The Real Genetic Code

 
This is the genetic code. It shows the relationship between a sequence of nucleotides in messenger RNA (mRNA), or DNA, and the amino acids that are inserted into a growing polypeptide chain.

Each codon consists of three nucleotides and you read them from 5ʹ ("five prime") to 3ʹ ("three prime"). The first one is one the left of the box, the second one is at the top, and the third one is along the right-hand edge. The genetic code tells you that codon CUU encodes leucine (Leu), and so do codons CUC, CUA, and CUG. (The Genetic Code is redundant.)

The three STOP codons tell the protein synthesis machine to stop making protein. The methionine (Met) codon (AUG) is usually the start codon that tells the machinery to start making a protein. There are a few unusual variants of the genetic code that aren't shown in the figure.

The Genetic Code was cracked in the early 1960's when the meaning of each codon was worked out. Since then it has become routine to decode any message in the coding regions of DNA and RNA by simply referring to the genetic code shown above. For example, you can decode the following sequence of RNA if you know that it starts on the left at the initiation codon AUG.


This is the same procedure that we use to translate a string of dots and dashes sent over a telegraph line. The string of dots and dashes is the message, the Morse Code is the lookup table that we use to decode the mesage. We do not say that the string of dots and dashes is the Morse Code. We say that it's a message encrypted using the Morse Code. Similarly, we do not say that a string of nucleotides is the genetic code. It's the message that's translated using the Genetic Code.

The Wrong Version of the Genetic Code

 
Hsien Hsien Lei over at Genetics & Health has posted a recommendation for winter reading [Freakenetics: The Freakonomics of Genetics]. She suggests that Survival of the Sickest by Dr. Sharon Maolem and Jonathan Prince might be a good read.

Here's a quotation from the book,

…DNA isn’t destiny–it’s history. Your genetic code doesn’t determine your life. Sure, it shapes it–but exactly how it shapes it will be dramatically different depending on your parents, your environment, and your choices. Your genes are the evolutionary legacy of every organism that came before you, beginning with your parents and winding all the way back to the very beginning. Somewhere in your genetic code is the tale of every plague, every predator, every parasite, and every planetary upheaval your ancestors managed to survive. And every mutation, every change, that helped them better adapt to their circumstances is written there.

Now, this may or may not be a good book but I'd like to use the quotation as a way of introducing one of my pet peeves. In doing so I don't mean to impugn the sense of what's said in the quotation.

The sequence of DNA in your genome is not the "genetic code." The Genetic Code is the lookup table shown in the accompanying posting [The Real Genetic Code]. The sequence of nucleotides in your genome is the message that may be interpreted using the genetic code in the same sense that the message received over a telegraph may be interpreted using the Morse Code.

It's appropriate to say that somewhere in this message is the record of your survival but it's inappropriate to say the genetic code is altered by evolution. (At least in this context.)

I realize that when science writers use the term "genetic code" they are writing for the general public. Those writers may know the difference between the real Genetic Code and what they say in a popular article. They may know the difference, but somehow I doubt it. Most people who know the difference wouldn't make the common mistake of confusing the code with the message.

In any case, the book would be no less accurate if it talked about the message in your genome instead of the genetic code. So why not use the correct term?

Similarly, I'm getting tired of hearing about the latest sequencing project that "cracked" the genetic code. The real Genetic Code was cracked forty years ago in an astounding display of technology that earned the decoders a Nobel Prize. What sequencing projects do is determine the sequence of a genome, not its genetic code. The standard Genetic Code is (almost) universal. All species use the same Genetic Code.

Dilbert Parody

 
This is priceless. I know every one of my blogger friends is going to post this parody of Dilbert by The Bronze Blog but I can't resist. For those of you who haven't been following the saga of Scott Adams and his IDiocy, see "Is Scott Adams an IDiot?."

Click on the cartoon to enlarge.

Nobel Laureates: Arber, Nathans, and Smith

The Nobel Prize in Physiology or Medicine 1978.

"for the discovery of restriction enzymes and their application to problems of molecular genetics"


Werner Arber, Daniel Nathans, and Hamilton O. Smith received the Nobel Prize in 1978 for working out the mechanism of restriction enzymes (see Restriction, Modification, and Epigenetics).

