"The Little Soul And The Sun"

by Neale Donald Walsch, Conversations With God

Once upon no time, there was a little Soul who said to God, "I know who I am."

And God said, "That's wonderful! Who are you?"

And the Little Soul shouted, "I'm the Light!"

God smiled a big smile. "That's right!" God exclaimed. "You are the Light."

The Little Soul was so happy, for it had figured out what all the souls in the Kingdom were there to figure out.

"Wow," said the Little Soul, "this is really cool!"

But soon, knowing who it was was not enough. The Little Soul felt stirrings inside, and now wanted to be who it was. And so the Little Soul went back to God (which is not a bad idea for all souls who want to be Who They Really Are) and said,

"Hi, God! Now that I know Who I am, is it okay for me to be it?"

And God said, "You mean you want to be Who You Already Are?"

"Well," replied the Little Soul," it's one thing to know Who I Am, and another thing altogether to actually be it. I want to feel what it's like to be the Light!"

"But you already are the Light," God repeated, smiling again.

"Yes, but I want to see what that feels like!" cried the Little Soul.

"Well," said God with a chuckle, "I suppose I should have known. You always were the adventuresome one."

Then God's expression changed. "There's only one thing..."

"What?" asked the Little Soul.

"Well, there is nothing else but the Light. You see, I created nothing but what you are; and so, there is no easy way for you to experience yourself as Who You Are, since there is nothing that you are not."

"Huh?" said the Little Soul, who was now a little confused.

"Think of it this way," said God. "You are like a candle in the Sun. Oh, you're there all right. Along with a million, gazillion other candles who make up the Sun. And the sun would not be the Sun without you. Nay, it would be a sun without one of its candles...and that would not be the Sun at all; for it would not shine as brightly. Yet, how to know yourself as the Light when you are amidst the Light -that is the question."

"Well," the Little Soul perked up, "you're God. Think of something!"

Once more God smiled. "I already have," God said. "Since you cannot see yourself as the Light when you are in the Light, we'll surround you with darkness."

"What's darkness?" the Little Soul asked.

God replied, "It is that which you are not."

"Will I be afraid of the dark?" cried the Little Soul.

"Only if you choose to be," God answered. "There is nothing, really, to be afraid of, unless you decide that there is. You see, we are making it all up. We are pretending."

"Oh," said the Little Soul, and felt better already.

Then God explained that, in order to experience anything at all, the exact opposite of it will appear. "It is a great gift," God said, "because without it, you could not know what anything is like. You could not know Warm without Cold, Up without Down, Fast without Slow. You could not know Left without Right, Here without There, Now without Then."

"And so," God concluded, "when you are surrounded with darkness, do not shake your fist and raise your voice and curse the darkness. Rather be a Light unto the darkness, and don't be mad about it. Then you will know Who You Really Are, and all others will know, too. Let your Light shine so that everyone will know how special you are!"

"You mean it's okay to let others see how special I am?" asked the Little Soul.

"Of course!" God chuckled. "It's very okay! But remember,'special' does not mean 'better.' Everybody is special, each in their own way! Yet many others have forgotten that. They will see that it is okay for them to be special only when you see that it is okay for you to be special."

"Wow," said the Little Soul, dancing and skipping and laughing and jumping with joy. "I can be as special as I want to be!"

"Yes, and you can start right now," said God, who was dancing and skipping and laughing right along with the Little Soul.

"What part of special do you want to be?"

"What part of special?" the Little Soul repeated. "I don't understand."

"Well," God explained, "being the Light is being special, and being special has a lot of parts to it. It is special to be kind. It is special to be gentle. It is special to be creative. It is special to be patient. Can you think of any other ways it is special to be?"

The Little Soul sat quietly for a moment. "I can think of lots of ways to be special!" the Little Soul then exclaimed. "It is special to be helpful. It is special to be sharing. It is special to be friendly. It is special to be considerate of others!"

"Yes!" God agreed, "and you can be all of those things, or any part of special you wish to be, at any moment. That's what it means to be the Light."

"I know what I want to be, I know what I want to be!" the Little Soul announced with great excitement. "I want to be the part of special called 'forgiving'. Isn't it special to be forgiving?"

"Oh, yes," God assured the Little Soul. "That is very special."

