How life works!

I wrote this article as an assignment for a course "Culture of Scientific Research" where we discussed the events leading to the discovery of the structure of DNA and debated on the ethics behind Watson and Crick's actions. The assignment was to assume the role of one of the people involved in DNA research during the 1950's and write what they might have written. I decided to be Linus Pauling!

A double helix structure for the nucleic acid is now the accepted DNA structure. The nucleic acid is christened D.N.A.   I appreciate how James Watson and Francis Crick used ball and stick models to figure out the elusive structure. It is much similar to my methods and Crick most graciously declared the structure as a tribute to me. They were of course aided by the excellent photographs taken by Rosalind Franklin. I would have been much more pleased by these gentlemen if they had had the scientific courtesy of accrediting peers for their contribution. 

I myself was keenly interested in studying the structure of nucleic acid. My first interest in large molecules arose in 1930s while I was studying haemoglobin. Even since 1929, I wanted to learn how life works. Genes being a part of chromosomes was a new discovery then. Between the two components of chromosomes (nucleic acid and proteins), I felt proteins, having more complexity must be the unit of inheritance overseeing the growth of organisms. Robert Corey and I had studied the molecular structure of amino acids and protein subunits for almost two decades. In the spring of 1951, we published papers detailing protein structures at the molecular level most importantly that of alpha helix. X-ray diffraction was a newly discovered technique and was used widely to study many large molecules. 

Astbury and Bernal had published X-Ray data for numerous biomolecules including nucleic acid present in the chromosomes and certain glandular tissues, then called thymonucleic acid. Its sodium salt forms viscous solutions from which oriented preparations could be made that gave excellent x-ray fibre photographs. Though I had referred Astbury’s X-ray data for proteins and tried to fit it to a model (which I had failed to do), I had not put much effort into understanding the nucleic acid structure. It was not until the summer of 1951 that my interest shifted to nucleic acids. I heard about the work done on sodium thymonucleate by Dr. Maurice Wilkin’s laboratory at King’s College, London. But Wilkins, quite understandably was not willing to share the experimental data and wished to publish independently. Astbury published one more photograph of thymonucleic acid  in 1947. The strongest period along the fibre axis was at 3.34 Angstrom. The molecule had high density and the solid state was fibrous. Astbury proposed a structure where a column of nucleotides were piled up on each other. He also believed that each nucleotide in a nucleic acid is linked to its neighbours through phosphoric acid.

 In 1951, Edward Ronwin outlined a possible structure of DNA based on Astbury’s data. Ronwin proposed that the phosphate groups were present in the middle of the molecule and the large bases stick out to the sides.  This structure again sparked my interest. There were many inconsistencies in Rowin’s structure. His proposed structure would decompose rather rapidly in presence of water which seems to be abundant in DNA. I myself was contemplating a helical structure for nucleic acid which seemed logical for any molecule with repeating units. A helix with the nitrogen bases at the centre would be constrained sterically and hence phosphates in the centre and bases towards the outer side made more sense. Yet, I continued to work on protein structure which was in a very exciting stage then.

 
In the summer of 1952 at a meeting in France, I realized from the Hershey-Chase experiments that DNA, indeed contained the gene and I shifted my attention to it. I expected the structure of DNA to be much easier to eludicate as it was made of just four nucleotides as opposed to proteins made of 20 amino acids.  Subsequent papers from different research groups described different aspects of the bonding between the numerous groups in DNA. Linkages between atoms of nucleotides and nitrogen bases as well as sugar and phosphates were known. Electron micrographs by R.C.Williams seemed to support the helical model.  The meridional reflection in the X-Ray with spacing of 3.40 Angstrom indicated a unit consisting of three nucleotide residues. This could not be found in a single helix structure. Hence, we proposed a three stranded helix where each the three strands coiled around each other.  The biggest mistake I made was in putting phosphate groups having no net charge at the centre of the helix. I ignored the crucial fact that at physiological pH, the phosphate groups would not possess hydrogen atoms and hence there would be no hydrogen bonds to hold the structure together. Also so many negative charges could not be accommodated in the core of the molecule as they would all repel each other. The model also did not account for the formation of sodium salts of DNA as sodium ions could not be accommodated within the core. This model failed to obtain acceptance. I had sensed this and started to correct some of the mistakes. I still thought our proposed structure needed more empirical evidence to be proved right which would require a couple of years.

 Meanwhile Peter sent me an advanced manuscript by his collegues at the Cavendish which described a double helix D.N.A structure with phosphates towards the outer side and bases towards the inner side, paired according to Chargaff’s rules and held together by hydrogen bonds. I still hadn’t seen the photograph taken by Rosalind Franklin which aided Watson and Crick’s discovery and hence considered it prudent to withhold my judgement. In April 1953, I was at last able to have a look at the model of the double helix as well as the now famous photograph 51. Then, I realized, I was wrong and James and Watson, indeed had the right model. They are jubilant on winning their “race”!

