His was a lovely mind who never stopped having important ideas
- James D. Watson
— AMAR J. S. KLAR —
1947 - 2017
Amar J.S. Klar was an influential yeast geneticist and a pioneer in epigenetics research. As a member of the Cold Spring Harbor Laboratory yeast group, he and his colleagues deciphered the genetic and molecular biological mechanisms of mating type switching in yeast, demonstrated the role of gene silencing in switching, and showed the directionality of switching as a result of specific chromosomal location. In subsequent work leading from his study of yeast mating systems, Amar investigated the asymmetry of DNA chains, asymmetric cell division, and DNA strand-specific segregation that was driven by somatic strand-specific imprinting and selective chromatid segregation. This research led to investigation of instances of left-right symmetry in congenital limb development anomalies, visceral organ laterality, brain hemisphere asymmetry, and piebald wing color in beetles.
Klar was born on April 1, 1947 in Punjab, India. He earned his undergraduate degree in biochemistry (1967) and Master’s Degree of Science in microbiology (1969), both from Punjab Agriculture University, Hissar India. He then went on to receive his Ph.D. in bacteriology at the University of Wisconsin in 1975 under the eminent microbiologist Harlyn O. Halvorson. Amar studied genetics as a postdoctoral fellow at the University of California, Berkeley with molecular biologist and yeast geneticist Seymour Fogel.
A phone call from Jim Watson brought Amar to Cold Spring Harbor Laboratory in 1978. Watson told him that “We are opening a yeast lab to work on mating-type switching. Whatever you need, I will arrange it.” Amar joined Jeffrey Strathern, Jim Broach, and Jim Hicks in April in Davenport Lab. Although Broach left for SUNY Stony Brook soon after, the remaining three comprised as the “yeast group” until 1983–1984.
Klar also served as director of the Delbrück Laboratory from 1985 to 1988. He was a seminal figure in the organization of the Molecular Biology of Yeast meetings at CSH and well as the highly regarded 1984 Cold Spring Harbor Symposia on Quantitative Biology Genetic Recombination at the DNA Level.
Dr. Klar left Cold Spring Harbor in 1988 to join the ABL-Basic Research Program as Head of the Developmental Genetics Section. In 1999, Klar joined the National Cancer Institute Center for Cancer Research as a Principal Investigator in the Gene Regulation and Chromosome Biology Laboratory at NCI-CCR.
Dr. Klar stayed in touch with his roots at Cold Spring Harbor Laboratory as an organizer of the Yeast Cell Biology meeting (1989), and the Epigenetic Mechanisms of Gene Regulation (1993) at the Banbury Conference Center. He attended meetings and was a frequent seminar speaker at the Yeast Genetics course held each summer at CSHL.
In 2002 Dr. Klar donated his laboratory research notebooks, photographs, and correspondence documenting his work at CSHL. Yeast collaborators Jeff Strathern and Jim Hicks followed suit with their yeast laboratory notebooks in 2002 and 2012, respectively. The Yeast Collection documents the work of the triad of the yeast genetics group at CSHL from 1978–1988. Dr. Klar died on March 5, 2017 in Fredrick, Maryland.
— GALLERY —
MEMORIES AT COLD SPRING HARBOR LABORATORY
—CONVERSATIONS WITH AMAR—
—MEMORIES & CONDOLENCES—
Amar Klar, Scientific Giant
A memory from a colleague and friend
To be a giant, one must believe in giants. Amar Klar certainly believed in giants, having cut his principal investigator teeth among those at the Cold Spring Harbor Laboratory. Those critical years that inspired and grounded his future thinking in developmental genetics were before my days of knowing Amar or knowing about his work on DNA strand asymmetry as a molecular feature of asymmetric cell divisions in early organismal development.
In my first encounter with Amar, I did not meet him personally. In the mid to late 1990’s, I served as a member of the scientific advisory board for the NCI-Frederick Cancer Research and Development Center. In my final days on the SAB, Amar’s research program was reviewed for continued support. David Botstein was the external invited chair for the review. At the time, I was in awe to be sitting at the same conference room table with Botstein.
Years earlier, as a freshman at Harvard College, I had selected a phage genetics article from Botstein’s lab as the topic for my final research review paper in an upper level graduate course given by Richard Losick and Jan Pero. The paper I chose was quite a dense genetics thicket for a freshman who was just learning to read scientific research reports, let alone decipher and explain the rationales and interpretations of genetics experiments from a lab as sophisticated as Botstein’s. As I remember it, although Professor Losick indicated that I had more work to do on delineating the salient features of a research paper, he was quite impressed that a freshman undergraduate had been so able to describe accurately such an advanced research report.
Though that advisory review started with my attention on Botstein, it ended with my full focus on Amar. Amar announced to the advisory committee that he was starting a new research program on the genetics of human handedness. It was my suspicion that only two people on the more-than-10-member review committee had any inkling of an understanding of what Amar was proposing. They were Botstein and I. The ensuing committee rebellion against Amar’s new proposal, which was somehow inspired by DNA strandedness concepts developed in his earlier yeast epigenetics research, evidenced the members’ general bewilderment with Amar’s presentation. Why would he abandon a very productive research program in yeast genetics, which had justifiable relevance to human carcinogenesis, to enter a field of human genetics that had little if any established disease relevance, and certainly not to cancer?!