"Okay," said the Little Soul. "That's what I want to be. I want to be forgiving. I want to experience myself as that."

"Good," said God, "but there's one thing you should know."

The Little Soul was becoming a bit impatient now. It always seemed as though there were some complication.

"What is it?" the Little Soul sighed.

"There is no one to forgive."

"No one?" The Little Soul could hardly believe what had been said.

"No one!" God repeated. "Everything I have made is perfect. There is not a single soul in all creation less perfect than you. Look around you."

It was then that the Little Soul realized a large crowd had gathered. Souls had come from far and wide ~ from all over the Kingdom ~ for the word had gone forth that the Little Soul was having this extraordinary conversation with God, and everyone wanted to hear what they were saying. Looking at the countless other souls gathered there, the Little Soul had to agree. None appeared less wonderful, less magnificent, or less perfect than the Little Soul itself. Such was the wonder of the souls gathered around, and so bright was their Light, that the Little Soul could scarcely gaze upon them.

"Who, then, to forgive?" asked God.

"Boy, this is going to be no fun at all!" grumbled the Little Soul. "I wanted to experience myself as One Who Forgives. I wanted to know what that part of special felt like."

And the Little Soul learned what it must feel like to be sad. But just then a Friendly Soul stepped forward from the crowd.

"Not to worry, Little Soul," the Friendly Soul said, "I will help you."

"You will?" the Little Soul brightened. "But what can you do?"

"Why, I can give you someone to forgive!"

"You can?"

"Certainly!" chirped the Friendly Soul. "I can come into your next lifetime and do something for you to forgive."

"But why? Why would you do that?" the Little Soul asked. "You, who are a Being of such utter perfection! You, who vibrate with such a speed that it creates a Light so bright that I can hardly gaze upon you! What could cause you to want to slow down your vibration to such a speed that your bright Light would become dark and dense? What could cause you ~ who are so light that you dance upon the stars and move through the Kingdom with the speed of your thought--to come into my life and make yourself so heavy that you could do this bad thing?"

"Simple," the Friendly Soul said. "I would do it because I love you."

The Little Soul seemed surprised at the answer.

"Don't be so amazed," said the Friendly Soul, "you have done the same thing for me. Don't you remember? Oh, we have danced together, you and I, many times. Through the eons and across all the ages have we danced. Across all time and in many places have we played together. You just don't remember."

"We have both been All Of It. We have been the Up and the Down of it, the Left and the Right of it. We have been the Here and the There of it, the Now and the Then of it. We have been the male and the female, the good and the bad; we have both been the victim and the villain of it."

"Thus have we come together, you and I, many times before; each bringing to the other the exact and perfect opportunity to Express and to Experience Who We Really Are. And so," the Friendly Soul explained further, "I will come into your next lifetime and be the 'bad one' this time. I will do something really terrible, and then you can experience yourself as the One Who Forgives.

"But what will you do?" the Little Soul asked, just a little nervously, "that will be so terrible?"

"Oh," replied the Friendly Soul with a twinkle, "we'll think of something."

Then the Friendly Soul seemed to turn serious, and said in a quiet voice, "You are right about one thing, you know."

"What is that?" the Little Soul wanted to know.

"I will have to slow down my vibration and become very heavy to do this not-so-nice thing. I will have to pretend to be something very unlike myself. And so, I have but one favour to ask of you in return."

"Oh, anything, anything!" cried the Little Soul, and began to dance and sing, "I get to be forgiving, I get to be forgiving!"

Then the Little Soul saw that the Friendly Soul was remaining very quiet.

"What is it?" the Little Soul asked. "What can I do for you? You are such an angel to be willing to do this for me!"

"Of course this Friendly Soul is an angel!" God interrupted. "Everyone is! Always remember: I have sent you nothing but angels."

And so the Little Soul wanted more than ever to grant the Friendly Soul's request. "What can I do for you?" the Little Soul asked again.

"In the moment that I strike you and smite you," the Friendly Soul replied, "in the moment that I do the worst to you that you could possible imagine ~ in that very moment..."

"Yes?" the Little Soul interrupted, "yes...?""Remember Who I Really Am."

"Oh, I will!" cried the Little Soul, "I promise! I will always remember you as I see you right here, right now!"

