Tiny RNAs, big risks

by emptypockets

Last night I wrote why more public dollars should be spent on basic research than on disease-directed research. I used this year's Lasker prize and recent Nobel prizes as examples to bolster my case. This morning, the Nobel committee (who apparently read TNH) decided to recognize an extremely basic discovery that, while it will likely impact medicine in ways we can't yet foresee, is for now just the kind of research I talked about -- the hunt for little endings, for clear answers to interesting but straightforward problems that won't cure anything anytime soon.

This year's Nobel in medicine or physiology is going to Andy Fire and Craig Mello for the discovery of RNAi (short for RNA interference, and named in the age of the iMac, around 1998). There are two things that are remarkable about this story -- three, really. First, it's how young this discovery is. In scientific terms, the result is barely dry. Perhaps even more remarkable is that it is the second prize in 5 years for work done in the tiny worm C. elegans, a system that people began studying only in the last few decades and a field so young that nearly everyone who works on worms either came out of one lab or was trained by someone from that lab. Second, the way RNAi was discovered is a wonderful story, that I'll come back to, about having the curiosity and intellect to pursue a weird result that you would never get funding to work on. Finally, there is the story itself -- small molecules floating in our cells, never before detected, that are probably the remnants of an ancient war between cellular life and viral life. (The cells won.) (For now.) Let me get into it by saying what RNAi is -- if you want to jump right to the politics, skip the next paragraph.

RNAi is a phenomenon where small RNA, which is like DNA but less stable, if it is formed into a double helix just 20 base pairs (or "letters") long, can shut off the expression of a single gene while leaving all other genes alone. The sequence of the RNA needs to be very similar to the gene you want to shut off -- but because RNA is easy to synthesize in a lab, that means you can custom order double-stranded RNA to shut off any gene you want. One obvious implication is that this could be developed into a drug to shut off troublesome genes that cause disease. That is pretty amazing on its own. But it gets weirder. A tiny dose of double-stranded RNA is enough to shut off every copy of that gene in an organism -- for days or weeks -- or even into the next generation. It sounds bizarre, but a drop of double-stranded RNA targeted against a gene of interest is enough to shut off that gene in all the cells of the organism, and in all the cells of that organism's children. Strong stuff. What's even more interesting is that this effect isn't just some artifact -- rather, it's a real piece of biology that our cells are doing all the time. It turns out that we naturally make little double-stranded RNAs that our cells use to control gene expression. It is thought that they were a primordial "immune" system, a way of specifically turning off the genes of viruses that were trying to co-opt our cells. The way many viruses reproduce means they have to make some double-stranded RNA, and there was selection for cells that could chew up double-stranded RNA. That system took on new functions during evolution, changing from a purely defensive system to a way of regulating normal genes.

Not only were the experiments that led to the discovery of RNAi not intended to cure disease, they probably wouldn't even have gotten past an NIH grant review. I won't go into the details now (ask me below if you're interested, I'm happy to say more), but the essence of it is that an experiment to shut off gene expression by a traditional, logical trick worked. Then the negative control, which should have had no effect, worked just as well! After much puzzling, it turned out that the gene was not being shut off by what they thought they were adding to the cells, but rather by an impurity in the reaction -- an extremely potent impurity. This observation, just about ten years or so ago, was the serendipitous discovery of the powerful effects of short lengths of double-stranded RNA. Can you imagine the NIH grant application? "We aim to investigate why our controls didn't work." It was not disease-oriented. It was not even strongly hypothesis-driven, although the experiments were done with terrific care and intellectual rigor. It was careful play.

It's not news that some of the biggest discoveries are made by accident. You may all know the story of the discovery of penicillin, although as that link shows it was not just serendipity but the carefully controlled work of a thoughtful and prepared mind. RNAi is in that category. But we can't distribute NIH funding to the people who are luckiest -- say, to the clumsiest scientists who are most likely to have a contaminant on their petri plate or an impurity in their RNA prep. Is there any budget policy that would increase the rate of "luck" in American science?

