Monday, December 12, 2011

My Professor's Dilemma

K.K.Vinod and M. Maheswaran

Yesterday my Professor, Dr M Maheswaran wrote me after reading the book “Emperor of All Maladies- A Biography of Cancer” by Siddhartha Mukherjee.

He wrote,

Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm.

If the data did not fit the dogma then the dogma, not the data, needed to be changed.

After reading the book and understanding the biological causes behind the cancer genetics I felt very bad about things what we are teaching and doing in understanding the genetics of many of the traits we deal with crops and exploit the results in practical plant breeding. Many of the concepts of predictions we make based on the classical genetics, whether it is Mendelian or Galtonian, remain irrelevant considering the biological implications on a particular phenotype. For example, p53 gene, an unassuming name, has major role in the development of human cancer than any other component of the genome. The gene get its name from the product it encodes, p53, which is a polypeptide having a molecular weight of 53 kilo Daltons. p53 was thought for number of years to be a dominantly acting oncogene, but in 1990, it was recognized as the tumour suppressor gene that, when absent, is responsible for a rare inherited disorder called Li-Farumeni syndrome, whose victims are affected with a very incidence of certain cancers, including breast cancer and leukaemia (though there are separate and specific genes for breast cancer and leukaemia). Like individuals with the inherited form of retinoblastoma, persons with Li-Farumeni syndrome inherit only one functional copy of the p53 tumour suppressor gene and are thus highly susceptible to cancer as the result of random mutations that knock out the function of the remaining copy of the gene. Further, if we see the development of cancer in humans (for any type of cancer development), the possible sequence of genetic changes in a cell lineage are given below.

The complexity of cancer can be better understood if you read the above book. But in plant genetics we decide the genes based on the prediction methods and most of the gene predictions are based on the “breeder friendly phenotyping methods (whatever be the trait we have the simple means and many models to predict the genes). The advent of molecular marker technology made this simpler. Once there is co-segregation of DNA marker, the gene discoverer assumes he/she got gene for the phenotype (some where I read that there are 83genes identified for resistance to rice blast disease and we have 26 genes for brown plant hopper resistance in rice- just go back and read the situation of gene for Li-Farumeni syndrome). Gene identification based on breeder friendly phenotyping and pyramiding of those genes without knowing the functionality of the genes is a wasteful exercise. In recent times people started asking questions whether it is good to pyramid dominant genes or recessive genes without understanding the situation of obscurity prevailing over dominance or recessiveness. This can be remedied if every gene discoverer realizes the importance understanding the biology behind each of the phenotypes instead of evolving prediction methods.

My Professor stops his letter by saying “Predictions are always based on perceptions”.

Concern of my professor was of a genuine teacher, who attach paramount importance to imparting current and competitive knowledge to his students. He laments that except a very few teachers of plant genetics, none are ready to change the way science unfolds life’s mysteries. So instead of changing the dogma, we are often bending the data fit the dogma. Are we ruthlessly incompetent because we are afraid of deviating from the conventions?

Saturday, December 03, 2011

A tribute to Damodar Dharmananda Kosambi


Scientists and students of genetics studying linkage and recombination are familiar with Kosambi’s mapping function. Chances are that they never had heard of Kosambi before. The reason - Damodar Dharmanada Kosambi was not a geneticist by training and profession, but a mathematician. He was also a statistician, historian, marxist, linguist, writer – he was everything – a multi-faceted scholar. His famous mapping function was published in 1943, in Annals of Eugenics (Kosambi, 1943). How he got into this work is not known, but Kosambi’s works generally spanned across many disciplines from mathematics to children’s literature. At the time of this publication he was teaching mathematics at Fergusson College, Pune.

Recently, Professor Kosambi’s birth centenary was celebrated, in Pune mainly by the historians and scholars. I as a student of genetics, came to know more about Kosambi after this celebrations. Ignorant of a great scientist, whose name I would have used thousands of time while doing genetic map constructions, I decided to put this tribute.

Kosambi’s mapping function estimates the recombination fraction (c) between two loci as a function of the map distance (m) between the loci, by allowing some interference, as
c = ( e4m -1) / 2( e4m +1)

The estimate of the map distance between two loci can be obtained from
m = ln [ (1+2c)/(1-2c) ] /4

Kosambi’s function go intermediate between actual recombination fraction taken as map distance (no interference) and Haldane’s map function (Haldane, 1919), closely predicting recombination fractions especially when the loci are linked.

My article on Kosambi and the mapping function was published in the popular science journal Resonance in its Kosambi commemorative issue in June 2011. This article can be accessed from this link

Damodar Dharmanand Kosambi (D.D. Kosambi) was born at Goa on 31 July 1907 to Acharya Dharmananda Damodar Kosambi and Balabai. After his early schooling, young Kosambi moved to Cambridge, MA (USA) and studied grammar and Latin. After successful schooling at Cambridge, he joined Harvard University in 1924 studying mathematics. He discontinued his studies for a brief period and returned to India, again to join back in 1926, where he was awarded with Bachelor of Arts degree. Returning to India soon after, he joined Banaras Hindu University as a professor, teaching German and mathematics. Here he started his personal research and started publishing his findings. He got married in 1931 with Nalini, and in the same year joined Aligarh Muslim University as the professor of mathematics. He continued his mathematical research more vigorously here, and publishing his papers regularly in European languages.

Two years after he joined Fergusson College in Pune, and continued to teach mathematics. His two daughters Maya and Meera were born here. It was during this period his famous paper on mapping function was published in 1943. Kosambi had done extensive research on many areas of mathematics and published many papers. However, many of his publications went unnoticed by Indian scholars and eventually a great scientist and a historian was getting ignored to a great extend. No students of genetics were told Kosambi was an Indian scientist.

It was probably Homi J Bhabha, who recognised his talents and made him to join Tata Institute of Fundamental Research (TIFR) in 1945. He was professor of mathematics and worked there for next 17 years. During this period, Kosambi published 40 research papers, mostly on mathematics. However, his interest was shifted to history and social sciences in the later years, extensively researching on ancient Sanskrit works, numismatics and ancient history of India. Probably these later works made him to be remembered as a historian rather than a mathematician.

Kosambi authored 9 books including edited ones and 127 articles. But this number is not authentic as there are many childrens’ stories written by him. As a prolific writer, thinker, mathematical genius, linguist and historian Professor Kosambi, as Dale Riepe wrote, ‘deserves to be remembered as one of the highly gifted and versatile scientific workers and indefatigable scholars of modern India for whom a relentless search for the highest human values was the only natural way of life’.

After leaving TIFR, in 1964, Kosambi was appointed as a Scientist Emeritus of the Council of Scientific and Industrial Research (CSIR) and worked in Pune. He got involved in many historical, scientific and archaeological projects, including stories for children. But most of his works that he produced in this period could not be published during his lifetime.

Professor Kosambi died at Pune, at the age of 59, on June 29, 1966. He was posthumously decorated with the Hari Om Ashram Award by the government of India's University Grant Commission in 1980.
A biographical sketch of Prof DD Kosambi written by Chintamani Deshmukh can be downloaded from here.

References (Click on the title to download)