"Good," said the Friendly Soul, "because, you see, I will have been pretending so hard, I will have forgotten myself. And if you do not remember me as I really am, I may not be able to remember for a very long time. And if I forget Who I Am, you may even forget Who You Are, and we will both be lost. Then we will need another soul to come along and remind us both of Who We Are."

"No, we won't!" the Little Soul promised again. "I will remember you! And I will thank you for bringing me this gift ~ the chance to experience myself as Who I Am.

" And so, the agreement was made. And the Little Soul went forth into a new lifetime, excited to be the Light, which was very special, and excited to be that part of special called Forgiveness.

And the Little Soul waited anxiously to be able to experience itself as Forgiveness, and to thank whatever other soul made it possible. And at all the moments in that new lifetime, whenever a new soul appeared on the scene, whether that new soul brought joy or sadness--and especially if it brought sadness--the Little Soul thought of what God had said.

"Always remember," God had smiled, "I have sent you nothing but angels."

Note To Self: Linux CLI Commands

On Digg today, there's an article with 743 diggs that reads: Explained: 9 useful Linux commands everyone should use! Of all the commands mentioned, this is the only command that I didn't know:

$ free

At the end of that Digged article, there were links to the Ubuntu Community Documentation for the Terminal, which introduces new users to the command line, and a Unix commandline cheat sheet.

The following commands are new to me and will serve me well in the future:

ctrl+a or Home	Moves the cursor to the start of a line.
ctrl+e or End	Moves the cursor to the end of a line.
ctrl+b	Moves to the beginning of the previous or current word.
ctrl+k	Deletes from the current cursor position to the end of the line.
ctrl+u	Deletes the whole of the current line.
ctrl+w	Deletes the word before the cursor.

This one is worth a million dollars:

ctrl+r

Searches for commands you've already typed. When you have entered a very long, complex command and need to repeat it, using this key combination and then typing a portion of the command will search through your command history. When you find it, simply press Enter.

There are so many times when I scroll up looking of a command I used days ago that I used, but can't recall the full syntax. ctrl + r should remdy this problem. Here is another guide to Bash which clarifies how to use the CTRL + R feature:

1. Easily recall previous commands
Bash keeps track of the commands you execute in a history buffer, and allows you to recall previous commands by cycling through them with the Up and Down cursor keys. For even faster recall, "speed search" previously-executed commands by typing the first few letters of the command followed by the key combination Ctrl-R; bash will then scan the command history for matching commands and display them on the console. Type Ctrl-R repeatedly to cycle through the entire list of matching commands.

Note to self: gnome themeing

When I fix Ubuntu, use this gdm theme and try this cool gnome panel, both of which are found at gnome-look.org.

no title

Check out this atrocity committed by the British military in Iraq:


UK News Of The World Shows British Troops Beating Iraqi Youth - The most amazing videos are a click away

McCain-RP election victory, world order, China and the Middle East

If, let's say, the McCain campaign managers buy Ron Paul's recent argument (that Washington policy makers have been behaving like drug addicts since 9/11) and McCain's campaign managers pick RP as McCain's running mate on Sept. 2, promising to abolish the IRS laced with revolutionary Founding Father rhetoric, McCain-Paul would definitely win the 08 election. And let's say that over the course of 4 years in office McCain does everything Ron Paul says in his revolutionary book, then there would be a very different world order. Ron Paul opposes all supranational government bodies, like the UN so McCain would evict the UN from their NY HQ.

This probably won't happen because the Republicans prolly won't pick RP to be McCain's running mate. I'm not making predictions here. I'm just speaking hypothetically. This is an outlandish possible scenario. I'm just theorizing...for kicks.

So with a true gold standard (with the Fed abolished) the prices of goods and services (including oil) traded internationally would stay the same for Americans. Inflation would effectively be abolished. Actually, that's a half truth. Oil would no longer increase in price, as long as OPEC doesn't overcharge. And goods like electronics like computers manufactured in Chinnese factories would stay the same, as long as China doesn't start setting unfair prices, they could, after all, because they have a monopoly in this industry, if you add together all the electronics manufacturers.

