floral meristem to an indeterminate, vegetative state, which in turn lead to late flowering. Finally, carpel factory1, a mutant that produced extra carpels (female plant parts) in mutant flowers with the central floral meristem, stuck in an indeterminate state (it’s supposed to turn into petals, pollen..sepals..etc). So, evidently, various stages of development were blocked. Eventually, some lab thought to clone a carpel factory1 allele and map the sin1 and emb76 alleles. Finally, they noticed these alleles had homology to the Drosophila Dicer gene.

Saxe, J. G. (1865). The blind men and the elephant. In Clever Stories of Many Nations, pp. 61-64, Ticknor and Fields, Boston, USA.

R.C. Lee, R.L. Feinbaum and V. Ambros. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14, Cell 75: 843–854.

Parrish, S., Fleenor, J., Xu, S., Mello, C., and Fire, A. (2000). Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference. Mol. Cell 6: 1077-1087.