Nobel Laureates: Christiane Nüsslein-Volhard and Eric Wieschaus

 

The Nobel Prize in Physiology or Medicine 1995.

"for their discoveries concerning the genetic control of early embryonic development"

Christiane Nüsslein-Volhard (1942 - ) and Eric F. Wieschaus (1947 - ) received the Nobel Prize in Physiology or Medicine for their contribution to understanding the genetics of development in the fruit fly, Drosophila melanogaster.

Their main contribution was to identify a number of genes that controlled the development of the embryo. The approach was to create mutations at random then screen large numbers of flies for recessive lethals affecting various stages of early embryogenesis. The initial large scale experiment was carried out at the EMBL Labs in Heidleberg, Germany. They established 27,000 lines containing mutated chromosomes and characterized 139 mutations affecting embryogenesis. Of these, 15 were described in the classic 1980 Nature paper. (See Silver Screen, a tribute to the paper on it's 25th anniversary.)

The original 15 genes were: cubitus interruptus, wingless, gooseberry, hedgehog, fused, patch, paired, even-skipped, odd-skipped, barrel, runt, engrailed, Kruppel, knirps, and hunchback. To anyone familiar with the field this reads like a who's who of Drosophila development. Dozens (hundreds?) of papers have been published on each of these genes.

The experimental approach is described in the Press Release below. I am only including the part that refers to Nüsslein-Volhard and Wieschaus. They shared the prize with Edward Lewis.

THEME:
Nobel Laureates

Brave decision by two young scientists

Christiane Nüsslein-Volhard and Eric Wieschaus both finished their basic scientific training at the end of the seventies. They were offered their first independent research positions at the European Molecular Biology Laboratory (EMBL) in Heidelberg. They knew each other before they arrived in Heidelberg because of their common interest: they both wanted to find out how the newly fertilized Drosophila egg developed into a segmented embryo. The reason they chose the fruit fly is that embryonic development is very fast. Within 9 days from fertilization the egg develops into an embryo, then a larvae and then into a complete fly.

Fig. 1 Regions of activity in the embryo for the genes belonging to the gap, pair-rule, and segment-polarity groups. The gap genes start to act in the very early embryo (A) to specify an initial segmentation (B). The pair-rule genes specify the 14 final segments (C) of the embryo under the influence of the gap genes. These segments later acquire a head-to-tail polarity due to the segment polarity genes.

They decided to join forces to identify the genes which control the early phase of this process. It was a brave decision by two young scientists at the beginning of their scientific careers. Nobody before had done anything similar and the chances of success were very uncertain. For one, the number of genes involved might be very great. But they got started. Their experimental strategy was unique and well planned. They treated flies with mutagenic substances so as to damage (mutate) approximately half of the Drosophila genes at random (saturation mutagenesis). They then studied genes which, if mutated would cause disturbances in the formation of a body axis or in the segmentation pattern. Using a microscope where two persons could simultaneously examine the same embryo they analyzed and classified a large number of malformations caused by mutations in genes controlling early embryonic development. For more than a year the two scientists sat opposite each other examining Drosophila embryos resulting from genetic crosses of mutant Drosophila strains. They were able to identify 15 different genes which, if mutated, would cause defects in segmentation. The genes could be classified with respect to the order in which they were important during development and how mutations affected segmentation. Gap genes (Fig 1) control the body plan along the head-tail axis. Loss of gap gene function results in a reduced number of body segments. Pair rule genes affect every second body segment: loss of a gene known as "even-skipped" results in an embryo consisting only of odd numbered segments. A third class of genes called segment polarity genes affect the head-to-tail polarity of individual segments.

The results of Nüsslein-Volhard and Wieschaus were first published in the English scientific journal Nature during the fall of 1980. They received a lot of attention among developmental biologists and for several reasons. The strategy used by the two young scientists was novel. It established that genes controlling development could be systematically identified. The number of genes involved was limited and they could be classified into specific functional groups. This encouraged a number of other scientists to look for developmental genes in other species. In a fairly short time it was possible to show that similar or identical genes existed also in higher organisms and in man. It has also been demonstrated that they perform similar functions during development.