I think there is. I think there are two factors that strongly contribute to the level of "play," by which I mean experiments with no clear publishable result at the end of them. One is time, the other is money. When research funding is reduced -- as Bush has done, for the first time in 30 years -- people get stressed. A colleague told me this morning that the current success rate for NIH grant applications is down to 6%. That is abysmal. When you hear that, you don't want to play. You don't want to pursue that quirky result, that control that didn't work. You just want to stay on the well-worn path, doing experiments that you know will give solid results that will lead to papers that will enhance your chance of funding. You don't want to take risks.

Following up the RNAi observations was a big risk, and it paid off in a big way. In the 1990s, I'd like to think I also would have gone after it. Today, I don't know. I might, just because I do things like that (often foolishly). But I might just note it in my idea book, stick it in the freezer, and leave it alone until the "safe" experiments paid off and the next grant came through. Doing science is like investing, balancing risk and gain, time and money. A tiny observation may have a big pay-off -- but the uncertainty that Bush has introduced into the market by starving NIH is making a lot of scientists more risk-averse. Today's Nobel award is a good reminder of how important it is to do something risky, something weird, every once in a while -- and how important it is for the country to continue to provide an environment where that kind of play can go on.

Comments

[Jodi]

emptypockets,

you are correct, but you are not.

The question is simply how big is the money pot, and who decides on how it is doled out.

I have a father and a brother who are currently doctors, and a mother who was a nurse, but retired (maybe "tired" is better) and now owns a flower shop which is much less stressful.

I have heard all my life about how medical care is doled out in spurts, in pieces, about how the Medical Insurance companies, the MalPractice Insurance companies, and the Drug companies fight for share in that medical money pot.

The bottom line is we don't provide basic care for many people including children in America, as it is. Yet we provide some people with multiple transplants, we have people on life saving support systems of machines and drugs that cost 50,000 or 100,000 a year.

There is a pull and tug on the whole system. It goes back and forth.

Some solutions and many similar plans have been offered and actually are in place in foreign countries are to do some or all of the following and other things as well:
put a cap on long term care at say 10,000 per year, to not provide extraordinary care (transplants, expensive cancer treatments, etc.) for patients over some age, perhaps 60, or 65, and certainly over 70, and to also consider the general and activity of the person. There are other things too, but that gives you an idea.
Britain has become a joke because its national plan doesn't cover dental, and people are unwilling to get it themselves.

Well that money (or some of it) from stopped current care medical care could go into long view basic research, where scientists investigate interesting or "curious" things.
You see the public resistance that would pop up!

Now some would say we could put the money spent in Iraq on research. That is true. But everytime we go to the polls the public decides on who they want, and those people go to war, or give the surviving families of the 911 attack large sums of money where soldiers' families fighting the 911 war get much, much less.
Likewise they build rainforest museums in the midwest, libraries for politicans, subsidies to farmers, to cattlemen, to oil companies, to industry, two home morgage deduction, limits on new car sales tax, and on, and on. Now this is not a Democrat vs Republican issue, or a State or a Country issue. This is (let's say for fun) a pandemic!

I am in the tech side, and deal with a lot of funding. I see first hand how money is parceled out. There is a lot of losses, and a few wins that make it worthwhile, and a lot of stuff that just moves along with no gains or losses. But the point is there is limited funds to begin with.

Ok, I explained some, and postured some.
What would I do. I will postulate just a few
interesting solutions to show what the choices are:
1) If you reduced (above say 5) by one room every house in America you would save money to go into a more future directed and current caring budget.
2) Or you reapply the old luxury tax.
3) Or just increase taxes in general.
4) fund TV ads for elections directly with nobody else able to buy ads, . The money this would save the country would be 100 times what it would cost the taxpayer, because politicans wouldn't be beholden to large donors.

Well you see the public outcry, and indeed the political outcry.

Legislators really like that double morgage deduction.

