Aaron Ciechanover and Avram Hershko from the Israel Institute of Technology, and Irwin Rose from the University of California, pioneered research that unravelled the part ubiquitin plays in the degradation of proteins. Ubiquitin is now known to be involved in several other cellular processes as well, including quality control of nascent proteins, membrane trafficking, cell signalling, cell cycle control, X chromosome inactivation and the maintenance of chromosome structure, to name but a few. How can a tiny, 76-amino acid protein have so many varied roles? Ubiquitin (UB) acts through its attachment to other proteins (ubiquitinylation), and these protein modifications can alter the function or location of the protein, or target it for destruction. The C-terminus of UB extends as a 4-residue tail (Leu-Arg-Gly-Gly), where the terminal glycine residue can form an isopeptide bond with the amino group of a lysine side chain in a target protein. Alternatively, it can make an isopeptide bond with a lysine in another copy of UB to form a UB chain that ultimately attaches itself to a target protein. In general, the number and placement of UB molecules added to a protein helps to determine its future: a single copy of UB acts to modify a proteins function, while multiple copies of UB will either modify a proteins function or target it for degradation by the 26S proteasome, depending upon the position of the UB subunits.
Cunningly, several pathogenic bacteria have developed the ability to tap into eukaryotic UB-mediated processes to manipulate their hosts. In particular, the host immune response can be suppressed through the inhibition of the NFkB signalling system. The transcription factor NFkB is responsible for activating genes involved in the immune response, but is inhibited by its association with the inhibitor IkB. The immune response is triggered by the ubiquitinylation of IkB to target it for degradation, which releases NFkB so it can enter the nucleus and transcribe genes required to mount an immune reaction. Certain bacteria are able to interfere with this system by either preventing the ubiquitinylation of IkB (as is found with non-pathogenic enteric bacteria that form part of the intestinal microflora), or by cleaving ubiquitin from IkB (as with the ubiquitin-like cysteine proteases found in several animal and plant pathogens) either way, IkB evades degradation and suppresses the immune response by inhibiting NFkB.
Ubiquitin-mediated Protein Degradation
The addition of a chain of multiple copies of ubiquitin (UB) targets a protein for destruction by the intracellular protease known as the 26S proteasome, a large complex that breaks down proteins to their constituent amino acids for reuse. The proteins targeted by this system are short-lived proteins, many of which are regulatory proteins, whose actions are controlled in part by rapid synthesis and degradation, much like an on/off switch; as such, the UB system itself is an important regulatory tool that controls the concentration of key signalling proteins. For example, many cell cycle regulatory proteins, such as cyclin, are controlled by UB-mediated proteolysis to allow a rapid transition between cell cycle stages, and to drive the direction of the cell cycle by preventing regression to an earlier stage. The selective UB-mediated degradation of proteins is also involved in the stress response, antigen processing, signal transduction, transcriptional regulation, DNA repair and apoptosis. 㰀⼀瀀㸀㰀瀀㸀 In addition, the 26S proteasome targets misfolded, damaged or mutant proteins with abnormal conformations that could be harmful to the cell. UB-dependent proteolysis provides the cell with a proofreading capacity for nascent polypeptide chains, whereby faulty polypeptides are targeted for destruction. Sequences that signal UB-mediated destruction can be buried in a hydrophobic core, which only becomes exposed after misfolding, providing a convenient way to distinguish misfolded proteins from functional ones - however, the presence of chaperones protects a polypeptide from degradation from the time it is synthesised until it is fully folded. Damaged proteins are also targeted. For example, hepatic cytochromes P450 are haemoproteins engaged in the oxidation of endo- and xenobiotics, during which they can become damaged by reactive intermediates; these damaged liver enzymes are rapidly removed by the UB-dependent proteolytic system. 㰀⼀瀀㸀㰀瀀㸀 It is important for a cell to be able to select specific proteins for degradation so as to avoid degrading proteins vital to the functioning of the cell, as well as to precisely control the delicate balance that exists between the proteins in a regulatory system, and to cope with the cells ever-changing protein requirements. The ubiquitin-mediated pathway achieves a high level of specificity, selecting only UB-tagged proteins to be destroyed. In addition, there exists a class of enzymes that function to remove UB from substrate proteins, thereby rescuing them from destruction by preventing indiscriminate degradation. Thus, for a protein to be degraded, it must not only have some type of UB-tagging signal, but also must escape the de-ubiquitinylation enzymes. The attachment of UB to a target protein requires the action of three enzymes, called E1 (UB-activating enzymes), E2 (UB-conjugating enzymes) and E3 (UB ligases), which work sequentially in a cascade:㰀⼀瀀㸀㰀瀀㸀 Ubiquitin activation㰀⼀瀀㸀㰀瀀㸀 E1 enzymes are responsible for activating UB, the first step in ubiquitinylation. The E1 enzyme hydrolyses ATP and adenylates the C-terminus of UB, and then forms a thioester bond between the C-terminus of UB and the active site cysteine of E1. To be fully active, E1 must non-covalently bind to and adenylate a second UB molecule. The E1 enzyme can then transfer the thioester-linked UB to the UB-conjugating enzyme, E2, in an ATP-dependent reaction.㰀⼀瀀㸀㰀瀀㸀 Ubiquitin conjugation