By the time the Nobel Prize was awarded it was quite clear that the discovery of restriction enzymes was transforming biology and the new era of recombinant DNA technology was upon us. Read what this meant for Hamilton Smith below the fold.

The short history of this remarkable transformation was nicely summarized in the presentation speech by Peter Reichard.

Restriction enzymes are the tools which make it possible to open the sealed book. Werner Arber discovered these enzymes in the early 1960s when he analyzed an apparently obscure phenomenon in bacteria, discovered 10 years earlier by Bertani and Weigle, called host-controlled modification. In a series of simple but elegant experiments Arber showed that this phenomenon was caused by a change in DNA and apparently served to protect the host from foreign genes. Foreign DNA is degraded, and Arber postulated that bacteria contain restriction enzymes with the capacity to recognize and bind to recurring structural elements of DNA. At these locations the DNA-helix is severed: the pages of the book are separated.

Hamilton Smith verified Arber's hypothesis. He purified one restriction enzyme and showed that it could cleave foreign DNA. He determined the chemical structure of the regions of DNA which were severed by the enzyme and discovered certain rules which later could be applied to other restriction enzymes. Today maybe 100 such enzymes are known. They all cleave DNA, each at different, defined regions. With their aid, these giant molecules can be dissected into well-defined segments which subsequently can be used for structural investigations or in genetic experiments.

'The last step in this development was taken by Dan Nathans. He pioneered the application of restriction enzymes in genetics and his work has been a source of inspiration for scientists all over the world. He constructed the first genetic map using restriction enzymes by cleaving the DNA from a monkey virus. The methodology devised by him for this purpose was later used by others to construct increasingly more complicated maps. Today we can write the complete chemical formula for the genes of the monkey virus that Nathans started to investigate.

By the early 1990's the revolution had passed Hamilton Smith by. He lost his funding in 1989 and was relegated to sitting on committees and puttering in the lab on small projects. Then he met Craig Venter.

Venter was about to fund TIGR (The Institute for Genome Research) and he needed a man like Hamilton Smith. Now only did Smith have the magic hands of a brilliant bench scientist, he also had a Nobel Prize. It's not clear which of these was more important to Ventor but the result was astounding.

Smith was responsible for making the libraries that allowed genome sequencing. He was very good at it and that's why TIGR turned out the sequence of Haemophilus influenzae in record time. (H. influenzae was the organism that Smith had worked on all his life. Later on Smith built many more bacteria libraries and in 1998 he made the Drosophila melanogaster (fruit fly) library that really put TIGR on the map and led to the creation of Celera.

Craig Venter and Celara could not have entered the race to sequence the human genome without the technical expertise of Nobel Laureate Hamilton Smith. I recommend The Genome War by James Shreeve. It's a wonderful account of Venter, Celera, and the race to sequence the human genome. Here's an excerpt,

On the morning of July 7, 1998, Hamilton Smith drove down from his farm in Howard County and pulled into the TIGR parking lot. His 1987 Mercury Grand Marquis rumbled along the rows of cherry Corollas and silver Civics like an old tug trying to dock in a marina. The car had a long piece of trim missing on the driver's side, exposing a parallel row of rusted holes, as if the car had been strafed long ago. The odometer read 244,000 miles. The radio was playing—the knob had stuck in the "on" position a couple of months before—and a sucking sound was emanating from somewhere deep in the steering column. Smith didn't mind, because he had his hearing aid turned down low. The Mercury was among his most beloved possessions. He was more ambivalent about his Nobel Prize.

Smith maneuvered the car into a spot, gathered up his briefcase, and quietly made his way through TIGR's elegant lobby. He was on his way to pop in on Craig when the receptionist called out to him, "Something came for you FedEx, Dr. Smith," she said.

Canadian Scientists Are Refusing to Sit on Grants Panels

 
The results of the September 2006 CIHR grants competition are now available. The Canadian Institutes of Health Research (CIHR) is the main funding body for biological research in Canada. The funding crisis will have a devastating effect on the careers of many of my colleagues.

A total of 310 grant renewals were submitted and 91 were funded. This represents a renewal rate of 29%. Keep in mind that most of these applications were submitted by well-established scientists with a long history of funding and publications. At this rate of renewal, 71% of functioning labs might have to shut down unless they're successful in the next competition.