You talk about 6%. That is applying a microscope to the problem, but perhaps it is your problem and you are really interested in that tiny niche.

There are much bigger issues.

I think the main thing we could do is eliminate lobbyist control of our government. But even with the current scandal, you see how that goes. It is not a Democrat or Republican issue. It is actually a voter issue where the voters put in the candidate that promises them the most. Greed begets greed, bagets waste.

[DemFromCT]

viva science!

The politicization of the NIH (and CDC) cannot be underemphasized, and the lack of respect science gets from this crowd is shameful. "If it's not useful against bioterror, what good is it?"

[DemFromCT]

Jodi, i don't know if you meant to post that here, but I agree. However, just because the GOP can't govern doesn't mean no one can.

[emptypockets]

The point here is that when Bush cuts the NIH budget, it is not just less science being done while the quality stays the same. The quality of the funded research goes down, for the reasons I talk about above.

I'm also not saying we should shovel as much money into science as we have into Iraq (though that would be lovely). But sharp cuts in real dollars after a decade of doubling budgets is irresponsible management -- that kind of precipitous drop breeds fear and uncertainty. It's possible to decrease the national commitment to research, if that's what the country really decides to do (it isn't), in a responsible well-planned manner that keeps the level of the remaining science close to the same as it had been.

But then this administration has never been big on responsibility or planning.

[Ken Muldrew]

Well said, Emptypockets.

Funding risky research is just not even on the radar screen these days; for risk implies failure and failure would be a waste of public money. The reason for doing science is to discover things not already known. How on earth can one guarantee results when studying the unknown? And yet, scientists who know all this will turn squeamish when they serve on a grant review panel and put the most conservative proposals first.

Last year I put a proposal into a special competition for "high risk" research. The institute went to great pains to instruct the panel that no pilot data was required for this competition. But the reviewers were having none of it: "The hypothesis may not even be correct! We cannot recommend funding this project without first seeing some compelling pilot data."

It is a sad time. The public doesn't want to fund curiosity driven research and neither do the scientists want to see it funded (at least the majority of scientists who serve on grant review panels). The historical record is stuffed to overflowing with anecdotes showing the practical value (not to mention the immense intellectual value) of curiosity driven research. If I wasn't so damn lazy I'd write a book about it.

[Jodi]

DemFromCT,

yes it is in the right place though I thought it was got lost putting it in.

I am afraid I don't see in the current Dem vs Repub system any solution. The parties are run by their fringe groups and lobbyists. We had 8 years of Clinton and though I was insulated somewhat from politics most of that time, I haven't heard that much great stuff. Obviously it wasn't great enough to get Gore elected and I didn't vote for him. I did vote against Bush when he ran against Sen Kerry. My Dad still talks about Jimmy Carter and not very complimentary.

I don't see much good in any party. It may be that our Presidential system doesn't work very well, but then I see Canada, and Britain and they have the same problems.

Our country is the greatest in the world but greed and self service is destroying it from the inside. As was predicted.

Democracy... is a charming form of government, full of variety and disorder; and dispensing a sort of equality to equals and unequals alike.
Plato (427 BC-347 BC)

EmptyPockets,

I don't know what the history of the NIH is as far as funding. My brother was there and at Walter Reed but didn't say much about it, but your statement
" But sharp cuts in real dollars after a decade of doubling budgets is irresponsible management" makes me wonder if people there just got used to an ever increasing supply of money and then the balloon popped. Few places ever have a decade of doubling budgets.

But, I am sorry that it is affecting you adversely.
I hope you get the grant you want, so you can keep us all alive when that time comes.

[Compound F]

Forgetting the funding consequences for the moment, I recall a seminar by Valerius Geist, a Canadian ungulate biologist, in which he recalled being called into a lawsuit concerning cross-border transportation of a certain "species" of bison, in this case a wood versus a plains bison. After a few short generations, he noted that one transplanted species living in a nearby clime without actual interbreeding became no longer distinguishable in terms of outward appearances, where before, the differences were absolutely distinct. In short, they had no good definition of "species," in this case. I'm no gene jock. Explain it to me.

