ABSTRACT
Micromanipulators, more than any other instrument, opened the early doors to developing the powerful genetics of yeast that underlies much of the molecular work today. The ability to separate the spores of a tetrad and analyze their phenotypes generated the genetic maps and biology upon which subsequent cloning, sequencing, cutting edge molecular and cell biology depended. This work describes the development of those micromanipulators from garage to barn to factory and the developer of the sophisticated instruments we use today. For more than 30 years Carl Singer and his family were staunch and generous supporters of the International Conferences on Yeast Genetics and Molecular Biology meetings both in Europe and America. Carl Singer's displays at meetings became a traditional fixture and engaged the appetites of many students and advanced researchers to employ a technique that many perceived as too complicated or difficult, but which he made simple and easy to learn. His experiences also document a sketch of the international yeast meetings, their venues and how they developed through the years.
EARLY DAYS OF SINGER INSTRUMENTS—CARL WITH A C
My father, A.E. Saunders-Singer (1905–1985), was an industrial chemist who, early on, participated in development of the concoctions used to whiten women's shoes. He then moved on to developing processes to purify imported waxes for the shoe-polish industry. In 1934, he moved from London to Reading. There he met and married my mother Evelyn Gwendoline Barrett (1918–2004) with whom he founded Singer Instrument Co Ltd that made all kinds of laboratory apparatus (Fig. 1B). Everything was going hunkeydory, when World War two broke out and the firm's expertise in glassware was used to produce machines to make the envelopes for thermionic valves. Six years later, after the war and glassware importation became outdated, the company concentrated on making laboratory equipment for schools and universities. I arrived in December 1945, six months after the war ended. My parents named me Carl, which despite being spelled with a C rather than K, was clearly a German name.
(A and C) Carl and father Arthur working on Singer MkI and MkIII; (B) Arthur's wife and business partner Evelyn, using a pair of MkIII and an injection kit in the shop in Reading; (D) Arthur, with gear in the Rolls Royce, embarking on a sales trip in continental Europe.
FIRST MICROMANIPULATOR–1948–1950
Reading was on the rail line from the west of England to London with good connections to Oxford University where my dad met Dr. Robert Barer, a Reader in Human Anatomy and Fellow of the Royal Microscopical Society. Barer was an expert microscopist who was keen to do micromanipulation and microsurgery of cells under high magnification. The problem—he needed a micromanipulator. The best instrument was the pneumatically operated DeFonbrune manipulator designed by the brilliant French microbiologist Pierre DeFonbrune. The instrument, however, was expensive, fragile and onerous to repair. Barer saw a market for a robust, all-mechanical device, but doubted that Singer could develop it.
My dad was undeterred. The challenge—hold and move a hand-held control that in turn moved some kind of tool smoothly in three dimensions, with easily controlled movements of a quarter of a micron. Quite tricky! How to do it? After various prototypes (Mk1, Figs 1A, C and 2A), designed and made by my father and rigorously tested by the nit-picking Barer, the micromanipulator was not only born, but could be batch produced in Singer workshops using normal machine tools and methods. Their 1948 paper, A New High-Power Micromanipulator, let the science world know that a new instrument was on the market. Soon, Singer High-Power Micromanipulators (later to be renamed the MkIII, Fig. 2B) in mahogany instrument cases, packed in sawdust in heavy wooden boxes were being shipped to the far-flung reaches of the British Empire, the US and the free parts of Europe (this was just after the war).
Earliest models of the Singer micromanipulators, (A) Mk1 (still sold today) and (B) MKIII.
WELCOME MR HEMINGWAY
Unlike the rest of war-torn Europe, Britain was not invaded and occupied. The ‘Continent’, although only twenty-one miles across the Channel, was very foreign. Travel anywhere outside Britain was expensive and considered exotic. In 1950, at age 5, I accompanied my parents to Eisenstein, Germany, at the Czech border. We stayed in a guest house whose landlady viewed us with great suspicion. Only 60 years later, on my way to Prague, did I realize Churchill's Iron Curtain descended right across the Eisenstein railway station platform, one end part of Russian-dominated Czechoslovakia and the other in West Germany. Not a single train passed through for 45 years. No wonder the landlady appeared threatened.
That trip was the first of many that we made as a family visiting universities and meetings at first by train and then by car, with my sister Anna, brothers, Jan and Kim, and micromanipulators in the back of my father's 1953 Rolls Royce (Fig. 1D). My father never did anything half-way. He couldn't drive, but my mother could and did so enthusiastically. We must have looked a little bohemian with mother's striking good looks, black hair with a prominent, grey streak in front, and father's full beard driving a Rolls Royce full of kids. On a trip to Austria we pulled up in front of a rather grand hotel in Vienna. We all waited in the car while Dad went in to see if they had rooms available. A few minutes later, out he came followed by porters, doormen and the manager. They grabbed our luggage with great enthusiasm and deference, and fussed over we kids and my mother, escorting us to wonderful rooms with their own bathrooms and balconies, and at a good price. Later, when Dad completed registration formalities, he learned that he had been mistaken for Earnest Hemmingway (Fig. 1D). Thereafter, the staff was not quite as attentive. Over the years we went everywhere: Paris, Lille, Bruxelles, The Hague, Amsterdam, Basel, Bern, Geneva, Luxembourg, Saltzburg, Basel and many other European cities. These were happy times: we loved the foreignness, the different smells and food. We liked frankfurters and appfelsaft but hated the taste of foreign milk.
FROM READING TO TREBOROUGH LODGE
We had large business premises in the centre of Reading: a retail shop in front, a wholesale business behind and a factory, assembly rooms, offices and laboratory in back. We lived in a large apartment over the front shop. From early on, I had unbridled access to machine tools, materials, compressed air and gasses, electricity and every chemical a boy's heart could desire. Fortunately for me, as a well-trained chemist of the old school, my father instilled in me a deep-seated respect for methodology that taught me to handle concentrated acids, poisons, high-voltage electricity and powerful machine tools with respect. This meant that I didn't burn the roof off our house as he did to his parents’! But I had a great time.
One of Dad's employees was a salesman, Ian Abercromby. When Ian's father died, he inherited his title. It was good having a knight working for the company. Sir Ian became a firm family friend and often turned up for breakfast before a day's work. At one breakfast Ian gave Dad a copy of Country Life magazine explaining that he bought it for the property pages where scores of large country houses were available at very reasonable post-war prices. Country Life became essential reading and soon my father was off purchasing a country house. To cut a long story short, we settled into Treborough Lodge in Somerset in the west of England in 1960 with its 13 bedrooms, a ballroom and large gardens. It was a great place but soaked up money like mad.
GOOD FOOD BUT NO SALES
I studied engineering and joined the company in 1968 in my early twenties. I didn't really know what I wanted to do and I joined the family firm by default as the eldest child. Also, I felt that if I didn't, the whole thing would eventually collapse. I learned the principles of designing scientific instruments and how to make things. We developed a number of other micromanipulators and a microforge for making microscopic glass tools. I met and talked to a lot of our researcher customers, visiting them in Great Britain, on the continent and in the US. My first trip to America was in’69 with my mother. We went to a big scientific instrument exhibition in, of all places, Atlantic City, New Jersey. This was pre-Donald Trump Atlantic City: no casinos, just the beach, the boardwalk, loads of bars and restaurants, big steaks, enormous lobsters and everything covered in butter. Delicious! We met really nice people, experienced very warm hospitality, talked to many scientists, but we sold absolutely nothing. As a sales trip, it was a bust, but I liked America and Americans.
We soldiered on through the sixties and early seventies, not easy times in England. Treborough Lodge was soaking up a lot of money and the company and our products were becoming old-fashioned. Luckily, I married my wife, Elizabeth in 1974, the same year we moved our manufacturing from town-center to the outskirts of town. My parents moved into Treborough Lodge permanently and we into a small house near the new factory.