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[Photo Credits: Nüsslein-Volhard - Encylopaedia Britanica, © Patrick Piel/Gamma Liaison, Wieschaus -News at Princeton]

Nobel Laureate: Sidney Altman

 

The Nobel Prize in Chemistry 1989.

"for their discovery of catalytic properties of RNA"



In 1989, Sidney Altman (1939 - ) was awarded the Nobel Prize in Chemistry for discovering that the RNA component of RNase P was the catalytic component of the enzyme [Transfer RNA Processing: RNase P]. He shared the prize with Thomas Cech who worked on self-splicing ribosomal RNA precursors.

The presentation speech was delivered by Professor Bertil Andersson of the Royal Swedish Academy of Sciences.
THEME:

Nobel Laureates

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

The cells making up such living organisms as bacteria, plants, animals and human beings can be looked upon as chemical miracles. Simultaneously occurring in each and every one of these units of life, invisible to the naked eye, are thousands of different chemical reactions, necessary to the maintenance of biological processes. Among the large number of components responsible for cell functions, two groups of molecules are outstandingly important. They are the nucleic acids - carriers of genetic information - and the proteins, which catalyze the metabolism of cells through their ability to act as enzymes.

Genetic information is programmed like a chemical code in deoxyribonucleic acid, better known by its abbreviated name of DNA. The cell, however, cannot decipher the genetic code of the DNA molecule directly. Only when the code has been transferred, with the aid of enzymes, to another type of nucleic acid, ribonucleic acid or RNA, can it be interpreted by the cell and used as a template for producing protein. Genetic information, in other words, flows from the genetic code of DNA to RNA and finally to the proteins, which in turn build up cells and organisms having various functions. This is the molecular reason for a frog looking different from a chaffinch and a hare being able to run faster than a hedgehog.

Life would be impossible without enzymes, the task of which is to catalyze the diversity of chemical reactions which take place in biological cells. What is a catalyst and what makes catalysis such a pivotal concept in chemistry? The actual concept is not new. It was minted as early as 1835 by the famous Swedish scientist Jöns Jacob Berzelius, who described a catalyst as a molecule capable of putting life into dormant chemical reactions. Berzelius had observed that chemical processes, in addition to the reagents, often needed an auxiliary substance - a catalyst - to occur. Let us consider ordinary water, which consists of oxygen and hydrogen. These two substances do not react very easily with one another. Instead, small quantities of the metal platinum are needed to accelerate or catalyze the formation of water. Today, perhaps, the term catalyst is most often heard in connection with purification of vehicle exhausts, a process in which the metals platinum and rhodium catalyze the degradation of the contaminant nitrous oxides.

As I said earlier, living cells also require catalysis. A certain enzyme, for example, is needed to catalyze the breakdown of starch into glucose and then other enzymes are needed to burn the glucose and supply the cell with necessary energy. In green plants, enzymes are needed which can convert atmospheric carbon dioxide into complicated carbon compounds such as starch and cellulose.

As recently as the early 1980s, the generally accepted view among scientists was that enzymes were proteins. The idea of proteins having a monopole of biocatalytic capacity has been deeply rooted, and created a fundamental dogma of biochemistry. This is the very basic perspective in which we have to regard the discovery today being rewarded with the Nobel Prize for Chemistry. When Sidney Altman showed that the enzyme denoted RNaseP only needed RNA in order to function, and when Thomas Cech discovered self-catalytic splicing of a nucleic acid fragment from an immature RNA molecule, this dogma was well and truly holed below the waterline. They had shown that RNA can have catalytic capacity and can function as an enzyme. The discovery of catalytic RNA came as a great surprise and was indeed met with a certain amount of scepticism. Who could ever have suspected that scientists, as recently as in our own decade, were missing such a fundamental component in their understanding of the molecular prerequisites of life? Altman's and Cech's discoveries not only mean that the introductory chapters of our chemistry and biology textbooks will have to be rewritten, they also herald a new way of thinking and are a call to new biochemical research.

The discovery of catalytic properties in RNA also gives us a new insight into the way in which biological processes once began on this earth, billions of years ago. Researchers have wondered which were the first biological molecules. How could life begin if the DNA molecules of the genetic code can only be reproduced and deciphered with the aid of protein enzymes, and proteins can only be produced by means of genetic information from DNA? Which came first, the chicken or the egg? Altman and Cech have now found the missing link. Probably it was the RNA molecule that came first. This molecule has the properties needed by an original biomolecule, because it is capable of being both genetic code and enzyme at one and the same time.