Additionally, w/o an American hegemonic order on the planet, there would be a political vacuum and political crisis in Iraq with US troops arriving home before the end of 2009. All military and financial aid to Israel would cease. All 700 military bases strategically placed around the globe would be disbanded. If this were the case, with total international anarchy, then China could do what ever it pleases, perhaps establishing its own order over the planet, an anti-humanist order at that. Let's say China invades the entire middle east starting in 2012, after McCain and RP do everything RP promises. China at this point would have a monopoly over oil resources, exploiting the political crises of the US withdrawal from Iraq. If this were the case (this is a pretty flippin outrageous scenario) ALL Middle Eastern Arabs and Muslims would be united against their new imperial oppressors, a spectacular challenge for the religion of Islam. The West's War on Terror problem would be solved because America would no longer be the target of Islamic fundamentalists. Cool, eh?

I'm probably overlooking all sorts of logical possibilities resulting from an unlikely revolutionary McCain-Ron Paul election victory. What do you think could happen after US hegemony?

Now let's say some of Alex Jones' conspiracy theories are true, (not the 9/11 inside job ones, the other ones about the NWO that are argued for in Jones' (2007) "End Game") and the CFR, the Bilderbergh Group and Trilateral Commission members are indeed planning an Asian Union (AU) and North American Union (NAU) cooperating with the Chinese business class in secret, outside the public eye. What follows from this? The world's Power Elite could pull off a NAU and AU, if there were a need for it, like an inflationary crisis which provoked the ignorant public to demand a solution, trusting their governments and expert economists. If this were the case (I could be wrong, but let's pretend I am right), the Power Elite's behaviour would be tyrannical, similar to the behavior of Hitler who exploited an economic crisis to gain support from the insecure Middle Class in Wiemar Germany. Mugabe in Zimbabwe has drawn the world's attention to his tyranny based on (in part) hyper inflation. Informed Ron Paul revolutionaries (a passionate bunch) are well aware of how tyranny works. Ron Paul essentially argued this point in the senate in mid of June of this year. RP argues that governments are known for exploiting economic crises to gain more power, a humble and useful lesson. Check it.

InfoWars is Alex Jones' really intense blog, so popular among young people that it gets more comments below each story than DailyKOS stories get. "We Are Change" is Jones' legion of dangerous revolutionary activists. I am not one of these activists, but I read InfoWars every day because I am fascinated by the anarchy and freedom of the internet. Without internet censorship, conspiracy theories flourish. I suppose if these conspiracy theorists get out of hand who, by getting violent in the streets, become a danger to the peaceful domestic order provided by the state in America, then maybe the state will have to intervene and start censoring the internet.

Hitting the on switch

NATURE | Vol 448 | 23 August 2007

Erika Check
San Francisco

That looks perfect,” murmurs Robert Place as he watches a smooth line trace across his monitor. “It never works this well.” Place, a molecular biologist at the Veterans Affairs Medical Center and University of California, San Francisco, is using a spectrophotometer to measure the purity of a series of samples. Every sample contains a tiny drop of micro RNA (miRNA), a type of genetic regulator that dampens gene expression — or so the story goes. The experiment Place is absorbed in is the last he must complete before he submits a publication that could upend that story. He and his colleague, Long-Cheng Li of the University of California, San Francisco, think they have found some miRNAs that boost, rather than silence, gene expression in cells.

Their work could shake the foundations of one of the hottest topics in biology — RNA interference — which studies how short pieces of RNA regulate the expression of genes. Place knows that his experiment will draw intense scrutiny from other researchers, and therefore it has to go perfectly. And as far as he can see, it has. His spectrophotometer displays a series of flawless curves, free of impurities; it looks as if he and his colleagues are finally seeing the pay-off after a three-year saga of frustration and exhilaration.

Since about the turn of this century, scientists have realized that 50 years of focus on DNA had blinded them to the wide range of biological roles held by its chemical cousin, RNA. The old view was that DNA contained life’s instructions, proteins carried them out, and RNA served as little more than a go-between. It’s now become clear that RNA has vast potential for controlling how cells interpret the instructions embedded in the genome.

The RNA revolution began in 1998 with the discovery honoured by last year’s Nobel Prize in Physiology or Medicine that small strands of RNA stuck together in pairs, like the strands that make up DNA, could turn off specific genes in roundworms1. RNA interference was born.