[emptypockets]

Jodi, the NIH funding situation in a nutshell is that Clinton inititated a 5-year doubling of the NIH budget in 1998 that was completed in 2003. Since then Bush has held the NIH budget flat or cut it slightly (.1%), both of which are significant cuts in real dollars (it would need about a 4% annual increase to keep up with inflation; holding it flat is not unlike a 4% annual cut).

It may surprise you, since I always argue for increased NIH funding, but I don't think the 5-year doubling was good policy or very helpful to NIH -- I've said so before in this science funding post you might appreciate:

Budgets should be set to increase a minimum of 5% per year over fifty years -- not doubling in five or ten. Look at NIH. It just completed its doubling, then in a year went from 15% per year increases down to just keeping pace with inflation, then sharply into its first real cut in 36 years. Now it is flat again. That is a boom-and-bust cycle -- something any Texan can recognize.

Research demands a steady investment, with slight annual increases over inflation, continuously. Big jumps or big cuts for political reasons just breed uncertainty. It is not sustainable to try to double the amount of quality PhDs in the country every 5 years, and it is not helpful to crank up the PhD factory and then take away all the jobs a few years later. Slow, steady, sustainable.

As to my own funding situation, I'll be ok until 2008 -- when the first budget drafted by the Congress we elect this year kicks in.

[emptypockets]

Compound F, I'm not familiar with that story and if you really want to know and give me a link I'll see what I can understand. But on the surface of it, from what you said, there are two separate observations here that may be what interest you: first, that different species can look the same; and second, that a single species can look different in two environments.

The first, that different species can look the same, is not so surprising. There is no a priori reason they should look different -- the definition of species is a venerable and thorny problem, not least because it is more an invention of the human urge to classify than a real biological construct, but most definitions center on the ability of two populations to interbreed not on their physical appearance. There are many stories of two species being thought for years to be a single species because they look so similar (good examples in butterfly taxonomy, I will look for the link if you're interested to read more). So the fact that two species can look the same is not startling.

The second, that a single species can look different in different environments, is curious and fun to think about but I'm not sure how strange it is. We have plenty of experience with animals' appearances changing depending on diet, temperature, and other conditions -- sometimes within a season, sometimes over a generation. So the idea that picking up a species that has certain physical attributes, moving it somewhere with different climate and different food supplies, and finding that within a generation its appearance has changed -- it's interesting, and it would be interesting to know what the environmental variable that matters is (is it diet? what part of the diet? how does eating more or less of some vitamin end up changing thickness of fur or whatever?) but it doesn't go against sort of the way I expect the world to behave.

[kim]

Despite my penchant to criticize I agree with most everything you're saying, I'd just be more negative and cynical.

[emptypockets]

kim, I'll work on it :)

[Jodi]

I think that a great mistake people make is to be negative and cynical at anytime or anywhere, ESPECIALLY IF they have to then go work with other people. I see it a lot. People are presenting something or requesting something, and all of a sudden they make a really sharp remark, and then quickly apologize for losing their cool or being "too cynical." What has happened is that they have shown a weakness.

Emptypockets, I totally agree on the funding.
The difference sometimes is a start up, or inital seed or development money where you put in money to get going. Equipment, hiring, rewards. A partnership.
Then you provide a number of years at a certain rate, where the people feel confident. One thing I like to do is fund for a minimum of 2 years and then at the end of the first year extend the contract to cover the next 2 years. Or 3 years, and then after the 2nd, extend. Now you may change direction, or even people if there is a problem, but the important thing is that generally people have confidence that their families are ok.
Sometimes I can't do that, because of a limit imposed on me. The old "sink or quickly swim when you have been tossed off the pier" mentality that some have. Sometimes it is only one or two "principals" that you can give that "secure feeling" to.

But your point about people's feelings is correct.

