How to Get Into Graduate School

 
Shelley Batts has all the right answers [Guide to Getting Into Graduate School for the Sciences]. You need to read her entire posting but here's the short version to tempt you ...

1. Spend your spare time doing research.
2. Cultivate awesome letters of recommendation.
3. Take the relevant classes, but have a few other interests too.
4. Have a reason why you want to do research.
5. Read the literature, know the basics, and a few tough surprising facts.
6. Know your interviewers, and their research.
7. Shell out the money for a GRE tutor if you are a nervous test-taker.
8. Apply to schools based on labs, not the US News and World Report Rankings.
9. Email professors you are interested in working with.
10. Follow the funding.
11. Good scientists don't always make good mentors.
12. Don't be afraid to get out if it isn't working.
13. Stand up for yourself, and keep at it.
14. Share most of your ideas, but keep a few to yourself.
15. Apply for NRSAs.
16. Be curious.
17. Know some science lineage.
18. Know who won the Nobels that year, in your field.
19. Email the students in the program, and in the lab.
20. Find out where/what students from that program are doing now.
21. No second-choices. Nothing but science will do.
22. Be professional, talk shop, ask what projects their students are doing.

Some of these only apply to Americans but on the whole it's excellent advice for everyone. Be sure to pay close attention to #21. Ignoring that advice is problably the second most common mistake that applicants ever make. The most common mistake is ignoring #2 or thinking that there's no relationship between #2 and #21.

Cracking the Genetic Code: The polyU Experiment of Nirenberg and Matthaei

 
By 1960 it was widely recognized that DNA was transcribed to yield messenger RNA (mRNA) and mRNA was translated to yield proteins. The translation step could be carried out in vitro by using extracts from E. coli cells that had been primed with purified RNA. Some of the favorite messages were RNAs from viruses such as TMV or yeast cells. By measuring the amino acids that were incorporated into protein it was possible to show that the RNAs from different sources were making different proteins.

The relationship between the RNA and the protein product was obvious. There was something about the sequence of nucleotides in the RNA molecule that determined the sequence of amino acids in the protein. The RNA encoded the amino acid sequence. What was this genetic code?

Marshall Nirenberg was a scientist working at the NIH labs on the outskirts of Washington D.C. He and his post-doc Heinrich Matthaei realized that they could program their cell free extracts with synthetic RNAs and crack the genetic code.

Their first attempt was with a synthetic RNA called polyU because it was composed entirely of uridine residues [Monday's Molecule #28]. They added polyU to various test tubes containing one amino acid that was radioactively labelled. They then looked for incorporation of this labelled amino acid into high molecular weight protein that could be precipitated from the extract.

Here's how the experiment is described on the NIH website [The poly-U Experiment]

On Saturday, May 27, 1961, at three o'clock in the morning, Matthaei combined the synthetic RNA made only of uracil (called poly-U) with cell sap derived from E. coli bacteria and added it to each of 20 test tubes. This time the “hot” test tube was phenylalanine. The results were spectacular and simple at the same time: after an hour, the control tubes showed a background level of 70 counts, whereas the hot tube showed 38,000 counts per milligram of protein. The experiment showed that a chain of the repeating bases uracil forced a protein chain made of one repeating amino acid, phenylalanine. The code could be broken! UUU=Phenylalaline was a breakthrough experiment result for Nirenberg and Matthaei.

The two kept their breakthrough a secret from the larger scientific community–though many NIH colleagues knew of it –until they could complete further experiments with other strands of synthetic RNA (Poly-A, for example) and prepare papers for publication. They had solved with an experiment what others had been unable to solve with theoretical explanations and mathematical models.

Shortly after discovering the very first codon, Matthaei returned to Germany. Nirenberg assembled a team of scientists to crack the rest of the genetic code by adding various synthetic RNAs to the cell free extract. The first few codons were simple; polyA stimulated incorporation of lysine and polyC stimulated incorporation of proline. (PolyG didn't work.) A random mixture of U and C, poly(U,C), incorporated leucine and serine.