In 2001, scientists discovered that the process works in mammals, too2. They found that interference could be triggered by ‘short interfering RNAs’ (siRNAs) or ‘short hairpin RNAs’ (shRNAs). Both work by using a pair of scissors, actually a complex of proteins known as RISC, to cut apart the longer messenger RNAs (mRNAs) that take information from the genes to the cell’s protein making machinery. The small RNAs target mRNAs because their sequences match, and by destroying the messenger, RNA interference stops genes from making proteins. Both siRNAs and shRNAs are being tested in clinical trials against conditions in which an overactive gene needs to be shut down3.

Scientists then discovered miRNAs, which also trigger the interference pathway, but unlike siRNAs and shRNAs are naturally encoded by cells’ DNA. So far, more than 500 miRNAs have been identified in the human genome4. They can act like siRNAs, using the same protein complexes that slice through messenger RNA. But for the most part, miRNAs are content to muzzle the message or mark it for degradation, rather than chop it up.

All these techniques were still quite new back in 2004, when Li began to investigate RNA at the San Francisco Veterans Affairs Medical Center in the laboratory of Rajvir Dahiya, a urologist. Li, also a urologist, was studying epigenetics — stable modifications to the genome that change how it is read without altering its sequence.

He was particularly interested in DNA methylation, the addition of chemical tags called methyl groups to regions of DNA. Methyl tags often silence nearby genes, which can be disastrous for genes that usually suppress tumours. So Li was trying to find ways to reverse this process. He decided to try an RNA-based technique to control methylation that hadn’t yet been used in animals, as far as he knew, although it had been demonstrated in plants a decade earlier5.

Unexpected boost
Li purchased two pieces of double-stranded RNA that were complementary to a DNA control sequence — known as a promoter — upstream of the gene that encodes the tumour-suppressor protein E-cadherin. Then, his colleague Hong Zhao added the doublestranded RNA to two lines of prostate cancer cells and measured how it affected E-cadherin expression. Three days later, Zhao noticed something shocking: the experiment had boosted levels of the E-cadherin protein by 4- to 14-fold. “I couldn’t believe it,” Li says. The work defied everything that scientists had ever reported about small, double-stranded RNAs. They were only supposed to dampen gene expression. Li seemed to have stumbled on a phenomenon that could rewrite the textbook understanding of RNA interference and might offer new therapeutic potential.

Li re-ran the experiment many times, each time with the same result. He found that two other cancer-related genes, VEGF and p21, could also be activated by double-stranded RNAs. The evidence seemed solid. At least in the prostate cancer cells he was working with, short, doublestranded RNAs activated genes. “It was so easy to observe — I didn’t understand how people could have ignored it for such a long time,” Li says.

But apparently they had. So Li knew he was going to have to put together a atertight case to convince other scientists. He started to realize how difficult that would be when he first submitted his work forpublication to Science in August 2004. It was promptly rejected. He then submitted his paper to Nature that December; when it was rejected, he resubmitted it with new data in April 2005. He presented his findings at the annual conference of the American Association for Cancer Research in Anaheim, California, in May 2005, and the reception wasn’t warm. “I got a lot of sceptical questions,” Li says. Then, after an extensive delay, Nature again rejected Li’s paper in December, 2005. Without evidence for a mechanism, he says he was told the results weren’t convincing enough. Unsure how to proceed, Li got some unexpected help in the form of Place, who joined the lab in October 2005. Fresh from earning his PhD, Place was excited by the novelty of Li’s findings. But he could tell that the lab had a lot of nitty-gritty molecular biology work to do. Place helped plan experiments to help convince the sceptics. For instance, he helped Li and his technician Deepa Pookot to perfect assays, called immunoblots, that detect proteins so that they could measure how RNA activation boosts levels of E-cadherin and other proteins.


Filling in the details

Place and Li also started to think about the mechanism behind RNA-directed gene activation, a major stumbling block for the editors and reviewers who had seen the paper. If it worked in the same way as gene silencing, the sequence of the trigger RNA should matter, and the pair found that it did. Changing five letters at one end of the 21-letter sequences rendered them inactive. The pair also found that activation used some of the same key proteins that are involved in silencing, such as Dicer, which cuts up strands of RNA so that they can be used by RISC to target mRNA. They began to experiment with activation, trying to find out what worked best. “We started to modify the RNA duplexes to get optimal activation, tweaking their chemical structures,” Place recalls. “There came a point when we were working in synchronization, and we really started to click.”