UB is linked by another thioester bond to the active site cysteine of the E2 enzyme. There are several different E2 enzymes (>30 in humans), which are broadly grouped into four classes, all of which have a core catalytic domain, and some of which have short C- or N-terminal extensions that are involved in E2 localisation or in protein-protein interactions. The different E2 enzymes are able to interact with overlapping sets of E3 ligases.㰀⼀瀀㸀㰀瀀㸀 Ubiquitin ligation㰀⼀瀀㸀㰀瀀㸀 With the help of a third enzyme, E3 ligase, UB is transferred from the E2 enzyme to a lysine residue on a substrate protein, resulting in an isopeptide bond between the substrate lysine and the C-terminus of UB. UB ligation provides the key steps of substrate selection and UB transfer to the protein target, with the E3 ligases being responsible for substrate specificity and regulation of the ubiquitinylation process. Hundreds of putative E3 ligases have been identified, which bind to specific substrate sequences, or degrons (as they are targets for degradation), permitting the substrate specificity associated with this enzyme. There are at least four classes of E3 ligases: HECT-type (IPR000569), RING-type (IPR001841), PHD-type, and U-box containing (IPR003613). The E3 ligases are the only one of the 3 enzymes that is subjected to regulation, however balance in the UB system is also achieved through a set of de-ubiquitinylating isopeptidases that cleave UB off substrates.㰀⼀瀀㸀㰀瀀㸀 Ubiquitin elongation
Additional UB molecules can be linked to the first one to form a poly-UB chain, which occurs through a particular type of E3 ligase sometimes referred to as a UB-elongation enzyme, or E4. There are seven lysine residues in UB that can be used to link UB molecules together, resulting in diverse structures. Poly-UB chains linked at different positions alters the destiny of the target protein to which it is added: Lys(11)-, Lys(29)- and Lys(48)-linked poly-UB chains target the protein to the proteasome for degradation, while Lys(6)- or Lys(63)-linked poly-UB chains (as well as mono-ubiquitinylation) signal reversible modifications in protein activity, location or trafficking. The length of the UB chain appears to be important as well, such as with Lys(48) poly-UB chains where its length influences its affinity for proteasomes. Therefore, E3 ligases provide the exquisite specificity in regards to which proteins should be targeted with UB, how many UB molecules are added to the target, and at what positions the poly-UB molecules are linked, thereby determining the future of the protein and the precise role it will play.
Proteasome
The 26S proteasome is a large (>60 subunits) complex with a 20S barrel-shaped proteolytic core consisting of alternating a and b subunits, and two 19S regulatory caps at either end (see diagram above). The 19S caps recognise, de-ubiquitinylate and unfold the target protein before it is pulled through the hollow core of the 20S catalytic centre, where it is dissembled into reusable amino acid components.㰀⼀瀀㸀㰀瀀㸀 Disease
Inappropriate UB-mediated protein degradation has been implicated in a number of pathological conditions, especially neurodegenerative disorders that involve protein aggregation and inclusion body formation, such as Alzheimers disease, Parkinsons disease, Huntingtons disease and ALS, where protein misfolding may play a role. Several Parkinsons disease-causing mutations have been identified in genes encoding for UB-mediated degradation pathway proteins, such as the PARK2-encoded Parkin protein that causes autosomal recessive juvenile parkinsonism (AR-JP), and which appears to function as an E3 ligase. This degradation pathway is also implicated in certain forms of cancer as well.㰀⼀瀀㸀㰀瀀㸀
I was born in Berne, a northeast Indiana farming community proud of its Swiss heritage. Life was not easy for my parents, Noah J. Schrock, the second of six children, and Martha A. Habegger, the second of ten children. They married in 1933 during the Depression. My oldest brother, Luther, was born in 1934, Theodore in 1939. A few months after I appeared in 1945, the family moved to Decatur, about 13 miles north of Berne, where we lived until the summer after my fifth birthday. My most lasting memory of our first home is its proximity to the city swimming pool where I spent many happy summer days.㰀⼀瀀㸀㰀瀀㸀 We moved into an old house on the west side of South 13th Street in 1950. The house required a good deal of work, but my father, who had been a carpenter for fifteen years, accomplished the renovation over a period of several years. The house was located on what seemed to me to be an enormous plot of land (one acre); the backyard took forever to mow on a steamy summer day and the vegetable garden produced quantities of corn, strawberries, melons, tomatoes, and raspberries. A large vacant lot extended south toward a small railroad that dove beneath the highway on its way east to a mill where tiles were made from the clay dug on the west side of the road. The process of mining the clay created ponds, which I explored along with the surrounding woods at length. In the summer I would fish, catch snakes and frogs, and build simple huts in the woods, which probably were the first indications of my love for designing and building, and for the outdoors. In the winter I learned how to ice skate and often (so it seemed) would come close to actually freezing toes and fingers. We never had much money, but the house was comfortable (except during the first, and especially cold, winter) and the food (fresh in the summer, canned in the winter) was plentiful for the five of us.