Eventually, with the help of Gobind Korhana, the team was able to synthesize RNAs with defined triplets of nucleotides and the entire genetic code was worked out. Nirenberg, Korhana, and Robert Holley (for determining the structure of tRNA) received the Nobel Prize in 1968.

It's important to note that the cracking of the genetic code for E. coli proved to be universal (almost). All species use the same genetic code. It's also important to note that cracking the genetic code, which was done forty years ago, is not the same as sequencing a genome ["Cracking the genetic code" and "mapping the genome"].

The standard genetic code is shown below. The column on the left represents the first nucleotide in a codon, the row on top (2nd position) represents the middle nucleotide, and the column on the right is the third position. You can see why poly(U,C) encoded serine and leucine because one of the codons for serine is UCU and one of the leucine codons is CUC.

Shhh. Don't tell Larry.

 
The Tim Horton's fans have all migrated to Pharyngula [Shhh. Don't tell Larry]. I'm not sure but I think some of the comments are making fun of Canadians. Get on over there and teach those Yankees about good coffee and a good country.

Besides, PZ could use the traffic. He's down to less than 25,000 per day.

Oh, and don't forget to tell all those pharyngulites about all the other yummy things at Timmy's. Mmmmm ... honey crullers , timbits, chili, turkey bacon club sandwich, cream of broccoli soup.

SCIENCE Questions: How Can a Skin Cell Become a Nerve Cell?

 
"How Can a Skin Cell become a Nerve Cell?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Vogel, Gretchen (2005) How Can a Skin Cell Become a Nerve Cell 309: 85.
[Text] [PDF]

Gretchen Vogel is a contributing correspondent for Science magazine. She is based in Berlin.

This question is really about developmental biology but it's framed as a question about how (animal) oocytes can reprogram somatic cell nuclei.

Scientists have been investigating the reprogramming powers of the oocyte for half a century. In 1957, developmental biologists first discovered that they could insert the nucleus of adult frog cells into frog eggs and create dozens of genetically identical tadpoles. But in 50 years, the oocyte has yet to give up its secrets.

The answers lie deep in cell biology. Somehow, scientists know, the genes that control development--generally turned off in adult cells--get turned back on again by the oocyte, enabling the cell to take on the youthful potential of a newly fertilized egg. Scientists understand relatively little about these on-and-off switches in normal cells, however, let alone the unusual reversal that takes place during nuclear transfer.

Now developmental biologists may disagree, but I think we pretty much know the answer to this question. Oocytes contain the right transcription factors to activate the genes required for early development. Somatic cells don't have these proteins. When you isolate nuclei from somatic cells and put them in an oocyte you dilute out the various transcription factors than maintained control of gene expression in the differentiated cell. This makes the somatic cell chromatin competent for transcription that's under the control of oocyte factors.

I disagree with Gretchen Vogel when she says, "scientists understand relatively little about these on-and-off switches in normal cells." I think we understand a great deal about the regulation of gene expression. I doubt very much whether there are any mysteries than need to be explained.

Scientists are just beginning to understand how cues interact to guide a cell toward its final destiny. Decades of work in developmental biology have provided a start: Biologists have used mutant frogs, flies, mice, chicks, and fish to identify some of the main genes that control a developing cell's decision to become a bone cell or a muscle cell. But observing what goes wrong when a gene is missing is easier than learning to orchestrate differentiation in a culture dish. Understanding how the roughly 25,000 human genes work together to form tissues--and tweaking the right ones to guide an immature cell's development--will keep researchers occupied for decades. If they succeed, however, the result will be worth far more than its weight in gold.

This is just one more example of confusion about the difference between knowledge and technology. Observing what goes wrong when a gene is mutated has led to huge advances in our knowledge of development. It's fair to say that we understand the basic principles. For some of us that's enough to answer the most important question. But for some Science journalists it's only the beginning. They won't be happy until we can use that knowledge to cure human diseases or repair injuries.