Li resubmitted the work to Science with Place’s additional molecular biology results, but it was again rejected. The letter he received said that because the work “would represent a substantial paradigm shift”, the evidence just wasn’t strong enough. Again, editors required demonstration of a mechanism. So, in June 2006, Li talked to leaders of the RNA-regulation field at a meeting in Cold Spring Harbor Laboratory, New York. Li recalls asking David Bartel of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, if he thought RNA activation — not just inhibition — was possible. Bartel said he didn’t think so, Li says. Bartel says he doesn’t remember the=conversation, “I was probably just trying to find out how solid the evidence for activation really was,” he explains. Li was after all a junior researcher in an unrelated field, and he hadn’t been able to publish his findings.

Exasperated, Li considered sending his findings to an online journal with less stringent criteria than Nature or Science. But Dahiya thought that the work would get buried in obscurity, and convinced Li to try the Proceedings of the National Academy of Sciences instead. In August 2006, the lab submitted its work there — and finally got its breakthrough.

The journal reviewed it in weeks and published the work online in November6. Two months later, vindication: another lab, led by biochemist David Corey of the University of Texas Southwestern Medical Centre in Dallas, published a paper essentially duplicating the results in Nature Chemical Biology7. “It was really good for us,” Place says. “Before that, it seemed like everyone just thought we were crazy.”

Back at the Veterans Affairs Medical Center, Place and Li were now working closely together, although Li was preparing to move to his own lab at the University of Califorinia, San Francisco. They had already devised a series of experiments that they hoped would bolster their activation hypothesis. Although some changes
to the sequence can render RNA useless, others fine-tune the activation. The trigger doesn’t have to match the target sequence exactly, and a few tweaks to the double-stranded RNA produces less activation. And that’s exactly how miRNA works.

So the pair started hunting for a miRNA that might activate E-cadherin. It wouldn’t prove that activation was a natural phenomenon, but it would strengthen the case, because miRNAs are encoded in the genome.

Place and Li used a bioinformatics tool to search for miRNA in the human genome that had sequences roughly complementary to the E-cadherin promoter sequence. They found a handful of candidates and transferred them into the prostate cancer cell lines. The experiment was so simple they half-expected it wouldn’t work — but it did. The pair found one miRNA, miR-373, that boosted E-cadherin expression. “When that worked, we were totally pumped, because it was a potential example of natural function,” Place says.


On the right track

But it still wasn’t proof. So Place designed an miRNA precursor that, according to the model of miRNA biogenesis, should work as well as the miRNA itself. It did. Place also found that if he knocked out Dicer, then miR-373 stopped working, and that Dicer could also activate another protein with a promoter sequence similar to E-cadherin’s. All these experiments supported the idea that miRNA could use the interference pathway to activate genes. It was a strong hint that Li and Place were on the right track. On 6 August, they submitted the work to Nature Chemical Biology.

The question now is how this work will be received. Many are still sceptical about activation, as David Corey can attest. “Last time I talked about this at a meeting, a couple of leaders in the field jumped all over me and told me it wasn’t true,” Corey says. “We’ve received grant and manuscript reviews that seem to express irritation more than anything else. I just wish they would look closely at our data.”


Indeed, it sometimes seems as though the idea of activation is struggling because it contradicts the interference dogma. The RNA interference field is quite young, but already seems to have acquired a certain amount of inflexibility. On scanning through archives of biology message forums, Place has found that other scientists — often graduate students — have also seen evidence of RNA activation. But they have been encouraged to discount it.

Phillip Sharp, a Nobel-prize-winning biologist whose lab at the Massachusetts Institute of Technology in Cambridge pioneered much of the work on RNA interference, admits that RNA-mediated activation might be possible, but says that “the results I have seen do not prove this”. Echoing the demands of manuscipt editors, he says, “I think further papers on the subject must address the mechanism if they are to be published in a high-profile journal.”


