Robert L. Metzenberg Memorial Webpage

Robert L. Metzenberg

(1930-2007)

1950 Technician, Dept. of Chemistry, University of Chicago
1951-1955 Graduate assistant, Dept. of Biology, California Institute of Technology
1955-1958 Postdoctoral fellow, Dept. of Physiological Chemistry, University of Wisconsin, Madison
1958-1996 Assistant Professor to Professor, Dept. of Physiological Chemistry, University of Wisconsin, Madison
1996- Professor Emeritus, Dept. of Biomolecular Chemistry, University of Wisconsin, Madison
1996-2002 Visiting/Research Professor, Dept. of Biological Sciences, Stanford University
2002-2005 Visiting Professor, Dept. of Chemistry and Biochemistry, University of California, Los Angeles
2005- Adjunct Professor, Dept. of Biology, California State University, Northridge

Honors and Fellowships

1951 Phi Beta Kappa, Summa cum Laude
1956 Thomas Hunt Morgan Award, Cal Tech
1955-1958 American Cancer Society Postdoctoral Fellow
1985-1963 John and Mary R. Markle Scholar
1963-1973 U.S.P.H.S. Research Career Development Award
1977 John Bascom Professor (undergraduate teaching), University of Wisconsin
1983 Guggenheim Fellow, Stanford University
1990 President, Genetics Society of America
1994 Medical School Dean's Award for Teaching, University of Wisconsin
1996 Fellow of the American Academy of Microbiology
1997 Wisconsin Medical Alumni Award
1997 Elected to National Academy of Sciences
2005 Thomas Hunt Morgan Medalist, Genetics Society of America

Contributed by Howard Metzenberg

Robert Metzenberg was born in Chicago, Illinois, on June 11, 1930. In 1951 he graduated Phi Beta Kappa from Pomona College in Claremont, California, where he majored in Chemistry. Between 1951 and 1955, he earned a PhD at California Institute of Technology in the Division of Biological Sciences. His teachers included Herschel Mitchell, George Beadle, Ed Lewis, A. H. Sturtevant, and Max Delbrück. As a graduate student at Cal Tech, he met his wife Helene Fox, who grew up in Pasadena, California. They were married on June 26, 1954, in Vermont.

In 1955, Bob and Helene moved east, to Madison, Wisconsin. Metzenberg became a professor in the University of Wisconsin, Madison’s Department of Physiological Chemistry (since renamed Biomolecular Chemistry), in the School of Medicine. Throughout his career, Robert Metzenberg conducted research on genetic regulation and metabolism with Neurospora crassa, a fungus that is studied worldwide as a model eukaryotic organism. When he was elected to the National Academy of Sciences in 1997, the academy credited him with the discovery that a cascade of positive- and negative-acting enzyme products of regulatory genes, operating together as a feedback mechanism, can act to govern gene expression. In 2005 he was awarded the Genetics Society of America’s Thomas Hunt Morgan award for lifetime achievement.

Following his retirement from the University of Wisconsin in 1996, He became a research professor at Stanford University. Bob and Helene relocated to Northridge, California in 2002, so that Helene and Bob could live near family. His survivors include his wife, Helene, sons Howard and Stan, daughter-in-law Aida, and two grandchildren.

Bob's last experiment

Memorial tribute to Bob Metzenberg

(Perspective by Eric Selker published in Genetics at bottom)

Bob Metzenberg gathered friends and collaborators around him so easily. On the science side, whenever discussions started about some research project or proposal, Bob was immediately entrapped. He could not do other than become engaged, make certain to understand the research questions, and then often to suggest improvements which would confirm and support the investigation. There seemed to be nothing more rewarding and exciting than to imagine a new explanation of some biological/biochemical mystery, and then consider if it might lead to additional discoveries.

To illustrate his considerate and generous ways: he wouldn't accept full credit for his imaginative proposals but often passed the credits on to his collaborators. He wouldn't accept that I was little more than a technician cleaning the glassware in a current project. He proposed that because my name began with a B, I would be first author while he would be in disguise because his name began with M and was in the middle of the alphabet of the five, six, or so suggested authors. Of course he regarded the investigation (his idea) as an extraordinary contribution. It is. And then as the work went on there was a flood of additional questions raised in his mind that would be investigated as follow ups. The day he died he was physically at work with the research stocks, all the while knowing his health was failing.

Bob would put aside or modify his own activities to assist others with their needs, giving up the convenience and ease of working in his own lab at Wisconsin to move to Stanford, then moving on from Stanford, setting up his laboratory at home so that he would be there to assist family members with their needs. Notably, he could not stop inventing and researching. He would nicely pull such a wide variety of others into collaboration and assistance. Though his field was perhaps molecular biochemistry he could and would look through a microscope or across a bunsen burner or, his choice, an alcohol lamp. Grow cultures and make crosses to develop the right mutant strains. Make media and then improve the chemical contents to better support his creations. Test their genetic characteristics and then insert or extract additional genes as needed.He was so complete.! am very much at a loss without him. We need his guidance.

-Ed Barry

I include in this e-mail a picture of the Yanofksy & Perkins groups at the time Bob was a member of the Perkins lab at Stanford. I knew Bob from his legendary work in Neurospora but I met him personally during the two summers that I spent at Stanford as a visiting scholar in Charley's lab in 1996 and 1999. At the time, Bob has retired from his University post and had decided that the Perkins lab was a fine place to spend his retired time as an active scientist. I was surprised and delighted by his brilliance and wit and by the interest that he showed to anyone coming to his desk to discuss a scientific problem. Finding him continuously at work and tinkering with fluffy tester plates at his tiny lab bench was an inspiring sight. The presence of Charley, David, and Bob just around the corner at Stanford University was an enriching experience. I'm sure that Bob's presence in the fungal research community will be sorely missed.

The group picture was taken in September 1999 while we were having a small farewell party just before my departure after spending the summer in Charley's lab. The participants in the picture are from left to right: Charley Yanofsky, Feng Gong, Vincent Konan, Bob Metzenberg, Bheong-Uk Lee, Kristin Black, Joe Sarsero, David Perkins, Namboori B. Raju, Luis Corrochano, Janet Elder.

- Luis M. Corrochano

Bob, Joan Bennett and David Perkins

I met Bob in 1961 at the very first Neurospora Information Conference in La Jolla, California. The meeting was free for all, in both senses of the phrase, and Bob and I began talking at the free bar after the last-night banquet. Characteristically, he drank Coke, and I drank Canadian Club. Even as I became less articulate, he became more so, and I remember only one thing from that night: I had made one of the best scientific friends of my life.

He was then at Wisconsin;; I had taken a job at the University of Michigan. I kept seeing Bob at meetings, and in the early 1970s, our labs exchanged visits. In Ann Arbor, Bob inspired one of my most daring experiments one I had thought impossible if he had not said, "Why not?" At that point, almost whimsically, he rattled off a protocol that might do the job, and within a month we accomplished the task. This was his habit: using his multitasking imagination to explore, at the speed of light, landscapes of possibilities in ways Mozart might have done to choose harmony and orchestration. As we, his friends, coupled our imaginations to his, we felt that even his hypothetical dead ends were more illuminating than a close scrutiny of quantitative data. He proved repeatedly Francis Bacon's point that the truth is better served by error than by confusion. He remains a model of how much sheer fun science and talking about science could be.

Out of context, one of his remarks about himself might sound ridiculous: "I had no talent!" But the context is illuminating. Having taken instruction in musical composition in earlier times, he had completed several string quartets. He related this to me over lunch one day at Stanford, saying, "They were competent, but they simply followed the rules. Derivative of Haydn and all. But I discovered I simply had no talent!" This not only illustrates Bob's aesthetic refinement, but his curious blend of modesty and ambition, an ambition to use his mind to the fullest. It also explains his symphonic understanding of the complex biochemical systems that he probed with a sensitivity to detail, subtle complexity, and the surprising formal beauty of cascade regulatory systems.