Professor Altman, Professor Cech, you have made the unexpected discovery that RNA is not only a molecule of heredity in living cells, but also can serve as a biocatalyst. This finding, which went against the most basic dogma in biochemistry, was initially met with scepticism by the scientific community. However, your personal determination and experimental skills have overcome all resistance, and today your discovery of catalytic RNA opens up new and exciting possibilities for future basic and applied chemical research.

In recognition of your important contributions to chemistry, the Royal Swedish Academy of Sciences has decided to confer upon you this year's Nobel Prize for Chemistry. It is a privilege and pleasure for me to convey to you the warmest congratulations of the Academy and to ask you to receive your prizes from the hands of His Majesty the King.

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Cocktail Parties and the Two Cultures

I can't tell you how many times I've been in the company of "intellectuals" who can discuss at great length their operatic preferences or how many novels by Gabriel García Márquez they've read, but who don't know what DNA is or which planet is closest to Earth. In many cases these "intellectuals" seem to be downright proud of the fact that they "can't do math." Scientific ignorance is not a only acceptable among this group but seems to be almost a badge of honor.

Imagine the response if one were at a cocktail party and admitted that you didn't know who Gabriel García Márquez was, and what's more, you don't care.¹ The concept of two cultures, science and humanities, isn't new—it dates from the time of the scientific revolution almost 500 years ago. The conflict is almost always characterized as the lack of respect shown by humanities toward science. Here's how C.P. Snow put it in his writings on The Two Cultures.

A good many times I have been present at gatherings of people who, by the standards of the traditional culture, are thought highly educated and who have with considerable gusto been expressing their incredulity at the illiteracy of scientists. Once or twice I have been provoked and have asked the company how many of them could describe the Second Law of Thermodynamics. The response was cold: it was also negative. Yet I was asking something which is the scientific equivalent of: Have you read a work of Shakespeare's?

I now believe that if I had asked an even simpler question -- such as, What do you mean by mass, or acceleration, which is the scientific equivalent of saying, Can you read? -- not more than one in ten of the highly educated would have felt that I was speaking the same language. So the great edifice of modern physics goes up, and the majority of the cleverest people in the western world have about as much insight into it as their neolithic ancestors would have had.

Much has been written on this topic including a book by Stephen Jay Gould (The Hedgehog, the Fox, and the Magister's Pox) that has to be the most useless contribution to the debate that has ever been published. (I say this as an unabashed fan of Gould.)

Two bloggers have recently re-opened the debate. Chad Orzel at Uncertain Principles got the ball rolling with The Innumeracy of Intellectuals and Janet Stemwedel (Adventures in Ethics) picked up on the discussion with Fear and loathing in the academy. The latest contribution from Janet is Assorted hypotheses on the science-humanities divide, in which she offers several hypotheses to explain the two cultures problem.²³

The comments on both sites are interesting. They bring up related issues such as why do we have courses like "Astronomy for Dummies" and "Science for Poets" while all science majors take pretty much the same courses as the humanities students. You don't usually find examples of dumbed down philosophy courses for biologists.

What's so amazing is that Janet even has one commenter (Shawn) who's willing to defend the superiority of the humanities over the sciences. Here's part of his comment ...

As for the topic generally: it really speaks to the elitism in the hard sciences that everyone from the "science side" is more than happy (either implicitly or explicitly) to lump the soft sciences in with fine arts and literature without batting an eye. It's also rather ironic that many people on the "science side" of this debate seem to have no problem with trotting out tired cliches, culture war bugaboos, and fourth hand anecdotes to shore up their, frankly childish, arguments regarding the irrelevancy of the humanities.

Everything from ascot-ed and monocled patricians, to post-modern mandarins, to smug artsy conformists, a rouges gallery of stereotypes and cartoons presented as if it were actual evidence. But I guess what do you expect from a bunch of nerds who have no knowledge of real life. (See? It's such an easy game to play.)