A new pathway

As the field has moved apace, such requests are warranted, and providing proof of a mechanism is Li and Place’s main challenge. Some have suggested that activation is simply inhibition in disguise. It could be the accidental result of silencing an upstream repressor or of blocking another silencing RNA. Although they can’t rule out these possibilities, from their experiments, they say that these mechanisms look unlikely. For instance, they can elicit activation predictably at specific genes by targeting their promoters. There are intriguing differences between the known silencing pathways and the observed activation phenomenon. Silencing is triggered within hours and ceases in about seven days, whereas activation takes days to appear but can last for weeks. The different kinetics suggest that some mystery process is involved, Place says. “People say this could be RNA interference with another name, but it’s so blatantly different.” Major questions also remain about how RNA regulation might act at gene-promoter regions. In the classic interference pathway, the RISC complex guides siRNAs or miRNAs to a target mRNA in the cell’s cytoplasm. But to regulate a promoter, a small RNA would have to sneak into the cell nucleus, where DNA is transcribed. There is mounting evidence that this happens in silencing pathways, but again the mechanism is unclear.

In 2004, two groups published papers that suggested that siRNAs that target gene-promoter regions can silence genes if they are delivered into cell nuclei. Although one group has since retracted its paper, the other group, who published in Science8, showed that the inhibition was accompanied by epigenetic marks associated with silencing. Kevin Morris, of the Scripps Research Institute in La Jolla, California, an author of that paper, has continued to study how this occurs, and sympathizes with Li and Place’s position. “I was there in 2004, when 50% of the people love your work and the other 50% think you’re full of it,” Morris says. “It’s a frustrating place to be.”

Frustrating, indeed. As the deadline for this news feature approached, Place received word that the group’s manuscript on miRNA activation had been rejected. The reason given: without proof of a mechanism, the evidence isn’t substantial enough. Li is still adamant that the field will come around. “We have no doubt that RNA activation is an endogenous mechanism,” he says. And Place seemed unsurprised. “We knew the mechanism would be the sticking point. That’s the hardest part to prove.” But, he predicted, if the group can just get someone to just take a look at its data, the strength of its evidence will prevail. “If we can get it into review, we’ll be okay,” Place says. When RNA interference first hit the scientific radar, it was a slow climb from something written off by many as artefact to a revolutionary paradigm. That same uphill battle confronts Place, Li and their collaborators as they try to rewrite, or at least refine, the revolution. Call it what you will — stubbornness, confidence or optimism — this group just isn’t going to give up. ■


Erika Check writes for Nature from San Francisco.

© 2007 Nature Publishing Group

Endnotes

1. Fire, A. et al. Nature 391, 806–811 (1998).
2. Elbashir, S. M. et al. Nature 411, 494–498 (2001).
3. Check, E. Nature 442, 614–615 (2006).
4. http://microrna.sanger.ac.uk/sequences
5. Wassenegger, M. Cell 76, 567–576 (1994).
6. Li, L. C. Proc. Natl Acad. Sci. USA 103, 17337–17342 (2006).
7. Janowski, B. A. et al. Nature Chem. Biol. 3, 166

Biology's Big Bang: The RNA Revolution

Abstract:

For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which the genes encode and which do the donkey work of keeping living organisms living. The past couple of years, however, have seen the rise and rise of a third type of molecule, called RNA. RNA has been known about for a long time. Until the past couple of years, however, its role had seemed restricted to fetching and carrying for DNA and proteins. Now RNA looks every bit as important as those two masters. It may, indeed, be the main regulator of what goes on in a cell--the cell's operating system, to draw a computing analogy--as well as the author of many other activities. As important, molecular biologists have gone from thinking that they know roughly what is going on in their subject to suddenly realising that they have barely a clue. That might sound a step backwards; in fact, it is how science works. It is too early to be sure if the distinguishing feature of the 21st century will be biological technology, but there is a good chance that it will be. If RNA is controlling the complexity of the whole organism, that suggests the operating system of each cell is not only running the cell in question, but is linking up with those of the other cells when a creature is developing. To push the analogy, organs such as the brain are the result of a biological internet. If that is right, the search for the essence of humanity has been looking in the wrong genetic direction.



Leaders: Biology's Big Bang: The RNA revolution

The Economist. London: Jun 16, 2007. Vol. 383, Iss. 8533; pg. 13
Periodical
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What physics was to the 20th century, biology will be to the 21st--and RNA will be a vital part of it

NATURE is full of surprises. When atoms were first proved to exist (and that was a mere century ago), they were thought to be made only of electrons and protons. That explained a lot, but it did not quite square with other observations. Then, in 1932, James Chadwick discovered the neutron. Suddenly everything made sense--so much sense that it took only another 13 years to build an atomic bomb.