In retrospect, I rushed towards finding the structure. Some more research on chemistry of purine and pyrimidines would have helped a lot in the same way that Chargaff’s rules helped Watson and Crick. As a parting note, I stress on the importance of this discovery. It will contribute immensely to the field of molecular genetics.

Linus Pauling

References:

1. Horace Freeland Judson(1979) The Eight Day of Creation.
2. Francis Crick(1988). What Mad Pursuit.
3. Watson, J. D. (1968). The Double Helix: A Personal Account of the Discovery of the Structure of DNA. 
4. W. T. Astbury. (1939) X-ray studies of the structure of compounds of biological interest. Annu. Rev. Biochem. University of Leeds 113-133

5. Linus Pauling and Robert B. Corey. (1952) A Proposed Structure for the Nucleic Acids. Proc. N. A. S. (39)

6. J. D. Watson and F. H. C. Crick. (1953) Molecular Structure of Nucleic Acids. Nature. Vol. 171

7. https://paulingblog.wordpress.com/2009/04/28/the-pauling-corey-structure-of-dna/

Acknowledgements:

The course instructors and teaching assistants for the idea and help in execution.

To the parent of a son

Okay.

I will stay at home at night.

I won’t drink.

I won’t party at clubs.

I won't wear short clothes.

I won’t talk and laugh openly in public.

I know it’s for my good. I will take care of me.

But what will you do for my good?

When will you tell your sons?

She’s not asking for it;

She’s not all breasts and vagina;

She’s not supposed to look thin or fair.

She’s not supposed to be whistled at,

Winked at or blown kisses at.

That

He is supposed to see her as an equal,

A living entity-a whole made of many parts.

That

"No" means exactly that!

Women don't have a separate language.

That

Perverts who objectify women

Are the ones “asking for”-

A slap on their face.

The day you teach him that-

Then- I will truly be safe.



Recently, I heard a crazy remark on the "Teach your sons not to rape" quote: What parents teach their sons to rape? 

Parents do no teach them to rape;NEITHER DO THEY TEACH THEM NOT TO RAPE. We need to impregnate our sons with the need to respect women, that eve teasing and rape is lowly. We need to spell that out. We need to teach the meaning of no and of a less known concept of "consesual sex". We need to make teaching this a cultural norm!

Once, at dusk.

It was nearing dusk,but there was still good light. Arrowhead had just mesmerized one and all with her glamorous walk down a long dusty road before disappearing into the thickets. She seemed to have food on her mind. Twenty days ago her tiny,tiny cubs-just orange fur balls-had peeped out of green grass and left one and all in bouts of puppy love. All the Gypsys dispersed with this momentous sighting. We moved towards the nearest forest chowki to end the day around a warm oven with stories of the wild from the tongues of the forest guards . We might have traveled some 750 km when Arrowhead emerged from the bushes right behind us. I could have stretched my hand and patted her arrowed head. We waited, unable to fathom the mother's intended path and afraid to startle her by any movement. Soon it became evident that she wished to continue on the path right before us. Our gypsy was blocking her way.

She did nothing "wild" or "tigery".

She moved through the undergrowth and crossed a chain separating two zones. On the other side, she gracefully raised her tail and sprayed her fluid over some stones. Wordlessly, soundlessly and like a queen, she declared the place to be her own. We moved away from the area to avoid disturbing her again.

A day later, the zone was shut down to prevent any disturbance to Arrowhead and her kids housed in an ancient hunting palace that lay right at the end of the chained road.

I chose

I chose this.
I chose to be intoxicated:
With the lust of search,
With the process of curiosity,
With the rhythm of an experiment,
With the blinding beauty of an answer.
I chose to be possessed by questions:
Questions troubling my sleep,
Questions robbing my sleep,
Questions invading my dreams,
Questions giving rise to questions.
It's my ecstasy.
It's my euphoria.
It's what makes me alive.

Explaining to people why I actually like science and not ruining my life by "studying" constantly! 