Botstein saved the day. Knowing Amar and his general scientific prowess better than any other member of the review committee, he assured the other members that they didn’t need to understand what Amar proposed to pursue. If Amar had a hunch about something, it was better than a hunch. It was gold waiting for Amar to reveal it. Botstein was right…for betting on Amar, his genius, and his little concern for the resistance of others to his new ideas.
The essence of Amar’s new concept was that mutations in embryonic development processes that determined bilateral body features, like handedness, would result not in loss of the bilateral feature, but instead in its randomization. This genetic signature would occur because such bilateral features were the result of early cell divisions during development that occurred with a specialized non-random DNA strand segregation process. With the rescue by Botstein, Amar was on his way to investigating his new hypothesis in developmental genetics in many different organismal species, including humans, and in many different types of tissues.
The second time I encountered Amar was more up close and personal. Amar invited me to give a seminar at NCI-Frederick after the publication of my lab’s 2002 report of the demonstration of non-random chromosome segregation in cultured cell lines as first proposed by John Cairns for tissue stem cells in 1975. Our report presented the demonstration of the non-random, strand-specific segregation of the entire set of mouse chromosomes in cells undergoing asymmetric self-renewal divisions, providing an experimental model for study of the process Cairns had invoked decades earlier for adult tissue stem cells in vivo. Non-random DNA strand segregation was an event that Amar had proposed to occur for at least one mouse chromosome during embryonic development.
There is no greater gift one scientist can give another than his/her pure and supportive interest in incipient findings, public acclamation of the scientific merit and importance of the new ideas in the work, whether in the longer term they prove to be as initially concluded or different. That’s what Amar gave me, in his hugely generous and gracious way. We spent two days discussing our respective findings and ideas and possible mechanisms that could account for how a postnatal tissue stem cell (as predicted by Cairns) or an early embryonic precursor cell (as predicted by Amar) could distinguish the age of DNA strands and direct their pattern of inheritance into phenotypically distinct or anatomically distinct daughter cells.
I left my visit with Amar energized to answer that question for tissue stem cells and forever grateful to him for his interest and encouragement that I do so. However, at the time, I did not think he and I were studying the same cellular mechanism. In the ensuing years of our developing intellectual collaboration and friendship, Amar would convince me otherwise.
The next time I saw Amar, a few years later, we were still not friends yet. Though I liked his attention, I was still wary of his motivations and intentions. We were both attending a Gordon Conference organized by Ting Wu from the Genetics Department at Harvard Medical School. One of Ting’s goals for this particular Gordon Conference was to introduce to the community of epigenetics scientists new investigators who studied highly unusual properties of DNA. Amar and I were ideal participants.
Amar was walking up with his impish smile just as I was arriving at the conference. He called out to me and immediately began to tell me what he thought about my review of his manuscript. I was completely caught off guard. I did not know that he would be at this meeting. I had not communicated with him since my 2002 visit with him at NCI-Frederick. But now, here he was, smiling and critiquing my review of his most recent report on DNA strand asymmetry during embryonic development. He didn’t actually know for sure that I had reviewed the manuscript. He was speculating based on his having requested me as a possible reviewer and comments in the review regarding how the manuscript had not considered p53 effects in the studies. P53 effects played a major role in my group’s research.
Though Amar had indeed sleuthed out my role as the reviewer, I demurred from either confirming or denying his speculation, which set us off on a rollicking, tongue in cheek, discussion for the rest of the meeting. It was at this meeting that my friendship with Amar began. From then on, we sent each other our papers to read. I tried to start a DNA strand asymmetry club with Amar and several other members of our small, but then growing, community of scientists to share pre-prints, published papers, and new ideas. Amar was the most enthusiastic member. Long after our short-lived little club became inactive, he and I continued to share any new tidbit we discovered that we thought relevant to DNA strand asymmetry. We often mused (one might even say dreamed) about organizing a future conference to bring together the international group of scientists who investigated DNA strand asymmetries. I invited Amar to participate in every book project that I edited or conference that I organized that had relevance to DNA strand asymmetry; and I received so many of his pre-prints and publications over the years that I now have an “Amar docs” folder in my computer just for
Whenever Amar visited Boston to give an invited talk or attend a research conference, sometimes that we were both attending, we got together for a long dinner to discuss progress in our research. It was these far-ranging discussions that revealed to me the great depth of Amar’s conviction that DNA strand asymmetry was a fundamental principle of organismal development; and also revealed his growing frustration with the pernicious resistance to this new concept that he encountered. The human geneticists spurned his intrusion to revoke their models grounded in older ideas of penetrance and polygenic disease mechanisms; and proponents of the morphogen model for development of body bilaterality were his perennial detractors.
