Archive for June 2022

My Postdoc Years

June 22, 2022

I visited my youngest sister in London on my way to NY. She picked me up, and I stayed a night in London. Even at 3:00 in the morning, there was daylight. She purchased me a few clothes and a pair of shoes. By the time I landed in NY, the shoe mocked me with a big bruise. I made it past immigration and collected my baggage. The baggage needed to be checked into the next flight, so we needed to tag it again. I was too tired from the bruised foot, so I asked a random guy to take care of my baggage while I got the tags from the counter. By the time I returned, neither my baggage nor the guy were there (my first culture shock). The most important stuff in my suitcases were the printouts from all the computer code I had written during my graduate school, without which I could not survive in the US. Nervously, I followed the porters who were dragging other suitcases. I spotted my pathetic suitcases without a destination way beyond where passengers were not allowed. By the time I tagged the bags, I was running late for the flight to Richmond, which was to leave from East Terminal. I ran with my shoes in hand fearing I might miss the flight. What a sight it must have been! Finally, I landed in Richmond, where my sister and brother-in-law received me. With no money, I have no idea what I would have done if I had missed that flight.

In Richmond, I was provided with some warm clothes and a black and white TV. Since I already had too many suitcases, I carried the TV on my back. The neck ache from that persisted for months after reaching Buffalo. When I landed in Buffalo, I was spotted by our admin, Deborah, based on my nose pin and my pathetic look. She drove me to her place, where I was to live for the next 6 months. She, her boyfriend, and another roommate lived in a run-down house in an even more run-down neighborhood. To be frank, I had no idea it was a run-down place at that time. But I felt safe walking to my institute 2 miles away. Deborah would also drive me to the institute often. I ate bread and butter every day along with ice cream until my sister visited me that summer. Work was hectic and my boss was demanding. Soon, the brand-new Evans and Sutherland PS390 graphics system arrived, and I was told I was hired to write codes for it. Really! However, it made sense because the system had a super sophisticated graphics display tube, and I had experience developing algorithms for 3D rendering. Conceptually, the system is like a plotter, which took instructions from a host computer to print/draw objects. We had a VAX VMS mainframe computer to drive the PS390 system. The language PS390 could interpret was called Function Network, which was more sophisticated than the instructions interpretable by HP plotters. I was assigned a master’s student, Dennis McGruder, to help with implementing Function Network while I wrote the code in Fortran IV that drove the PS390.

The PS390 was a 3D graphics display unit equipped with a special polarized pair of glasses to allow visualization of objects in 3D. One eye sees one image that is rotated in favor of the right eye, and the other the left. The way the images are hidden from the other eye is by orthogonal polarization on the lenses (see picture below). The tool for biophysics application developed and widely used on PS390 was called Frodo. A printout of this software, as thick as a pillow, was given to me to get started. All I recall was that my mind was fully occupied by algorithms that would allow manipulation of molecules on their rotatable bonds (dihedral angles). Within months, our tools worked seamlessly enough to visualize how two large tRNA molecules may be interacting on one end with the codons on the mRNA molecule and on the other end carrying amino acids. Interactively, the conformational changes between the two codons with two tRNAs on the mRNA molecule could be dynamically adjusted to bring the two amino acids in proximity at the other end of the large tRNA molecules to create a peptide bond. Below, my boss literally watching over my shoulder as I proudly displayed molecules on the tool we just developed.

Many algorithms developed by me during the graduate school in Chennai were readily applicable. For example, rendering of spheres in 3D using equally separated points on the surface of the spheres, like vertices of bucky balls, developed during my PhD days. Although, originally, the points on the sphere were used to compute the surface areas of complex folded proteins, on PS390 systems, these points were displayed to render atoms in proteins. The same points were also used to compute accessible surface on proteins for the identify the shapes of drug binding pockets (see below). The red and blue defines the shape of the drug binding pockets on the protein (green). The figure is stereo diagram so you can see 3D if you can cross your eyes. The code and the algorithm enabling the display in the following figure, like pymol of those days, was developed by me for PS390 system during my postdoc years in Buffalo and was called MOSES, which stands for Molecular Simulations in Evans and Sutherlands. When we visited the comoputer museum in Palo Alto, I was too sad to note that PS390 system was missing from their inventorty.