When your grant is not renewed, you revert to the "new" category of applications. In the latest competition, 240 "new" applications were funded out of 1707 submissions. This is a 14% success rate. Remember, most of these "new" applications are from scientists who are in the prime of their career but who failed in their renewal last year.

Of those grants that were funded, 26.1% of the funding awarded by the peer review committees was clawed back in order to spread the money a bit further. What this means is that some of the "renewals" were funded at lower levels than the current grants. Post-docs and research assistants will be let go even when a grant is renewed.

The average grant was $109,000 and no equipment was funded. This is not enough money to run an effective biochemistry lab.

Pierre Chartrand is the Vice President, Research Portfolio, at CIHR. He posted a wimpy message on the CIHR website [A Word on the September 2006 Operating Grants Competition]. Here's part of what he had to say.

Competition for available funding has grown increasingly intense. This trend is unlikely to change as Canada continues to expand its infrastructure for health research. For this reason, within the Research Portfolio of CIHR, we cannot afford to be consumed by disappointment. Canada owes its reputation for research excellence to an open, accountable and very rigorous peer review system for funding applications. We must re-double our efforts to ensure that the peer review processes used to guide CIHR's funding decisions are the very best that they can be. In light of the recent competition results, we have heard from a small number of active peer reviewers and others who are frustrated to the point of no longer wishing to participate in the peer review process. Such frustration, no matter how limited, leaves me gravely concerned because CIHR is at a point in time where the participation of the absolute best in its peer review processes is critical.

Let me tell you, Pierre, you damn well better be "gravely concerned." Some of my friends are sick and tired of sitting on committees where they have to reject excellent grants from their colleagues knowing that this will be a knockout blow to their future careers as scientists. Is it any wonder that they don't want to act as executioners?

Now you tell us that things aren't likely to change but you still expect Canadian scientists to volunteer to do the dirty work. Not gonna happen. About 70% of those volunteers whose grants were up for renewal have just stopped being "peers." Don't expect them to be happy. As for the rest, I urge them to boycott the process until there's a change in the CIHR leadership that got us into this mess.

God Doesn't Like Chicago

 

Here's a picture of the winning football team praying together after the big game on Sunday [New York Times]. I assume they're thanking God for the victory. I wonder what was going on in the other dressing room? Do you suppose there was a mass conversion to atheism?

Restriction, Modification, and Epigenetics

Bacteria have the ability to restrict bacteriophage (virus) infection by cutting up the 'phage DNA once it's injected into the cell. The enzyme that cuts DNA is called a restriction enzyme, or more properly, a restriction endonuclease.

Endonucleases are enzymes that cleave DNA internally by binding to the middle of a DNA strand and breaking one of the linkages that join the nucleotides. In the case of restriction endonucleases, both strands of the double helix are cut thus breaking apart the 'phage DNA before it can make new proteins and new virus particles.

The enzymes don't cut randomly. They bind to specific sequences and only cut at those sites. An example is one of the restriction endonucleases from Escherichia coli called EcoR1. It binds to the sequence GAATTC.

The top figure shows EcoR1 bound to DNA. Notice that the restriction site is palindromic—it reads the same way in opposite directions on opposite strands (see below). In order to appreciate this you need to understand that the two strands of DNA run in opposite directions and the direction of reading is important. We always read a DNA strand in the 5ʹ to 3ʹ direction. Thus, on the top strand the sequence is GAATTC while on the bottom strand the sequence is also GAATTC but read in the opposite direction.

The two identical subunits of EcoR1 (blue and purple) bind to opposite strands of the double helix and cut at exactly the same spot; in this case between the G and the A. The DNA is chopped in two.

The sequence GAATTC will occur, on average, once every 4096 base pairs (4⁶). This means there's a good chance of cutting any bacteriophage DNA that enters the cell since most bacteriophage genomes are much larger than 4096 base pairs.

This is an effective way of restricting bacteriophage infection except for one minor problem. How does the bacterium prevent it's own DNA from being cut by the restriction endonucleases?