[morinao]

emptypockets,

So if it wouldn't have passed grant review, do you happen to know how this research did get funded? Leavings from existing grants? Institutional award? Private donors? Startup package? Children's college fund?

[emptypockets]

morinao, good question -- the experiments probably didn't get funded, strictly speaking. The way funding works is the lab head submits a proposal to NIH for a set of experiments to do over the next 5 years (typically). But of course research isn't that predictable -- sometimes you actually do what you propose in the grant application, sometimes things turn out differently. There is some oversight year to year to make sure you're on track and they can refuse to renew the grant year-to-year if you're going off the deep end. But it's understood that what you say you're going to do and what you end up doing will likely be a little different.

Also, the kinds of experiments that got the RNAi work started are cheap to carry out, and as long as overhead and salary is already paid for they are not a big burden to do on the side, at all.

So mostly the "leavings from existing grants" category, I would guess, although probably in reality a bit of all of the above (some private donors, especially the Howard Hughes Medical Institute which funds Andy Fire though I'm not sure he was HHMI at the time this work started, especially encourage high-risk experiments that you couldn't get traditional funding for). So, as long as time and resources are not spread too thinly within the lab and one's anxiety level about the future is not too high, it's not a big deal to do these kind of playful curiosity-driven experiments on the side. But if he were to have written the standard NIH R01 grant proposal on this topic, when they were first starting out and just had some preliminary results showing something weird might be going on, I'm fairly confident it would not have been funded -- too weird, too unlikely to be interesting, too out-of-left-field to fund.

[Dop]

'The sequence of the RNA needs to be very similar to the gene you want to shut off -- but because RNA is easy to synthesize in a lab, that means you can custom order double-stranded RNA to shut off any gene you want'

Dr. WMD probably knew this while she was in her lab in Iraq. She was freed by the Iraqi courts the day Plame posed for 'Time.' Maybe she made a deal?

So, if a virus is introduced, based on the research so that the cell looses, we could delete DNA for body parts, etc, and infect everybody in North America. The virus would also be lethal to the host, whether or not they decided to have babies. Travel would have to be handled by bio IDs at borders or the 'virus' would spread. The population would die off, not being able to reproduce.

The two Americans who found this seem to have no history on the work, other than it was Americans who found it and not a Dr. WMD. Maybe it's a 'buy.' So, we get bio IDs implanted for the borders and finances, etc. It's a real good movie I've seen before.

[emptypockets]

Dop, I only followed about a third of that but I guess I'd just say it is easier to fly a plane into a building than to engineer and release a deadly virus, particularly one that can "delete DNA for body parts." I remember there was a major experiment being done on Long Island (I believe) several years ago that was designed to reproduce, on a very small scale, the conditions of the big bang. There was an extremely remote chance that a black hole would be created and the entire solar system would be sucked into Long Island. I would put your movie idea into that category.

[kim]

Thought I'd take the occasion of another Kornberg Nobel to go slightly negative and cynical. :-)

There is an issue of knowledge diffusion in science, so people who have worked with Nobel winners often win Nobels (in this case father and son, Fire also worked with Sharp BTW). An extreme explanation for this says Nobels pick future Nobels and favor their former collegues, but I think it is more just that real scientific understanding and insight doesn't diffuse well (both because this requires close social relationships and because people who go to places like Boston and San Francisco tend to stay there).

Then there's the image of the the old warhorse Arthur Kornberg hoisting the flag for chemistry on the Newshour, raising the spirits of academic chemists everyhwere. Of course most research these days is biological, what do chemists know of cultured cells or living organisms, so chemists still co-opt bio discoveries to seem relevent (and misleading their students for going on 40 years now - you probably see signs of old bio-chem rivalries and my bias showing here).

Lastly, I seem to remember that there was a plant biologist who did important experiments (in petunias?) leading to the RNAi story and perhaps should get some credit (BTW, Fire worked with Sharp, another Nobelist and RNAi enthusiast). Reminding me also of George Gamow who might have gotten an award for predicting the Big Bang and microwave radiation.