In August of that year, one of the most unexpected surprises was that I met Sucha, who was a colleague at American College Madurai. He had moved from Eugene, Oregon to Buffalo as a graduate student. We became great friends, helping each other settle, and Sucha provided intellectual companionship that I was lacking. As a single mother of two kids, Sucha would often take care of the kids when I left town for conferences. This was the beginning of a beautiful friendship.

By now, it was time for me to go to India. I had secured 15 days off from work with a promise to return to the US on October 22, 1984. I had done enough research to dare not secure visas for the boys at the consulate in Chennai for fear of rejection. Sri did try and failed. On arrival at JFK, after making it past the special interrogation chamber at the port of entry, finally, I was relieved. I made it into the US borders again, this time with my boys. The happiness was soon to be shadowed by sending Bhu temporarily with my sister to Richmond until I settled in Buffalo with Shanker. I left Bhu with my sister at the airport before rushing to catch my connecting flight to Buffalo, NY. Before bringing my kids I had stayed with my administrative assistant close to the Peace Bridge connecting Buffalo and Canada. However, before bringing my kids, I had a planned to move into a flat associated with Roswell Park Memorial Institute. The new flat was right across from my lab. Unfortunately, I could not secure a place for Shanker in the Day Care center at the institute. Before leaving for India, I had admitted Shanker at a remote Day Care center and had arranged for his pickup early morning the day after we arrived in Buffalo. How cruel? This is made even crueler if one realizes Shanker did not speak a word of English.

Shanker and I soon settled in 12A Roswell Park apartment on 666 Elm Street with another acquaintance of mine from Chennai, Lalita. The apartment was allotted to Lalita who qualified because when she came to the US, around the same time as me, she did not pass the health test and was operated for a cyst in the uterus. Soon she left for India in frustration from post-surgical complications. So Shanker and I occupied the house. Bhu was settling in my sister’s place. However, my sister had to get custody of Bhu to be able to send him to school. This made Bhu very nervous, and he called me to get him out of there. During the week of Thanksgiving a month later, I took a Greyhound bus to State College and my sister drove Bhu there. Both my boys were united again with me in Buffalo. Believe it or not, I did not have a car and winter was setting in.

Bhu walked to a nearby school. It was in a black neighborhood. I’m not sure how Bhu got along in the school, but I never heard him complain. Soon after, Shanker got admitted to the daycare within the campus. So, not having a car was only an issue for grocery shopping. By now, my boss was becoming dependent on my work and provided me with a device using which I could connect to the mainframe computer using a phone line at a speed of 300 baud rate, meaning 300 bits per second. One would laugh at it today, but I was so happy as I could work until late at night from home. The speed was barely enough to send a command-line instruction to the computer to start and stop a task.

Winter was setting in, and we had to purchase a lot of winter clothing from the Salvation Army. We also got mattresses for all of us from the Salvation Army and replaced the sponge bed we had dragged from the hospital. On day one at 10A Roswell, I had two boys, two sponge beds from the hospital, and a black and white TV that I got from my sister. Life was simple, good, and full of hopes. I used to be too scared of the silence and couldn’t sleep. So, the TV would be blasting all night. One day, I woke up at 4 hearing Indira Gandhi’s name. Sure enough, all channels were airing her assassination by her own bodyguard. I was very upset. The only adult I could call and talk to those days was Sucha. I woke him up from sleep and told him about her assassination.

Soon, winter was showing its real face. This was my first winter in the US and in Buffalo, NY, which is notorious for snow and double winters. One weekend, I had to go to a mall to get gloves and a cap for Shanker, which he had lost the previous day. Without those, kids could not go to school, and I could not go to work. We took a bus and purchased what we needed. By the time we were out of the mall, a winter storm had started and the bus never showed up. It was so cold that my brain started to freeze, and I was starting to forget the yellow cab number I had memorized for use in case of an emergency. Bhu was very sharp and was good with numbers, so he gave me the number and we called for a cab from a payphone. The first promise I made to myself that night was to learn driving and buy a car as soon as the winter calmed down.