吀栀攀 匀挀栀爀漀挀欀 昀愀洀椀氀礀 椀渀 㤀㐀㘀⸀ 㰀⼀瀀㸀㰀瀀㸀 䴀礀 昀愀琀栀攀爀 戀甀椀氀琀 愀 眀漀漀搀眀漀爀欀椀渀最 猀栀漀瀀 椀渀 琀栀攀 琀眀漀 挀愀爀 最愀爀愀最攀 愀琀 琀栀攀 爀攀愀爀 漀昀 琀栀攀 栀漀甀猀攀 眀栀攀爀攀 䤀 愀氀猀漀 猀瀀攀渀琀 洀甀挀栀 琀椀洀攀 搀椀猀挀漀瘀攀爀椀渀最Ⰰ 愀洀漀渀最 漀琀栀攀爀 琀栀椀渀最猀Ⰰ 琀栀愀琀 椀琀 椀猀 渀漀琀 攀愀猀礀 琀漀 搀爀椀瘀攀 渀愀椀氀猀 椀渀琀漀 洀愀瀀氀攀⸀ 䤀 眀愀猀 渀漀琀 愀氀氀漀眀攀搀 琀漀 漀瀀攀爀愀琀攀 瀀漀眀攀爀 琀漀漀氀猀 愀琀 愀 礀漀甀渀最 愀最攀Ⰰ 戀甀琀 洀礀 昀愀琀栀攀爀 椀渀琀爀漀搀甀挀攀搀 洀攀 琀漀 猀攀瘀攀爀愀氀 愀猀 䤀 戀攀挀愀洀攀 漀氀搀攀爀Ⰰ 攀砀挀攀瀀琀 栀椀猀 瀀爀椀稀攀 㤀㐀 䐀攀氀琀愀 琀愀戀氀攀 猀愀眀Ⰰ 眀栀椀挀栀 䤀 攀瘀攀渀琀甀愀氀氀礀 椀渀栀攀爀椀琀攀搀 眀栀攀渀 栀攀 搀椀攀搀 漀昀 氀攀甀欀攀洀椀愀 椀渀 㤀㠀 愀琀 愀最攀 㘀㤀⸀ 䠀攀 眀愀猀 愀 瀀愀琀椀攀渀琀 琀攀愀挀栀攀爀 攀瘀攀渀 琀栀漀甀最栀 䤀 搀椀搀 渀漀琀 昀甀氀氀礀 愀瀀瀀爀攀挀椀愀琀攀 琀栀攀 搀椀昀昀攀爀攀渀挀攀 戀攀琀眀攀攀渀 愀 挀栀椀猀攀氀 愀渀搀 愀 猀挀爀攀眀搀爀椀瘀攀爀 漀爀 挀氀攀愀爀 瀀椀渀攀 愀渀搀 愀 瀀爀椀稀攀搀 瀀椀攀挀攀 漀昀 戀椀爀搀猀 攀礀攀 洀愀瀀氀攀 眀栀攀渀 䤀 眀愀猀 礀漀甀渀最⸀ 䤀 氀攀愀爀渀攀搀 洀愀渀礀 琀栀椀渀最猀 戀礀 琀爀椀愀氀 愀渀搀 攀爀爀漀爀 戀甀琀 渀攀瘀攀爀琀栀攀氀攀猀猀 最爀攀眀 琀漀 愀瀀瀀爀攀挀椀愀琀攀 眀栀愀琀 漀渀攀 挀愀渀 搀漀 眀椀琀栀 眀漀漀搀 愀渀搀 琀栀攀 爀椀最栀琀 琀漀漀氀猀 甀猀攀搀 琀栀攀 爀椀最栀琀 眀愀礀⸀ 䤀 洀愀椀渀琀愀椀渀 琀栀愀琀 椀渀琀攀爀攀猀琀 琀漀 琀栀椀猀 搀愀礀⸀ 䰀椀欀攀 洀漀猀琀 礀漀甀渀最 䠀漀漀猀椀攀爀 洀攀渀 愀琀 琀栀愀琀 琀椀洀攀Ⰰ 䤀 瀀氀愀礀攀搀 