Where are the secrets of everyday life, in proteins or DNA?

11 Jun Where are the secrets of everyday life, in proteins or DNA?

There has been much excitement about the promise of molecular genetics and in particular the Human Genome Project in curing various diseases. Ever since the double-helical structure of DNA was published by James Watson and Francis Crick in 1953, DNA has been billed as the repository of the secrets of life.
Within DNA resides the genetic instructions driving life itself. Countless scientists and billions of dollars have been expended worldwide to crack that secret. Indeed, the code has been cracked and we now know – as announced in 2003 (a half century after the double helix was first revealed) – the complete sequence of a human genome.
Still, progress has been slow to convert that overwhelming volume of information – three billion base pairs spread over 46 chromosomes of human DNA – into useful knowledge. The war on disease continues and diseases remain uncured (many still incurable). With the continued emphasis on the genetics of disease, these shall remain largely incurable.
Why is this so? Conventional military strategy holds that the decapitation of central targets, command and control centers or better yet the highest-level leaders of the enemy are the most effective means toward achieving victory.
Surely a cell’s DNA – a command and control center like none other – would be the ideal target for therapy. What better is there to strike at or manipulate than the very secrets of life? The secret of life that’s embodied in DNA is not the same as the secret to life that resides in the proteins. Proteins are where the action is.
Protein versus DNA
Prior to 1953, there was still considerable debate as to whether DNA was actually the genetic material of cells.
In fact, many scientists believed that only proteins – composed of 20 different amino acids in all sorts of configurations – had the necessary “information content” and “information complexity” to store the massive amounts of genetic data that would be required, for example, to build an entire human being from scratch.
While it was mind-boggling for mere molecules to give rise to such complexity in the absence of religious miracles, molecules it had to be.
Proteins were a more likely candidate than any other intracellular substance. On the other hand, DNA was a rather bland molecule. A DNA molecule – when broken down into its constituents – was composed of only four (not 20, as in proteins) subunits. These four substituents (termed “nucleotides”) were adenine, thymine, guanine and cytosine.
The apparent paucity of information content was further exacerbated by the fact that – in all chromosomal DNA isolated to date – the stoichiometric (or numerical) quantity of adenine was absolutely identical to that of thymine and likewise the quantity of guanine was identical to that of cytosine. It was difficult to imagine such a blandly appearing molecule as being capable of holding so much information.
Many regarded it as biological “filler material” or fulfilling some other obscure role. Like Aristotle before who had used his brain to theorize that the brain was merely a cooling mechanism for the blood, many scientists believed that DNA served only a mundane role within the cell.
This view was to change with the famous Hershey-Chase “blender” experiment of 1952. This used extracts of viruses to demonstrate that genetic traits were propagated through DNA rather than proteins.
The rise of DNA
Of course, the double helix and 1953 confirmed that on a biophysical and mechanistic level. People could see that – despite the blandness of the constituents of DNA – infinite variety would result from a different sequence of nucleotides. As well, perfect replication would be assured through a double-helical copying mechanism.
The excitement over DNA and the sudden reversal of its fortunes was infectious. Proteins became the more staid characters on the stage of life. They carried no information and were simply dutiful workhorses that were produced and dictated by the magical genetic codes emanating from the cell’s nucleus. They did their jobs with no questions asked.
While the action of life took place at the level of proteins, the action of laboratory biology took place at the level of genes. For a time, cloning a gene was enough to publish a major paper or earn a doctorate. Elucidating a set of genetic mechanisms or regulatory pathways was a sure step to a Nobel Prize. Of course, this is a simplification.
Major work has been done around proteins. Sequencing proteins – insulin, for example – or solving the three-dimensional structure of a protein – myoglobin, for example – have led to substantial accolades including Nobel Prizes and (most important) significant progress. The point, however, is two-fold.
First is to emphasize the natural bias in favor of DNA. DNA captures the imagination and still excites scientists and laypeople alike. The combination of utter uniformity and infinite variety makes DNA both relatively easy to study and impossibly mysterious to fathom. It is a potent and emotional combination. Proteins, on the other hand, are both more prosaic and more complex.
They do not extend (nearly infinitely) in a single, double-helical structure. Instead, they manifest in a myriad of shapes. Some are more or less spherical (like hemoglobin) and others are elongated (like myosin). Still others are thin as cables (like collagen) and others are a mix of the globular and extended (like antibodies and the other immunoglobulins).
To study a single protein molecule could be a life’s work. To study DNA could be the work of life that in a nutshell explains the appeal of genetic research and its expansive outlook over its more single-minded partner: protein chemistry. To be sure, proteins are more dynamic creatures than the staid drones described above. Whatever the case may be, proteins are truly where the action is.
Protein the prime mover
Nearly all drugs act on proteins. Aspirin binds to a protein (cyclooxygenase). Penicillin binds to a protein (transpeptidase). Morphine binds to a protein (the ì-opioid receptor). Most congenital diseases result from the presence of abnormal proteins. Cystic fibrosis results from a mutation in the CFTR protein involved in chloride transport across cell membranes.
Sickle cell anemia results from a mutation in the hemoglobin gene. Hemophilia results from any number of disrupted coagulation factor proteins. While it is the DNA of these patients that harbors and transmits the mutations, it is the resultant proteins that create disease and hence represent the potential targets for intervention.
Stay tuned for part two of this column.
Previous articles by Ogan Gurel
• Ogan Gurel: Italian view on invention and innovation
• Ogan Gurel: Socialized risk not confined to subprime mess; healthcare impacted
• Ogan Gurel: Innovation versus invention: Why accelerating development makes sense
• Ogan Gurel: Fostering innovation doesn’t occur in a vacuum
• Ogan Gurel: Innovation vs. invention: Knowing the difference makes a difference