NGS prep at Lab 3,National Center for Biological Sciences

THE FRUITFUL LIGHT

“I have no special talent. I am only passionately curious”, said Albert Einstein and these words of his are regarded as epitomic of scientific thought and motivation. Scientists has always been imagined as someone poring over books or into a microscope or staring deep into space. They are viewed as aloof creatures who are not interested in the day-to-day rigors of life. Less often is a scientist imagined to be tinkering with machines and trying to build something. This is surprising seeing that we live in an era where our lives have been influenced by science like never before. If a scientist is someone who is not concerned with material life and comfort how come science has led to such a materialistic and technology driven era? This itself is proof for how over the years science has transformed from a Gentleman’s hobby to a directed, applicative profession.
Even though science seems to have turned into a more fruit bearing activity, scientists still find curiosity as the driving force for their research. This brings us to the widely discussed question about what is the “better” method of scientific inquiry. That which is driven by curiosity called experiments of light or that which is driven by the requirement to fulfil a need called experiments of fruit.

Men of scientific repute have commented at length about both methods of inquiry. Flexner a strong advocate of experiments of light had commented,”...the less they (institutions) are deflected by considerations of immediacy of application, the more likely they are to contribute not only to human welfare but to the equally important satisfaction of intellectual interest”(1).

John Cornforth winner of the 1975 Chemistry Nobel, attributed his prize to ‘a lifelong curiosity about the shapes, and changes in shape, of entities that we shall never see; and a lifelong conviction that this curiosity will lead us closer to the truth of chemical processes, including the processes of life’(3). Cornforth is one of several Nobel Prize winners who have attributed their success in research to curiosity which is ironic seeing that Nobel prizes are mostly awarded to applicative research. Daniel Sarewitz, Professor of Science and Society in Arizona State University argues that technology and not curiosity has heralded most of the innovations in today’s era. He considers what Vannevar Bush- M.I.T. engineer who headed the United States World War II research, stated about scientific progress resulting from “the free play of free intellects, working on subjects of their own choice, in the manner dictated by their curiosity for exploration of the unknown” as a “beautiful lie” which has since then caused science to get “trapped in a self-destructive vortex.”(2) I found Robert Djikgraaf's explanation of how basic research supplements the knowledge required for applicative research which in turn spurs the need for more information and more basic research resulting in a cycle very convincing.(4)

Curiosity driven research is essential as with limited knowledge, humans cannot perceive the connections between different entities. Only on acquiring more knowledge does one get to know how different entities interact and can then use this knowledge to address problems in that field. The discovery of Taq polymerase is one example out of many of how a curiosity driven experiment- a “mere” study of thermophilic bacteria led to the development of a technique which has almost universal usage.

Applicative research is as essential as basic research. There is no use of knowledge if it cannot solve problems. Initially science was a hobby with rich men fiddling with science just out of curiosity and to while away time. Now, science is more of a profession with taxpayer’s money being used to pay scientists and fund research. It is inevitable that a common man will ask about the use of something his money is being used for. In today’s times when human health is endangered by numerous illnesses, agriculture is unable to feed all, wildlife is at high risk of extinction , non-renewable resources are at an all time low and countries prevent war by threatening each other with weapons, “useful” and “relevant” research is of utmost necessity. Yet, basic research should not be discouraged and must be funded sufficiently. Discontinuing curiosity driven research and funding only translational research will be equal to pushing down science into Sarewitz’s “self-destructive vortex”.

Scientists must carry out experiments of fruit but should be unbiased enough to accept fruits different from what they expected and also to identify those fruits which were unexpected. Serendipity in science has given rise to many objects of utility from the microwave to the pacemaker.(5) Scientists should be conscious of not ignoring such results in the race to publish translational research.

How research funding should be divided between basic and translational research is something to think about. How applicative research could lead to unproductive results is visible in the results of breast cancer research funded by Department of Defense of the USA.(2) Billions of dollars were utilized with no constructive results. Margaret Thatcher is the first name which comes up in policy making for research funding. Having herself worked in the field of Science, Thatcher emphasized on the importance of basic research. She argued that the rewards of basic research could not be judged immediately and hence it is difficult to make a decision on distribution of Government funding.
She recommended providing support to “those teams, however small, which can demonstrate the intellectual flair and leadership which is driven by intense curiosity and dedication”(3). This curiosity could be directed towards applicative research, not necessarily basic research. Curiosity driven research would prevent science from being biased in a singular direction.
Thus, curiosity should be maintained as the driving force for research –even translational research. Experiments of light should lead one to experiments of fruit.

References:

1. The Usefulness Of Useless Knowledge by Abraham Flexner. Harpers Issue 17. June/November,1939.
2. Saving Science by Daniel Sarewitz. The New Atlantis. Spring/Summer 2016.
3. The Curious History of Curiosity-Driven Research By Jon Agar doi:10.1098/rsnr.2017.0034
4. https://blogs.scientificamerican.com/guest-blog/knowledge-is-a-kind-of-infrastructure/5. https://www.sciencealert.com/these-eighteen-accidental-scientific-discoveries-changed-the-world?perpetual=yes&limitstart=1