TETRAD DISSECTION—WHATEVER THAT IS
We had been making the MKIII micromanipulator unchanged since 1948. Although we sent them all over the world, we had very little knowledge of how they were used. Just as labs bought microscopes to do microscopy, they bought micromanipulators to do, well, micromanipulation. But we were getting many sales and inquiries from yeast labs. Notable users in GB were Drs. Brian Cox at Oxford, Alan Bevan of Queen Mary College, London, Frank and Dorothy Spencer at Goldsmith's College, London, Don Williamson at NIMR, Mill Hill and Jean Beggs at Imperial College and later Edinburgh. We also sold a number overseas. I think it was Alan who told my father of an international yeast genetics conference that was going to be held in Schliersee, Germany. Off Mum and Dad went and came back with enthusiastic stories of yeast as an intriguing research model and some of the 300 scientists they met there.
Dad visited Alan Bevan and his postdoc, Dianne Mitchell, who introduced him to yeast tetrad dissection, whatever that was. Intrigued, I asked a number of our UK yeast labs to teach me. It was very difficult but after some long sessions I managed a few tetrads and a lot of damage to the agar. The technique they used, common in the UK, was to place a Petri dish on the stage of a microscope face up and remove the lid. They placed a glass tool in the micromanipulator and arranged it at an angle so that the tip could touch the agar surface and could be viewed under the microscope. The glass tool was made with a microforge and the end was formed into a small, closed loop which could lie flat on the agar surface. The loop was used to separate the four ascospores, then drag them across the agar and deposit them in a line of four. The Petri dish was moved by hand and the layout made it very easy to break the needle. Brian and Dianne were very skilled at tetrad dissection, but I noticed the layout of the spores was untidy and often the agar had holes in it where they had dug out some kind of contamination.
I didn't want to do tetrad dissection for a living but thought I could make it a bit easier. I designed and made some devices on which our micromanipulator could sit and at the press of a lever would angle the needle downwards and present it to the agar surface. It helped with setting-up and reduced needle breakage. Although not exactly making us a fortune, we sold them to multiple laboratories. It prompted my parents to attend the Louvain-la-Neuve meeting in 1980, attended by over 500 researchers and clear signs the field was expanding.
In 1979, when Harry was a year old, we sold our house and factory in Reading. Elizabeth, Harry and I moved to Treborough Lodge and set up a small factory in a village on Exmoor National Park (Fig. 3). At Christmas 1980, when Liz and I were on holiday in Florida, my father had a stroke. As these were days before mobile phones and email, my mother could not get in touch with us for four or five days. By the time we got back, he was over the worst of it and was able to talk a bit, although his left side was very weak. After that, it was clear that his travelling days were over.
The Singer workshop in Roadwater; (A and B) 1970 Outside and inside of the workshop; (C and D) 2000 Outside and inside of the original building still visible by those surrounding it.
THIS IS FRENCH CUISINE?
Traveling was now up to me. I decided to go to the 1982 Yeast Meeting in Montpellier in the South of France. Elizabeth looked after my father and our two children (George was born in 1980) while Mum and I packed all the stuff into our Volvo and headed toward the Mediterranean. I didn't know quite what to expect of a yeast meeting. We turned up at the registration desk and were warmly welcomed. We were given an information pack of local travel brochures and a cardboard carrier with three bottles of local wine. We got hold of a table and some chairs, unloaded the car and set up our micromanipulator. We were then off to our allocated student rooms situated some distance away necessitating a trudge up to a rather bleak, barracks-like building. The more domestic aspects of the meeting, as I'm sure our French hosts agreed, were entirely forgettable. However, some things are burnt into the memories of all who were there. The food, which was served with little grace and even less humor was, to say the least, most un-French. It remains to this day, even to me as an Englishman, a mystery how perfectly good white fish could be turned into a grey mass which resisted both chewing and swallowing and how akin to paint-stripper our daily rations of wine were. But seeing 600 potential customers all in one place was most exciting. I recognized some of the faces, but many more I did not.
NAME ONE!!
It was my mother who introduced me to Prof Seymour (Sy) Fogel, an American from Berkeley California. Soon we arranged that he and his companion, Julie Welch, my mother and I would go for dinner in a small fishing village that he knew. Fogel was a very friendly fellow. He looked like a brigand. Unlike some stay-at-home Americans, Sy was urbane, spoke French and was very much at home in Europe. I found out that he had spent a year working in France and was most open-minded and approachable. Over bouillabaisse in a typical, harbor-side brasserie, Sy explained his entry into yeast genetics. He had gone west to Berkeley after his corn genetics research was cut short. His New York University had turned his maize field into a car park. At Berkeley he decided to work on yeast; it was not only interesting but, given his experience, more controllable. During the meeting, Sy invited us to visit his lab and see how tetrads were dissected in California: the American way, which he claimed was far superior to the technique used in British labs. Despite my good impression of him, I rather thought this claim was stereotypical American and didn't take his offer seriously. However, meeting Sy turned out to be very important to me and my business.
It was through Sy that I met Prof Fred Sherman (Fig. 4). Sherman was compact and restlessly energetic to the point of aggression. He took a swift glance at our instrument and said that he knew of it and asked if we'd sold any in America. I said that we'd sold quite a number to various yeast researchers and he replied, ‘name one’! I couldn't remember a single name! At that he said that our instrument was ‘s–t’ and turned on his heel. Fred's remark stuck in my mind, as did the fact that he was wearing the most ridiculously tight and skimpy pair of running shorts I'd ever seen.
Fred Sherman (left) and Gerry Fink (right) at Cold Spring Harbor.
WHY DIDN'T YOU COME
Liz and I and our two sons moved into a new house and I went on trying to build up the business. The next international meeting was in Edinburgh in 1984, organized by Prof Ian Dawes who was a long-term customer of ours (Fig. 5). We had a very good week seeing many of the researchers that we'd met in Montpellier, including Sy Fogel, who again brought up the question of my visiting Berkeley. ‘I invited you when we met in France, why didn't you come?’ I suppressed my English reticence and asked when would be the best time. ‘March next year’ said Sy, ‘Then you'll be here for Chinese New Year’.
Carl Singer (left) and Ian Dawes (right) at the 25th International Conference on Yeast Genetics and Molecular Biology, Olsztyn Poland; July 2011.
TETRAD DISSECTION THE AMERICAN WAY—CHEEK TO CHEEK
With the pound and dollar at parity, I flew into San Francisco, in 1985, rented a car and followed Julie's directions. I was completely unprepared for the drive north from the airport when rounding a bend I was suddenly, without warning, confronted by an amazing view of the city. I drove on over the Bay Bridge, on to hilly, twisting roads leading to Kensington where Sy and Julie lived (Fig. 6A). Their house was very pleasant indeed and set in a small garden with lemon and lime trees and lots of flowering shrubs. They welcomed me in. The house was long and narrow with most of the rooms on the ground floor and a small flat upstairs which was occupied by a student.
(A) Sy Fogel and Julie Welch; (B) (1973–1974) Micromanipulator produced by Lawrence Precision machine for friends of Sy Fogel; (C) Robert (Bob) Mortimer.
Sy's lab was a low, timber-clad building opposite the main entrance to the UC Berkeley campus. I arrived and was introduced to Dan Malone and Karen who both worked for Sy, as did Julie. After some very delicious coffee and a short explanation, Sy showed me the ‘Californian technique’ I'd come to see. What a revelation! Rather than the Petri dish being placed face up and open to the air, his was upside-down. He explained, ‘air conditioning blows contamination everywhere. Inverting the plate radically reduces contamination’. The plate sat on a mechanical stage which had X and Y mechanical screw drives operated via drum-like hand-wheels with scales engraved on their circumferences (Fig. 6B). Each turn of the wheel produced a movement of 1 mm of the stage. There were also scales on the X and Y elements of the stage with rulings at 5 mm intervals allowing a virtual grid to be generated within the boundaries of the dish.