If we were to ask a general question like "What Are the Fundamental Concepts in Development and Differentiation?" then I might agree that it ranks in the top 25 science questions. But this particular question, like so many others, is misguided and anthropomorphic. Furthermore, in terms of fundamental principles, it overlaps extensively with several other questions such as "What Controls Organ Regeneration?", "How Does a Single Somatic Cell Become a Whole Plant?", "What Genetic Changes Make Us Uniquely Human?", and "Can We Selectively Shut Off Immune Responses?"

Department of Biochemistry Research Day

 

SCIENCE Questions: What Controls Organ Regeneration?

 
"What Controls Organ Regeneration?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Davenport, R. John (2005) What Controls Organ Regeneration 309: 84.
[Text] [PDF]

John Davenport is Science magazine's editor for the Science of Aging Knowledge Environment (SAGE KE).

He writes,

Unlike automobiles, humans get along pretty well for most of their lives with their original parts. But organs do sometimes fail, and we can't go to the mechanic for an engine rebuild or a new water pump--at least not yet. Medicine has battled back many of the acute threats, such as infection, that curtailed human life in past centuries. Now, chronic illnesses and deteriorating organs pose the biggest drain on human health in industrialized nations, and they will only increase in importance as the population ages. Regenerative medicine--rebuilding organs and tissues--could conceivably be the 21st century equivalent of antibiotics in the 20th. Before that can happen, researchers must understand the signals that control regeneration.

This is another example of a "fundamental" science question that's put in the context of technology development. I find this disappointing. Rather than simply expressing an interest in organ regeneration for the sake of understanding developmental biology, the writer assumes that the question has to be rationalized by making it relevant to medicine.

Animals such as salamanders and planaria regenerate tissues by rekindling genetic mechanisms that guide the patterning of body structures during embryonic development. We employ similar pathways to shape our parts as embryos, but over the course of evolution, humans may have lost the ability to tap into it as adults, perhaps because the cell division required for regeneration elevated the likelihood of cancer. And we may have evolved the capacity to heal wounds rapidly to repel infection, even though speeding the pace means more scarring. Regeneration pros such as salamanders heal wounds methodically and produce pristine tissue. Avoiding fibrotic tissue could mean the difference between regenerating and not: Mouse nerves grow vigorously if experimentally severed in a way that prevents scarring, but if a scar forms, nerves wither.

Unraveling the mysteries of regeneration will depend on understanding what separates our wound-healing process from that of animals that are able to regenerate. The difference might be subtle: Researchers have identified one strain of mice that seals up ear holes in weeks, whereas typical strains never do. A relatively modest number of genetic differences seems to underlie the effect. Perhaps altering a handful of genes would be enough to turn us into superhealers, too. But if scientists succeed in initiating the process in humans, new questions will emerge. What keeps regenerating cells from running amok? And what ensures that regenerated parts are the right size and shape, and in the right place and orientation? If researchers can solve these riddles--and it's a big "if"--people might be able to order up replacement parts for themselves, not just their '67 Mustangs.

These are interesting questions but they're hardly fundamental question on the frontiers of scientific knowledge. The article alludes to the answers—it's a question of regulating gene expression. There are no profound mysteries here. What controls organ regeneration is almost certainly the same thing that controls other aspects of development; namely, signals (such as hormones), and transcription factors.

We may not know the details but it sure looks to me like we already know the principles. Recall that the special issue was introduced by an essay on "In Praise of Hard Questions" [see: SCIENCE Questions: Asking the Right Question]. The type of questions were defined as,

Science's greatest advances occur on the frontiers, at the interface between ignorance and knowledge, where the most profound questions are posed. There's no better way to assess the current condition of science than listing the questions that science cannot answer.

So the question is whether understanding organ regeneration is really on the frontier or whether it's part of a mopping up exercise behind the front lines.

Monday's Molecule #28

 
Today's molecule looks a little complicated but all we need is the trivial name. If you can supply the correct chemical name that would be impressive

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate(s). This one is an indirect connection but it should be obvious to anyone who has studied biochemistry/molecular biology.

The reward (free lunch) goes to the person who correctly identifies both the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There are no ineligible candidates for this Wednesday's reward since recent winners have declined the prize on the grounds that they live in another country and can't make it for lunch on Thursday. (A feeble excuse, in my opinion. )

Comments will be blocked for 24 hours. Comments are now open.