Finally, he became one of the best friends of all of us in our scientific community. Always good humored and anxious to help, he willingly suffered fools, hoping at first he might show them to the light. A lack of success would then bring out advice in an advanced play on words that at least he could enjoy. Finally, the fools would retire, yielding Bob’s attention to others better equipped to enjoy it. I believe Bob made few enemies, largely because he retained a reserve that few people myself included fully penetrated. But what overlay that reserve amounted to an incomparable friend and scientist, one who will glow in the dark for years to come.

- Rowland Davis

Bob and Ron Morris

I only heard this week that Bob Metzenberg died. It has been quite a year of passage for icons of the Neurospora world. The message I pass along is from February 1984, and I think if provides a good example of Bob's sense of humor. I assume many people received correspondence from him in the typed postcard format, and this was one of those. It was just before I attended my first Neurospora conference. Bob had deposited some strains which comprised the so-called big RFLP mapping kit, as the first paragraph notes. He had addressed the package containing them to Dr. Craig Wilson. I kidded him about awarding me an honorary Ph.D. and his response is in the second paragraph.

Here's a quick story which is also illustrative. One day I came into the office just as Patti Hubbard was concluding a phone conversation. It turned out she had been talking to Bob. She had a perplexed look on her face, and when I gave her a quizzical look in return, she said "Bob Metzenberg is just too nice!"

It was a bit hard to believe anyone could be such a nice guy.

- CRAIG WILSON, ex-FGSC

Bob, like David Perkins, was one of the finest people I have known in science. He deserves a lot of memorials.

During a conversation in 2000, I asked Bob which scientific accomplishment he was most proud of in his career. His answer, without even a slight hesitation, was the use of RFLPs for genetic mapping. Although Ray White and David Botstein described the use of RFLPs first (1980), Bob had independently worked out the concept of using naturally occurring polymorphisms for genetic mapping and his group published in 1984 an extensive RFLP map of Neurospora crassa and a detailed protocol that is still used to this day. I was struck by the fact that one of his most prized accomplishments was strictly personal - no glory or credit, just the satisfaction of doing good science.

- Wayne Versaw

Bob and Michael Freitag Bob and Barbara Valent

Bob had an overall knowledge of Neurospora. He was interested in the whole organism from new methods to isolate tetrads, new mapping procedures, biochemcal genetics, moecular biology and new techniques in working with DNA. He was frequent contributor with his ideas to the Neurospora Newsletter and later to the Fungal Genetics Newsletter. His ideas were always useful and unique. He was a wonderful person to talk to you about your reserach. He always had good questions and ways to help you achieve the results you wanted. We shall miss Bob's comments about research and Neurospora in general. His interest in Neurospora did not end with his retirement to California. There is no one else working with Neurospora like him. He made major contributions to the field of Neurospora.

- Mary Case

Bob Metzenberg had not a thing to do with why I first started in Neurospora, but an enormous impact on why I am still working on Neurospora. For people such as myself who tend to become tongue tied around “giants in the field”, Bob was a tonic. He’d relish in any good discussion and always cut to the core in the most matter of fact way. This is not to say that Bob suffered fools with what would be described as the milk of human kindness. Bob could be very direct, but was never unkind. But for anyone new to a field, he was just the kind of senior person who personified a field with which you’d want to be associated.

Of course, his knowledge of basic genetics, and of Neurospora biology, was phenomenal. The problem that lacked a genetic solution simply did not exist in Bob’s book. I think everyone can remember one scheme or another that Bob cooked up to solve a problem;; they were always really clever (sometimes a bit too clever), presented with an air of genuine and almost breathless enthusiasm, and relied on strains or aspects of Neurospora biology that most folks had forgotten, if they’d ever even learned them. His original invocation of transvection to explain what became MSUD (I remember saying, “huh”, when he first explained this to me), and his extrapolation of this to other problems in genetics (like haplo-insufficiency), was one such example.

Another was his novel and ultimately correct interpretation of the QA-1F and QA-1S complementation and heterokaryon data in terms of distinct interacting proteins – in 1979, well before the molecular denouement. And of course his analysis of the genetic cascade in phosphorous regulation was rightly viewed as a tour-de-force;; you know something is complicated when the “summary figure” is the first one in the paper rather than the last. Bob thought deeply about problems, cherished the exceptions to prevailing models, and brought to bear on everything he touched both a native and unquenchable enthusiasm as well as a synoptic knowledge of Neurospora biology and genetics. Such are the people that define fields.

Probably the thing I will best remember about Bob, though, is his wonderful word craft. He loved to use words in the way a carpenter loves to use wood. He was an artist with words. I still have notes from talks and discussions where he dropped verbal gems, and some I have since adopted for my own. I remember one discussion about heterokaryons where someone (probably me) advanced (without sufficient forethought) the idea that the final nuclear ratio in the heterokaryon might reflect the relative numbers of homokaryotic nuclei mixed. Bob shot back, “Well, that sounds good if you say it fast”, which was indeed true. It’s a phrase I’ve often since used myself for glibly pronounced but poorly thought out explanations. Another was the phrase “low hanging fruits” to describe the easy scientific pickings available when a field is newly populated.

Always a ready ear, always a new idea, always a novel screen and a mutant that I had never even thought of thinking about, always the perfect word and the apt phrase, and always the word of encouragement for science that he thought was going somewhere – how could anyone not want to work on Neurospora with someone like Bob Metzenberg to talk to?

- Jay Dunlap

Bob and Colleagues

I remembered hearing Bob's name for the first time from my Ph.D. supervisor, Louise Glass. Bob was Louise's postdoctoral mentor, and she always had the nicest things to say about him. According to Louise, he was intelligent, helpful, kind, and witty. Having known him in person, he was all of the above, and then some.

My first encounter with Bob was in a conference. Like the perfect gentleman that he was, he gave me encouragement and advice on my project concerning mating-type genes (which incidentally, were first characterized by his and Charley Yanosky's groups). Even as the legend he was, he never made people feel intimidated.

Upon retirement, Bob moved to David Perkins' lab at Stanford and began his "second career" as a Visiting Professor. Having been informed of my imminent graduation, Bob invited me to work with him as a postdoctoral fellow. Although I had my mind set on working with another brilliant scientist (Nancy Keller) at the time, I could not pass up the opportunity to learn from my academic grandfather (and risk having Louise be mad at me).

My best memories in science remain to be my tenure at Stanford. I remembered having daily lunch meetings with Bob, Perkins, Jacobson, Raju, and many other visitors (and there were many of them, especially during the Asilomar meetings in March). The conversations were not just about the crazy ideas that he had (many of which turned out to be big discoveries in science). Bob was extremely well-read and he could start an interesting conversation on any topic - history, art, politics, cultures, breweries, and the taste of horse meat, just to name a few.

As an employer, he was the perfect boss - he took care of his employees' needs. Many of his protégés went on to have a very successful career. As a friend, he was as loyal as they come. During Christmas and Thanksgiving, he would open his home to me (and other singles alike) and made me feel like I was a part of his extended family. I remembered singing Christmas carols after the turkey dinner, and Bob would be able to play any song you threw at him, ad lib. That was amazing to me, considering that he never had any official piano training.

Bob was never the prototypic principle investigator. You would never find him paper pushing at his desk, since he was too busy working on the bench. He was the MacGyver of our generation - nothing was too crazy to be utilized in the name of science (e.g. screws joined together as a 96-pin library replicator). He would rather fabricate an instrument himself and not waste taxpayers' money.

Bob was a mentor, a friend, and a father to many of us. He will be sorely missed.

- Patrick Shiu

Bob and Mary Anne Nelson

Bob was a very special person to me. My Ph.D. is in Microbiology from the University of Georgia (1975) and my research was under the direction of Branch Howe. My problem involved genetic crosses of N. tetrasperma. As you know, in N. tetrasperma normally each of the four ascospores resulting from a fertilization event has nuclei of both mating types and so is self fertile. This does not lend itself to genetic anallysis and in order to do the research, I had to try to find the RARE dwarf ascospores which would hopefully have only one nucleus. Things were not going well, and I might still be trying to get enough data except for the help of Bob Metzenberg.