The secret lies in blocking the restriction site in host DNA so that the restriction enzyme doesn't recognize it. One of the nucleotides is modified by an methylase enzyme (modification enzyme) that attaches a methyl group to one of the bases. The restriction enzyme doesn't bind to sites where one of the bases is modified by methylation; so all you have to do is make a methylase enzyme that recognizes the same site as the restriction enzyme.

EcorR1 methylase binds to the sequence GAATTC and methylates the first A to form N⁶-methyladenine (see Monday's Molecule #12). Like the endonuclease, the methylase has two subunits that bind symmetrically to double-stranded DNA. Both of the A's on opposite strands are methylated so neither strand can be recognized by EcoR1 and neither strand will be cut.

So far, so good, but we still have a problem. Why isn't the 'phage DNA methylated as well?

This is the cool part. Look at the figure on the left. Imagine that both strands are methylated. Following DNA replication, the sequence GAATTC will be copied but the newly synthesized strand isn't methylated. The hemimethylated DNA won't be recognized by the restriction enzyme so it's in no danger of being cut. In a very short time the methylase will bind and methylate the new strand of DNA.

The methylase binds specifically to hemimethylated DNA and not to unmethylated DNA. Thus, it will keep the host DNA fully methylated but it won't methylate the incoming 'phage DNA since the 'phage DNA is completely unmethylated.

As bacteria grow and divide they continue to inherit DNA that's methylated at the restriction site even though this inheritance isn't your typical genetic inheritance. It's called epigenetic inheritance. If something happens to the methylase, the cell will commit suicide by chopping up its own DNA. If both the methylase and restriction enzyme genes are mutated the cell survives quite nicely except that it's more susceptible to bacteriophage infection.

Epigenetic inheritance is common in mammals, including us. In this case it's not related to restriction/modification. It's a separate phenomenon where gene expression is controlled by the presence or absence of 5-methyl cytosine. The cytosine methylase works just like the modification enzymes—it binds preferentially to hemimethylated DNA. In this way, methylated regions of DNA are inherited from one generation to another.

Paula Zahn Should be Fired from CNN

 
I've just about had it with Paula Zahn. She's almost the most stupid "journalist" on TV, a fact she demonstrated in her January 31st report on atheism in America. [TRANSCRIPT]

Several bloggers have been all over this. The disgusting part is the so-called "discussion" that follows the airing of a short segment on discrimination against atheists. Paula let her invited guests get away with the most stupid and outrageous statements. She should apologize on air for inviting them on the show.

Did it never occur to CNN that having an atheist-hating Jew and two evangelical Christians discuss atheism was a bad idea? Where were the atheists on a show about atheism?

(UPDATE: Read the discussion at RichardDawkins.net.)

Here are two quotations from the ignorant atheist-hater named Debbie Schlussel. The first was in response to a question from Paula Zahn. Following a rant by the evangelical Christian Karen Hunter, Paula asked whether anyone was going to defend atheists .

No, I agree with her 100 percent. I think that the real discrimination is atheists against Americans who are religious. Listen, we are a Christian nation. I'm not a Christian. I'm Jewish, but I recognize we're a Christian country and freedom of religion doesn't mean freedom from religion. And the problem is that, you have these atheists selectively I believe attacking Christianity. You had a case in California where school children were forced to dress as Muslims and learn from the Koran. In Michigan they're saying high school (INAUDIBLE) in high school where they say Muslim prayers at the football games, public high school, (INAUDIBLE) in high school. You don't see atheists complaining about that. I really believe that they are the ones who are the intolerant ones against Christians.

Did you get that? America is a Christian country and freedom of religion doesn't mean freedom from religion! What cave did they find her in? Do you think that Debbie Schlussel might have a slight problem with Muslims as well as atheists?

Look where there are more atheists and where they've lost God, where the church is not that strong. Europe is becoming Islamist. It's fast falling and intolerance is increasing. That's the one reason our country has not become like Europe because we have strong Christians and because atheists are not strong. And I think that's a good thing.

See the complete show here.

Prince at the Superbowl

 
Apparently there was a big game last Sunday. I heard the Prince was there so I looked him up on the Uncyclopedia [Prince].

Prince Charles is one of the most widely respected individuals alive today. He is renowned for his intelligence, bravery and hard-working nature. The Prince is considered to be an expert in the fields of nuclear astro-physics, ancient Egypt, paper cutting and contemporary literature.