The dissecting needle was made from a 3 mm × 150 mm long glass rod that was heated in the middle with a Bunsen-burner. The two ends of the softened glass were sharply pulled apart, and then folded parallel to one another. The glass was then cut in the middle. The idea was to produce a right-angled needle. If necessary, the thinner part could be re-heated so that it could be pulled out again. The end of the needle was cut with a razor blade against a slide to produce a planar end about 40–50 microns in diameter. Quite a fiddly business! The needle was held in a clamp Sy designed, a centrally-pivoted see-saw beam with a vertical screw which when turned, raised and lowered the needle. The needle was arranged so that the tip stood vertically in the center of the field. Effectively, the micromanipulator only gave vertical needle movement. A label atop the micromanipulator said, ‘Lawrence Precision, Hayward, Ca.’
Sy took a YPD dish, heated what he called a ‘cookie cutter’ and used the metal shape to melt through the agar to produce a narrow, elongated island across the center of the dish. On this he spread a streak of his sporulated, digested strain. We sat side-by-side, cheek-to-cheek, each looking down one of the binocular eyepieces with one eye. The first thing I noticed, the needle was just a black disc. The spores could not be seen, only inferred. The tetrads were small, but recognizable by their cruciform shape. Sy showed me that one knew when the needle touched the surface of the agar by observing the meniscus. Using the stage-hand wheels, he searched for and brought a tetrad to the center of the field. He then dabbed the needle on the tetrad by turning the small screw on the needle clamp. By dabbing quickly, two or three times, the tetrad disappeared from the agar, hopefully having transferred to the needle and clinging to it by surface tension. He then moved the stage to one of the points on a 5 × 5 grid generated by the stage screws and by dabbing the needle up and down again, he separated the tetrad and then placed each of the four spores in a column, repeating the process for each tetrad in another column.
He then left me alone to get on with it. Apart from turning the knobs the wrong way a couple of times and burying the odd spore in the agar, I soon got the hang of it. But there were a couple of things I didn't like. There were lots of knobs to turn: stage, micromanipulator and focus. That meant that one had to move one's hands about a lot and grope for them. Interestingly, the screw knob that moved the needle up and down was a sloppy fit so it could be wiggled around a bit. This was an essential feature of the way the instrument worked. Not only could the knob move the needle up and down, but by wiggling the screw from left to right and back and forth, I could move it just a little, in X and Y directions. This was very useful. The other, very strange thing I noticed was that the controls were all for a left-handed person.
I found that I had less difficulty in dissecting the tetrads than in remembering where I put them, so I ended up writing little diagrams. Within a couple of days I was getting quite good at it. However, learning that Sy was dissecting 300 tetrads a day brought me back to reality with a bump. Sy's claim that his method was much better than our European one was clearly correct. It was simpler, easier to learn, faster and contamination resistant. By the end of the visit I had the idea, however self-centered, that not only could a better micromanipulator be made, but that I could do it. I just couldn't quite say how.
Sy seemed to know everyone involved in yeast genetics and there were lots of them on the Berkeley campus. Through him I met Drs. Jasper Rine, Jeremy Thorner, Clinton Ballou, Randy Scheckman, David Schild, John Game (who I'd met at NIMR Mill Hill), Michael Esposito and Bob Mortimer. Thanks to my connection with Sy and because many had heard of our original micromanipulator, they were all very kind to put up with my stupid questioning. But perhaps the most intriguing character was Prof Bob Mortimer (Fig. 6C). Bob, a quiet and private man, had the reputation of being a profound geneticist and consummate experimenter. He and Sy had been close, but some family matters had come between them and, sadly, they kept their distance from one another. To this day, I never thought it necessary, or my place, to ask further about this. Anyway, Bob and a Scot named Johnny Johnston were the first to use an enzyme to digest the tough ascus thereby releasing the spores and allow dissection: before that they were forced out purely mechanically in a painstakingly slow way.
MADE TO ORDER
Sy suggested that I might like to visit Wally Lawrence (of Lawrence Precision) and see his machine shop. Sy called and Wally kindly came over from Hayward to pick me up. Wally, who was in his fifties, wore a check shirt and drove an open Ford Mustang. This made the drive to Hayward very exciting. Wally's ‘shop’ was a fair-sized machine shop that was clean and tidy and had the usual range of machine tools. But there was no one working in the shop. Just Wally. I asked him about Sy's micromanipulation setup and he said that he made them individually to order for contacts of Sy's. He didn't seem at all bothered about me as a potential competitor and was friendly and open about his engineering.
Sy and Julie were fantastically kind hosts. I really got to like Berkeley. I felt really at home at their house and in the lab. After three most enjoyable weeks, I left Berkeley with a love of California, a good knowledge of yeast laboratory methods, many new friends, a new pair of Timberland shoes and the seeds (or perhaps spores!) of an idea.
CHANGING OF THE GUARD
Back in England what I had seen and learned in Berkeley was beginning to crystallize. I visited as many yeast labs as I could and concluded that there was a market for the micromanipulation of yeast. One needed a manipulator that was easy to set up, simple to use, quick to learn and, above all, one that could be used by anyone who wished to have access to the power of classical genetics. On June 8, 1985, my father passed away watching a match for the Featherweight Boxing Title, a favorite pastime. Although my father had not been active in the business for some time, he was still the titular head of the business, and the family. His death not only spurred me on to work hard but gave me the freedom to do what I thought best without constraint.
THE BEGINNINGS OF A LONG RELATIONSHIP
By early 1986, I had just about worked out what the new Singer tetrad dissector would be like. This was all very well, but without help I'd struggle. I needed someone to bounce ideas around with; someone I could trust; someone who had the same feel for engineering as I did. It was at a local auction of machine tools that I ran into a self-employed engineer and toolmaker, Trevor Clarke. He was about to bid on the same tool that I wanted. Trevor seemed like a very interesting fellow so I asked him if he'd place bid for the tool. He said that he would and ring me after the sale. He did, telling me that I'd lost the bid. A couple of weeks later I told him about my ideas and he expressed great interest. A few days later, he came back and it was clear that we had a similar way of thinking. I offered him a contract to help me develop the MSM System. To my delight, he agreed. For some time, Trevor worked for me on a self-employed basis, sending in invoices for batches of work done. He would work seven days a week, was clever, skillful and spoke my language. So I offered him a full-time job and he accepted. That was over 25 years ago and he's still at Singers as a Director and shareholder.
NO TIME FOR POSSIBILITIES
We started in May 1986. The next IYGMB Meeting was in Banff, Canada in August just over two months away. I agreed with Trevor that, although it sounded impossible, we should launch a prototype at Banff. Trevor worked on drawings for the microscope and I worked on the micromanipulator. Within a couple of weeks we had a wooden mock-up which enabled us to sit at it and make sure that the controls were situated properly to the hand. It felt ‘right’. We worked 18 hours a day, 7 days a week. Trevor did the milling and I the turning. As we knew nothing about electronics, we employed a local electronic engineer to produce the drivers for the motors: no microprocessors. Thinking back on it, lack of time forced us to make decisions quickly and immediately implement them. We didn't have the luxury of considering possibilities; We had to go with what we had, even if we weren't quite sure that it was right.
THE GAMBLE PAYS OFF
I bought a ticket to Calgary and booked the hotel. I knew this trip would make or break me, and probably Singers. So much had gone into the prototype in time and money that failure did not bear thinking about: so I didn't—think about it! The day of my flight everything was ready, although nothing had been tested. I had two pieces of luggage to check-in on the Air Canada flight: a small suitcase and the very heavy aluminum box containing the MSM100 (Fig. 7B). In those relaxed, pre-911 days I was waived through Canadian customs with ‘genetics? Get it outta here’. The next day I drove up to Banff and set up my stuff on a small table near the poster sessions. There were 700 delegates at the ‘86 IYGMB meeting in Banff. The British contingent was there in force as were many of the Americans that I'd met through Sy. I made it my business to get introduced to as many people as possible and had long chats about dissection techniques with anyone who would spare the time. The talks dominated the days, but in the evenings we drank beer and networked.