The next three years were filled with intense work. Bhu and Shanker made friends in the apartment building and were settling in nicely. I must confess that I never asked them what they learned in school. I was too busy with work, cooking, and cleaning. Eventually, I managed to get a better car by borrowing $2K from Padmini, my elder sister in Richmond. This allowed us to drive to Pittsburgh, where we would spend time at the temple and visit Sridhar (Padmini’s brother-in-law). The boys seemed generally happy. We also made several trips to Toronto to eat dosa on Gerrard Street. Slowly, my salary increased from $16K to $19K per year by the end of 1987. It’s not much and can be totally mocked. But with a J1 visa, I had no option to try any other job. I made the best of the constraints. With a more decent car, we made several road trips to Richmond. The boys were slowly getting to know their cousins in the US.

Early 80s saw the emergence of personal computers (PCs). At that time, every household only had what was called the Commodore 64. This was mainly used as a gaming system. The device would be plugged into the existing TV for use as a monitor. I recall that one of our friends in the same apartment complex had it, and Bhu and Shanker would often go there to play. Since that family had no kids, they would always entertain Shanker. In 1986, I purchased a PC called Amiga. It came with a computer and a dedicated high-res monitor. The computer was ahead of its time and had apps that could talk. Buying a PC in those days was so uncommon that my boss would often ask, “How is your Amigo doing?”. I taught Bhu how to write computer code in Basic to do simple math. This was a great toy for kids and gave them an edge with kids in our neighborhood.

My parents moved to Richmond, VA in 1987 and visited Buffalo for a month. During that time, efforts to change my visa from J1 to H1 were underway. This was a painful process because I had to procure clearance from Ranchi University (Bihar), Madras University, and the Government of India stating that I did not owe any money to any organization in India. In 1987, when communication and travel were so strained, this seemed like an impossible task. Without help from many in my family, this would not have been possible. Appa took care of Ranchi University, Srinivasan took care of Madras University, and Chellam, my brother-in-law living in Delhi, took care of securing clearance from the Government of India. Not sure where they had to go and who they had to convince, but all the clearances arrived, and my application was considered filed with the immigration office. However, there were weeks of delay between the expiration of the J1 visa and the filing date of the application, which resulted in a visaless status for a few weeks. Gap in visa status is subject to deportation. Sure enough, I received a deportation notice from the US Department of Justice. The only way to get a visa again is from a consulate outside of the US. This was a problem because I only had a single-entry visa into the US and had already used it while bringing my boys to the US. One of the ideas was to cross the border and get the visa stamped at Toronto. However, with no reentry visa to the US, Canada would require a visa to enter Toronto. Ayyayo! The only way to get a Canadian visa is to have a flight ticket to India in case my reentry visa to the US is rejected at the Canadian consulate in Toronto. My boss came to the rescue. He purchased three one-way tickets for Bhu, Shanker, and myself on his American Express card, which I would not be able to pay if my visa was declined. But my boss was very sure I was going to come back, and he would be able to cancel the tickets without any problem. God helps in many disguises!

It had been over three years since I joined Roswell Park. I learned a lot and developed many tools to aid in modeling protein structures and visualizing them. I recall a day when my boss handed me a journal article by Crippen and Havel and told me to decipher the Distance Geometry algorithm implemented for molecular modeling. He added that if I couldn’t understand the algorithms described in that paper, he would have to hire a mathematician. Having studied the MSc curriculum in mathematics with Hema decades ago, came in handy. I was able to understand and develop a software tool for homology modeling using distance geometry. Sadly, during those days, I wasn’t aware that the idea of using distance geometry for homology modeling was patentable. However, several years later, in 1993 I did receive a US patent for this method, which was enforced on a company (Insight Biosciences) that commercialized a homology modeling package called Consensus.

