Obituary - Håkon Hope (1931 - 2018)

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Håkon Hope (1931 - 2018)

ACA RefleXions, Spring 2019

Håkon Hope, professor emeritus of chemistry at the University of California - Davis, passed away on November 22, 2018, at the age of 87. Håkon Hope has been called the Father of Cryo-crystallography and his work is recognized as resulting in a transformation of macromolecular crystallography. Following are the remembrances of several of our community who knew Håkon well.

Ada Yonath: Prof. Håkon Hope was an exceptional scientist who made seminal methodological contributions. His insights and experimental design were decades ahead of his time. As such, he advanced not only my research beyond my wildest expectations, but also made extraordinary contributions to the entire field of structural biology.

I met him first when I was a student. Håkon was collaborating with Fred Hirshfeld on accurate charge density distribution, focusing on very small molecules. We, the students, were ridiculing: “Håkon and Freddy know the location and charge of each portion of each electron at each fraction of time, in all two-atom molecules…” Who could imagine that he would even consider ribosomes? That he would challenge the extreme deterioration of ribosome crystals during data collection at ambient (or slightly cooled) temperatures, as performed until the late eighties, kept at controlled humidity in glass capillaries. To reduce or eliminate this terrible damage, which actually led me to consider stopping the ribosome-structure project, Håkon suggested applying his unique cryo temperature procedure, which greatly reduces internal thermal vibrations. It required uniform flash freezing (thus did not allow capillaries) by dipping the crystals, which contained about 2.5 M salts, into an inert viscose solution. It sounded impossible, but Håkon did not give up. He came to Israel for almost a year, during which we sacrificed almost 100 crystals… The result is well known. It is among his most exciting key achievements. Thus, his bold attitude led to the development of what, almost instantaneously, became routine worldwide. Not only several ribosome structures were determined at atomic resolution, over 50,000 new and significant structures were elucidated at cryo temperature, many of which were not suitable for traditional data collection methods.

Sue Byram: Professor Håkon Hope was a mentor and a friend, and directly responsible for my joining the single crystal diffractometer company Syntex Analytical Instruments, which later became the X-ray group at Bruker. I was writing crystallographic software at National Research Council in Canada with Eric Gabe when I moved back to the San Francisco Bay Area near Stanford. I asked Eric for suggestions on working in crystallography, and he said "contact Håkon Hope at UC Davis." That’s a bit far away from Stanford, I thought, but I rang up Håkon. In his typical whimsical fashion, Håkon explained nothing further than to say "contact Carl Djerassi at Stanford." Hmm, thought I, I’m not sure what that is all about. With some trepidation I rang up the great Professor Djerassi and explained who I was to his Administrative Assistant. The next day I was invited to visit Syntex Analytical Instruments and offered a software position working for Bob Sparks. Professor Djerassi, unknown to me but well known to Håkon, was the Director of Research at Syntex and was Bob Sparks’ boss’ boss. Thank you, Håkon, for the rest of my career!

For decades, Håkon kept us all in line crystallographically and linguistically. He regularly read and offered improvements to our manuals and was central to the design of our low temperature devices. We spoke often and met regularly at ACA, ECM and IUCr meetings, often with his wife Sally and children Erik and Mollie. I much admired their multi-lingual family – Håkon spoke only Norwegian with the children, while Sally spoke English with them. Quite an achievement for all of them. Marilyn Olmstead: My interest in crystallography was first sparked by Tom Dunne, my senior thesis advisor at Reed College who had been a post-doc with F. A. Cotton in 1963 and had determined a structure of a cobalt complex. Then Larry Dahl, a member of my Ph.D. thesis committee at the University of Wisconsin, assured me that I would love crystallography and besides, "women were good at it." However, my research up until then had nothing to do with crystallography. I decided to follow that crystallography interest a few years after moving to UC Davis with my husband, Alan, in 1969. I was hired as a half-time lecturer in the Department of Chemistry. Since I had experience with computers and computer programming, I was able to convince newly appointed associate professor Håkon Hope to take me on as a parttime post-doc.