(A) Terry Cooper (left) and Jack von Borstel (right) at the 20th International Conference on Yeast Genetics and Molecular Biology, Prague, Czech Republic; August 2001. (B) Singer MSM100 micromanipulator.
Carl Singer at home in Somerset, April 2011. Spring was Carl's favorite time of the year.
The bit of the meeting that I had really come for went really well. Quite arbitrarily I had set the price of the MSM100 System at £10 000 and I came away with promises of three orders: Tennessee, Edmonton and St Louis. The first person who committed to buying an MSM (when it was ready) was Prof Terry Cooper from Memphis, Tennessee and the second, Prof. Jack von Borstel from Alberta (Fig. 7A). Both of these characters were very well known in the yeast genetics field and we have remained firm friends over the past twenty-five years. But the orders were a tremendous boost and having three, well-known labs endorse the product gave me heart that we were on the right track. Plus, of course, it meant that my gamble had paid off: at least so far.
The Missing PART
I got back to Somerset and basked for a while in the glory of the successful hunter back from the chase. But it wasn't long before reality struck home. Although we had a mock-up of the future instrument, and we had three orders at £10 000 each, we actually had nothing to sell. Making a prototype was one thing, but production-engineering a finished instrument was quite another. Another body blow was that the local electronics engineer who had done the circuitry for the prototype announced that he was no longer interested in being involved in the project. Trevor and I bounced ideas off one another and gradually, working seven days a week, the mechanical parts started to take shape. The big question of computer control and all the electronics was still hanging over us.
JOHN AND DAVID—PROCESSORS ON THE FLOOR
My younger brother, Kim, had read mechanical engineering at the University of Exeter. Kim told us of a very clever electronics engineer, John Matthews who might be able to help us. I rang John and invited myself to see him at his house. John was tall and thin, with red hair, a greying beard and bright, very busy, twinkling eyes. Later, I learned that John taught himself electronics as a boy by mending neighbors’ radios and televisions. He'd taken a degree at Cambridge and rather than pursue a PhD and academic career, opted to take a teaching job at Exeter in the school of engineering.
After much conversation, John asked me to compose an enormous flow chart of all the operations of the motor-driven functions, showing all messages on the display, all inputs (key strokes or joystick movements) and all outcomes (movements of the stage, new messages or warnings). I found that the only way to do it was on the floor using felt-tip pens on A2 paper. As we had no expertise in electronic construction, nor the time to do it, we got in touch with David Brogden, a ‘nerd’ (my words) who John had recommended. What John actually said was that David was very clever, but ‘needed constantly kicking in the arse’ as he was lazy. David was slight and wore large glasses, had a kind of shy, but high-energy nervousness about him and an obsessive interest in things electrical and electronic. So, I'd take John's schematics round to David, he would design the printed circuit board artwork and we would send that off to a prototype board maker in London who would turn them out. The boards would then be returned to David, who would solder on the components and test them.
John really came up trumps, not only in designing the bomb-proof hardware, but in writing a program that worked first time and did exactly what was required. In fact, John's attitude to us changed from one of challenging our motives to one of encouraging us in every way he could and I cannot thank him enough for what he did.
NO NEEDLES—GAME OVER
By now, our customers had been waiting nearly a year for their instruments and they were ‘getting shirty’. The MSM manipulator was nearly done but it occurred to me that however good our new tetrad dissection workstation was, successful dissection is only possible with a good needle. And since this new instrument was designed as enabling technology that could bring a notoriously difficult procedure to those who had, for one reason or another, avoided it like the plague, this paradox had to be resolved. Earlier, I described how I'd learned to make dissecting needles in Sy's lab by pulling out a glass rod in a Bunsen burner flame and then cutting it off. If a would-be dissector had never made a good needle and could not do so or didn't even know what a good needle ‘felt’ like, the game was over.
In my discussion in Berkeley and elsewhere, I'd heard suggestions that suitably sized optical fibres might be used. I contacted a fiber manufacturer and arranged for some samples of suitable diameter to be sent to me. I played around with the fibers for a bit and found that they were very good for dissection if stuck on the side of a bent piece of glass. But clearly, the tiresome business of gluing the fibers would be alright for some, but I was developing an expert, easy-to-use system. With all the angles covered. I'd had a lot of experience with microforges, cutting glass and pulling pipettes. I thought that if the fiber were placed inside a glass tube with a pulled-down end, not only would it be self-supporting, but easier to handle and quick to replace.
Using some capillary tubes and a small, home-made pipette puller, I pulled down some experimental pipettes with lumens just big enough take the fibers and with tapers that looked about right. I used a UV-curing adhesive to bond the fibers in place and then cut off the distal ends to let light through. The new needles were great. The light transmission properties made it easy to see anything on the tip of the needle and the combination of the envelope and fiber gave the needles perfect flexibility and made handling easy. An additional benefit was that the outer envelope could be made sufficiently long so that when it was placed in our special holder, the tip of the needle could be easily adjusted to a perfect height relative to the agar. We have since sold thousands of them and we even make holders for ‘other’ micromanipulators. Trevor and company worked non-stop on the mechanics and soon we had the four instruments ready to be packed up in large, wooden cases to be shipped to the US and Canada. And Germany, thanks to a very eventful interim trip with my wife to see Prof Ulf Stahl at the University of Berlin. Liz and I got into trouble with the police one night on the East side of the wall, but that's another story.
ESPOO 1988–LITTLE CUPS, LARGE PRICE
After the tremendous efforts of the past few years it was time to re-group. We got things a bit better organized and prepared for the 1988 International Yeast Genetics and Molecular Biology Meeting to be held in Espoo, Finland. All the stuff was packed in the back of our bright-red Volvo estate car (station wagon) and my mother and I departed on the long trip to Espoo outside of Helsinki. The whole gang was there: all the people that I'd met in Berkeley and Banff. And we had a steady stream of MSM inquiries. Sy Fogel and Julie were in top form and as the conference restaurant seemed to serve reindeer at every meal, we suggested that the four of us go out to dinner. I inquired at the hotel front desk for a recommendation of a small, typical seafood restaurant. When we got there, the place was a bit more palatial than I'd expected. The meal was not memorable, but the bill certainly was as it seemed to me to be in the same league as the GDP of a small country. To rub salt into the wound, we each had coffee served in small cups to finish off and the waitress came round two or three times to offer refills. Little did I realize that each refill was charged for and that each cup was about £3! But we came away with fond memories and a wad of expressions of interest in the MSM. It turned out to be the last Yeast Conference that my mother would attend.
DISSECTING BANANAS
At Espoo, I spoke to yeast geneticists working on yeasts other than Saccharomyces cervisiae. Quite a few were using an African beer-making yeast, Scizosacharromyces pombe. I understood that they too employed micromanipulation. I talked to Prof Peter Fantes from Edinburgh and he told me that, rather than picking up the asci and spores, pombe people just dragged them over the surface of the agar into some sort of order, because they were difficult to pick up. I phoned Sy Fogel and asked him if he knew anything about pombe tetrad dissection and he said that I should contact Prof Gutz of Braunschweig, Germany. I duly rang Gutz, who was very charming, and asked him if pombe tetrads could be picked up on a glass needle. He said they could. I nosed around and found out that the nearest pombe person was Prof Steve Aves, an ex-colleague of Prof Paul Nurse at Exeter University.
Having never seen a pombe tetrad, let alone having dissected one, I was a little nervous as we set up the MSM in Steve's lab, inoculated the dish and looked down the microscope. Steve had explained what fission yeast tetrads looked like and now I saw them: banana-shaped with four spores lying inside a sack: the ascus. I tried picking them up on the tip of the needle and after a couple of attempts I started to do it quite well. I could easily transfer the whole tetrad to the usual lay-out grid, or matrix as we called it. This opened a whole new avenue of opportunity for Singer. Steve Aves has remained a friend ever since. Despite my best efforts, he continued to persist with his old micromanipulation set-up for the next twenty years until 2010, when he finally bought the latest version of the MSM, the 400.