Bob had produced hybrids between N. tetrasperma and N. crassa. The hybrids produced asci with eight ascospores allowing for genetic analysis. Bob sent me cultures that were: 3tetra:1crassa;; 2tetra:2crassa;; 1tetra:3crassa. I was able to cross my tetrasperma mutants to these hybrids and thus transfer the genes) we were interested in to an N. crassa system with eight ascospores/ascus with each ascospore containing nuclei of only one mating type. From this, my work moved along and I was able to map and analyze the genes we were interested in. And, also, very importantly, to complete my degree. This help, which Bob so willingly gave to me, is characteristic of the man he was and how dedicated he was to science and how concerned he was about others.

He will be missed.

- Sare Neville Bennett

Bob was a wonderful scientist and intellectually adventurous person. He had a remarkable grasp of metabolism and its integration into the physiology of an organism. From the time I began an independent career, Bob was my resource for any baffling interaction that I couldn't make heads or tails of. On one occasion I mentioned a peculiar growth behavior of a mutant in the glyoxalate pathway. Bob always greeted such puzzles with an affectionate broad grin. This was the kind of problem that tickled his fancy, even though it was my problem. Without hesitation, he made a key connection between glyoxalate metabolism and gluconeogenesis that had completely eluded my students and me. The connection he made formed the basis for many important discoveries in my laboratory. Like so many of his colleagues, I found my career influenced by Bob's unique scientific style and generous spirit.

- Gerald R. Fink

Bob was always very interested in our physical mapping work. He provided advice along the way and always encouraged me to finish it even after the publication of the sequence. We have done so, and he would be pleased to know that we have finished and integrated our physical map of N. crassa with his RFLP map. He remains an inspiration to all of us,

- Jonathan Arnold

Bob and Louise Glass

Bob is and has been an inspiration to me, both on a personal and professional level. I first met Bob at a Keystone meeting, where we discussed possible post- doctoral projects. I was semi-comatose (after a week long meeting and rooming with John Hamer and Melanie Yelton), but I remember vividly Bob's passion and enthusiasm for approaching biological issues. I had never met anyone before who showed such a love for biology and experimental science. That passion continued to be apparent when I was a post-doc in Bob's lab. Our lab meetings often dwelled on biological questions other than projects in the lab and how to approach them on an experimental level. Since leaving Bob's lab, I often talked with him about "how Neurospora does it" and the development of methods for genetic research. I will sorely miss those mind-broadening, educational and motivational discussions. He also was a terrific supporter of new scientists in Neurospora biology, including new assistant professors, post-doctoral associates, graduate students and even undergraduates;; he always made time for us. In addition to being the most inspirational scientist that I have known, Bob, along with David Perkins, was also the most selfless. He habitually gave out strains and ideas prior to publication and refused to be an author on publications unless he actually contributed experimental work. Now that Bob is gone (in the physical sense), he still remains an inspiration to me. I often find myself asking "How would Bob approach this question?" and "What kind of tools need to be developed to help to address this aspect of Neurospora biology?" and sometimes, I think I hear a few suggestions that help me along the way.

- Louise Glass

Bob's "retirement" lab and outdoor autoclave

Bob Metzenberg and the FGSC

In comments after being awarded the 2005 Thomas Hunt Morgan Award at the 23rd Fungal Genetics Conference, Bob Metzenberg took a moment to acknowledge the role of the Fungal Genetics Stock Center in providing an even playing field for scientists interested in fungal genetics. He called the FGSC an "open source" for fungal genetics, comparing it to the open source software movement. This was not just a passing comment, but rather the culmination of a career of support and use of the resources at the FGSC.

Bob Metzenberg has deposited 254 strains into the FGSC collection including 231 Neurospora crassa strains as well as N. sitophila, and N. tetrasperma strains, interspecific hybrid strains and even Gelasinospora strains. The first strain Bob deposited, FGSC 1769, reached the FGSC in October of 1969 in a group of eleven strains. They were described as hybrids between N. crassa and N. sitophila useful for transferring genes between species (Metzenberg and Algren, 1969). Demonstrating the value of long-term collections, most of these strains were not requested from the FGSC until after 2000 but have been distributed a number of times since then.

Correspondence between Bob and Bill Ogata, the first FGSC curator, suggests that strain 1226 which has the genotype rib(76R5) and which was deposited by Walter S. McNutt in 1965 may be Bob Metzenberg's first strain deposited into the FGSC. This is the level of detail that early correspondence between Bob and FGSC director Ray Barratt included.

The next group of strains deposited were aryl sulfatase mutants of N. crassa which were the first of a number of mineral metabolism strains Bob developed. These ars-1 strains were the result of UV irradiation but also coincided with a description of variation in aryl sulfatase proteins among wild strains from a number of Neurospora species.

Many later strains were specific purpose strains such as RFLP mapping, heterokaryon maintenance or manipulation or even transformation strains. These were all useful and widely used.

Bob was also very supportive of the evolution of the FGSC into a repository for molecular genetic materials and first suggested this in a January 1980 letter to Bill Ogata. The FGSC collection of molecular clones now numbers nearly 650 plasmids. Of these, up to ten percent were deposited by Bob Metzenberg or his academic progeny (or theirs).

Bob also used the resources in the FGSC collection. Since 1987 he ordered 317 strains, including mutants, wild type strains, and many strains with translocations or inversions. Bob also used the molecular resources he promoted and received nine plasmids and three gene libraries.

Bob supported the FGSC in other ways. He donated a supply of the cell wall synthesis inhibitor polyoxin B to assure that it would remain available. He was generous with his energy, ideas and time. This is truly a remarkable heritage and establishes Bob Metzenberg as one of the giants upon whose shoulders future generations will stand.

- Kevin McCluskey

Bob and Colleagues (Mary Anne Nelson, Tom Randal, Bob, his car, Mary Anne Nelson and Seogchan Kang
Jeff Grotelueschen and David Butler) on a collecting trip on a collecting trip

I’ve known Bob since the second Neurospora Information Conference, at Rice University in 1964, when I was a young graduate student. That’s a long friendship, and I’ll certainly miss him. He was one of the giants of our community, with a phenomenal intellect and a propensity for thinking out of the box. He gave us sulphur and phosphorus uptake and metabolism, regulatory cascades, RFLP mapping, tRNA and rRNA genes, and so much more from his own work. He gave so many of us, so freely, novel insights and suggestions regarding our own research. Over the last few years, I’ve really appreciated his support and encouragement as the e-Compendium has been developed, but that was typical of Bob. He was one of the key people who set the style of the Neurospora community – that of cooperation and mutual support, and that may be as important to us in the future as his research output.

- Al Radford

Bob and P. Maruthi Mohan & Bob at the bench

My meeting with this noble soul was very short, but his work is of great influence. My first attempt to meet him in Wisconsin could only materialize with a brief telephonic talk. He was gentle and apologetic that he cannot meet on that day (in 1988), but was willing to help with the lab protocols for preparation of protoplasts and transformation. Only in 2003 I got the oppurtunity to meet this extraordinary scientist with a pleasing smile.

- P. Maruthi Mohan

Bob before Helene & Bob after Helene

Bob and Helene were married for 53 years. Helene was an important contributor to Bob's love of life and the pursuit of science.

(Perpsective for Genetics)

BOB METZENBERG: GENETICIST EXTRAORDINAIRE AND "MODEL HUMAN" by Eric U. Selker

Kooert L. lVIetzenoerg, June 11, • :;U-JWY 1: lJenencist

Perspectives

Anecdotal, Historical and Critical Commentaries on Genetics

Edited by James F. Crow and William F. Dove

Robert L. Metzenberg, June 11, 1930–July 15, 2007: Geneticist

Extraordinaire and ‘‘Model Human’’

Eric U. Selker1

Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403-1229

The genetics world was saddened by the recent death of Bob Metzenberg. We invited Eric Selker to write an informal biography and tribute and several others to write remembrances. These illustrate the high esteem in which he was held by his colleagues. Among other honors, Bob was elected to the National Academy of Sciences and in 2005 was awarded the Thomas Hunt Morgan Medal by the Genetics Society of America.