What I recall about Håkon in those early days was how much more he knew than I did and how he enjoyed impressing me with his superior knowledge. I was a willing subject. I did love crystallography. He and his assistant, Karen Swanson, taught me everything I needed to know to solve my first structure, starting from the Weissenberg camera and then to the new green machine, the 4-circle Picker diffractometer. His pride and joy was the low temperature apparatus that he had built, able to collect data at an amazing 85 K. Not only was he a gifted experimentalist, his knowledge of theory was far more advanced than anyone needs to know today. I still have copies of his lecture notes from 1978, filled with integrals and operators. He wrote a Fortran program that would read in reflection data and output the seven reflections with the most statistically significant Bijvoet differences. Those seven reflections would then be carefully remeasured, including their Laue equivalents, and the absolute configuration determined. It worked most of the time.

I have an assortment of other memories. We had champagne glasses in the X-ray lab in order to celebrate the determination of each new structure. He ate canned tuna directly from the can for lunch. He ate a pomegranate by chomping down directly on the fruit, not caring about the seeds and juice spilling everywhere. Bruce Noll and I still chuckle about that scene today. He clearly believed that, because he was Norwegian, he was a first-class cross-country skier. His knowledge of crystallography and passion for the science was passed down to his students, colleagues, and both small molecule and protein crystallographers worldwide. The Department benefited a great deal from the strong program in crystallography he initiated. The legacy he left behind will not be forgotten. I am so very glad he came into my life.

Ed Stevens: It has been 50 years since I arrived at the University of California, Davis, as a new chemistry graduate student. I knew very little about X-ray crystallography, but the idea that the 3-dimensional structure of molecules could be determined by experiment was intriguing, and I chose Håkon Hope as my research advisor.

Håkon’s lab had a Weissenberg camera and a precession camera for unit cell determination, and a Picker 4-circle diffractometer for data collection (state-of-the-art at the time). The diffractometer was not computer controlled but was automated with an IBM card reader. The card reader would read the h,k,l and 4 setting angles of a reflection to be measured and the values were stored in binary in a large box of electromechanical relays. Motors drove the diffractometer to the given angles, the reflection was scanned, and the background and scan counts were punched on a following blank card.

To determine the crystal orientation, reflections were located and centered manually on the diffractometer, and positions plotted on polar graph paper in order to index the reflections. The orientation matrix was then determined by leastsquares refinement of the indexed reflections using the departmental PDP8 computer. With the aid of the university main-frame computer, the orientation matrix could then be used to produce a deck of IBM cards that contained the predicted setting angles of each reflection for data collection. If the crystal orientation changed during data collection, it was necessary to repeat the process, and get a new deck of cards punched.

Data collection required frequent monitoring because the IBM card reader was prone to card jams, and the contacts of the electromechanical relays needed frequent cleaning. For long data collections, at night I slept on a cot in the lab with the hope that the silence of a malfunctioning instrument would awaken me.

After several group meetings where the basic theory of X-ray crystallography was introduced, Håkon gave me the task of writing a FORTRAN computer program for calculating a 3D Fourier summation for acentric structures (we had a program from UCLA that was only valid for centrosymmetric structures). For my Ph.D. dissertation, I measured the experimental electron density distributions of 3 compounds, and I wrote a computer program to correct X-ray intensity measurements for thermal diffuse scattering using crystal elastic constants.

Håkon was passionate about collecting accurate data, and was always eager to demonstrate that, with proper attention to experimental detail, it was possible to measure effects that would be lost in the noise of routine experiments. Examples include his interest in the measurement of electron density distributions and the determination of absolute configurations of structures using MoKα radiation with no elements heavier than oxygen.

Håkon loved to tinker. He invented a glass device for recrystallizing samples that relied on circular convection of a solvent to carry the solute from the heated side to a cooler side where it crystallized. While I was still at UC Davis, he had already started working on an improved nozzle for low temperature data collection that only required a single gas stream. I copied his design while doing postdoctoral research with Philip Coppens in Buffalo and constructed a similar nozzle that I used for a number of low temperature charge density studies, including two studies of samples that were liquids at room temperature, and one that was a gas.

