Tackling the hairy beast – Tetrahymena genome

ResearchBlogging.org

Just thought I would put out a little self-promotional posting here on a paper we have published today on the genome of a very interesting organism called Tetrahymena thermophila. This organism is a single-celled eukaryote that lives in fresh water ponds.

This species has served as a powerful model organism for studies of the workings of eukaryotic cells. Studies of this species have led to some fundamental discoveries about how life works. For example, telomerase, the enzyme that helps keep the ends of linear chromsomes from degrading, was discovered in this species. This may not seem too important, but many folks think that degradation of chromosome ends in humans is involved in aging. Perhaps even more importantly, (to me at least) studies of this species were fundamental to the discovery that RNA can be an enzyme. This discovery of catalytic RNA revolutionized our understanding of how cells work and how life evolved. Tom Cech and Sidney Altman were given the Nobel Prize in 1989 for this discovery.

Many (including myself) believe that having the genome sequence of this species will further spur research and its use as a model organism. In addition, we believe that some of the findings we report in our paper will further cement the importace of this species. For example, this species, though single celed, encodes nearly as many proteins as humans and possesses many processes and pathways shared with animals but missing from other model single celled species.

The project that led to this publication was undertaken while I was at TIGR (The Institute for Genomic Research) and involved a collaboration among people at dozens of research institutions around the world. It all started in 2001 when Ed Orias and his colleagues sought to see if anyone at TIGR would be interested in putting in a grant to sequence this species’ genome. I responded to the email saying I was interested, especially since I had interacted with multiple people who used this species as a model system (e.g., Laura Landweber at Princeton and Laura Katz at Smith). So I went to a FASEB meeting where the Tetrahymena Genome Steering Committee was meeting and discussed with them how TIGR might help sequence the genome. And after talking to other genome centers, they selected TIGR to put in a grant proposal with them.

We ended up getting funding from two grant proposals – one from NIGMS and the other from the NSF Microbial Genome Sequencing Program. The sequencing was done in a rapid burst at the new Joint Technology Center which TIGR shares with the Venter Institute. And then we spent ~1.5 years analyzing the sequence data (and assemblies) that came out and in the end we fortunately were able to get our paper into PLoS Biology, in my opinion the best place available to publish biology research.

Importantly PLoS Biology is Open Access which allows anyone anywhere to read about our work. This goes well with the free and open release we made of the genome sequence data. In fact, many people published papers on the genome before we did (sometimes scooping us). In the end, I accepted the risks of releasing the genome data with no restrictions inexchange for advancing research on this organisms. I think this risk was well worth it as we still got our big paper published and the field has advanced more rapidly than if we had not released the data.

Other links that may be of interest to people:

Eisen, J., Coyne, R., Wu, M., Wu, D., Thiagarajan, M., Wortman, J., Badger, J., Ren, Q., Amedeo, P., Jones, K., Tallon, L., Delcher, A., Salzberg, S., Silva, J., Haas, B., Majoros, W., Farzad, M., Carlton, J., Smith, R., Garg, J., Pearlman, R., Karrer, K., Sun, L., Manning, G., Elde, N., Turkewitz, A., Asai, D., Wilkes, D., Wang, Y., Cai, H., Collins, K., Stewart, B., Lee, S., Wilamowska, K., Weinberg, Z., Ruzzo, W., Wloga, D., Gaertig, J., Frankel, J., Tsao, C., Gorovsky, M., Keeling, P., Waller, R., Patron, N., Cherry, J., Stover, N., Krieger, C., del Toro, C., Ryder, H., Williamson, S., Barbeau, R., Hamilton, E., & Orias, E. (2006). Macronuclear Genome Sequence of the Ciliate Tetrahymena thermophila, a Model Eukaryote PLoS Biology, 4 (9) DOI: 10.1371/journal.pbio.0040286

The Disgrace of the Royal Society

I am astonished at the behavior of the Royal Society regardling publication. As dozens of funding agencies and societies and individuals move towards Open Access for publications, the Royal Society crawls back into the medeivel hole from which it originated.