J. F. Crow and W. F. Dove

first met Bob Metzenberg (Figure 1) when he came to Reed College to give the Gabriel Lester Memorial Lecture in 1974. He made a convincing case for using the fungus Neurospora crassa to investigate gene regulation in eukaryotes. This was, of course, before DNA-mediated transformation of Neurospora and other eukaryotes, before the invention of recombinant DNA techniques, and even before a reliable method of extracting nucleic acids from Neurospora had been described. However, as anyone who has heard Bob give a presentation, formally or informally, knows, he had a knack for arranging information into tight stories and his special blend of humor and style ensured that even potentially sleepy undergraduates remained tuned in. Bob described his investigations on regulation of sulfur and phosphorus utilization at a time when little was understood about gene regulation in eukaryotes. His identification of mul- tiple regulatory mutants and his demonstration that the underlying genes exist in a hierarchy to turn on families of unlinked structural genes was clearly a major advance. Indeed, Bob was the first to discover a cascade of positive- and negative-acting products of regulatory genes acting to govern eukaryotic gene expression. These studies fore- shadowed the discovery of similar signal transduction systems in other organisms. Bob Metzenberg was not a person who tooted his own horn, however. ½For example, he was not the type who ‘‘casually’’ mentioned that he was a member of the National Academy of Sciences, was awarded a MERIT grant, and had one of the longest-

1Author e-mail: selker@uoregon.edu

Genetics 178: 611–619 (February 2008)

running National Institutes of Health grants ever (over
38 years) or that he had been awarded a slew of other prestigious honors, including the Thomas Hunt Morgan Medal (Selker et al. 2005).]
Visiting the Metzenberg laboratory 4 years later left me with two other strong impressions of Bob: his approachability and the breadth and depth of his in- tellectual tool chest. I discovered that he was a chemist disguised as a geneticist. The disguise was effective be- cause he was an extraordinary geneticist, but his core of chemistry served him well: as an award-winning bio- chemistry professor, as a molecular biologist, and as an advisor for thousands of students and colleagues who learned to seek his advice. Those who interacted with Bob quickly discovered that the value of his extensive knowledge base was amplified by his uncommon imag- ination and by his legendary generosity. Gerry Fink recently noted,

Bob was a wonderful scientist and intellectually adventur- ous person. He had a remarkable grasp of metabolism and its integration into the physiology of an organism. From the time I began an independent career, Bob was my resource for any baffling interaction that I couldn’t make heads or tails of. On one occasion I mentioned a peculiar growth behavior of a mutant in the glyoxalate pathway. Bob always greeted such puzzles with an affectionate broad grin. This was the kind of problem that tickled his fancy, even though it was my problem. Without hesitation, he made a key connection between glyoxalate metabolism and gluconeogenesis that had completely eluded my stu- dents and me. The connection he made formed the basis for many important discoveries in my laboratory. Like so many of his colleagues, I found my career influenced by Bob’s unique scientific style and generous spirit.

‘‘DEFINING CORE,’’ EDUCATION, AND CAREER

Robert Metzenberg was born on June 11, 1930, in Chicago, where his great-grandfather had settled. Apparently Bob’s great-great-great-grandfather, the

612 E. U. Selker

Figure 1.—Bob Metzenberg. Bob loved thinking about science in his free time. The handwriting in the background is from letters written by him while waiting for planes. In one he suggested a possible way to recognize N-methyl adenine in conjunction with the Church–Gilbert genomic sequencing method. The two additional people in the bottom image are Joan Bennett and David Perkins.

‘‘Stammvater,’’ or first Metzenberg with a surname, was a fairly successful furrier, dyer, and leather worker in Germany. Bob owed his life to the fact that one of his great-great-great-grandfather’s sons decided to stay in Ireland after going there to buy a supply of leather. After I told Bob about visiting Germany to participate in a tri- bute to relatives of mine lost in the Holocaust, he wrote to me that he had tried to trace relatives who had lived on the Continent but his research invariably led to ‘ in Buchenwald gestorben’’ (died in Buchenwald). He concluded,

It seems that nobody in my patronymic family survived the Holocaust. I have no living relative on the Continent on my mother’s side either.. . . The Holocaust was much talked about in my family when I was a small child. I have no doubt that horror of it was, and is, the defining core of my life. I have never lost my gratitude for having been born in this country, nor have I ever taken my luck for granted.

From an early age Bob lived intensely and made the most of life. Growing up, he focused on competitive swimming, photography, and baseball and excelled in
arithmetic and spelling at the expense of English and art. He earned spending money mowing lawns, which financed movies, dates, etc. He cared about the world and idolized Adlai Stevenson. After graduating from high school, Bob headed west to Pomona College and made firm ties in California.
At Pomona, Bob majored in chemistry and minored in physics and biology, which he noted were ‘‘almost immiscible with chemistry’’ at the time. His Pomona and life-long buddy George Becker reflected,

The Chemistry Department was anything but stuffy. Prof. R. Nelson Smith and his partner Corwin Hansch were constantly pranking one another and set the tone for their students. Partly as a result of his own DNA and certainly as a result of being in that Chemistry Depart- ment, ‘‘Metz’’ was emboldened to pull pranks constantly. No one enjoyed it more.

Becker also noted,

Metz was bright, very bright and used to astonish his friends by ‘‘testing out’’ of classes. He seemed to be able to

Perspectives 613

avoid taking beginning classes and in doing so he was very self denigrating saying he was ‘‘lucky’’ etc.

In 1951 Bob graduated Phi Beta Kappa and enrolled in the Division of Biological Sciences at the California Institute of Technology for graduate studies. He worked with Herschel Mitchell on the synthesis of certain amino acids and interacted with an impressive group of ge- neticists and biochemists, including George Beadle, Ed Lewis, A. H. Sturtevant, and Max Delbru¨ ck. Matt Mesel- son commented, ‘‘Bob greatly helped to make CalTech the humane and intellectually exciting place it was in those days.’’
Bob did manage to find time for necessary fun,
however. For example, Bob Lester recalls ‘‘many fine memories of extracurricular hijinks while we were still bachelors, e.g., skinny dipping on a hot deserted beach in Mexico with Bob and Len Hertzenberg and paying for the sunburn where the sun doesn’t usually shine.’’
While at CalTech, Bob married Helene Fox of Pasa-
dena, and afterwards they moved to Madison, Wisconsin, so that he could do postdoctoral research in the De- partment of Physiological Chemistry at the University of Wisconsin School of Medicine. Bob worked with Philip Cohen on enzymatic reactions involved in urea synthesis in mammals and amphibians, but he became increas- ingly interested in the underlying gene regulation. He therefore took a 1-year visiting scientist position in the group of Ernst Hadorn in Zurich to do some ‘‘reading and listening’’ and to get ‘‘hands-on experience in de- velopmental genetics.’’ In 1958 Bob returned to the Department of Physiological Chemistry as an assistant professor and decided to study the regulation of enzyme synthesis in a simple eukaryote. He chose Neurospora, with which he had become familiar as a graduate stu- dent. He wanted to answer such questions as: (1) How many genes are involved in the regulation of typical families of adaptive enzymes?, (2) Do these genes act by preventing the activity of spontaneously active genes or by engendering the activity of otherwise inactive genes?, (3) If several genes are involved in the regulation of such pathways, do they exist as parallel, alternative sig- naling mechanisms or as a hierarchical series?, and (4) Do the structural and regulatory genes involved in a family of adaptive enzymes tend to map close together or are they scattered throughout the genome? In a tour de force, in the 1970s Bob and his colleagues answered all of these questions for genes required during depri- vation of phosphorus or sulfur.
In 1977 Bob visited Stanford, where I was a graduate
student, and we exchanged notes about our respective efforts to clone interesting Neurospora genes. After I extolled the virtues of building genomic libraries in phage rather than in plasmids, Bob invited me to visit his lab to help them set up some things. My visit, in May
1978, was pivotal for me, leading to decades of enjoyable collaborations and enduring friendships. Although
neither of us had been successful in isolating the genes in which we were most interested, we tried to make the best of those that came relatively easily, such as rDNA genes. A joint ‘ side project,’’ to characterize the 5S rRNA genes of Neurospora, became central to both of our ef- forts (Selker et al. 1981). We exchanged countless let- ters and phone calls on everything from technical details to potential mechanisms of concerted evolution of dispersed genes. Bob’s colorful writing livened up even mundane topics. Here are a few snippets from a rep- resentative letter of 1981:

That should be impossible, I think, because there should be no RI site with lambda sequences on both sides of it. I’m trying again, and hope nothing so interesting happens next time.

