Cytoplasmic polyadenylation

The polyadenylation of mRNAs is usually thought of as a process that occurs in the nucleus, and indeed this is the cellular compartment in which pre-mRNA processing and polyadenylation does occur. However, mRNA polyadenylation is not restricted to the nucleus. Indeed, one of the more fascinating and important mechanisms that control gene expression during oogenesis and early development, stages in some organisms (such as animals) when the nucleus is not “active”, is mRNA polyadenylation. In these cases, the process occurs in the cytoplasm.

During oocyte development, a large population of maternally-encoded mRNAs are synthesized and stored for “use” in particular stages of development. These maternal mRNAs typically possess short poly(A) tails (20-40 nts) and are not available for translation (being “masked” by a complex of RNA-binding proteins). During oocyte maturation or following fertilization, these masked mRNAs become polyadenylated and thus activated for translation. This activation is a regulated process that helps to coordinate the ballet of gene expression attendant with meiotic maturation and early development. As such, it touches on many tangential phenomena (such as movement of stored mRNAs within the cell).

What is of particular interest for this blog is the nature of the mechanism that mediates polyadenylation in the cytoplasm. As indicated in the following figure, this mechanism includes some familiar players as well as some equally-intriguing partners.

Associations of alternative poly(A) sites with transposable elements

Previously, I discussed alternative polyadenylation, noting the extent (as many as 50% of human genes) of the phenomenon.  While there is some conservation of patterns of alternative poly(A) sites in animals, many of these events are species specific.  This suggests a relatively active evolutionary dynamic, one that shapes mRNAs in many ways.  A soon-to-be published study recently-published study in Nucleic Acids Research shed light on this dynamic, showing that species-specific poly(A) sites are often associated with transposable elements (TEs).  The abstract of the paper:

Obama and McCain on funding basic research

From Sciencedebate 2008, we learn of the candidates’ visions (it isn’t really fair to call them plans, or promises) for the scientific enterprise in this country.

What I’ll focus on here are the responses to question 13:

Research. For many years, Congress has recognized the importance of science and engineering research to realizing our national goals.  Given that the next Congress will likely face spending constraints, what priority would you give to investment in basic research in upcoming budgets?

Obama’s reply:

Federally supported basic research, aimed at understanding many features of nature— from the size of the universe to subatomic particles, from the chemical reactions that support a living cell to interactions that sustain ecosystems—has been an essential feature of American life for over fifty years. While the outcomes of specific projects are never predictable, basic research has been a reliable source of new knowledge that has fueled important developments in fields ranging from telecommunications to medicine, yielding remarkable rates of economic return and ensuring American leadership in industry, military power, and higher education. I believe that continued investment in fundamental research is essential for ensuring healthier lives, better sources of energy, superior military capacity, and high-wage jobs for our nation’s future.

Yet, today, we are clearly under-investing in research across the spectrum of scientific and engineering disciplines. Federal support for the physical sciences and engineering has been declining as a fraction of GDP for decades, and, after a period of growth of the life sciences, the NIH budget has been steadily losing buying power for the past six years. As a result, our science agencies are often able to support no more than one in ten proposals that they receive, arresting the careers of our young scientists and blocking our ability to pursue many remarkable recent advances. Furthermore, in this environment, scientists are less likely to pursue the risky research that may lead to the most important breakthroughs. Finally, we are reducing support for science at a time when many other nations are increasing it, a situation that already threatens our leadership in many critical areas of science.

This situation is unacceptable. As president, I will increase funding for basic research in physical and life sciences, mathematics, and engineering at a rate that would double basic research budgets over the next decade.

Sustained and predictable increases in research funding will allow the United States to accomplish a great deal. First, we can expand the frontiers of human knowledge. Second, we can provide greater support for high-risk, high-return research and for young scientists at the beginning of their careers. Third, we can harness science and technology to address the “grand challenges” of the 21st century: energy, health, food and water, national security, information technology, and manufacturing capacity.