Now, Håkon is perhaps most noted for his promotion of the technique of flash cooling of crystals of macromolecule samples, and the use of low temperature data collection to limit radiation damage in those samples. As a research mentor he was always calm, patient, and friendly. He continued to be helpful as my career developed, and I always looked forward to seeing him and having a chance to talk at meetings. Whenever I see the Travelocity commercial with the Norwegian gnome, I am reminded of the twinkle in his eye when he would have some new result or idea to share.

Four generations of crystallographers at UCD: Håkon Hope, Marilyn Olmstead, James Fettinger & Kamran Ghiassi

Martha Teeter: I first met Håkon Hope at the Japan IUCr meeting in 1972. I learned he was a highly respected experimentalist and good with low temperature techniques. Independently, I had been intrigued by the power of low temperature to improve X-ray data of protein crystals held in capillaries. While at Boston University, my graduate student Marc Whitlow and I devised an iso-propanol system for cooling protein crystals on our Syntex P21 diffractometer, using a commercial low temperature device. It had its difficulties.

When I met Håkon again at the Hamburg IUCr in 1984, he had cleverly devised a way to stabilize pyrophoric small molecules for cryocrystallography using a drop of neutral oil at the end of a fine capillary mounted in a copper pin. With this ingenious method, he could mount the crystal air free, cool it in liquid nitrogen, and transfer it to a nitrogen stream on a diffractometer. He made special tongs with a high thermal mass block to keep the crystal cool from the microscope to the diffractometer.

At the Stanford ACA meeting in 1985, we discussed applying his method to protein crystals. They lose solvent and decay in air and in the X-ray beam. Ordinarily, we mount protein crystals in capillaries sealed with wax, but that method seemed to interfere with low temperature data collection. The capillary often created turbulence in the cool gas stream, resulting in ice formation.

Håkon and I proposed to cool crystals of the protein I was studying (crambin) to liquid nitrogen temperatures with his method, and he collected diffractometer data to 0.83 Å later that year. It worked beautifully. This was the pioneering first use of his capillary-free mounting technique in liquid nitrogen for protein crystals. Now those techniques are routinely used. He continued to develop these cryo-crystallography techniques and popularize them, extending later work to liquid helium data collection. He worked closely with several synchrotron sites to freely share his experimental procedure and apparatus.

A second example of Håkon’s inventiveness and experimental prowess came to my attention in 1987. I was visiting the Weizmann Institute and found that Håkon was also there. He had just created a small glass, double platform support for ribosome crystals grown by Ada Yonath. With this physical stabilization and application of liquid nitrogen to the crystal, they were able to extend the lifetime of ribosome crystals in the X-ray beam. It was this pivotal event, coupled with Ada’s persistence in looking for better crystals and large heavy atom clusters, that led her and others to the solution of the ribosome structure and Ada’s sharing the 2009 Nobel Prize in Chemistry. She has referred to Håkon as the Father of Cryo-crystallography.

Finally, Håkon delighted in teaching crystallography both in class and in informal conversations. He had accomplished this both at UC Davis Department of Chemistry and at ACA and IUCr meetings, which he had attended since 1968, hardly missing one. He was always advocating for his very high standards of data collection and refinement for determination of accurate structures.

At meetings, Håkon engaged me and others in dialog around accurate structure determination and held others to the high standards he himself used. He challenged many to think about their crystallography, in order to create the best possible structures. He was able to insure this attention to detail on an international level as a member of the IUCr Commission on Crystallographic Apparatus (1974-1984).

Håkon was a brilliant and inventive experimentalist, a caring and highly principled crystallographic educator, and a friend. He is sorely missed in Davis and in the crystallographic world.

Charles Campana: I first met Håkon Hope in 1980, when I joined Nicolet Instrument Corporation in Cupertino, California, as an applications scientist for single-crystal diffraction. The company was founded in 1968 by Bob Sparks and Tom Workman, as a division of Syntex Research. Håkon was instrumental in convincing Carl Djerassi, president of Syntex Research (and Stanford Professor), to fund the development of computer- controlled diffractometers (Syntex P-1, P21, P3/R3, etc.). Arild Christensen, a Håkon Hope postdoctoral fellow, was also hired as a crystallographer at Syntex Research and later Syntex Analytical Instruments, Inc. (SAI).