...

Well, that’s all woolgathering at this point, but the experiments to be done are fairly obvious. Or at least some of them are. Give me your thoughts on this too!

...

Everything seems to violate common sense, but perhaps a few solid facts will shape it up.

...

I couldn’t help thinking of something wild: parsley is one of those plants, along with (at least) celery and parsnips, that contain psoralens at quite substantial concen- trations.. . . It would certainly be interesting if the gene in a living plant ever turned into snapback DNA in response to infection or injury, but I admit it’s a crazy idea.

Two years later, when I joined Bob’s lab after a stint in Germany, I found him still working on the 5S genes. In an application for a Guggenheim Fellowship (awarded for his sabbatical in 1983), Bob commented, ‘‘In the last couple of years, accidental events have sparked my interest in a biological problem on which I had not previously done any research.’’ To map the 5S RNA genes, Bob developed RFLP mapping for Neurospora (Metzenberg et al. 1984, 1985). In reference to this, Wayne Versaw, Bob’s last graduate student wrote,

During a conversation in 2000, I asked Bob which sci- entific accomplishment he was most proud of in his career. His answer, without even a slight hesitation, was the use of RFLPs for genetic mapping. Although Ray White and David Botstein described the use of RFLPs first (1980), Bob had independently worked out the concept of using naturally occurring polymorphisms for genetic mapping and his group published in 1984 an extensive RFLP map of Neurospora crassa and a detailed protocol that is still used to this day. I was struck by the fact that one of his most prized accomplishments was strictly personal—no glory or credit, just the satisfaction of doing good science.

In the late 1980s and early 1990s, Bob and members of his laboratory made important contributions in other areas, including characterizing the structure and func-

614 E. U. Selker

Figure 2.—Bob and his home laboratory. Clockwise from top left: Bob, January 2007;

‘‘stockroom’’; microscope and work table; ‘‘auto-

clave.’’

tion of mating genes of Neurospora (Glass et al. 1988,
1990a,b; Metzenberg 1990; Metzenberg and Glass
1990; Nelson and Metzenberg 1992; Randall and Metzenberg 1995; Ferreira et al. 1998), discovering a premeiotic process resulting in drastic changes in the number of tandem rDNA repeats in the genome (Butler and Metzenberg 1989) and isolating and characterizing the phosphorus family genes (Mann et al. 1988; Kang and Metzenberg 1993; Peleg et al.
1996) that Bob had identified genetically in the early
1970s (for review, see Metzenberg 1979). He also continued to design and share imaginative technical advances, such as a method to use ‘‘sheltered RIP’’ (repeat-induced point mutation) to identify and study essential genes (Harkness et al. 1994) and a new chemical method to couple DNA to glass slides for microarray experiments (Dolan et al. 2001). Mary Case noted,

Bob had an overall knowledge of Neurospora. He was interested in the whole organism from new methods to isolate tetrads, new mapping procedures, biochemi- cal genetics, molecular biology and new techniques in working with DNA. He was a frequent contributor with his ideas to the Neurospora Newsletter and later to the Fungal Genetics Newsletter. His ideas were al- ways useful and unique. He was a wonderful person to talk to you about your research. He always had good questions and ways to help you achieve the results you wanted.. . .

Bob’s generosity and creativity together yielded count- less contributions to the community. A typical multi-page letter from Bob in 1991, describing a new idea for iden- tifying recessive mutations in essential genes, started with, ‘‘I have no special reason to think you need this
procedure, but I wanted to give you, Mary Anne and
Louise copies of this in case it proves useful.’’ Immediately before ‘‘retiring’’ in 1996, Bob and his
postdoctoral fellow discovered a remarkable and un- expected new epigenetic phenomenon in Neuros- pora, initially called meiotic transvection and later renamed ‘‘MSUD’’ for meiotic silencing by unpaired DNA (Aramayo and Metzenberg 1996; Shiu et al. 2001). Elegant work, largely devised and carried out by Bob independently, showed that any sequence that is un- paired during meiosis elicits an RNAi-like mechanism that silences all homologous sequences in the genome, paired or unpaired, for the duration of meiosis. The finding that MSUD is mechanistically related to RNAi came from one of Bob’s characteristically imaginative genetic schemes for selecting suppressor mutations.
As detailed below in the remembrance by Namboori B. Raju and David J. Jacobson, while fighting cancer, Bob worked his last 10 years as an emeritus professor, first at Stanford, followed by UCLA, California State University at Northridge, and, finally, up until his final day, in his home laboratory (see Figure 2).
In his marvelous style, in January of 2007, Bob wrote a piece entitled ‘‘Research in your retirement house’’ (p. 7 of http://www.genetics-gsa.org/pdf/newsletter_jan07. pdf), which starts out:

Retirement can be one of the most productive and satisfying times of your scientific career. All you need is a spare, dedicated room, an understanding and patient companion, neighbors who don’t suspect you of brewing up anthrax bacilli, and a small amount of money.

He goes on, suggesting,‘‘do not be shy about doing a bit of dumpster-diving at an institution near you’’ and

Perspectives 615

notes that ‘‘younger people will see you as a harmless eccentric.’’ He then proceeds to explain that when normal job constraints are suddenly removed, ‘‘one discovers how severely they limit our ability to follow up high-risk, high-payoff ideas.’’

STYLE AND HUMOR

Bob’s enjoyable and interesting style was not only evident in his writing and speaking—it came through in all aspects of his life. He made the extra effort to add flair, consistent with his entry in a ‘‘Grandfather Re- members’’ book that he filled out when his granddaugh- ter was born in 1985. He said that a simple statement that sums up his attitude about life is: ‘‘it should be enjoyed and lived with a little enthusiasm and flair. We should be ready to leave when it’s over.’’
Clearly, Bob had no shortage of ‘‘enthusiasm and flair.’’ Craig Wilson, who was curator of the Fungal Genetics Stock Center, contributed the following from a typical Metzenberg postcard:

I apologize for calling you Doctor, and didn’t know whether it applied or not. When people ask me if I like to be called Dr. or what, I tell them my real preference would be to be called ‘‘Oh, Venerable One,’’ but too often it comes out

‘‘Venereal One.’’ My second favorite name is ‘‘Bob.’’

Probably everyone who interacted with Bob has at least one example of his humor coupled with his hu- mility. I selected the following examples from e-mails that Bob sent me over the last few years, written while already fighting for his life:

Thank you for your kind words. I still think they made a clerical error and some poor secretary is going to be fired.

...

Sorry it’s taken me several days to answer your letter. My mind seemed to be going ta-pocketa on one cylinder, but this morning a second cylinder seems to be coughing fitfully into action. Let me try to state the problem to see if I have got it right.

...

Some or all of you may tell me I have devised the Neurospora equivalent of an appendix transplant. I await your criticisms! Alternatively, would anybody be willing to pick a few interesting, obviously essential genes and try a proof-of-principle? I would try to be helpful.

...

I finally clicked into Genetics, and, lo and behold, there I was. At last I understand how a ‘‘woman of a certain age’’ feels when she gets an extreme makeover at a top-of-the- line spa and likes the stranger she sees in the mirror. I haven’t forgotten that, despite your kind profile, I’m still me, warts and all. Nevertheless, it was more than generous of you to airbrush them out.

...

As far as I am concerned, fruitcakes are one of the crowning achievements of Western civilization, and will

persist after the Sistine Chapel has crumbled into ruins and the late Beethoven Quartets have been forgotten. Well, almost, anyway.

...

With a little luck, I will be around for a long time to bedevil my friends and family, but if that’s not in the cards, I want things to be left reasonably shipshape.

...