KNOCKING ON DOORS
Our first sales in the UK, in 1989, were to Prof Jean Beggs, who had moved from Imperial College, London (where she had used our old MkIII micromanipulator) to Edinburgh, Melainie Lee at Glaxo and Paul Nurse at Oxford (Fig. 9A). It became clear that sales potential on the Continent was greater than that in the UK and that the best way to drum up business was to visit labs and demonstrate the product live. The only way to do that was for me to get in my car with the MSM in the back and go and see the customers.
(A) Nobel Laurate Paul Nurse standing next to the Singer MSM400 Micromanipulator; (B) Carl Singer demonstrating the MKIII Micromanipulator to students attending the 25th International Conference on Yeast Genetics and Molecular Biology, Olsztyn, Poland; July 2011.
One such visit was to Prof Yves Le Moine in Strasbourg, France. I spoke to him on the phone and arranged to go over. It was Easter time and the children were on holiday from school. I asked my son, Harry, if he would like to join me, with a promise of going by hovercraft and a stop in Paris on the way back. We found that Strasbourg was a gem of a place. A rich city with a wonderful, pink-stone gothic cathedral surrounded by a network of narrow canals. On the banks of which stood well-preserved medieval houses with vast pitched roofs dotted with windows which once let in the air to dry skins hanging inside. Situated on the Rhine, Strasbourg had swapped between being German and French, was a center of gastronomy (French food with German portions!) and was an altogether enjoyable place. Yves was a charming man, as were the members of his lab, some of whom introduced Harry to computer games while I taught others to dissect. They agreed to buy an MSM and we thanked them and packed up and left for Paris.
BOTTOM-UP TECHNIQUE
This became the pattern of my life for the next few years: on getting an enquiry I'd immediately arrange a demonstration. I'd then search through the lists of delegates to the international yeast meetings and select the ones whose labs were in route. I did not bother to contact them as I found it far more beneficial to just turn up. In the late eighties and nineties security was nowhere near as tiresome as it is today and it was easy just to walk into a university department and find the yeast people. I would then say that I would like to show them something new that would enable each of them to do their own tetrad dissection and all I needed was some bench space and half-an-hour of their time.
Most agreed and I'd nip out to the car and carry everything in and set up in about twenty minutes. The trick was to get not just the professor, but all the people who were doing the wet science to see the MSM and have a go (Fig. 9B). With any luck, I'd teach a couple of them how to dissect—something they thought they'd never manage to do—and they would sell the stuff to their boss! The other way around—top down—not so good. The boss, who spent his or her time in the office fighting for grant money or worrying about getting a paper finished and who may never have dissected a tetrad in their lives, might not be as keen!
ROARING NINETIES AND A NEW HOST
The nineteen nineties were a frenetic decade at Singer. We seemed to be getting things right and continued to expand. We carried on with the international meetings which continued to be family affairs. The children were on school holidays and hence would come along with Liz and me. The 1990 Hague meeting was huge with about a thousand delegates, and the Vienna in 1992 was nearly as large both successful with sales and possibilities.
Surprisingly, the biennial meeting in 1994 was postponed to 1995. This decision was taken so that the American Genetics Society of America (GSA) and International Conference on Yeast Genetics and Molecular Biology (ICYGMB) meetings would occur in alternate years. The GSA also replaced Cold Spring Harbor Laboratories which had hosted the American meeting since 1975.
1995 PORTUGAL—THEY EVEN CHARGE FOR THE PLANTS
The 1995 meeting was held in Lisbon Portugal, that bewildering jewel of a multi-level city whose grand and elegant shopping boulevards were connected by ancient trams. These trams ran on cobbled lanes, to hidden layers above where, for the less-patient, an ornate cast iron elevator whisked pedestrians up and down for a few Escudos. The actual meeting was in a modern, somewhat faceless, conference center right down near the water where Vasco da Gamma set sail for the New World. Our hotel was a bus ride away up a dusty gorge flanked by gravity-defying favelas clinging to the sides like bee swarms and on up to where modern, high-rise apartments jostled for space with hotels. The Meeting was very successful, but more expensive than we'd bargained for, particularly as Portugal was, at that time, one of the cheapest European destinations. Experience has since taught me that whenever a commercial conference center is involved, in contrast to a university, costs skyrocket. The cash register rings up every chair, table, electrical outlet, light and potted plant. The local organizer, Prof Claudina Rodrigues-Pousada, could not have been more charming and helpful. She also bought an MSM for her lab, and later took George and me out for dinner in her favorite fish restaurant by the sea.
1997 STELLENBOSCH—GREAT MEETING—SADNESS LEAVING
The '97 Stellenbosch, South Africa meeting was a good bit smaller due to its distance from Europe and America with pre-meeting applications at only about three hundred plus. Liz and I attended but were loath to haul all of the equipment over land and sea. Not to worry, we had a customer in Stellenbosch, Sakkie Pretorious, Prof of Genetics at Stellenbosch University. We borrowed his instrument for demonstrations at the Meeting and were greatly helped by his charming colleague, Florian Bauer. We stayed at quaint guest house about half a mile from the university which is right in the wine-growing part of the Cape. Often we saw a man, sitting in a meditative, cross-legged position next to the small swimming pool. He turned out to be Prof Carlo Bruschi, an Italian Yeast Geneticist from Trieste who became a good friend. Although the Stellenbosch Meeting was a success, we learned later, with some sadness, that many of the South African yeast people were leaving. Sakki became head of a wine institute in Australia and Prof Hennie vanVuren in Canada. We sold both of them multiple instruments! Florian Bauer is still going strong in Stellenbosch.
1999 –RIMINI—MEETING BY THE BEACH
We had always thought of Rimini as a rather commercialized, Italian Adriatic resort, a bit along the lines of Margate in the East of England. Accommodation for the 1999 meeting was in a series of local hotels not far from the Conference Centre. Off the bat, we chose Hotel Duomo, not by the sea-front, but in the old town. This turned out to be a very good choice as it was away from the hustle and bustle of Rimini's coast and near some very nice, small restaurants. All the usual gang were there and business was good, despite the conference center's indifferent atmosphere. We had many an evening with customers: a notable one being with Prof Dick Dickinson from Cardiff and Hanelore Breitenbach from Salzburg, who insisted on buying an armful of trinkets from a gypsy street-seller. Her husband, Michael, had become a very good friend and good customer. He had a very busy and stylish lab in Salzburg working on ageing. He even put an MSM in an oxygen-free atmosphere for a long-term study!
2001 –PRAGUE—THE BEER SOUNDS GOOD
Prague, the capital of the Czech Republic, not Czechoslovakia as it once was. The Slovak Republic is next door, but a different place. Prague was a bit of an unknown quantity, although we had heard good things, mostly associated with beer. The Prague meeting was also a very good one, our Czech hosts were very friendly and we made lots of new friends. I even made a silly speech wearing a pin-striped suit and bowler hat that seemed to go down well (Fig. 10).
Carl Singer giving an after-dinner speech at the 20th International Conference on Yeast Genetics and Molecular Biology, Prague, Czech Republic; August 2001.
2003 –GOTHENBURG—THE FUTURE LOOKING GOOD
Next stop, Sweden in 2003. We shipped all of our stuff and flew to Gothenburg, where Liz and I stayed at the hotel attached to the conference center. The whole thing was very large and very smart. All the conference staff were tall, blonde and dressed in blue and yellow, just like the Sweden football team, except prettier. The first evening we were kindly invited to a party in the house of Prof Stefan Hohmann—a German researcher who moved to Sweden in 2001 and who we'd met at many yeast meetings. Stefan was very active in the international yeast community and later became its leader. Prof Anders Blomberg, another old pal of ours and Lennart Adler, my first Swedish customer, and the whole Scandinavian crew was there, plus the great and good from the wider yeast community. The meeting was huge with over one thousand participants and set the scene for a lot of future business in Sweden.