Håkon Hope established a world-class X-ray crystallographic facility at the University of California – Davis, where he mentored generations of faculty, staff and students. I was a frequent visitor to UCD where HåkonΩ demonstrated his techniques for collecting all small molecule datasets very quickly at 140K. From that point forward, I collected nearly all datasets using the Hope method.

The 1985 Stanford ACA meeting was a turning point in low-temperature crystallography of macromolecules. Prior to that time, low temperature crystallography of proteins was done on four-circle diffractometers running in cold rooms at 4⁰ F. Håkon Hope and Martha Teeter presented a paper at the Stanford meeting in which they had collected a complete overnight dataset on crambin at 140 K. This experiment defied the conventional wisdom that protein crystals could not be frozen - leading to the development of cryo-crystallography of proteins. 2009 Nobel Prize winner Ada Yonath has called Håkon “The father of cryo-crystallography” and claimed that none of her research could have been done without Håkon’s contributions.

On a personal note, I always enjoyed long conversations, in person or over the telephone, with Håkon. Håkon’s discussions were logical, but not always concise. I would never interrupt him, knowing that he would ‘rewind’ and start over to include all the details of his explanation. Patience in listening to Håkon was always worth the effort!

Paul Swepston: I was attending my first ACA meeting and making my first poster presentation as a graduate student. I was nervous as I stood by my poster for the first time, hoping (perhaps praying) nobody would ask me any questions. Up walks this grizzled looking guy who I assumed was a professor somewhere. He stared at my poster and stared at my poster and stared at my poster and finally asked, in a Norwegian accent, how I had managed to isolate and crystallize the phosphine compound that I was presenting a structure of. I think I must have had a blank look on my face and then looked closely at my poster title and my eyeballs almost popped out: I had inadvertently written the formula for my triphenylphosphine group as “PPH3” rather than “PPh3.” The discovery of that mistake led to a rather detailed review of my poster by Håkon Hope. That day he taught me a lesson about the importance of accuracy that I will never forget. The funny thing is that he was the only one to find the mistake during the whole poster session. I think the fact that he took the time to even look at my poster says a lot about his serious interest in helping students.

After that encounter there was never an ACA or IUCr meeting that I did not talk to Håkon and discuss a wide range of topics from the proper way to collect data to the most efficient way to cool crystals. He was one of those people who didn’t blindly accept common scientific knowledge. Before Håkon very few people believed that you could successfully collect data on protein crystals at liquid nitrogen temperatures, but his pioneering work in that area transformed protein crystallography. He will be missed but his impact on structural science will be felt for a long time.

Bruce Noll: I met Håkon Hope in my first summer as a graduate student at UC Davis. When I joined the program in 1988, X-ray crystallography was something completely unknown to me. We may have covered it in one lecture of physical chemistry when I was an undergraduate, but that day was lost to me. This meant that Håkon’s discussions were as foreign to me as his Norwegian! Fortunately, things became more clear during the lectures of his course. I grew to love the distinctly non-Cartesian relationships of crystals and fell into the X-ray lab as my second home.

Prior to college, I worked a number of years as a mechanic, so I was able to make a trade with Håkon and Marilyn Olmstead. I would help to maintain the hardware if they would teach me crystallography. Håkon always seemed to find a project on Friday afternoons, perhaps polishing the target of the rotating anode generator, or maybe exchanging the water in the heat exchangers for the instruments. So, it was on a Friday afternoon when I was submitting some refinements to the computer queue that Håkon entered the lab. As I was looking forward to spending a little time with friends over a beer or two, I did my best to ignore Håkon’s inspection tour of the facility. Out of the corner of my eye, I spied him walking into the enclosure for the rotating anode system. I did my best to look down and focus on my work. I thought I might just get to the pub. Suddenly, over the din of the pumps and fans of the lab, I heard a plaintive “Uh oh, uh oh, uh oh….” I looked over to the enclosure to see Håkon bouncing on his clogs and holding firmly to the cooling-water supply hose for the anode. Water was rushing from the hose! I calmly asked “Do you need help?” and walked to the chiller to turn off the supply. Well, I didn’t make it to the pub, but I did spend time with Håkon mopping the floor, crawling around the instrument to soak up all the spilled water, and repairing the water connection. A Haskris chiller can really pump some water!