"Cracking the genetic code" and "mapping the genome"

 
Dear scientists and science journalists. Next time a genome sequence is published please do not refer to it as "cracking the genetic code" (that was done back in the early 60's) or "mapping the genome" (it's not the same as sequencing).

For a more complete explanation of why these terms are wrong see Cracking the Code by Ryan Gregory. I agree with his take on science journalism...

I think this is another symptom of too much journalism and not enough science in science journalism. Instead of resorting to the standard catchphrases and clichés, why not introduce your readers to some accurate terms and concepts with which they may not be familiar? You can catch the interest of readers and educate them on the basics rather than appealing to their misconceptions or lack of prior knowledge.

SCIENCE Questions: How Much Can Human Life Be Extended?

 
"How Much Can Human Life Be Extended?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Couzin, Jennifer (2005) How Much Can Human Life Be Extended? Science 309: 83.
[Text] [PDF]

Jennifer Couzin is a San Francisco-based news writer for Science magazine. She also wrote on "To What Extent Are Genetic Variation and Personal health Linked?".

With respect to the sort of fundamental questions that are described in the lead article [SCIENCE Questions: Asking the Right Question], this is a stupid question. It isn't really a science question at all; it's a question about technology, or the application of science. If a leading magazine like Science can't get the difference between technology and fundamental science questions then we're in a lot more trouble than I thought.

Compare this question to one of the valid questions that is asked, "What Is the Universe Made of?" Does anyone really think that a question about how to prolong human lifetimes is in the same category as a question about dark matter?

Not only is this not a "science" question, it's a question that reflects a huge bias in favor of a single species, Homo sapiens. If our goal is to teach science literacy then surely one of the most important ways to advance this goal is to convince people that there's a lot more to science than just it's interface with medicine. As long as the general public continues to treat science as a means to an end then we're never going to convince them that knowledge for its own sake is valuable.

SCIENCE Questions: To What Extend Are Genetic Variation and Personal health Linked?

 
"To What Extend Are Genetic Variation and Personal health Linked?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Couzin, Jennifer (2005) To What Extend Are Genetic Variation and Personal health Linked? Science 309: 81.
[Text] [PDF]

Jennifer Couzin is a San Francisco-based news writer for Science magazine. She writes mostly on health-related issues and received the 2003 Evert Clark/Seth Payne Award for excellent science writing by a young journalist [Science Writers Honor One of Their Own].

The question may seem strange at first but don't be misled. Nobody is questioning whether there's a link between human diseases and genes/alleles. The question is exactly what it seems—how much linkage is there? It's the nature vs nurture question and that's surely an interesting question.

As Couzin writes,

These developments have led to hopes--and some hype--that we are on the verge of an era of personalized medicine, one in which genetic tests will determine disease risks and guide prevention strategies and therapies. But digging up the DNA responsible--if in fact DNA is responsible--and converting that knowledge into gene tests that doctors can use remains a formidable challenge.

Many conditions, including various cancers, heart attacks, lupus, and depression, likely arise when a particular mix of genes collides with something in the environment, such as nicotine or a fatty diet. These multigene interactions are subtler and knottier than the single gene drivers of diseases such as hemophilia and cystic fibrosis; spotting them calls for statistical inspiration and rigorous experiments repeated again and again to guard against introducing unproven gene tests into the clinic. And determining treatment strategies will be no less complex: Last summer, for example, a team of scientists linked 124 different genes to resistance to four leukemia drugs.

But identifying gene networks like these is only the beginning. One of the toughest tasks is replicating these studies--an especially difficult proposition in diseases that are not overwhelmingly heritable, such as asthma, or ones that affect fairly small patient cohorts, such as certain childhood cancers. Many clinical trials do not routinely collect DNA from volunteers, making it sometimes difficult for scientists to correlate disease or drug response with genes. Gene microarrays, which measure expression of dozens of genes at once, can be fickle and supply inconsistent results. Gene studies can also be prohibitively costly.