I’m sorry it took me five days to respond to your letter. It was my druggy week, and I have been sleeping most of every day and spending my waking hours wandering on a strange, cratered planet on which I am the only life form. Finally yesterday I started to return to earth, and today I even drove into UCLA and got some samples ready for Patrick to work on tomorrow. The next two weeks will be fine—then it all starts over again, unfortunately. I should count my blessings: hardly anyone has it so easy.

...

Thank you so much for the letter, which is full of interesting ideas that I want to study further. It cheered me up to be hearing and thinking science again!

...

You were correct in guessing that I might be full of poisons that would keep me from responding promptly or even lucidly. It has been a less than perfect month, which finally culminated in a substantial stay in the hospital with a pulmonary embolism. Since I have only three of my original five lobes, losing function in one of them was very unwelcome. I am, thank goodness, now discharged from the hospital. However, no more bungee-jumping, sky- diving, or street-fighting allowed; I will be on blood- thinners from here on out.

After nearly succumbing to pneumonia in January
2006, Bob wrote,

... a few people have told me from time to time that I have walked the earth with no baggage, and that I am a completely uncomplicated person. I wish it were true, but the right moment to correct this impression has never presented itself. But after I go to that Big Lab Bench in the Sky, someone may say so again. I don’t want to have my character prettied up any more than my physical remains. I’ve elected you to say ‘‘It ain’t so!’’

The fact is that Bob’s character and credentials are not at all in need of being ‘‘prettied up’’: they are impressive in their native state. Bob was a model scientist, continuously doing research with his own hands and overflowing with ideas, energy, and flair. He was a natural tinkerer and educator who also inspired others to try ‘‘wild’’ things. Moreover, he was a model human being: caring and generous with a great sense of humor. And in spite of his talents, Bob was exceptionally modest. He was complex, but only in a positive way. We will continue to miss him tremendously.

REMEMBRANCES FROM THE WISCONSIN COMMUNITY

The following remembrances are from colleagues at the University of Wisconsin, where Bob Metzenberg

616 E. U. Selker

joined the faculty in 1958 as an assistant professor of physiological chemistry. Bob’s role on the faculty of that department in the medical school is expressed by his colleague Larry Kahan:
When I joined the Physiological Chemistry Depart- ment in 1973, I was given the opportunity of sitting in on Bob’s lectures to the medical students. I did this with more than a little interest since I was slated to take over some of those lectures the following year. I was surprised and impressed by the way in which Bob could take as relatively dry a subject as the biochemistry of blood clotting and weave in everything from European history to the similarities between genetic dissection of a pathway and biochemical dissection of a pathway in ways that captured the interest of the medical students. His lectures had everything—basic biochemical and genetic principles, clinical examples, and a good deal of very dry humor. Bob made it clear to the students that he was not just teaching them biochemical facts: he was also preparing them to understand and incorporate the biochemistry that they would encounter in the several decades of their careers as physicians.
Behind the scenes I had some long discussions about
teaching philosophy with Bob. At the time, the medical school was starting up a new, independent study cur- riculum. Bob had some very definite ideas about teach- ing, particularly about the value of integrating the basic science courses of the first semester by studying the sub- jects concurrently rather than serially, the unique learn- ing gained from hands-on laboratory experiences, the value of the lecture as a teaching method, and the proper way to test students, which were at odds with the then- current philosophy of the medical school. He was instru- mental in arriving at a compromise that maintained some of these elements even in the new independent study curriculum (eventually abandoned several years later).
Bob was truly a dedicated teacher. He loved being in
the laboratory with students during the enzyme kinetics laboratory, walking around and pointing out that they could see the tubes changing color as the reaction pro- ceeded. His lectures were classics. When introducing the subject of prenatal diagnosis, Bob began with the following:

‘‘A Whimsical Example Illustrating the Principle.’’ I have chosen prenatal diagnosis of Transylvanian Vampirism to emphasize that we don’t need to know the relation between the gene and phenotype to apply this method. The analysis is made possible by linkage of the gene governing this trait to the gene which determines round vs. square toenails. Vampirism is caused by homozygosis for the recessive allele, vp (genetic constitution vp/vp). Heterozygotes and homozygotes (Vp/vp and Vp/Vp, re- spectively) are not vampires. In the romance of the century, Melanie Moozendoodle and Gary Gazinkus courted, wed, and started procreating. Unbeknownst to them they were both descendants of the infamous Vlad Tepes the Impaler (Count Dracula) and were hetero- zygotes of constitution Vp/vp. This came to light when

their firstborn turned out to be a vampire.. . . When Melanie became pregnant again, she decided that nurs- ing one child from her jugular vein was enough. Gary, who was taking half the night feedings, agreed. Yet they knew that there was one chance in four the fetus she was carrying would be a homozygote, like its older sibling. The hollow saber incisors characteristic of vp/vp homozygotes appear only at birth, so there is no way this can be directly observed in the fetus. Can any predictions be made?

Bob then proceeded by analysis of linkage of the vampirism gene to the toenail-shape gene to the conclusion that:

The new Gazinkus child is the joy of her parents’ lives. The only sign of her heterozygous condition is that, like the parents themselves, she gets a craving for blood sausage when the moon is full.

After capturing the students’ interest, Bob then went on to introduce the students to prenatal diagnosis through the use of closely linked RFLPs.
Bob’s knowledge was truly encyclopedic. It was well known and appreciated that if you had a really strange question you could not answer that Bob was the person to ask, no matter how unrelated the question might be to his teaching or research. I took frequent advantage of this, and he never disappointed. He was always willing to take on extra teaching to help out a colleague, some- times giving a lecture literally on a moment’s notice.
Finally, Bob really cared about the students. He was willing to spend hours going over the material with students who were having difficulty. He delighted in working with students who wanted to extend the material that he had covered.
Within the mega-university of Wisconsin, as in many a research university, a faculty member could fully occupy himself with his research program and his departmental responsibilities. Not so, Bob Metzenberg, as explained in the following by Bill Dove:
Bob and I first came together as pioneers. Working with Walter Plaut (zoology) and Millard Susman (ge- netics), we (physiological chemistry and cancer biology) crossed the college and departmental matrix of the mega-university that is Wisconsin. We were driven only by our shared enthusiasm for the emergent fields of molecular genetics and molecular cell biology and by our enjoyment of the spectrum of undergraduates in this land-grant university who chose to join us to explore new fields of inquiry without boundaries. Our guiding educational principle was the importance of ‘‘The Experiment.’’ For a full year, we four designed a set of novel experiments in cell biology, biochemistry, and genetics. For decades afterward, Bob continued to de- sign experiments for Biocore as it grew from a cottage industry to one of the bulwarks of undergraduate edu- cation in biology at Wisconsin. Indeed, The Experiment was Bob’s lifeblood—for his own science and then for his teaching of others.

Perspectives 617

Another example of Bob’s talent for explanation of seemingly subtle ideas is offered here by Millard Susman:

In the Biocore course, Bob wanted to make the point that the various scientific disciplines were distinguished by the methods that they used and by the kinds of questions that they asked. He told the students that a biochemist who wanted to understand a motor car would grind it up, reducing it to a pile of little chunks, and then would separate the chunks from one another, studying each chunk separately to try to figure out what it did and how it did it. An anatomist would get a huge band saw and slice the car like a salami. The anatomist would then study the slices individually and in sequence to try to figure out the contours of the individual parts and to determine which parts were connected to one another and how they are connected. A geneticist would work with the whole car, removing one bit at a time—a valve here, a gear there—- and see how the removal of that one part affected the operation of the car. It was an immediately comprehen- sible and memorable analogy.