Yes, of course science saves lives and makes life better, but the actual business of living, 90% of the lifespan of the overwhelming majority of humans is dominated by subjects connected to the realm of humanities. The internet is the product of science and engineering (and massive government/tax-payer funded research), but in the end it's merely a vehicle for people to conduct their lives and maybe (or maybe not) enrich their lives. Science certainly can save your life, but the humanities make it worth living.

The humanities IS civilization and civilization is the sciences' natural habitat. Science is in fact inconceivable without the humanities.

This could be fun.

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1. That doesn't apply to me. I know who he is, and I just don't care. His main claim to fame is that he got his Nobel Prize the same year as Bergström, Samuelsson, and Vane and Aaron Klug.

2. As you might have guessed, this debate was way too tempting for John Wilkins. He has weighed in with philosopher's take on the subject: What philosophy of science and "postmodernism" have in common. John has some interesting things to say but I'll deal with them in a separate posting.

3. Razib at Gene Expression contributes: Humanities "vs." science.

[Image Credit: The cartoon is by Serge Bloch from The New York Times via Can the “Two Cultures” Become One Again?]

Testing the Macaque Genome

 
We've already been looking at the macaque genome for several months but now that the genome paper is being published I thought some of you might be interested in how the preliminary data stacks up to what we expect.

I'm interested in a family of gene known as the HSP70 gene family. The genes encode the major cellular chaperone that's responsible for correct protein folding. HSP70 is the most highly conserved gene known [Evolution of the HSP70 Gene Family].

We know how many genes there are in mammalian genomes so we can search the macaque genome at Rhesus Macaque Genome Resources to see if the expected genes are present. Here's the result.

HSPA1A: not present, probably due to incomplete sequence or annotation

HSPA1B: correct gene/protein

HSPA1L: correct gene/protein + one incorrect isoform that's really a splicing artifact

HSPA2: not present, probably due to incomplete genome or annotation

HSPA5/BiP: correct gene/protein + one incorrect alternatively spliced isoform that's really an artifact

HSPA8: one single correct gene/protein

HSP9B/mtHSP70: correct gene/protein + three incorrect isoforms generated by EST artifacts

That's not too bad for an initial draft sequence. Two genes are missing and so are several pseudogenes. I assume they'll turn up later when the genome sequence is being finished. Most of the splicing artifacts have been ignored by the annotators but a few have slipped through. They'll be deleted later on when the annotators are informed that the isoforms don't exist.

All in all, this is much better than most genome sequences at this stage. It's a bit better than the chimp genome but still a long way from the quality of the human genome. The mouse genome is almost as good as the human genome. Keep in mind that dozens of labs have been working on the human genome annotation for over six years since the sequence was first published. The cow, dog, frog and several fish genomes are in much worse shape and the chicken and sea urchin genomes are practically useless.

Horse, opossum, rat, pig, rabbit, cat, sheep, tree shrew, guinea pig, hedgehog, elephant, and platypus genomes are still at the assembly stage [Ensemble Genome Browser].

Gene Genie: The First Issue

 
Gene Genie is a blog carnival that discuses human genes.The first installment of Gene Genie has been posted on ScienceRoll.

Gene Genie is a new carnival and judging by the first issue it's going to be a great one. You can learn about all kinds of things. Check it out.

Here are the human genes covered today: GDF5, DARPP-32, HSPA5, GAA (acid α-1,4-glucosidase, SHH (sonic hedgehog). Only 23,995 to go!

The coffee plant genes, SUS1 and SUS2. are also described.

Nobel Laureate: Tom Cech

 

The Nobel Prize in Chemistry 1989.

"for their discovery of catalytic properties of RNA"



In 1989, Thomas R. Cech (1947 - ) was awarded the Nobel Prize in Chemistry for discovering that the ribosomal RNA precursor from Tetrahymena catalyzed its own self-splicing reaction. [Ribosomal RNA Genes in Eukaryotes]. He shared the prize with Sydney Altman who worked RNase P.

The presentation speech was delivered by Professor Bertil Andersson of the Royal Swedish Academy of Sciences.
THEME:

Nobel Laureates

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

The cells making up such living organisms as bacteria, plants, animals and human beings can be looked upon as chemical miracles. Simultaneously occurring in each and every one of these units of life, invisible to the naked eye, are thousands of different chemical reactions, necessary to the maintenance of biological processes. Among the large number of components responsible for cell functions, two groups of molecules are outstandingly important. They are the nucleic acids - carriers of genetic information - and the proteins, which catalyze the metabolism of cells through their ability to act as enzymes.