I like the sound of this. It shows that she's skeptical of the exaggerations in the scientific literature and that's good. It's what a science writer should be doing.

The problem is, this isn't one of the top 25 mysteries in science by any stretch of the imagination. We don't know the answer but that's because we don't yet have enough data. I don't think there's any profound scientific problem here. Some links between genes and disease are very clear [e.g., Glycogen Storage Diseases] and some will be more difficult to work out. Some diseases may not have a genetic component at all.

It's good to be skeptical about the rhetoric that comes out of the medical literature but the top questions in science should not be about medicine of technology and they should not be about things where we're just waiting for more data.

Towel Day

 



Today is Towel Day in honor of Douglas Adams. You're supposed to carry your towel with you all day but I left mine at home because I forgot what day it was. Thanks to my favorite daughter for reminding me, but next year try and remind me the day before.

If you don't know about towels, here's a reminder from the website ...

To quote from The Hitchhiker's Guide to the Galaxy.

A towel, it says, is about the most massively useful thing an interstellar hitch hiker can have. Partly it has great practical value - you can wrap it around you for warmth as you bound across the cold moons of Jaglan Beta; you can lie on it on the brilliant marble-sanded beaches of Santraginus V, inhaling the heady sea vapours; you can sleep under it beneath the stars which shine so redly on the desert world of Kakrafoon; use it to sail a mini raft down the slow heavy river Moth; wet it for use in hand-to-hand-combat; wrap it round your head to ward off noxious fumes or to avoid the gaze of the Ravenous Bugblatter Beast of Traal (a mindboggingly stupid animal, it assumes that if you can't see it, it can't see you - daft as a bush, but very ravenous); you can wave your towel in emergencies as a distress signal, and of course dry yourself off with it if it still seems to be clean enough.

More importantly, a towel has immense psychological value. For some reason, if a strag (strag: non-hitch hiker) discovers that a hitch hiker has his towel with him, he will automatically assume that he is also in possession of a toothbrush, face flannel, soap, tin of biscuits, flask, compass, map, ball of string, gnat spray, wet weather gear, space suit etc., etc. Furthermore, the strag will then happily lend the hitch hiker any of these or a dozen other items that the hitch hiker might accidentally have "lost". What the strag will think is that any man who can hitch the length and breadth of the galaxy, rough it, slum it, struggle against terrible odds, win through, and still knows where his towel is is clearly a man to be reckoned with.

SCIENCE Questions: What Is the Biological Basis of Consciousness?

 
"What Is the Biological Basis of Consciousness?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Miller, Greg (2005) What Is the Biological Basis of Consciousness? Science 309: 79.
[Text] [PDF]

Greg Miller is a news writer for Science. He begins by describing the classic mind/body problem in philosophy. Rene Descartes claimed that mind and body were two separate things.

Recent scientifically oriented accounts of consciousness generally reject Descartes's solution; most prefer to treat body and mind as different aspects of the same thing. In this view, consciousness emerges from the properties and organization of neurons in the brain. But how? And how can scientists, with their devotion to objective observation and measurement, gain access to the inherently private and subjective realm of consciousness?

This is a slippery slope. The real question is "Does Consciousness Exist?" There's no point in asking about the biological basis of something until you establish that the "something" actually exists. As Miller hints in his introduction, consciousness could be just an epiphenomenon—a kind of illusion that's produced when a brain operates.

If that's true then the right question would be something like "How Are Memories Stored and Retrieved?" As it turns out, that is one of the top 25 questions, but it's not this one.

The article ends by pointing to promising lines of research that might arise from asking the "right" question.

Ultimately, scientists would like to understand not just the biological basis of consciousness but also why it exists. What selection pressure led to its development, and how many of our fellow creatures share it? Some researchers suspect that consciousness is not unique to humans, but of course much depends on how the term is defined. Biological markers for consciousness might help settle the matter and shed light on how consciousness develops early in life. Such markers could also inform medical decisions about loved ones who are in an unresponsive state.

This is begging the question (in the old-fashioned sense of the phrase). The question we should be answering is not "why does consciousness exist?" but "does consciousness exist?" I don't think it does exist, so naturally this ranks as a very silly question as far as I'm concerned.