In article after article, the Royal Society’s publishing folks rant on and on about the evils of Open Access publishing. NOTE …. THANKS TO DBERGESSON FOR POINTING OUT THE MISTAKE IN THIS BLOG. I USED A QUOTE FROM THE WRONG ROYAL SOCIETY HERE. I AM LEAVING IT IN TO KEEP THE ORIGINAL POSTING. I STILL FIND THE REAL ROYAL SOCIETIES POSITION ON OPEN ACCESS TO BE ANNOYING. SEE COMMENTS FOR MORE DETAIL.

For example, in a recent article from RSC:

But the Royal Society of Chemistry’s director of publishing, Peter Gregory, disagrees. ‘We have absolutely no interest shown from our editorial board members, or our authors, for open access publishing,’ he said.

Gregory believes that the open access author-pays model is ‘ethically flawed’, because it raises the risk that substandard science could be widely circulated without being subjected to more rigorous peer review. This could be particularly problematic in chemistry, where rapid, open access publication could be used to establish priority ahead of more time-consuming patent applications from rival groups, he added.

What this basically means is that the Royal Society wants to continue to make money publishing the results of scientific research that is largely funded by the government and the public. And that they are willing to have people suffer (e.g., die unnecessarily because their doctors do not have a subscription to the Royal Societies journals) rather than use their supposedly brilliant minds to come up with a way to make money and simultaneously make the research freely available. The NIH, Wellcome Trust, and dozens of other groups are pushing for Open Access. Yet the Royal Society is sticking to their old boys club ways (to see how old boys clubbish they are go to here).
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If we actually go to the details of the Gregory quote above, I have a hard time knowing where to begin with the flawed logic here. For example, the idea that substandard science does not get published in non Open Access journals is just absurd. Consider the latest example of the Korean Cloning scam. Those articles were published in top non open access journals. Same thing with just about every other case of bad science or scientific fraud in the last twenty years. The claim by Gregory is simply unfounded. First, Open Access journals do not say there should be no peer review and they tend to be peer reviewed even more carefully than non-open access journals. Just try publishing a paper in PLoS Biology, which I have found to be more stringent than Science. Why is this? Becuase scientists are more willing to commit time to reviewing for such journals because their work benefits humanity rather than some publisher like Gregory.

Another reason Gregory’s claim is unfounded is evidenced by the physics community. They put preprints out for the world to see, which allows for global peer review, rather than peer review by a select list of people. The idea that peer review as it is in current non open access journals is perfect is completely ridiculous. Sometimes you get objective reviewers, but other times you get people that, even if they wished to be objective, would probably have a hard time doing so. This is unavoidable in any peer review system. The more open the publication system and the peer review system is, the more likely it is to avoid outrageous variation in quality.

The Royal Society should be ashamed. They are preventing the distribution of scientific findings and trying to maintain a publishing system that limits the speed of scientific advances and enriches the publishers at the expense of governments and the public.

So I suggest that anyone who knows someone harmed by a doctor who did not know what they were doing, or anyone who wishes for scientific advancement to proceed at a rapid pace, to consider writing to your favorite member of the Royal Society and asking how they feel about this.

To contact the Royal Society directly go here.

I have been unable to come up with email lists of society members but if anyone can find one I will post it.

Viruses as food additives

I find it sad that the world has come to this. The FDA announced that it has approved the use of viruses as a food additive. The particular viruses (known as phage in this case) target and kill common bacterial pathogens found in meat. It is entirely possible that this treatment will lead to reduction in deaths and illnesses. However, it is also possible that there will be unexpected consequences of this treatment and thus anything like this should be done with caution. What saddens me about this whole thing is that it is the wrong way to go about solving the problem. Most of the problem comes from the fact that our meat today in this country does not come to us in reasonable condition. The animals are usually kept in unsanitary conditions where diseases and nasty pathogens are prevalent.

The best way to think about this in my opinion is what I read in The Omnivore’s Dilemma, the new book by Michael Pollan. In this book he talks about how animals now frequently live in what can be considered the equivalent of the slums of the industrial revolution. Cities of animals, frequently wallowing in excrement, is not the best way to prevent bad microbes from getting in our food.

So in recent years all sorts of practices have been developed to kill these microbes in food products. Irradiation, for example. And now, viruses, sprinkled on your meat, to keep the bacteria from growing too much. Give me meat from animals that have not been swimming in their own shit and piss and I will be happy to take my risks without dumping viruses on top.