Genetic information is programmed like a chemical code in deoxyribonucleic acid, better known by its abbreviated name of DNA. The cell, however, cannot decipher the genetic code of the DNA molecule directly. Only when the code has been transferred, with the aid of enzymes, to another type of nucleic acid, ribonucleic acid or RNA, can it be interpreted by the cell and used as a template for producing protein. Genetic information, in other words, flows from the genetic code of DNA to RNA and finally to the proteins, which in turn build up cells and organisms having various functions. This is the molecular reason for a frog looking different from a chaffinch and a hare being able to run faster than a hedgehog.


Life would be impossible without enzymes, the task of which is to catalyze the diversity of chemical reactions which take place in biological cells. What is a catalyst and what makes catalysis such a pivotal concept in chemistry? The actual concept is not new. It was minted as early as 1835 by the famous Swedish scientist Jöns Jacob Berzelius, who described a catalyst as a molecule capable of putting life into dormant chemical reactions. Berzelius had observed that chemical processes, in addition to the reagents, often needed an auxiliary substance - a catalyst - to occur. Let us consider ordinary water, which consists of oxygen and hydrogen. These two substances do not react very easily with one another. Instead, small quantities of the metal platinum are needed to accelerate or catalyze the formation of water. Today, perhaps, the term catalyst is most often heard in connection with purification of vehicle exhausts, a process in which the metals platinum and rhodium catalyze the degradation of the contaminant nitrous oxides.

As I said earlier, living cells also require catalysis. A certain enzyme, for example, is needed to catalyze the breakdown of starch into glucose and then other enzymes are needed to burn the glucose and supply the cell with necessary energy. In green plants, enzymes are needed which can convert atmospheric carbon dioxide into complicated carbon compounds such as starch and cellulose.

As recently as the early 1980s, the generally accepted view among scientists was that enzymes were proteins. The idea of proteins having a monopole of biocatalytic capacity has been deeply rooted, and created a fundamental dogma of biochemistry. This is the very basic perspective in which we have to regard the discovery today being rewarded with the Nobel Prize for Chemistry. When Sidney Altman showed that the enzyme denoted RNaseP only needed RNA in order to function, and when Thomas Cech discovered self-catalytic splicing of a nucleic acid fragment from an immature RNA molecule, this dogma was well and truly holed below the waterline. They had shown that RNA can have catalytic capacity and can function as an enzyme. The discovery of catalytic RNA came as a great surprise and was indeed met with a certain amount of scepticism. Who could ever have suspected that scientists, as recently as in our own decade, were missing such a fundamental component in their understanding of the molecular prerequisites of life? Altman's and Cech's discoveries not only mean that the introductory chapters of our chemistry and biology textbooks will have to be rewritten, they also herald a new way of thinking and are a call to new biochemical research.

The discovery of catalytic properties in RNA also gives us a new insight into the way in which biological processes once began on this earth, billions of years ago. Researchers have wondered which were the first biological molecules. How could life begin if the DNA molecules of the genetic code can only be reproduced and deciphered with the aid of protein enzymes, and proteins can only be produced by means of genetic information from DNA? Which came first, the chicken or the egg? Altman and Cech have now found the missing link. Probably it was the RNA molecule that came first. This molecule has the properties needed by an original biomolecule, because it is capable of being both genetic code and enzyme at one and the same time.

Professor Altman, Professor Cech, you have made the unexpected discovery that RNA is not only a molecule of heredity in living cells, but also can serve as a biocatalyst. This finding, which went against the most basic dogma in biochemistry, was initially met with scepticism by the scientific community. However, your personal determination and experimental skills have overcome all resistance, and today your discovery of catalytic RNA opens up new and exciting possibilities for future basic and applied chemical research.

In recognition of your important contributions to chemistry, the Royal Swedish Academy of Sciences has decided to confer upon you this year's Nobel Prize for Chemistry. It is a privilege and pleasure for me to convey to you the warmest congratulations of the Academy and to ask you to receive your prizes from the hands of His Majesty the King.

---

[Image Credit: Structure of the self-slicing ribosomal RNA precursor from Tom Cech Lab]