The statement that "some researchers suspect that consciousness is not unique to humans" is very disturbing. It implies that most workers think otherwise, as does Greg Miller. Personally, I'm not aware of any serious research scientist who thinks that "consciousness" (if it exists) is something that only a human possesses and not a chimpanzee or even (gasp!) an octopus. (Readers are invited to post the names of anyone who thinks otherwise.)

And the idea that there might be "biological markers for consciousness" seems to portray sloppy thinking at best and profound misunderstanding at worst.

Questions about how the brain works rank right at the top of my list of important questions. This question is not one of those. It is badly formulated and the explanation in the article makes it even worse.

SCIENCE Questions: Why Do Humans Have So Few Genes?

"Why Do Humans Have So Few Genes?" is one of the top 25 questions from the 125th anniversary issue of Science magazine [Science, July 1, 2005]. The complete reference is ...

Pennisi, Elizabeth (2005) Why Do Humans Have So Few Genes? Science 309: 80. [Text] [PDF]

Elizabeth Pennisi is a news writer for Science magazine. She has been publishing articles there for at least ten years. She had previously written about genes and genomes, including earlier articles about the number of genes in the human genome.

Pennisi begins with the usual mythology about how surprised scientist were to discover that humans had fewer than 30,000 genes [see Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome]. She continues by using most of the standard excuses for the Deflated Ego Problem [The Deflated Ego Problem].

That big surprise reinforced a growing realization among geneticists: Our genomes and those of other mammals are far more flexible and complicated than they once seemed. The old notion of one gene/one protein has gone by the board: It is now clear that many genes can make more than one protein. Regulatory proteins, RNA, noncoding bits of DNA, even chemical and structural alterations of the genome itself control how, where, and when genes are expressed. Figuring out how all these elements work together to choreograph gene expression is one of the central challenges facing biologists. [Numbers 1,2,5,6,7]

It's downhill from then on. Pennisi goes on to briefly describe the leading contenders for solving the imaginary problem. Not once does she mention that these have all been challenged in the scientific literature and not once does she mention that they are not specific to humans even though they must be if they're going to get you out of the pickle.

Is this one of the "right" questions that I talked about earlier? [SCIENCE Questions: Asking the Right Question] Nope. Not even close. In fact, it's a very "wrong" question that reflects an ignorance of the scientific literature and a profound misunderstanding of evolution, developmental biology, and gene expression. Humans have exactly the number of genes that we expect. They don't need to have many more genes than fruit flies or worms because a small number of unique genes are all that's required to make significant differences in development. They don't need to have special complexity mechanisms to "explain" anything because there's nothing that needs explaining. Human genes are fundamantally the same as those in Drosophila melanogaster (fruit fly), Caenorhabditis elegans (nematode worm), and Arabidopsis thaliana (a small flowering plant).

This "top 25 question" illustrates exactly the problem that I alluded to earlier. You don't recognize the important questions in science by polling science writers and editors. The "right" questions are the ones being asked on the frontiers by the creative experts who are thinking outside the box. This is an "inside the box" question and very few of those ever turn out to be important.

The right question would have been "Why Were You Surprised?"

SCIENCE Questions: Asking the Right Question

 
In July 2005 Science magazine published a list of the top questions in science [Science, July 1, 2005]. I was reminded of this list when I attended a meeting last month because the publishers of Science were handing out a special isue devoted to those questions. There are two categories; the top 25 questions, and 100 other questions. (It was the 125th aniversary of the magazine, hence 125 questions.)

I'd like to spend some time discussing those questions because not only are they interesting from a scientific point of view but they also reveal a great deal about science journalism and the public perception of science.

The issue began with an essay titled "In Praise of Hard Questions." The author, science writer Tom Siegfried, notes that hard questions stimulate science. He says,

The pressures of the great, hard questions bend and even break well-established principles, which is what makes science forever self-renewing—and which is what demolishes the nonsensical notion that science's job will ever be done.