Deceptive advertising by Amtrak

There is this nice train out here that runs from Sacramento to Oakland called the Capitol Corridor. I really like this train overall since I can take it from dontown Davis to Berkeley and i takes about the same amount of time as driving but is much more relaxing. There are issues with the on time performance of the train but mostly even when it is late it is better than driving if you are going somewhere near a train station.

However, I am pretty pissed off at Amtrak for one of the things they advertise relating to this train. On the Capitol Corridor web site, the highlighted item is frequently a promotion saying “Take the train to Oakland A’s Games this season”. It sounds great since there is now an Amtrak stop right at the Oakland Colliseum where the A’s play. That is, until you look at the train schedule. For night games there is simply no way to take the train to games. This is because the trains stop leaving the stadium at about 8 PM, or just after night games start. Even for day games there is not much offered in the way of getting to and from games on a reasonable schedule. Even when there are technically late trains for Amtrak, most of the trains do not actually stop at the Colliseum. So I am having a hard time figuring out what they mean by “Take the train.”

In other cities in which I have lived they reserve a train to leave just after the game ends. Not here thye don’t (or at least they do not advertise this as an option). It seems lame to promote this idea and then to not have the trains to back it up.

Human Evolution and Neanderthals

Well, I suppose everyone should have seen this coming. An announcement has been made of plans to sequence the genome of a Neanderthal. The plan is to take DNA extracted from a Neanderthal fossil, and sequence it using a relatively new method from a company known as 454 Life Sciences.

I am torn about this project. Yes, it is cool to read DNA sequence from an extinct species, especially one that has not been around for some time and one of direct relevance to understanding human evolution. On the other hand, I would personally find it much more interesting to try and sequence an ancient Homo sapiens first. This is because the comparison of the Neanderthal to modern humans may not be the right comparison. It would be better to first compare an ancient Homo sapiens sample to modern humans, maybe with both being done with the same methods to be used in the Neanderthal study. This would be for two reasons. First, we do not really know how well the method(s) they are using work. And second, if the methods work well, it is possible that some of the differences they observe would actually be due to degradation or damage to the DNA sample. Therefore, if they simultaneously did work on an ancient Homo sapiens they might better be able to calculate which differences are do to real differences in the Neanderthal DNA and which are due to damage to the sample.

Assuming they do something like this and they are able to detect differences in the Neanderthal genome. What then? In the end, the major area of interest will be population genetic analyses trying to figure out how long Homo sapiens and Neanderthals were separated for and whether there was any interbreeding. To figure this out, they will need more Neanderthal samples and ancient human samples. Nevertheless, it is always good to do something that brings attention to the public for scientific research.

Open Access Rant: How Does Your Doctor Learn About the Newest Medical Findings??

Everybody would like to find a doctor who is knowledgable about the latest developments in medicine. Whether these developments relate to new treatments, or new methods of diagnosis, or treatments that are dangerous or do not work, we want our doctors to know this information. How do doctors find out about these things?

Well, there are many sources of this information, but one we hear a lot about these days is a little disconcerting. It turns out that a lot of doctors get the latest information from drug company reps who stop by the office and leave imformation pamphlets or who talk up their companies latest products. This could be OK, except for the fact that many of the drug company reps either purposefully provide misleading information, or in fact do not actually know what is good or bad information.

One reason this is such a big problem is that, like everyone else these days, doctors are really busy and overwhelmed. So they sometimes do not have any time to read the actual medical studies that might be relevant to what the drug company reps are saying. But that is a bit lame of an excuse, since it is their job to know these things. Thus I really think they should read more of the medical literature and not just drug company propaganda.

But herein is one of the biggest problems in modern medicine. Even if you have a really hard working doctor who is willing to read the latest papers, they may not be able to. This is because even though most of the medical studies were paid for by the government in some way, they are not freely available for the doctors to read, because they are published in journals that charge exceptionally high prices for subscriptions. Doctors in large institutions probably have good access to this information. But doctors in small groups may not. Imagine if congress passed laws but lawyers were not allowed to read them without paying a fee to someone. The system for medical literature is really absurd.