Håkon and I built a friendship over Macintoshes, spelling and grammar in software and user manuals, and of course, low-temperature devices. His command of languages was second to none, and we shared a disdain for language errors on user interfaces and in documentation. Together we performed a thorough beta test of some second-generation diffractometer software and made pages of notes on the grammar alone. He said we are all scientists, and as such, we should be held to exacting language. Håkon expected a lot from his colleagues and students. I’d like to think I earned his respect. I always looked forward to seeing him at the annual ACA meeting and will miss his presence.

Sean Parkin: I was Håkon’s last Ph.D. student at UC Davis, from 1989 to 1993. Although he formally retired shortly before I graduated, he never stopped working: the X-ray lab was his domain. In terms of experimental skill, Håkon had few peers, and his mastery of the practical was bolstered by a deep understanding. He had two laws of crystallography: ‘no two crystals are alike’ and ‘the highest observable symmetry is P1’. Both ‘laws’ have subtle hidden meaning, and if you didn’t ‘get it.’ he knew, and judged accordingly. I have far too many fond memories of Håkon from the last three decades that it would be impossible to recount anything but a tiny fraction of them here. Nevertheless, here are a couple that people who knew Håkon well enough might enjoy.

Shortly after joining Håkon, at about the time we were planning a little research project to get me up to speed in the X-ray lab, he suffered an attack of gout. That naturally got us to talking about uric acid crystals. The structure of pure uric acid had been known for years, but a dihydrate, thought to be orthorhombic, remained unsolved. There was even a published recipe to grow crystals of the dihydrate, so although they were extremely thin plates, we had a good dataset pretty quickly. It was also immediately obvious that the crystals were not orthorhombic, but monoclinic – good old P21/c. The structure solved easily but refinement was poor, even after accounting for pseudo-orthorhombic twinning. By that point I was fairly self-reliant in the lab, so even though the uric acid project was incomplete, for me it had served its purpose and was relegated to a back burner. Much later, upon seeing a massively distorted orthorhombic model in Acta B, I had a ‘smack my head’ revelation, added whole-molecule disorder to the twinned model and showed it to Håkon. The fit was spectacular! Håkon’s response was along the lines of “… oh good, I was wondering when you’d figure that out.” I use that same dataset as a teaching tool to this day.

In addition to his experimental genius, Håkon excelled in the written word. He always strove for an ideal balance between information density, precision, and readability. He had little tolerance for nonsense, especially if it came from supposed positions of authority. I’ve long since forgotten the exact context, but a couple of his responses to particularly boneheaded review comments were: “The referee invents situations that have no counterpart in reality, and then argues against them.” That was closely followed by: “The utility of a crystal structure determination is not measured by R, but by the scientific insight it provides.” Those always bring a smile to my face!

Joel Sussman, Felix Frolow & Håkon Hope

Even after I left Davis, Håkon and I were in regular contact until shortly before his death. On the (too few) occasions that my work schedule took me back to California, I usually tried to squeeze in a trip to Davis to see Håkon and Sally. On my last visit, in July 2017, we drove over to the Chemistry building to see the changes over the intervening quarter century. The X-ray labs were of course much changed – all modern equipment, many new faces etc. I was, however, delighted to find that Håkon was happily ensconced in the small lab in the annex that I had occupied as a grad student. There were still pictures on the walls and boxes of samples that I left there 24 years earlier! I’ll be forever grateful to Håkon for his guidance and friendship over the years. Crystallography, for me, is quite different without him. It is rare for a day to go by when I don’t think “… what would Håkon do?”