During the postdoc years at Roswell, we applied the tool to model the structure of bungarotoxin using its homology with cobratoxin and erabutoxin. The advantage of distance geometry is that it is independent of Cartesian coordinates, and distances between atoms from multiple sources, such as disulfide bonds and/or distances from multiple templates, can be pooled to constrain the model. When I was developing these tools, my boss would look over my shoulder to see if I made any progress. I recall him blaming Raghunathan, a postdoc in my lab, for slowing me down by keeping the computer busy. I recall Raghunathan getting very upset and storming out of the lab. At another time, I recall my boss commenting that Tom, one of the postdocs, is all talk, and Masayuki, another postdoc, is too perfect to produce results, and that I was able to get things done. This is when I realized, for the first time after landing in New York years ago, that I am also good enough for the Americas.

With the H1 visa in hand, I was permitted to explore job opportunities beyond the confines of Roswell Park. A group of scientists from the Immunology Department at Roswell Park were relocating to San Diego to join a startup company called IDEC. Since Tom from our group was moving with that group, he requested me to join them. He promised to transfer my H1 visa. My boss was very upset with me. I felt bad because he had gone out of his way to get me the H1 visa only a few months ago. But I had to move on. Besides, my salary was too low to support two boys. Believe it or not, with my salary and dependents, I could not even qualify for credit cards until 1987. I purchased a new car, a Mazda 323, and was very excited to move to California.

Sucha was to continue with his PhD, and I was sad to leave him behind. My three years in Buffalo cannot be separated from Sucha. My new job agreed to move all my stuff, including my car. Although all the stuff at 10A Roswell Park apartment was procured for a dollar each from the Salvation Army years ago and was not worth moving across the country, it was easier for me to move them than to dump them. Believe it or not, I also moved a heavy couch, which we picked from the roadside while living with Deborah, all the way to San Diego. I recall Sucha crying like a child in the empty house after the movers cleared it. Again, God had been cruel to mix excitement with sadness like water and milk.

In early December of 1987, I dropped my boys with my parents in Richmond and flew to San Diego. My dad was to fly with my boys after I secured a place. Until then, I was supposed to stay with Tom, who had already purchased a house. On the first day of work, I drove my brand-new car on the sunny freeways of California. My things arrived 11 days after I left Buffalo. The mover placed all my stuff as he found them in my Buffalo apartment. I was surprised to find ash in my ashtray and trash in my garbage can on day one, which were packed as is and were moved across the country.

A Thousand Deaths

June 19, 2022

As is usual for the Bay Area in the month of June, it is a beautiful sunny morning with mild and breezy weather. One can find no excuse not to go out for a long walk, which can lift both body and mind. However, my mood reflects dark and pregnant cloud about to burst into tears. It is as if my mind has withstood a thousand stabs and still pretends to be ready for more to come. There are no bloody spills that stands witness to this, yet, with every perceived stab I lost something, something I held so dearly. Can one grieve the living?

Anyone who lived more than seven decades on this planet will agree that life is complex. You know misery will last longer than moments of pleasures. You know adrenaline rush is a delta function embedded on an ocean of hormones that ebbs out based on the mundane events of the day. Here, mundane is used in the most positive sense. Thanks God, evolution has prepared us to handle mundane days. So did evolution not prepare us to handle a thousand deaths.

I see punching bags laughing at me and saying “Hey, I receive thousands of punches everyday but still keep hanging in there”. This brings me to the rituals that helps us mourn the death of loved ones in achieving normalcy. In the Hindu religion the four stages of grieving including the denial, the acceptance of loss, the actual mourning and restoration of quasi-normalcy are packaged in 13 days. Daah! But when you grieve the living, you are alone and perpetually stuck in the denial stage. You are arrogant to think you are in control and things will turn around if only …

Accepting loss of the living must invoke spirituality. God is the easy path to spirituality. However, how to start believing in somerthing that you never believed. Scientific thinking has long questioned the presence of God even though believers are believed to live a more normalized life, in general. Do nonbelievers lack imagination? Wait a minute, it could be the other way around. God may be in what you believe and what you love doing. According to the Hindu philisophy, God is omnipotent and omnipresent. This takes me to what I love doing. I find teaching very rewarding. I love cooking and it is the most meditative thing I do every day. Can these activities help provide the ultimate daily balance of adrenaline and other hormones required to reach a balance? If it did, I will not be writing this piece and I will not be struggling in Jack London’s Torture Ship.