I got thinking about this when re-reading Lance Armstrong’s autobiography “It’s Not about the Bike.” In the book, Armstrong describes how when he had testicular cancer he had a friend who was a doctor bring him the latest studies on this type of cancer and he read all of them. Well, this only was possible because his friend must have had access to all the publications through a university or very large medical group. Wouldn’t it have been better if Armstrong could have just gotten the studies himself, given that most were paid for by the US Government in the first place? Well, if people doing medical research published their finding in Open Access journals, then anyone could read the articles, from doctors, to patients, to family members, to journalists. We would all benefit if this was done.

Ancient DNA

Studies of “ancient DNA” are becoming all the rage these days in various circles. The term “ancient DNA” refers to DNA isolated from very old samples, lets say at least 1000 years old.

Many years ago, it was considered almost taboo among biologists to say you worked on ancient DNA. It was the cold fusion of biology. This was becuase a variety of esteemed scientists basically said it was impossible for one to study ancient DNA since DNA was not stable enough to survive for so long a period of time. It is clear now that these people were pontificating without any real evidence, but at the time, they carried a lot of weight.

At first, the papers published on ancient DNA seemed to support the naysayers. Many many early claims were found to be flawed. But as researchers learned the problems, they also learned how to circumvent them. They learned how to keep samples very clean and avoid the possibility of contamintions. And they learned how to help deal with fragile DNA (it is sort of the chemical equivalent of dealing with a crumbling manuscript of days past).

And most recently, ancient DNA has gotten a new kick in the pants. This comes from applications of methods originally designed for genome sequencing projects (like the human genome project) to the field of ancient DNA. The genome sequencing methods allow researchers to characterize in more depth samples that supposedly contain ancient DNA. The deeper sampling allows more statistical approaches to analyzing the data and this in turn allows one to test a variety of possible explanations for what one observed (e.g., one can do a test that distinguiushes contamination from other possibilities).

And one can tell that ancient DNA is really a hot topic again as it is getting covered in all sorts of popular mags (see the recent article in Wired magazine for example here).

What can one do by studying ancient DNA? Well, basically the same things that anthropologists and paleontologists and archaeologists and evolutionary biologists have been trying to do by examining fossils. Only now, by looking at the DNA contained within fossils, one can both test (i.e., confirm, deny) inferences made from other information OR one can frequently make inferences that were impossible previously (the article in Wired is about Eddy Rubin’s studies of Neanderthal DNA that to them suggests that many anthropology-based claims about human-Neanderthal interbreeeding are wrong). Note – for full disclosure (which someone nagged on my previously for not doing), I am just starting to work with Eddy Rubin on some ancient DNA analyses, but I had nothing to do with the Neanderthal work described in the article.

The real question I think for ancient DNA studies is now no longer can they work. The question is – how far back can they go? Most likely, as one goes further and further back in time, the DNA will be in worse and worse shape. And thus what one can learn from looking at it will decrease significantly. But here is where the genome sequencing methods come into play. If one can get a large enough sample size, it may not matter so much that the DNA is in bad shape. For example, if one had one blurry picture of someones face, you would not know what they looked like. But if you had 10000 blurry pictures of the same face, you could reconstruct it with high accuracy by combining the information from the different pictures.

So – stay tuned – ancient DNA studies may be turning up some interesting tidbits in the near future. We are not likely to get to Jurassic Park territory soon – but it is not longer as absurd as it once seemed to many.

John McCain on Evolution

Just got very interested in reports of a Q&A session John McCain had a the Aspen Music Festival, as reported in the Aspen Times here. He was apparently, his normal self. Most interesting to me is his quote in response to a question about evolution

“I think Americans should be exposed to every point of view,” he said. “I happen to believe in evolution. … I respect those who think the world was created in seven days. Should it be taught as a science class? Probably not.”

It’s too bad more of the Republican party is not like him on this issue. I would bet he really cannot stand Bush but he has been trying to be a little more policial recently and thus has not said anything too critical. But it is good to know that at least one (and maybe only one) of the possible Republican candidates for president is not as anti-science as the core of the party seems to be these days.

Interesting interview with David Botstein

There is an interesting interview of David Botstein in PLoS Genetics here.

Botstein has been at the heart of many key discoveries and innovations in genetics and genomics and he discusses some of these in this interview. In addition he discusses his initiative at Princeton to try a new way of teaching science to undergraduates. It is not the most comprehensive interview, but it still has some juicy tidbits. In particular, the discussion of his 1980 paper on genetic mapping has some things I have not read elsewhere.