It is probably no exaggeration to say that biology is now undergoing its "neutron moment". For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which the genes encode and which do the donkey work of keeping living organisms living. The past couple of years, however, have seen the rise and rise of a third type of molecule, called RNA.

The analogy is not perfect. Unlike the neutron, RNA has been known about for a long time. Until the past couple of years, however, its role had seemed restricted to fetching and carrying for DNA and proteins. Now RNA looks every bit as important as those two masters. It may, indeed, be the main regulator of what goes on in a cell--the cell's operating system, to draw a computing analogy--as well as the author of many other activities (see pages 91-94). As important, molecular biologists have gone from thinking that they know roughly what is going on in their subject to suddenly realising that they have barely a clue.

That might sound a step backwards; in fact, it is how science works. The analogy with physics is deeper than just that between RNA and the neutron. There is in biology at the moment a sense of barely contained expectations reminiscent of the physical sciences at the beginning of the 20th century. It is a feeling of advancing into the unknown, and that where this advance will lead is both exciting and mysterious.

Know thine enemy

As Samuel Goldwyn so wisely advised, never make predictions--especially about the future. But here is one: the analogy between 20th-century physics and 21st-century biology will continue, for both good and ill.

Physics gave two things to the 20th century. The most obvious gift was power over nature. That power was not always benign, as the atomic bomb showed. But if the 20th century was distinguished by anything from its predecessors, that distinctive feature was physical technology, from motor cars and aeroplanes to computers and the internet.

It is too early to be sure if the distinguishing feature of the 21st century will be biological technology, but there is a good chance that it will be. Simple genetic engineering is now routine; indeed, the first patent application for an artificial living organism has recently been filed (see page 96). Both the idea of such an organism and the idea that someone might own the rights to it would have been science fiction even a decade ago. And it is not merely that such things are now possible. The other driving force of technological change--necessity--is also there. Many of the big problems facing humanity are biological, or are susceptible to biological intervention. The question of how to deal with an ageing population is one example. Climate change, too, is intimately bound up with biology since it is the result of carbon dioxide going into the air faster than plants can remove it. And the risk of a new, lethal infection suddenly becoming pandemic as a result of modern transport links (see page 67) is as biological as it gets. Even the fact that such an infection might itself be the result of synthetic biology only emphasises the biological nature of future risks.

At the moment, policymakers have inadequate technological tools to deal with these questions. But it is not hard to imagine such tools. Ageing is directly biological. It probably cannot be stopped, but knowing how cells work--really knowing--will allow the process to be transformed for the better. At least part of the answer to climate change is fuel that grows, rather than fuel that is dug up. Only biotechnology can create that. And infections, pandemic or otherwise, are best dealt with by vaccines, which take a long time to develop. If cells were truly understood, that process might speed up to the point where the vaccine was ready in time to do something useful.

But physics gave the 20th century a more subtle boon than mere power. It also brought an understanding of the vastness of the universe and humanity's insignificant place in it. It allowed people, in William Blake's phrase, to hold infinity in the palm of a hand, and eternity in an hour.

Know thyself

Biology, though, does more than describe humanity's place in the universe. It describes humanity itself. And here, surprisingly, the rise of RNA may be an important part of that description. Ever since the human-genome project was completed, it has puzzled biologists that animals, be they worms, flies or people, all seem to have about the same number of genes for proteins--around 20,000. Yet flies are more complex than worms, and people are more complex than either. Traditional genes are thus not as important as proponents of human nature had suspected nor as proponents of nurture had feared. Instead, the solution to the puzzle seems to lie in the RNA operating system of the cells. This gets bigger with each advance in complexity. And it is noticeably different in a human from that in the brain of a chimpanzee.

If RNA is controlling the complexity of the whole organism, that suggests the operating system of each cell is not only running the cell in question, but is linking up with those of the other cells when a creature is developing. To push the analogy, organs such as the brain are the result of a biological internet. If that is right, the search for the essence of humanity has been looking in the wrong genetic direction.

Of course, such results are speculative and primitive. But that is the point. Lord Rutherford, who proved that atoms exist, knew nothing of neutrons. Chadwick knew nothing of quarks, let alone supersymmetry. Modern biologists are equally ignorant. But eventually, the truth will out.

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