After the paper that I reviewed was published, I thought Amar would set about using his lab’s new demonstration of DNA strand asymmetry during mouse embryonic stem cell development in culture as the basis for an experimental model system to discover the responsible molecular mechanism. But Amar had transitioned to a new scientific vision and plan. He would say, “James, James, who cares about mechanism! Everybody asks me about what is the, mechanism, mechanism, mechanism. I don’t care about how it’s done. I want people to understand that it is done so often throughout biology!” And that is what Amar was about at his untimely death. Identifying example after example of puzzling laterality phenomena, diseases (e.g., breast cancer), and genetic disorders that could be very soundly accounted for by the DNA strand asymmetry processes that he invoked to occur early in embryonic development. Each time we met, if he had not already sent me a pre-print describing a new example, he told me about a new one that he was writing about.
My last meeting with Amar was last August 2016, when he attended a Society for Developmental Biology conference in Boston. After the meeting was over, we got together for one of our long dinners to discuss new developments in DNA strand asymmetry. Amar was in particularly good spirits. He was elated about the recent wonderful wedding of one of his daughters and looking forward to a similarly wonderful wedding for his other daughter in September. At the meeting, he had encountered the usual resistance to his greatest discovery. A few years earlier, I had introduced Amar to the philosophies of Kuhn and Knudson. Kuhn, many know for his philosophy developed in The Structure of Scientific Revolutions. Alfred Knudson, also recently deceased, was one of my most dear mentors. Al used to say to me when I lamented to him the resistance I experienced to my own novel ideas, “James, when you meet so much resistance to your ideas, you are either off your rocker or onto something really important.”
Amar Klar was not off his rocker. As a giant of developmental genetics, he was living through the hardship of a paradigm shift of his own creation as described by Kuhn. His deductions of the essential mechanism of body bilaterality and genetic disorders of bilaterality were disruptive to the impinged fields of investigation. Amar deduced a fundamental aspect of embryonic development in life based on DNA on planet Earth. Amar’s studies establish that most of organismal life is a projection of the asymmetrically bilateral intrinsic structure of DNA. He concluded that, in addition to its well-studied information code, the physical structure of DNA is also an essential determinant of the body plan that develops in mature organisms. Amar in his survey of laterality in different organisms defined this new rule to operate in animals. I suspect, given the right eye, it will also be discovered to operate in plants as well. The projection extends to postnatal tissue stem cells, with a transition of physical laterality into the cellular asymmetry that provides tissue cell renewal in multicellular organisms. Yes, Amar did convince me that we studied the same phenomenon at different stages of development, embryonic and postnatal, respectively.
My last evening with Amar is a memory that I will hold dear forever. He was quintessential Amar on the evening I met him after the SDB meeting in Boston, beside himself with scientific conviction and satisfaction. After dinner, we stopped for a while at the final reception for the SDB meeting, but split up. I could hear Amar across the restaurant having it out with a group still skeptical of what he had presented in a poster at the meeting. Meanwhile, I found myself in an exchange with a group of young scientists who I overheard debating Amar’s work. They were talking about how he needed to determine the mechanism in order to convince others of the importance of his DNA strand asymmetry ideas. When I queried them, they had read nothing on the topic. So, I suggested that they read Amar’s paper on left-right dynein; and that if they were as bright as they projected, then they should do the experiments they wanted done their damned selves.
By that time, Amar was growing bored with the same refrain. So, we took off, with mutual amusement by our respective exchanges, to continue our discussion begun at dinner. On this occasion, Amar had brought a 750 ml bottle of Macallan 18. We proceeded to finish off this bottle together as he laughed and joked his way through sharing his latest example of how DNA strand asymmetry could explain yet another puzzling human genetic disorder, split hand/foot malformation. It was this presentation that had been dismissed by many at the meeting.
But Amar was beyond caring about the continuing resistance to his idea. He had reached a point that he considered experimental sufficiency and a point of self-satisfaction. He no longer sought nor needed the approval of others. He was quite at peace with his place in the history of the fields of DNA biology and developmental genetics. His most significant biological insight had cost him his reputation, his research funding, the closing of his laboratory, and for a short period, his self-esteem. Every bit of the intellectual capital that Botstein had accorded to Amar nearly 20 years earlier he had spent on this new idea of DNA strand asymmetry as the essential determinant of body plan laterality, that began with his seminal insight that mutations that result in randomization of hand preference could explain human handedness genetics. And that is what true giants of science do: Brilliantly pursue original scientific discovery, no matter what the cost.
Sadly, so sadly, Amar died before his remarkable paradigm shift was completed. Nothing would have made me happier than for him to finally experience the feelings of justification and satisfaction that widespread recognition for the genius of his discovery would have given him. His singular insight and incisive discovery will live on in his many cogent writings of the last two decades of his career and life, all laser-beamed on illuminating the essence of the role of DNA strand asymmetry as the priming determinant of body plan laterality. If the Nobel Prize for Medicine is ever awarded posthumously, Amar Klar should most certainly be the first candidate in the queue. Wherever you are now Amar, know that you were one of the giants of science when you were here.
James L. Sherley
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