His recent marriage to Wallis Simpson was one of the most glamorous weddings of modern times only marred slightly by the disappointment felt among many of his female subjects.

There is not a hint of genetic inbreeding in his appearance or his demeanor. He is furthermore regarded as one of the most intelligent species of moss known by current scientists.

How to Talk to a Scientist if You're an IDiot

 
Greg Laden reminds us that Wikepedia is not the only online encyclopedia. We mustn't forget the Uncyclopedia [And when Wikipedia is just not enough…].

Good advice Greg. I checkout the entry for Intelligent Design and found an excellent article that I highly recommend to everyone who doesn't suffer from ironic deficiency [Intelligent Design]. The site is approved by the Kansas State Board of Education.

I especially liked the suggestions on how to talk to a scientist. Here are some of my favorites.

• Say things like "Well if you remember chemistry, that just disproves evolution."
• Tell them the Second Law of Thermodynamics makes evolution impossible and try to sound really serious when you say it and then point out that all scientists say this all the time and it's an indisputed fact. [6] If they show any sign of understanding the Second Law of Thermodynamics, walk away really quickly!
• Show them movies of apes doing gross, disgusting things, like the YouTube movie of a Gorilla licking his [bleep] in the zoo. Nobody wants to be related to filthy embarassing animals (even if drunk human rock-stars or intern-hungry televanglists do the same things as the apes).
• Show them studies proving that believing in evolution makes you a hippie commie liberal. If that fails, accuse them of atheism. (This isn’t so effective outside the US, because atheists don’t face resentment and persecution in other places in the civilized world. Tell them they are French instead, they’re hated the world over. If it’s a French person you’re speaking to, tell them they’re English.)

Is Scott Adams an IDiot?

 
I few days ago I asked Is Scott Adams an IDiot or does he just play one on TV?. Bill Dembski has now posted a link to Scott Adam's pathetic attempt to explain himself [Dilbert vs. P. Z. Myers.]

I guess that answers the question. Scott Adams is an IDiot.

Science Bloggers' Vow of Chastity

 
Some 60 bloggers have vowed to write only about science for an entire week. You can see how they're doing by checking out Just Science.

The rules for The Week of Science Challenge are fairly complicated but here's the bottom line.

It boils down to this:
- One week of science blogging and only science blogging.
- At least one post a day of pure science content.
- No blogging about anti-science -- no creationism, no anti-vaccination, no global warming denialists.

Just Science from February 5 through February 11.

Those are too much for me so I'm not rising to the challenge. I'm too old for abstinence but I'm happy to see how chaste everyone else is for this week. Good luck!

Basic Concepts and the Seed Consortium

 
John Wilkins has been keeping a list of Basic Science concepts [here]. I'm on that list and so are 20 other bloggers at last count.

What disturbs me is a comment from Bora Zivkovic at Basic Terms and Concepts in Math and Science. He says,

I don't know how many of you check out the constantly growing list of links to posts that cover Basic Terms And Concepts in Science, but you should. Our Seed Overlords are cooperating and will soon set up a place where all those posts will be re-posted, commented upon, edited, etc. - a one-stop shopping for all basic stuff useful, for instance, in teaching at all levels from Kindergarden to Postdoc!

Bora, Seed is not my overlord. I don't think a private for-profit company has the right to re-post my articles and invite comment on their site. Please tell me this isn't what you meant.

Monday's Molecule #12

 
Name this molecule. You must be specific. We need the correct scientific name.

This is another easy one for everyone who has ever taken biochemistry. This compound is important for understanding the real science behind epigenetics, one of the latest fads in development. As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureates. Bonus points for finding the connection. (Extra bonus points for recognizing the indirect connection to Celera and the race to sequence the human genome.)

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

A Code of Ethics for Scientists

There's an article on today's ScienceDaily website about a code of ethics for scientists [Scientists Should Adopt Codes Of Ethics, Scientist-bioethicist Says]. The ScienceDaily article is based on a press release from Wake Forest University Baptist Medical Center. The press release highlights a paper by Nancy L. Jones. Jones has some experience in "ethics" according to the press release.