2005 –BRATISLAVA—LOST MY WIFE TO A VIENNESE WALTZ
The Czechs and Slovaks joined the EU together on May 1st 2004. But whereas Prague is well known, the Slovak capital, Bratislava, is perhaps less well so. To refresh your memories, Bratislava is just down the road and round the corner from Vienna, less than 50 miles up the Danube. The Bratislava Meeting was the launch of the prototype RoToR lab robot; more on that later. We got the RoToR in the back of our Mercedes wagon together with the exhibition stand and extras, but there was no room for an MSM System. Fortunately, Prof Kim Nasmyth, an Englishman, had a lab at the Biocentre in Vienna and I arranged to borrow it. So, I picked up the MSM from Kim and my son, Harry, from the airport so that he could help with the meeting as he was the expert on the new RoToR. The Meeting was a great success, with lots of interest in the MSM and the new RoToR. Harry got on very well with the customers, particularly the girls! The Meeting Dinner was held in the vast cellars of a nearby castle. Food and drink were set out on numerous tables under soaring, arched ceilings. There was music and dancing. We spent the evening with Prof Despina Alexandraki from Crete and her student, Athena and Prof Sepp Kohlwein from Graz. Sepp kept whisking my wife off for a Viennese Waltz at which he seemed to be expert. After he'd taught her to lean back further, they were soon twirling like dervishes and covering the floor at an alarming rate: good job she was an ex marathon runner!
2007 –MELBOURNE—JUST TOO FAR AWAY
We had committed to Melbourne quite early on, but as 2007 drew near it was clear that it was going to be a high-cost, small affair. Nevertheless, Jan represented us there and had a good time.
2009 –MANCHESTER—MANCHESTER UNITED FOOTBALL
Everywhere I've been, yeast-wise, over the last twenty years or so, Prof Steve Oliver, a yeast geneticist from Manchester, has always been there. Steve is on every committee, on the editorial board of every life-science publication and part of every international science collaboration going and Steve was organizing the Manchester Meeting. The arrangements at Manchester were excellent. The lecture theatre, poster sessions, coffee and catering were all in the same building, with very good people flow. For the first time we hosted a private reception for fifty or so prime customers. The dinner was at the Manchester United Football Club. The food was surprisingly good and I gave one of my silly talks. Harry entertained the young, the highlight of which, aided and abetted by Barry Young from Vancouver, was a pub crawl involving twelve pubs at which each participant had to drink a pint of strong beer. I understand that it was a great success. Manchester was good for us; we found it excellent value for money and great fun. Well done Steve. Later Steve moved on to Cambridge.
2011 –OLSZTYN—THOSE MOSQUITOES
Many of you will, of course, know where Olsztyn is. But for those who've forgotten it's in north eastern Poland near Gdansk in the so-called lake district. The University is relatively new and has conference facilities. We've had customers in Poland for some years and we were keen to support another meeting in the old eastern block. Communication was a bit difficult during the run-up so Harry and I booked flights to Gdansk, while Ian (support) and Anne (sales) arranged to drive in our van with all the stuff for the exhibit, including my kilt. Although Olsztyn was only seventy miles from Gdansk, it took us nearly two hours to get there as there were road works everywhere and heavy traffic. The campus was spacious and the new buildings very good. It turned out that the talks and food were in one place with the posters in a building about two hundred meters away. This did not look like a good arrangement for us as usually our maximum exposure is during the poster sessions when delegates have time to browse. But everything turned out to be fine.
The Poles were very friendly and the Meeting staff fantastically helpful. As usual, Harry was a great hit with the girls. We got lot of inquiries and gave away all of our t-shirts. I did another silly talk, this time wearing my kilt! One revelation was the food. Whilst we had expected it to be on the heavy side, it was far from it with salads, fruit, vegetables and very well-cooked meat and fish dishes. The closing barbeque, down by the lake, was simply the best barbeque that I've ever been to. Fantastic dishes, beautifully cooked, plenty of wine and beer, great folk-dancers and terrific music and dancing. We did, however, need to use the mosquito repellent!
ELIZABETH—MY INSPIRATION
I could never have done justice to the international meetings without the help of my wonderful wife, Elizabeth (Fig. 11). Although it sounds great to visit places like Vienna, Lisbon and Trieste, when you are there it really is wall-to-wall work. Apart from the physical help needed in setting up the stand, fetching and carrying and the like, Liz got very skilled at helping keep potential customers engaged when I was giving a demonstration to someone else. She was also fantastic at cementing many friendships with the wives or accompanying guests of many of our senior customers. Such techniques became the cornerstone of our sales and marketing effort and Liz became well known and thought of amongst the international yeast community. Apart from the trips that we made together and with the children, I was away from home a lot. Liz ran the household, looked after the kids and the dog, and had her own job. We did have various au pairs who were a great help, but Liz was the cornerstone of the whole thing. I am sure there were times when things were very difficult, but she never flagged and has always been an inspiration to everyone around her.
Carl Singer and Wife Elizabeth on the beach at home in Somerset.
AMERICA—BEER BY THE LAKE
I pinched many of the ideas for the MSM from America. Further, the number of yeast labs, the value of the funding for fundamental research, the quality and quantity of research in the US is staggering. So, it's not surprising that the USA was to become our biggest single market and I would spend a lot of time there. The International Yeast Meetings were attended by many Americans, but their numbers were sufficient to hold their own meeting every two years. I'd heard about them, so in the late eighties I contacted the organizers, the Genetics Society of America, and bullied them into letting us exhibit. In those days the meetings were held in rotation in Madison Wisconsin, Seattle Washington and the University of Maryland outside of Washington D.C. They were always in June when the students were back home with Mom and Pa. Madison in 1996 was great. The meeting was held in the Student Memorial Union. The campus dominates Madison and is right on the lake. Right outside of the Union is a vast terrace with seats, tables and a stage for rock bands. The cellar of the gothic building houses the so-called Union Rathskeller serving ‘quick-serve grilled specialties, Paul Bunyan burgers, Mexican entrees, soups, salads, sandwiches, and the Union's famous fudge-bottom pie’. Yum, yum!
But, with all my experience of Germany I suspected that this Rathskeller, literally ‘Council Cellar’, was actually a glorified pub. Doubt was partly dispelled when I saw the murals: stylised scenes of student youths knocking back foaming steins. But the clincher were the German slogans, written in gothic script extolling the benefits of education and a white skin! Wow! I can't imagine that's still there! The Rathskeller supplied beer to the terrace and despite being served in plastic ‘glasses’ it was just what the doctor ordered
I put all my stuff out on a big table outside the poster room which was fine. One problem was that since the building was open to the public well into the evening, I had to pack everything up every night and pack it in a cupboard. Ah well. The instant that the opening address kicked off a deafening siren started to wail. The public address system announced a tornado evacuation was in force and that we all had to go down to the basement until the all-clear was given. The meeting was great and much less structured than the International one and Madison was a wacky place. When all the shops in the main street were closed on Sundays, electrical power outlets were provided at the doors so that local bands could fire up their amps and play! Great idea.
AMERICAN VS. EUROPEAN—WHAT'S THE DIFFERENCE
The GSA meetings were much more relaxed than the International ones and there seemed to be a greater number of young researchers. Also, the International ones were much more formal and, indeed, hierarchical with the great and the good keeping to themselves in general and not mixing with the bulk of delegates. Generally, over the years, American informality, although irritating and even shocking to Europeans (and more so to Japanese) has been very good for science and scientific research. It was quite noticeable that senior and junior scientists mixed more freely at the US meetings and I liked that.