McCain’s reply:

With spending constraints, it will be more important than ever to ensure we are maximizing our investments in basic research and minimizing the bureaucratic requirements that eat away at the money designed for funding scientists and science. Basic research serves as the foundation for many new discoveries and represents a critical investment for the future of the country and the innovations that drive our economy and protect our people. I have supported significant increases in basic research at the National Science Foundation. I also called for a plan developed by our top scientists on how the funding should be utilized. We must ensure that our research is addressing our national needs and taking advantage of new areas of opportunities and that the results of this research can enter the marketplace. We must also ensure that basic research money is allocated to the best science based on quality and peer review, not politics and earmarks.

I am committed to reinvigorating America’s commitment to basic research, and will ensure my administration funds research activities accordingly. I have supported increased funding at DOE, NSF, and NIH for years and will continue to do so. I will continue my commitment to ensure that the funding is properly managed and that the nation’s research needs are adequately addressed.

The commitment on the parts of both candidates is encouraging.  As was mentioned here, Obama has a pretty clear vision, one that includes a further doubling of research budgets (all research, not just NIH) over the next decade.  Also as argued here, this would seem to be an excellent investment, and will probably pay for itself.  McCain is less willing to get specific, and seems to be satisfied with his efforts to increase funding at DOE, NSF, and NIH.  McCain also stresses better management, and implies that he will re-assign earmarked funds to peer-reviewed research.  These are also good ideas.

I won’t try to decide for readers which vision is better – the complexities and intrigues of Washington will inevitably confound these very good intentions.  But what I will note is the contrast between Obama’s specific and strong vision, and McCain’s vague and weaker hopes.   Obama is clearly the stronger and more forceful of the two.

The 2008 Winners

… of the Albert Lasker Basic Medical Research Award are Victor Ambros, David Baulcombe, and Gary Ruvkun.  These scientists are pioneers in the field of small RNAs, and have helped dissect the process in animals and plants.  Some snippets from The Lasker Foundation announcement:

The 2008 Albert Lasker Award for Basic Medical Research honors three scientists who discovered an unanticipated world of tiny RNAs that regulate gene activity in plants and animals. Victor R. Ambros (University of Massachusetts Medical School, Worcester) and Gary B. Ruvkun (Massachusetts General Hospital, Boston, Harvard Medical School) unearthed the first example of this type of molecule in animals and demonstrated how the RNAs turn off genes whose activities are crucial for development. David C. Baulcombe (University of Cambridge) established that small RNAs silence genes in plants as well, thus catalyzing discoveries of many such RNAs in a wide range of living things. His findings led to the identification of the biochemical machinery that unifies numerous processes by which small RNAs govern gene activity.

Ambros, Baulcombe, and Ruvkun did not set out to unveil small regulatory RNAs. Ambros and Ruvkun were studying how the worm Caenorhabditis elegans develops from a newly hatched larva into an adult. Baulcombe, in a seemingly unrelated line of inquiry, was probing how plants defend themselves against viruses. All three investigators possessed the open mindedness, wisdom, and experimental finesse to entertain the possibility—and then verify—that tiny RNAs could perform momentous feats. Their work has led to the realization that these molecules are pivotal regulators of normal physiology as well as disease.

A few paragraphs later:

Across the Atlantic, David Baulcombe, then of the Sainsbury Laboratory in Norwich, UK, was studying how plants resist viruses. When he and others added to viral-infected plants unusual versions of viral genes, the mRNA copies of the normal genes as well as the newly introduced ones disappeared. Similarly, experimentally added non-viral genes suppressed activity of plant genes that contained similar sequences. Baulcombe proposed that such gene silencing occurs when RNAs embrace target mRNA—through typical Watson-Crick base-pairing—and promote destruction of the mRNA or interfere with its translation into protein. However, no one could find such RNAs.

Baulcombe reasoned that the predicted RNAs might have eluded researchers because the molecules were shorter than anyone imagined and thus, experiments had not been designed to detect them. In 1999, he and a postdoctoral fellow in his laboratory, Andrew Hamilton, devised a hunt specifically for small RNAs. They added test genes to plants and found 25-nt long RNAs that matched; furthermore, these small RNAs appeared only under conditions in which target mRNA activity was shut off. The stunning similarity in size between the plant and worm RNAs suggested that small regulatory RNAs exist in many organisms. Furthermore, it hinted at the presence of cellular machinery that dedicates itself to creating these precisely sized molecules and then uses them to quash gene activity.