Everyone agrees with the sentiment behind this statement. We all know that asking the right questions is the essence of good science. We all know that hard questions challenge prevailing models. On the other hand, we also know that there is such a thing as a stupid question in spite of what your Professors might have told you. Stupid questions can mislead scientists and stiffle creativity.

The opening article quotes David Gross, the 2004 Nobel Laureate in Physics who says,

One of the most creative qualities a research scientist can have is the ability to ask the right questions.

So, what are the "right" questions to ask? In my experience, the "right" questions are not immediately obvious. As stated above, they often challenge the prevailing dogma and this means that in the beginning they are dismissed as silly questions. Over time, the idea that this is a good question becomes more and more acceptable until finally it starts to stimulate active research.

What this means is that at any given point in time the "right" questions are only known to a few scientists on the cutting edge. These are ones who have begun to understand that the old questions aren't working any more. The vast majority of scientists will be sticking with the paradigm that's about to be overthrown. If you were to take a vote they would overwhelmingly dismiss the very questions that need to be asked.

Now, don't get me wrong. This is the way science is supposed to work. We all know that 99.9% of all attacks on orthodoxy deserve to be dismissed. The wonderful thing about science is that the 0.1% of "right" questions will almost certainly bubble to the surface. The real tricky part is picking out that 0.1% in advance.

So, if you were the editors of Science magazine how would you identify the important questions in science without falling into the trap of reinforcing orthodoxy and missing those very questions that a small group of experts are beginning to pay attention to? One way would be to seek out those experts and ask their opinion. This seems to be what is being advocated in the lead article where Tom Siegfried says,

Science's greatest advances occur on the frontiers, at the interface between ignorance and knowledge, where the most profound questions are posed. There's no better way to assess the current condition of science than listing the questions that science cannot answer.

But, Science magazine did not ask the experts at the frontiers. The actual procedure is explained in the editorial accompanying the July 1, 2005 issue. According to editors Donald Kennedy and Colin Norman, here's what they did.

We began by asking Science’s Senior Editorial Board, our Board of Reviewing Editors, and our own editors and writers to suggest questions that point to critical knowledge gaps. The ground rules: Scientists should have a good shot at answering the questions over the next 25 years, or they should at least know how to go about answering them. We intended simply to choose 25 of these suggestions and turn them into a survey of the big questions facing science. But when a group of editors and writers sat down to select those big questions, we quickly realized that 25 simply wouldn’t convey the grand sweep of cutting-edge research that lies behind the responses we received. So we have ended up with 125 questions, a fitting number for Science’s 125th anniversary.

The "right" questions were selected by editors and science journalists. I'm going to examine some of these questions in the next few days, concentrating exclusively on biology questions. Let's see how well they did when asked to identify the top "hard" questions in science.

The Deflated Ego Problem

"How humans get away with having a small genome"

Believe it or not, that's actually the subtitle of a short article in this month's issue of SEED (June, 2007). Who knew that humans have a small genome?

The author, Yohannes Edemariam, is a frequent contributor to SEED. He lives here in Toronto. Edemariam begins with the usual mythology designed to make you think there's a problem with the human genome [see Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome]. This "problem" cries out for an explanation ...

Given our complexity—our capabilities for abstract thought, language, the building of civilizations—biologists were surprised at the relatively small number of genes we possess when they first began studying the human genome. It has since been become clear that our 20,000 to 25,000 genes can be manipulated by processes that statistically enhance the variety of ways in which each gene becomes manifest in our physical makeup.

This is typical of the rhetoric that pervades the popular science literature and, more importantly, the real scientific literature. The scientific evidence shows that our genome has about 25,000 genes and that's not much more than nematode worms or fruit flies. What this tells us is the same message that developmental biologists have been shouting for 35 years—small changes can have big effects. Clearly, some people haven't been listening.

The human chauvinists are disappointed that our genome isn't as complex as our brains and behavior suggest (to them). They expected to see tangible evidence that humans were at the top of the heap. I call this "The Deflated Ego Problem." The question before us is whether this is a real scientific problem or whether it stems from an incorrect understanding of evolution and development.