The GSA meetings were a great success and became a biannual must for Singer to attend. In the main, the facilities and accommodation were fine—once one got used to shaving and brushing teeth in communal washrooms. Maryland and Washington DC are not the places to be in high summer, particularly in non-air-conditioned rooms and it was a shock to find out that the University of Washington in Seattle was a ‘dry’ campus, so no beer! Of course, there are lots of paradoxes in the US: on the one hand relaxed and laisser-faire, and on the other victims of puritanical prudishness and mind-numbing bureaucracy. After the banquet at one of the Seattle meetings, the organizers had put on a fantastic band. By special arrangement, we had enjoyed a ration of beer and wine during the dinner and the dancing was in full swing. The evening was warm, we'd all worked hard and we were having a really good time. The bad news was that the beer ran out and the band had to finish at twelve. Prof Rodney Rothstein, from Columbia University New York and a keen dancer and whisky drinker, started a collection of twenty dollars a head to send for more beer and to pay the band to stay on. Everyone coughed up and Rodney took a great wad of notes to the organizers. They just said no! Rules were rules etc., etc. It was a shame for all of us and for Rodney, in particular because he had to go round and offer everyone their money back! Americans just don't trust young people!
COLD SPRING HARBOR LABORATORY—YOU NEED A ZAPPER
I got a call from Prof Jerry Hyams from University College London, a Londoner and fission yeast geneticist who had done a postdoc at Madison. Jerry participated in running a fission yeast course at the Cold Spring Harbor Laboratory (CSHL). As a customer and a friend, he asked me if I'd like to help by supplying some instruments and instruct the students in tetrad dissection. The course was to run for two weeks, starting at the end of October and, although I didn't know quite what to expect, I agreed with enthusiasm. Soon an official invitation arrived from CSH, with instructions of where and when to turn up and how to get from the New York airports out to Long Island. I shipped out the stuff I would need and arranged to borrow Rodney Rothstein's MSM. Rodney's always been generous and helpful to us (Fig. 12C).
(A)Carl Singer on Bungtown Road at the entrance of Cold Spring Harbor Laboratory, New York, U.S.A.; (B) Carl Singer, Peter Fantes, Maureen McCloud, and Jerry Hyams on the bridge at the front of Delbruck Laboratory; (C) Rodney Rothstein and Carl Singer at the 25th International Conference on Yeast Genetics and Molecular Biology, Olsztyn Poland; July 2011; (D) Cold Spring Harbor Yeast Genetics Course students, Gerry Fink and Fred Sherman are jumping.
Carl Singer reading one of his favorite publications in London during the Olympics, August 2012.
Driving from JFK out to Long Island was relatively easy and I found Bung Town Road—the address of the lab. Bung Town Road is more-or-less in the middle of nowhere and leads along the bank of one of the inlets on Long Island's north shore (Fig. 12A). The scenery was stunning, with the trees in their full autumnal colors of reds, pinks and yellows. CSHL consisted of a collection of new, old, large and small buildings of modern and traditional design, stretching along each side of the private road. The whole place looked deserted. I found Grace Auditorium and signs to the Meeting Office: it was shut. I looked around and found a notice that told me to ring a number and that someone would come and rescue me. I did and they did. I was taken to a small, traditional, timber-clad building strangely called Wawepex, given the key to my room and the front door, was told that I had missed dinner and that I could only park miles away. Things could only get better.
FROM CHAOS TO ORDER
In my welcome pack, I received a campus map and found the course lab, Delbruck. I drove up the road to check it out. Delbruck was another traditional, three-story building, built on a slope. Access to the lab, which was at the top and at the same level as the road, was via a short wooden bridge (Fig. 12B). I parked outside and went up to the door. To my surprise, the door was unlocked and so I went in for a quick scout around. There were cardboard boxes all over the place and stuff on all the benches. It all looked amazingly chaotic. I found my shipment. Just as I was thinking what to do next, I saw a police car—or cruiser as they say there—pull up alongside my car. I went out and said that I was just dropping something off and was relieved that they didn't make me assume any kind of position and/or, spread-eagle me on the bonnet of the car.
The next day, Jerry et al. turned up and introduced me to Prof Maureen McCloud from Brookline and to Prof Peter Fantes from Edinburgh who made up the three-man instruction team (Fig. 12B). Sunday was spent unpacking and arranging the microscopes and micromanipulators, setting out the benches for sixteen students and preparing all the media for the experiments (Fig. 12D). We lunched and dined at Blackford Hall which had a cafeteria on the ground floor and a bar below. The next day, I drove to Columbia University in New York city to pick up Rodney's MSM System. We'd sold our sixteenth MSM before we got our second order from the USA. It was from Rodney Rothstein. I can't recall the exact circumstances of the sale, but Rodney knew Sy and he saw our stuff at one of the meetings or something like that. Rodney had given me the name of his postdoctoral student, Serge Gangloff and I rang Serge from the front desk. As I stood guard, Serge brought all the stuff I needed down to the car. He's now back near Paris and we still keep in touch.
Back at base, things were heating up. Jerry and company had written the course manual last year, but there were quite a lot of changes that they needed to discuss and incorporate. I set up the MSM and Maureen supplied me with excellent tetrads and dissection plates. By the next morning everything was in place and we were ready to go. We met all the students who were from all over the globe, they were paired up and the course started. The format was that mornings were dedicated to practical experiments. After lunch there would be a seminar and then more practical until late in the evening. The labs were never locked and everyone at CSH seemed to work all the time.
I got on well with the students. Some picked things up quickly and some much slower. Watching them learn the fiddly techniques from scratch really gave me insight into how good the MSM really was and where the neophytes encountered difficulties. Some were more determined than others, but in a few days, everyone was dissecting quite competently and no one failed to master the technique. I did, however, as a result of one student's utter lack of coordination, resolve to develop the ‘zapper’. Let me explain. Tetrad analysis involves the separation of four microscopic spores and placing them individually in an ordered array. The initial separation of the spores is best done by vibrating the tip of the dissecting needle by sharply and lightly tapping the micro manipulator. Despite my best efforts and the patience of Job, one particular young woman could grasp neither tap, nor lightly. As a result, she could make beautifully smooth agar look like a ploughed field.
THE WORKAHOLIC PARADISE
Cold Spring Harbor is one of the world's premier research laboratories. It was headed at the time by Jim Watson of DNA double-helix fame. Without any warning Jim would suddenly appear from nowhere, look around, say a few things quietly and leave. Reed thin and slightly stooped, Jim's bright, insistent eyes peer around from under slightly raised eyebrows. With large, prominent and slightly yellowing teeth which he bares when talking, he has a rather bird-of prey- like appearance which to some, including me, can be quite disconcerting. With all facilities and accommodation on site, nothing in the immediate vicinity and labs open all the time, the place was clearly a workaholic's paradise. There was a big fridge in the lab. As I had a car I was dispatched into Huntington, the nearest town, to buy beer. Over the next twenty years I was to visit CSH on a regular basis for the fission yeast and the budding yeast courses. I've always loved it.
ANGLO JAPAN CELL CYCLE WORKSHOP
In early 1994, I got another invitation from Jerry Hyams who was organizing the second CC Workshop at St John's College, Cambridge. The first, in 1992, had been held in Kyoto. The idea was to alternate between the two countries every three or four years. Of course, I jumped at the chance as it would give me direct access to the Japanese market.
I didn't know St John's well but became very impressed with its beauty over the next few days. My accommodation was in a newish and very well-appointed wing overlooking the river in a place where the college punts tied up. In the morning, breakfast was held in the great hall. A long buffet was set up along one side of the very grand and historic room and breakfasters filed in to help themselves. I was surprised how many Japanese had come over for the meeting and soon found out that many rich Japanese labs had been able to send many of their younger members over. The Japanese were easily recognizable, not just because of their features, but also because they all dressed very formally in suits with the few women amongst them in smart dresses.
ALMOST SPLIT PERSONALITIES
The meeting went well for me and I was able to meet a number of senior Japanese professors, including Yanagida, Okyama and Matsumoto: all of whom were very friendly and all of whom became customers in the future. It was probably lucky that I was able to meet these senior people for the first time on foreign soil. Hierarchy is a much more powerful force in Japan than it is in the West. Senior Japanese scientists were used to foreign travel and had become a little more accustomed to our, and particularly America's, less formal ways. Later, when I went to Japan a lot, it became quite obvious that many of them had developed almost split personalities to enable them to cope with this vast cultural difference. One had to become sensitive to these personality changes: a scientist who was relaxed, chatty, outgoing and overtly friendly whilst abroad, would become stiff, formal, less animated and aloof when in Japan. I rather like it.