Jones, an adjunct associate professor at Wake Forest University School of Medicine, is an American Association for the Advancement of Science (AAAS) science and technology policy fellow at the National Institutes of Health. She is a fellow at the Center for Bioethics and Human Dignity and is a recent member of the Secretary’s Advisory Committee on Human Research Protection of the U.S. Department of Health and Human Services.

With credentials like that, you'd think she would know something about science and ethics.

Jones appears to be concerned about issues such as cloning, stem cells, and gene transfer. It's not clear to me that there are real ethical issues associated with those topics but one thing is very clear—she's focusing on the uses of science (technology) and not on pure science.

Jones wants all scientists to sign a code of ethics to regulate and control their behavior. What kind of a code is she talking about? The only example in the press release is,

“A code of ethics should provide guidance for which knowledge should be sought, define the ethical means of acquiring knowledge, emphasize thoughtful examination of potential consequences, both good and bad, and help society prescribe responsible use of the knowledge,” writes Jones.

Her prototype code compares the norms of life sciences to the Hippocratic tradition. In part, it reads, “In granting the privilege of freedom of inquiry, society implicitly assumes that scientists act with integrity on behalf of the interests of all people. Scientists and the scientific community should accept the responsibility for the consequences of their work by guiding society in the developing of safeguards necessary to judiciously anticipate and minimize harm.”

I have a problem with this. Let's unpack the mix and address each of the four parts separately.

1. Provide guidance for which knowledge should be sought.

What does this mean? What kind of "guidance" would be part of a universal code of scientific ethics? Would I have to limit my search for knowledge to that which is acceptable to a researcher at a Baptist Medical School? I'm never going to sign a "code of ethics" that restricts my ability to pursue knowledge.

2. Define the ethical means of acquiring knowledge.

This sounds okay, although I wonder how it's going to work in practice. I doubt that anyone has a scientific ethical problem with most of the work done by astronomers, physicists, geologists, chemists, and botanists. Am I correct in assuming that Jones is worried about medical researchers and is transferring her specific concerns to all scientists? Is she talking about animal research or clinical trials? Would those be the only things that require defining or is there an ethical way of using a telescope?

3. Emphasize thoughtful examination of potential consequences, both good and bad.

This is the tough one. I know it seems reasonable for scientists to consider the consequences of their quest for knowledge but, in practice, it's not that easy. In my most pessimistic moods I can imagine all kinds of evil things that might be done with the knowledge that biochemists have gained over the past few decades. What should I do about that? Should we force our colleagues to stop doing research whenever we can imagine a dire consequence? Of course not.

Does that mean we should never consider the consequences; no, it doesn't. But keep in mind that scientists have been badly burned whenever they have publicly stepped into this morass. It was scientists who raised the issue of possible consequences of genetic engineering. Even though the scientists decided that the possible risks were minimal, the lawyers soon took over and we were stuck with silly laws that impeded research for a decade. Many of us remember that fiasco.

The responsibility for the misuse of scientific knowledge lies with those who misuse it and not with those who discovered the knowledge in the first place. You can't inhibit the search for knowledge on the grounds that it might be abused by someone in the future. That's why this part of the code of ethics is naive, irresponsible, and ultimately counter-productive. It attempts to put the blame on science when it's technology that's at fault.

4. Help society prescribe responsible use of the knowledge.

This is a legitimate role for scientists as long as they are explaining science. I don't have a problem with scientists describing stem cell research, for example. They can explain how it's done and explain the probabilities of success and the consequences of failure. They can describe how the new-found knowledge might help patients with various diseases and injuries. In other words, scientists can be a valuable source of knowledge.

But are scientists any better than the average citizen at "prescribing responsible use of knowledge" in the sense that Jones implies? I don't think so. Almost all American scientists would advocate funding stem cell research. Are they being ethical? What about those religious scientists who say that stem cell research is unethical? If both types of scientist signed the same code of ethics then what does it mean to say that scientists should "help society prescribe responsible use of knowledge"? What about those stem cell researchers who choose to stay out of the public limelight and get on with curing Alzheimer's? Are they unethical because they remain silent?

As you can see, science ethics is a complicated problem. Any attempt to regulate scientists based on some individual's definition of ethics is doomed to failure. I can't wait to see what Janet Stemwedel has to say about this.