Having barely survived a major blow to their ego when the human genome turned out to have fewer than 30,000 genes, the deflated ones have fought back with various schemes to explain the "paradox." What they look for is some special mechanism that we humans possess in order to get a bigger bang for our buck. In other words, they're looking for their missing complexity in other places.

Ironically, the chauvinists don't realize that their "problem" can only be solved by discovering hithertofore unknown mechanisms that are confined to humans, or possibly mammals. The reason is obvious. If the mechanism is universal then fruit flies and worms have it as well and we can't use the new-found genome complexity to rationalize why we have so few genes compared to them. After all, the goal here is to explain why we only have a few thousand genes more than those "simple," "primitive," species and the explanation won't work if we all have the same complexity-generating mechanisms. I say "ironically" because many of the special mechanisms being proposed were first discovered in these "primitive" species. Now they're being used to solve the Deflated Ego Problem.

So, what are these magical complexity-generators that "statistically enhance the variety of ways in which each gene becomes manifest ...?" Are they going to solve the Deflated Ego Problem?

I'm not going to tell you which one is being promoted in the SEED article. You'll have to buy the magazine—which I highly recommend in spite of its flaws—to find out the answer. Here's the latest list of the sorts of things that may salvage your ego if it has been deflated.

1. Alternative Splicing: We may not have many more genes than a fruit fly but our genes can be rearranged in many different ways and this accounts for why we are much more complex. We have only 25,000 genes but through the magic of alternative splicing we can make 100,000 different proteins. That makes us almost ten times more complex than a fruit fly. (Assuming they don't do alternative splicing.)

2. Small RNAs: Scientists have miscalculated the number of genes by focusing only on protein encoding genes. Our genome actually contains tens of thousands of genes for small regulatory RNAs. These small RNA molecules combine in very complex ways to control the expression of the more traditional genes. This extra layer of complexity, not found in simple organisms, is what explains the Deflated Ego Problem.

3. Pseudogenes: The human genome contains thousands of apparently inactive genes called pseudogenes. Many of these genes are not extinct genes, as is commonly believed. Instead, they are genes-in-waiting. The complexity of humans is explained by invoking ways of tapping into this reserve to create new genes very quickly.

4. Transposons: The human genome is full of transposons but most scientists ignore them and don't count them in the number of genes. However, transposons are constantly jumping around in the genome and when they land next to a gene they can change it or cause it to be expressed differently. This vast pool of transposons makes our genome much more complicated than that of the simple species. This genome complexity is what's responsible for making humans more complex.

5. Regulatory Sequences: The human genome is huge compared to those of the simple species. All this extra DNA is due to increases in the number of regulatory sequences that control gene expression. We don't have many more protein-encoding regions but we have a much more complex system of regulating the expression of proteins. Thus, the fact that we are more complex than a fruit fly is not due to more genes but to more complex systems of regulation.

6. The Unspecified Anti-Junk Argument: We don't know exactly how to explain the Deflated Ego Problem but it must have something to do with so-called "junk" DNA. There's more and more evidence that junk DNA has a function. It's almost certain that there's something hidden in the extra-genic DNA that will explain our complexity. We'll find it eventually.

7. Post-translational Modification: Proteins can be extensively modified in various ways after they are synthesized. The modifications, such as phosphorylation, glycosylation, editing, etc., give rise to variants with different functions. In this way, the 25,000 primary protein products can actually be modified to make a set of enzymes with several hundred thousand different functions. That explains why we are so much more complicated than worms even though we have similar numbers of genes.

I don't think any of these explanations are valid because I don't think there's a problem that need explaining in the first place. I wish scientists and science writers would stop pretending that the Deflated Ego Problem is a real scientific problem and I wish they'd stop promoting their favorite, logically flawed, arguments to defend it.

Since that ain't going to happen, I'd like to offer a bit of advice designed to spare us from rhetorical overload. Here's a little template that all science writers can use next time they're tempted to write about this "problem."

(I/we/the authors) believe that the Deflated Ego Problem is a real scientific problem. (I/we/the authors) propose that explanation number (1/2/3/4/5/6/7) will account for the fact that we have too few genes.