By Christmas 1994 we had our first Japanese order for an MSM System from Prof Mitsuhiro Yanagida of Kyoto Univesity. Yanagida was probably the best-known yeast geneticist in Japan and ordered the instrument direct from us—an indication, we later discovered—of his influence. A number of other labs had expressed interest, but none seemed to be able to get over the bureaucratic hurdle of our needing a Japanese agent. Yanagida was to help us with this. This was my first Cell Cycle Workshop with more to follow, in Kyoto in 97, Cambridge in 2000 and Nara in 2004.
ATSUSHI OKADA—OKADA SAN AND THE CHINESE CONTRACT
Recognizing that we had potential customers in Japan who were unable to purchase directly from us because of the way that the Japanese like to work became frustrating. I discussed this with Mitsuhiro Yanagida and he came up with a recommendation of a small company, Minerva Tech k.k., run by a Mr Atsushi Okada. Okada was a very nice chap about five years older than I, had an office in Tokyo and a salesman based in Southern Japan. We got on very well and that seemed a good enough basis to start some kind of business relationship—but what kind of relationship? We struck a Chinese Contract. We shook hands on an agreement whereby he would have a sole agency for the distribution of Singer products in Japan; he was to do his best to market and sell such goods and he must not sell any competitive instruments. We would do everything we could to make Minerva Tech happy and together build a mutually beneficial business dealing only through him. We shook hands and it became the start of a relationship which has lasted for sixteen years.
Okada set up Yanagida's MSM for him and ordered one of his own for demonstration purposes and invited me to Japan to kick-start some sales. Business in Japan promised to be very good. I was particularly encouraged when at Tokyo University I saw strewn on tables outside in the rain, quite a few old, French De Fonbrune and Cailloux micromanipulators which they were throwing away. In 1995 we sold one MSM to Japan. In 1996, through Okada san, we sold nine.
PURSUE THE FUTURE—KEEP THE PAST
I came away from Japan with a very favorable impression. I loved the country and the people and particularly their spirituality: where else would you see a shrine in an underground station? I marveled at that three-dimensional nature of their cities, the order of their railway service, the politeness and reserved nature of the inhabitants. Railway ticket collectors wore white gloves and bowed and saluted travelers, elderly uniformed men helped motorists find spaces in car parks, people were slim, fit and supple. There seemed to me to be a strong air of collective responsibility in the country with a desire to be modern, but without a rush to destroy the culture of the past.
ROTOR—BEHIND THE SCENES NEGOTIATIONS
Sometime in 2003 I got an email from Prof Charlie Boone of the University of Toronto, asking if we would be interested in an idea they had about a novel laboratory robot for replica plating. I thought about it, talked it over with Trevor and made arrangements for a visit. Boone had a big lab with lots of robots in it dedicated to SGA: Synthetic Genome Analysis. The thing about SGA was that to discover what a particular (yeast) gene's function might be, the particular strain would have to be crossed with each of the functional genes in the genome, and then various subsequent steps, involving replications, to analyze the result. This was a mind-boggling amount of work and was slow, even with robotic pinners. The reason that such robotic devices are slow is because between each individual pinning operation, the metal pins had to be washed and sterilized: a process that takes at least a minute. Boone and Company came up with the idea of using a disposable, sterile, plastic pad, molded with a set of pins (or pips) on the surface, which would do the replicating and then be thrown away ready for the next one to be used immediately without the need for sterilization.
It turned out that there were a number of parties involved in the whole idea and we all got together in a round-table discussion: a South African wheeler-dealer, an Israeli professor of robotics at U of T, the owner of a robotics company, his employee, a quiet Polish fellow, and various others from the University and the Ontario Genomics Institute. Certainly, the negotiations were not comfortable. There seemed to be a lot of behind the scenes politics going on. I came away from the meeting with the impression that we could really make something out of the technology, but very unsure of how any further negotiations might go. Despite the perceived difficulties the idea was a goer. It would take a lot of time to develop, so we ought to start it straight away—so that's what we did (Fig. 14 ). Despite the fact, that we had no agreement with the other parties about royalties or anything else and that negotiations were ongoing, we decided to press on. It seemed the Singer way is just to get on with it. Behind the scenes, Trevor was talking to the folks in Toronto.
The Singer ROTOR HDA, for high-throughput screening, replica plating and colony array manipulation.
Elizabeth and Carl Singer at the Banquet dinner of an International Conference of Yeast Genetics meeting.
Son Harry and Carl Singer outside the new Singer factory extension in June 2011.
The negotiations took about another 18 months. The agreement that I signed was not very good for us and it proved to me that I am not a good negotiator. I still prefer my Chinese Contracts. My son, Harry, who is a good negotiator, subsequently re-negotiated the package, but only after Charlie's business partner incompetently failed to maintain the technology patents! Boone remains a bit of a mystery to me. Highly intelligent, highly competitive and a very, very good scientist, he remains a friend. Charlie is a driven man who, from time to time, holds his cards a little bit too close to his chest for my liking and sometimes, I suspect, there are one or two firmly up his sleeve!
MEN IN WHITE
The development of the RoToR brought Harry very firmly into Singer Instruments. Any small businessman, particularly a family businessman, worries about succession. I suppose that I had really put off thinking about succession and stuck my head in the sand about it. The company was doing well. We had money in the bank and plans for expansion. Certainly, I was still involved in the sales side and doing trips abroad, but not perhaps with the urgency of previous years. One of the unavoidable truths about getting older is that it is such a gradual and insidious process that one doesn't realize that it's happening at all. One imagines that one is just as quick witted, as skillful, as physically capable as one always has been, and in many ways better, at all these things as one has experience and wisdom to boot. But the sad truth is that you're not and the agent for change that you once were has become the agent of talking about change, rather than doing it.
Harry came out of University College London with a first class Masters Degree in Applied Physics and a PhD in quantum chaos. He also came out very much his own man. I was certainly in awe of his academic achievements and actually a little bit frightened of him and probably jealous of him too. I pushed to the back of my mind any possibility that one of my boys might take over from me.
After UCL, Harry was involved in film making, recruited by Channel 4 in Britain to be one of three presenters of a TV show called Men In White. The program was based on using technology to solve people's everyday problems. When I heard that his fee for the show was about £40k for eight weeks work, I naturally thought that was that! After MIW he did more shows for Discovery Channel, but he was never really enthused about the contents of the program. By 2004, Harry was working for Singer as our Senior Physicist and became responsible for developing the software for the RoToR and designing the user interface. We had the arrangement that he could take time off for his filming when he needed to. He also bought a very nice flat in Minehead, where we live.
WHO'S GOING TO WORRY ABOUT IT
Harry started to take Singer a bit more seriously. The quality of his work was excellent, he showed very good management skills and was first class on the sales side (although some of his projects involving young scientists and pubs are better not discussed by me!). Harry was also proving to be a much better delegator than I. I was still a bit intimidated by Harry, or so I thought, but on reflection perhaps it was my desire not to put him off taking over the company that made me reticent about stepping on his toes. I remember saying to him that I was worried about the sales and he replied that either he would worry about it, or I could, but if I was going to then he wouldn't bother. Harry was made managing director and I began working only two days a week. I also gradually realized how out of date I was and how my energy levels had dropped. When Liz and I returned from a holiday on Crete, I announced that I wished to stop going in except for meetings. Despite adverse tax implications I decided to transfer a good proportion of Singer shares to Harry to show him that I meant business. Retirement has been great for me. I have been able to be relaxed about the whole thing, particularly since I know that the company is in very good hands.
Conflicts of Interest
Harry Singer, PhD, CEO of Singer Instruments Co. Ltd.
Author notes
Material for this retrospective derives from the writings of Carl Singer, conversations with his son Harry, and Harry's conversations with multiple other sources.