Ah well, back to the world of truely remarkable discoveries and wonderful natural understanding that is modern science.

[emptypockets]

kim, again interesting points. I didn't have much to say about the chemistry award (obviously) but since you bring it up let me put my thoughts out there, pretty much as they occurred to me and without much organization. First, I thought of Roger Kornberg's brother Tom, who is also a scientist (he works on development in fruit flies) and just a really smart, nice guy doing extremely interesting stuff. And I wonder what it's like to be the "other brother," also a scientist, in a Nobel prize father-son pair. Tom also, iirc, is an outstanding cellist (that's cello the instrument not cells the unit of life) and nearly made that his profession (or did for a while? I've forgotten). So that's an interesting back-story to the Kornberg prizes, the third Kornberg who excels both in science and music but hasn't had that singular shining moment in either.

The second thing I thought about is how pissed the real chemists must be because this is the third time in four years that the chemistry prize went to a biochemist or biologist and not to a 'real' chemist. Is it just that there is more funding in biology so we are sapping great minds away from pure chemistry? Or is it that there are not really great questions to work on in pure chemistry right now? I don't know but if I were a straight chemist I would certainly be rolling my eyes and heaving a sigh at this choice.

The third thing I thought about is all the other transcription people who are probably kind of pissed too. Bob Roeder won the Lasker, I think, that "American Nobel" a few years ago and if they had given the medicine prize for transcription (rather than the chem one) you might think he'd have been included. Tjian too. To me it is even more remarkable that this prize went to just one person than it was for the RNAi prize. For RNAi, as you note there were some observations in petunias but I think that was all quite phenomenological -- I don't think they had any molecules or even the concept of double-stranded RNA though I could be wrong about that. If the RNAi prize went to anyone outside Mello & Fire I would have expected it to go to people who did some of the in vitro work figuring the mechanism of the proteins that generate the small RNAs. Who knows what politics and wangling feed into these decisions.

As to the pedigree or legacy issue -- that is just science I think generally, not specific to Nobel awards. Go to a good lab, get good training, get some doors opened to good positions, everything works in your favor. But I don't think that necessarily takes anything away from the individual accomplishment -- there are a lot of other people who came from the Sharp lab (and like I said even other scientific sons who came from the Kornberg line) who did not get the prize. Having Nobel connections helps, but it's certainly not necessary or sufficient.

[kim]

Interesting points EP, I agree Tjian and Roeder should get one (maybe also Ptashne? an old favorite of mine, classic experimentalist/theorist, also a musician). Maybe they're all lined up for the future.

[kim]

About T. Kornberg -- I though of him but didn't worry, sounds like he's got life worked out and wouldn't be bothered by dad and bro', might even be the best path after all. Drosophila is a great system though... who knows?

[Peter]

Why should Tjian or Roeder have a Nobel prize. I cannot recall any specific findings from their laboratories worthy of a nobel prize. Please remind me!

[emptypockets]

Peter, Roeder won the Lasker a few years ago for his discovery of RNA polymerase. Previously he shared the Passano award with Tjian, who identified much of the transcriptional machinery that works with RNA polymerase.

[neo]

Roeder is really the co-discoverer along with Pierre Chambon of the 3 different eukaryotic RNA polymerases. Tjian identified the transcription factor Sp1 and the TBP-associated factors (TAFs), but did not identify any of the general initiation factors required for polII transcription. Sole credit for discovery of the Mediator, which bridges transcriptional regulatory factors to the polII initiation machinery, belongs to Kornberg. Roeder extended these studies to show that Mediator is conserved form yeast to human cells, and Tjian later participated in the definition of the components of the human Mediator complex. Beyond his important biochemical work on identifying the polII general initiation factors and the initial discovery and description of the Mediator, Kornberg's elegant structural work on polII clearly set him apart from others working on the mechanisms of polII transcription.

[meri]

Thank for making this valuable information available to the public.e

[mason]

Wow!!!^

[Ron]

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