Bob’s life at Wisconsin, in the university and in the community, knew no boundaries. During the three decades following our foray into the wilderness of Biocore, many of our encounters involved mutually enjoyed musical events. Bob had a finely tuned sensitiv- ity to the differences among people—beyond the student body at Wisconsin. We would often exchange postcards from new travel discoveries. We and our wives jointly came forward to help preserve Wisconsin’s classical American Player’s Theater (APT), where Bob again demonstrated his ability to cross disciplines. Discovering with Louise Glass and others that the different alleles of the highly polymorphic mating- type loci of fungi each arose from a distinct sequence origin, Bob consulted with the classics professor of Beloit College who was directing one of the plays at APT. From that consultation was born the neologism
‘‘idiomorph.’’
Bob Metzenberg’s quick sense of humor was en- hanced by his ability to recall facts and events that allowed him to view events in unusual ways. Both within and outside of the laboratory and classroom he was well known for his encyclopedic knowledge of tastes and smells. Jim Dahlberg has noted how these latter abilities made him a very popular expert at wine-tasting gather- ings. He was said to have a ‘‘gas-chromatographic nose’’ for ketones and esters. He was a cofounder and an active member of a tasting group that still meets regularly, and his wry comments kept the group from becoming too serious about itself.
The decade in California, described below, generated the end of this story. We continued to exchange mes- sages about new ideas, and in 2005 Bob stepped for- ward to write a masterly essay on one of his Caltech mentors, Norman Horowitz, for the Perspectives article in Genetics (Metzenberg 2005). Our last encounter was in January 2006 when Alexandra and I briefly visited Bob and Helene in Northridge. Again, The Experiment
took first place. Bob announced that he was publishing with Patrick Shiu and others a study on the perinuclear localization of the RNA-directed RNA polymerase in- volved in meiosis in silencing the expression of unpaired genomic sequences (Shiu et al. 2006). This article was important enough to elicit a ‘‘Comment’’ (Kelly 2006).
‘‘I chose to submit this to the Proceedings by Track II,’’ said Bob, eschewing the option of coordinating its review himself as an Academy member. This message was cut from the same cloth as the final word of Bob’s tribute to Horowitz (Metzenberg 2005, p. 1448):

Somehow, Norm always managed to tell the truth without becoming a scold. There can never be enough of such people, and his legacy must be kept alive.

Operating outside the traditional academic bor- ders, enriching the scientific communities of Caltech, Wisconsin, Stanford, and Neurospora, engaging dis- ciplines beyond science, Bob Metzenberg created a remarkable life from three elements: experiment, com- munication, and truth.

REMEMBRANCES FROM THE CALIFORNIA COMMUNITY

Rowland Davis (University of California at Irvine):
I met Bob in 1961 at the very first Neurospora Information Conference in La Jolla, California. The meeting was free for all, in both senses of the phrase, and Bob and I began talking at the free bar after the last- night banquet. Characteristically, he drank Coke, and I drank Canadian Club. Even as I became less articulate, he became more so, and I remember only one thing from that night: I had made one of the best scientific friends of my life.
Bob was then at Wisconsin. I had taken a job at the University of Michigan. I kept seeing Bob at meetings, and in the early 1970s, our labs exchanged visits. In Ann Arbor, Bob inspired one of my most daring experiments— one I had thought impossible if he had not said, ‘‘Why not?’’ At that point, almost whimsically, he rattled off a protocol that might do the job, and within a month we accomplished the task. This was his habit: using his multi-tasking imagination to explore, at the speed of light, landscapes of possibilities in ways that Mozart might have used to choose harmony and orchestration. As we, his friends, coupled our imaginations to his, we felt that even his hypothetical dead ends were more illuminating than a close scrutiny of quantitative data. He proved repeatedly Francis Bacon’s point that the truth is better served by error than by confusion. He remains a model of how much sheer fun science—and talking about science—could be.
Out of context, one of his remarks about himself
might sound ridiculous: ‘‘I had no talent!’’ But the context is illuminating. Having taken instruction in musical composition earlier in life, he had completed several string quartets. He related this to me over lunch

618 E. U. Selker

one day at Stanford, saying, ‘‘They were competent, but they simply followed the rules. Derivative of Haydn and all. But I discovered I simply had no talent!’’ This illustrates not only Bob’s aesthetic refinement, but also his curious blend of modesty and ambition, an ambition to use his mind to the fullest. It also explains his symphonic understanding of the complex biochemical systems that he probed with a sensitivity to detail, subtle complexity, and the surprising formal beauty of cascade regulatory systems.
Finally, Bob became one of the best friends of all of us in our scientific community. Always good humored and anxious to help, he willingly suffered fools, hoping at first that he might show them the light. A lack of success would then bring out advice in an advanced play on words that at least he could enjoy. Finally, the fools would retire, yielding Bob’s attention to others better equipped to enjoy it. I believe Bob made few enemies, largely because he retained a reserve that few people— myself included—fully penetrated. But what overlay that reserve amounted to an incomparable friend and scientist, one who will glow in the dark for years to come.
Namboori B. Raju and David J. Jacobson (Stanford University) interacted with Bob after he retired from Wisconsin and provided the following comments on his time in California:
Bob Metzenberg was no stranger to California; he was here first as a student and later as a retiree. When Bob retired from the University of Wisconsin in 1996, he returned to California to be closer to his family. His two sons live in California: Howard in San Francisco and Stan in Northridge near Los Angeles. Bob chose Stanford for continuing his Neurospora research, mainly because of David Perkins and Charley Yanofsky in the Department of Biological Sciences. This was Bob’s second sojourn at Stanford, the first being a 6-month sabbatical in the Perkins laboratory in 1983. Bob’s re- search interests had long overlapped with those of the Perkins lab, especially in the areas of Neurospora sexual biology (Metzenberg 1995), mating-type genes, rRNA genes, and, more recently, meiotic silencing (Shiu et al.
2001). He was at ease with classical genetics as well as with molecular biology, and he practiced both at Stanford. In early collaborations, Bob provided molecular data for the analysis of a chromosome rearrangement, which has a breakpoint in the nucleolus organizer region that is com- posed of 150–200 rDNA repeats (Perkins et al. 1986).
In January 1996, Bob and his postdoc Rodolfo Aramayo settled into the Perkins lab. Here, Bob contin- ued his seminal research on a new phenomenon first called transvection, and since renamed meiotic silencing by unpaired DNA (MSUD) (Aramayo and Metzenberg
1996; Shiu et al. 2001). After Rodolfo left for a faculty position at Texas A&M in 1997, Bob, together with Patrick Shiu, Namboori Raju, and Denise Zickler in France, greatly extended meiotic silencing studies by
ectopically inserting single genes (at the his-3 locus), whose function is essential for meiotic progression. When such strains are crossed with wild type, the un- paired DNA sequences trigger RNAi-mediated silencing processes involving the RNA-directed RNA polymerases and dicers, in addition to several other components. Consequently, ascus development is abnormal in het- erozygous crosses because of meiotic silencing of un- paired genes, but their development is completely normal in homozygous crosses. Bob isolated two sup- pressor mutants of meiotic silencing, Sad-1 and Sad-2, whose wild-type gene functions are essential for meiotic silencing (Shiu et al. 2001, 2006; Shiu and Metzenberg
2002). The availability of GFP-tagged histone H1 and b-tubulin genes greatly facilitated the visual demonstra- tion of meiotic silencing and its suppression during ascus development (Freitag et al. 2004; Raju et al. 2007; Jacobson et al. 2008). Shiu and Raju had the privilege of collaborating with Bob on several of these research projects. The last of five joint articles with Raju was published in May 2007, barely 2 months before Bob passed away (Raju et al. 2007). Bob was extremely pleased that the article was among the ‘‘Issue High- lights’’ and that our Neurospora image was featured on the cover of Genetics.
Bob’s arrival at Stanford was warmly celebrated during a local Neurospora information conference on the Stanford campus in March 1996. His presence at Stanford also brought together Neurospora workers for
1-day ‘‘joint lab meetings’’ from the nearby University of California campuses of Berkeley and Santa Cruz. Bob especially enjoyed interactions with students and post- docs and often gave them valuable advice for solving their technical problems. During the 7 years at Stanford, Bob made many friends both in his host department and in the medical school. He also taught a biochem- istry course. Lunchtime conversations in the Perkins lab were very lively, with Bob doing most of the talking. He was always bubbling with new ideas and hypotheses, which he often tested within the next few weeks. It was during his time at Stanford that Bob started to suffer his own health problems, although this did not affect his productivity, as evidenced by his election to the National Academy of Sciences and being awarded the Genetics Society of America’s Thomas Hunt Morgan Medal.
In 2003, Bob moved to Northridge mainly to be close
to and help his son’s family. In southern California, he spent some time as a guest in the Department of Chemistry and Biochemistry at the University of California, Los Angeles, and afterward in the Depart- ment of Biology at California State University at North- ridge. However, he spent most of his work hours in his converted home laboratory. Bob’s enthusiasm for re- search was clearly seen in an essay on how to conduct research after retirement (http://www.genetics-gsa.org/ pdf/newsletter_jan07.pdf). He was actively thinking