Readers are encouraged to read the paper by Hamilton and Baulcombe that started to reveal the true scope of the RNA Underworld.  And another paper from Baulcombe’s group that ties in an underlying theme of this blog to the subject of small RNAs and silencing.  As always, enjoy.

Some numbers

From a recent issue of Biotechniques, we read the following (by Douglas McCormick):

“Washington, DC, Aug 30—If elected president of the U.S., Sen. Barack Obama (D-IL) would double government funding for the National Institutes of Health and other research agencies over the next decade. Obama repeated that pledge (first made during his primary campaign) in his answers to ScienceDebate2008’s “top 14 science questions facing America.””

At first glance, this sounds like another politician throwing money at some special interests*.  But a cursory glance at some numbers suggests something else:

• 1. NIH budget for 2008 – ca. $29 billion (from the NIH web site)
• 2. Receipts of the top ten pharmaceutical companies based in the US in 2006 – $230 billion (give or take, according to Wikipedia)
• 3. Total employees of the top ten pharmaceutical companies based in the US in 2006 – 700,000 (again, according to Wikipedia)
• 4. Receipts of the top ten biotechnology firms based in the US in 2006 – about $40 billion (according to Wikipedia)
• 5. Total employees of the top ten biotech firms based in the US in 2006 – about 60,000 (again, according to Wikipedia)

Granted that these are rough figures, that this is not a rigorous scientific or statistical analysis, and that there are other factors that alter the simple equation I make in the following.  But I think that these numbers are important to listen to in this upcoming election year.

A liturgy that rolls off the tongues of candidates of both parties is that government spending is wasteful, hence the rush on both sides to pledge this and that sort of spending cut (the exact nature of which depends on your political persuasion). What we also hear about is the treasured programs that the respective sides will continue to pour money into; again, the specifics depend on your redness or blueness. But what the voting public rarely hears is an honest accounting of the returns that each party’s favorite spending actually gives. I would argue that basic biomedical research (and indeed, all basic scientific research) yields excellent returns on federal investment, and offer the above numbers in support of this idea. The two industries I mention here – pharma and biotech – are intimately interwoven with the basic biomedical research enterprise, and a significant amount of the innovation that drives these industries originates (or originated) in the NIH-funded biomedical research laboratory. In this respect, the NIH budget is an investment, and a wildly-successful one. Even if we don’t take the face-value numbers I have pulled from Wiki here (that show an annual return of some 1000%, and more than 750,000 high-paying jobs the tax receipts from which would probably pay much of the NIH tab by themselves), and instead factor in that some of these receipts and jobs are not American, it is still easy to see that basic biomedical research returns considerably more than the investment made by the government. (And this doesn’t begin to weigh the intangibles, the ways that the research enterprise gives back to society as a whole.)

Is there room for growth in the many areas that are impacted by basic life sciences research? I would argue, most definitely. And I would argue that the rate of return of investment by the government, hinted at by the above, should be the same. Think about it – multiply by a factor of four the support for biomedical research, and we may add $1 trillion to our economy. (OK, OK, I know I’m using the most optimistic interpretation of the above, but even missing by a factor of two still translates into a huge shot in the arm.) If our government is going to be spending on something, an enterprise such as this would seem to be an excellent option.

So, as the campaign rhetoric becomes more heated and disconnected from reality, remember these thoughts, and ask yourselves if your candidate has the wherewithal to both admit that some government spending can actually have a positive rate of return, and to commit to some programs that will actually help the government’s and the nation’s balance sheets.

*Important disclaimer – much of my research is, and has been, supported by federal research grants.

Is ID a good thing???!!!

Now that’s I’ve hooked ya with the title, an admission – this essay has nothing to do with Intelligent Design (except in the sense, oft used by ID proponents, that genetic modification is intelligent design).  Rather, it’s about an interesting study that compared gene expression in rice plants that had been modified using “modern” genetic engineering with rice plants that had been subjected to more traditional means of introducing variability.  The abstract of the article, by Batista et al., is after the fold.  Enjoy.