Perspectives 619

about various experiments and writing his final paper just a couple of weeks before he passed away.
Bob’s energy for work was surpassed only by his ded- ication to others. He was devoted to his family, friends, and colleagues. His years in California were spent as much helping others as doing research. Bob’s sacrifices were legendary, even close to his own end. On learning that his close friend David Perkins was critically ill at the end of 2006, Bob, very ill himself, drove with his son the 7 hr from Northridge to Palo Alto to see David in the hospital. Although David was heavily sedated and un- responsive, Bob spent more than an hour at David’s side, analyzing the situation and making sure the best possible care was being provided. He flew home the next day, catching pneumonia on the plane, but with the satisfaction that he was able to do what he could for his friend.

Eric Selker thanks Joan Bennett, Stan Metzenberg, Mary Anne Nelson, Patricia Pukkila, and Matthew Sachs for contributing some of the photographs reprinted here. He also thanks Helene Metzenberg and friends and colleagues of Bob Metzenberg who contributed remembrances and he regrets that not all could be included in this brief tribute. A more complete collection of pictures and remembrances can be found at http://pmb.berkeley.edu/rvglass/Glasslab_site/Glass_ lab_research/bob%20website/bob%20memorial%20webpage.html. Above all, he wants to express his appreciation for Bob, who enriched his life and made this article relatively easy to write.

LITERATURE CITED

Aramayo, R., and R. L. Metzenberg, 1996 Meiotic transvection in fungi. Cell 86: 103–113.

Butler, D. K., and R. L. Metzenberg, 1989 Premeiotic change of nucleolus organizer size in Neurospora. Genetics 122: 783–791.

Dolan, P. L., Y. Wu, L. K. Ista, R. L. Metzenberg, M. A. Nelson et al.,

2001 Robust and efficient synthetic method for forming DNA

microarrays. Nucleic Acids Res. 29: E107.

Ferreira, A. V., Z. An, R. L. Metzenberg and N. L. Glass,

1998 Characterization of mat A-2, mat A-3 and DmatA mating- type mutants of Neurospora crassa. Genetics 148: 1069–1079.

Freitag, M., P. C. Hickey, N. B. Raju, E. U. Selker and N. D. Read,

2004 GFP as a tool to analyze the organization, dynamics and function of nuclei and microtubules in Neurospora crassa. Fungal Genet. Biol. 41: 897–910.

Glass, N. L., S. J. Vollmer, C. Staben, J. Grotelueschen, R. L.

Metzenberg et al., 1988 DNAs of the two mating-type alleles of Neurospora crassa are highly dissimilar. Science 241: 570–573.

Glass, N. L., J. Grotelueschen and R. L. Metzenberg, 1990a Neu- rospora crassa A mating-type region. Proc. Natl. Acad. Sci. USA 87:

4912–4916.

Glass, N. L., R. L. Metzenberg and N. B. Raju, 1990b Homothallic sordariaceae from nature: the absence of strains containing only the a mating type sequence. Exp. Mycol. 14: 274–289.

Harkness, T. A. A., R. L. Metzenberg, H. Schneider, R. Lill, W.

Neupert et al., 1994 Inactivation of the Neurospora crassa gene encoding the mitochondrial protein import receptor MOM19 by the technique of ‘‘sheltered RIP.’’ Genetics 136: 107–118.

Jacobson, D. J., N. B. Raju and M. Freitag, 2008 Evidence for the ab- sence of meiotic silence in Neurospora tetrasperma. Fungal Genet. Biol. (in press).

Kang, S., and R. L. Metzenberg, 1993 Insertional mutagenesis in

Neurospora crassa: cloning and molecular analysis of the preg1 gene controlling the activity of the transcriptional activator NUC-1. Genetics 133: 193–202.

Kelly, W. G., 2006 Standing guard: perinuclear localization of an

RNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. USA

103: 2007–2008.

Mann, B. J., R. A. Akins, A. M. Lambowitz and R. L. Metzenberg,

1988 The structural gene for a phosphorus-repressible phos- phate permease in Neurospora crassa can complement a mutation in positive regulatory gene nuc-1. Mol. Cell. Biol. 8: 1376–1379.

Metzenberg, R. L., 1979 Implications of some genetic control mechanisms in Neurospora. Microbiol. Rev. 43: 361–383.

Metzenberg, R. L., 1990 The role of similarity and difference in

fungal mating. Genetics 125: 457–462.

Metzenberg, R. L., 1995 The sexual cycle in Neurospora: from fer- tilization to ascospore discharge, in Biotechnology of Ectomycorrhi- zae, edited by V. Stocchi et al. Plenum Press, New York.

Metzenberg, R. L., 2005 Norman Harold Horowitz, 1915–2005.

Genetics 171: 1445–1448.

Metzenberg, R. L., and N. L. Glass, 1990 Mating type and mating strategies in Neurospora. BioEssays 12: 53–59.

Metzenberg, R. L., J. N. Stevens, E. U. Selker and E. Morzycka- Wroblewska, 1984 A method for finding the genetic map po- sition of cloned DNA fragments. Neurospora Newsl. 31: 35–39. Metzenberg, R. L., J. N. Stevens, E. U. Selker and E. Morzycka- Wroblewska, 1985 Identification and chromosomal distribu-

tion of 5S rRNA genes in Neurospora crassa. Proc. Natl. Acad. Sci. USA 82: 2067–2071.

Nelson, M. A., and R. L. Metzenberg, 1992 Sexual development genes of Neurospora crassa. Genetics 132: 149–162.

Peleg, Y., R. Aramayo, S. Kang, J. G. Hall and R. L. Metzenberg,

1996 NUC-2, a component of the phosphate-regulated signal transduction pathway in Neurospora crassa, is an ankyrin repeat

protein. Mol. Gen. Genet. 252: 709–716.

Perkins, D. D., R. L. Metzenberg, N. B. Raju, E. U. Selker and E. G. Barry, 1986 Reversal of a Neurospora translocation by crossing over involving displaced rDNA, and methylation of the rDNA segments that result from recombination. Genetics

114: 791–817.

Randall, T. A., and R. L. Metzenberg, 1995 Species-specific and mating type-specific DNA regions adjacent to mating type idio- morphs in the genus Neurospora. Genetics 141: 119–136.

Raju, N. B., R. L. Metzenberg and P. K. T. Shiu, 2007 Neurospora spore killers Sk-2 and Sk-3 suppress meiotic silencing by unpaired DNA. Genetics 176: 43–52.

Selker, E. U., C. Yanofsky, K. Driftmier, R. L. Metzenberg, B. Alzner-DeWeerd et al., 1981 Dispersed 5S RNA genes in N. crassa: structure, expression and evolution. Cell 24: 819–828.

Selker, E. U., R. H. Davis and D. D. Perkins, 2005 The 2005

Thomas Hunt Morgan Medal: Robert L. Metzenberg. Genetics

169: 503–505.

Shiu, P. K., N. B. Raju, D. Zickler and R. L. Metzenberg,

2001 Meiotic silencing by unpaired DNA. Cell 107: 905–916. Shiu, P. K. T., and R. L. Metzenberg, 2002 Meiotic silencing by un-

paired DNA: properties, regulation and suppression. Genetics

161: 1483–1495.

Shiu, P. K. T., D. Zickler, N. B. Raju, G. Ruprich-Robert and R. L.

Metzenberg, 2006 SAD-2 is required for meiotic silencing by unpaired DNA and perinuclear localizataion of SAD-1 RNA-

directed RNA polymerase. Proc. Natl. Acad. Sci. USA 103:

2243–2248.

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