漀渀 琀栀攀 猀挀栀漀漀氀 戀愀猀欀攀琀戀愀氀氀Ⰰ 戀愀猀攀戀愀氀氀Ⰰ 愀渀搀 昀漀漀琀戀愀氀氀 琀攀愀洀猀⸀ 䄀氀琀栀漀甀最栀 䤀 搀椀搀 渀漀琀 挀漀渀琀椀渀甀攀 琀漀 瀀氀愀礀 漀爀最愀渀椀稀攀搀 猀瀀漀爀琀猀 戀攀礀漀渀搀 愀最攀 琀攀渀 漀爀 攀氀攀瘀攀渀Ⰰ 猀瀀漀爀琀猀 瀀爀漀瘀椀搀攀搀 洀攀 眀椀琀栀 愀 爀攀猀瀀攀挀琀 愀渀搀 渀攀攀搀 昀漀爀 瀀栀礀猀椀挀愀氀 攀砀攀爀挀椀猀攀 琀栀愀琀 䤀 猀琀椀氀氀 栀愀瘀攀⸀
䴀礀 挀甀爀椀漀猀椀琀礀 愀渀搀 氀漀瘀攀 漀昀 戀甀椀氀搀椀渀最 琀栀椀渀最猀 瀀氀愀礀攀搀 椀渀琀漀 琀栀攀 栀愀渀搀 漀昀 洀礀 漀氀搀攀爀 戀爀漀琀栀攀爀 吀栀攀漀搀漀爀攀 眀栀漀 瀀爀攀猀攀渀琀攀搀 洀攀 眀椀琀栀 琀栀攀 瀀爀漀瘀攀爀戀椀愀氀 挀栀攀洀椀猀琀爀礀 猀攀琀 漀渀 洀礀 攀椀最栀琀栀 戀椀爀琀栀搀愀礀⸀ 䠀攀 眀愀猀 琀栀椀爀琀攀攀渀 愀琀 琀栀攀 琀椀洀攀 愀渀搀 戀攀最椀渀渀椀渀最 琀漀 愀瀀瀀爀攀挀椀愀琀攀 琀栀攀 戀攀愀甀琀椀攀猀 漀昀 猀挀椀攀渀挀攀⸀ 䠀椀猀 椀渀琀攀爀攀猀琀 椀渀 挀栀攀洀椀猀琀爀礀 挀漀渀琀椀渀甀攀搀 琀栀爀漀甀最栀 栀椀猀 挀漀氀氀攀最攀 礀攀愀爀猀 戀甀琀 栀攀 攀瘀攀渀琀甀愀氀氀礀 猀琀甀搀椀攀搀 洀攀搀椀挀椀渀攀 椀渀猀琀攀愀搀 愀渀搀 戀攀挀愀洀攀 愀 栀椀最栀氀礀 猀甀挀挀攀猀猀昀甀氀 猀甀爀最攀漀渀⸀ 䤀 眀愀猀 栀漀漀欀攀搀⸀ 䤀 挀爀攀愀琀攀搀 愀 猀洀愀氀氀 氀愀戀漀爀愀琀漀爀礀 愀琀 琀栀攀 攀渀搀 漀昀 愀 猀琀漀爀愀最攀 愀爀攀愀 昀漀爀 挀愀渀渀攀搀 最漀漀搀猀 愀渀搀 甀猀攀搀 洀礀 戀甀搀搀椀渀最 眀漀漀搀眀漀爀欀椀渀最 猀欀椀氀氀猀 琀漀 戀甀椀氀搀 猀栀攀氀瘀攀猀 昀漀爀 琀栀攀 攀瘀攀爀 攀砀瀀愀渀搀椀渀最 挀漀氀氀攀挀琀椀漀渀 漀昀 琀攀猀琀 琀甀戀攀猀Ⰰ 戀攀愀欀攀爀猀Ⰰ 愀渀搀 昀氀愀猀欀猀⸀ 䤀 漀戀琀愀椀渀攀搀 洀漀猀琀 漀昀 洀礀 攀焀甀椀瀀洀攀渀琀 琀栀爀漀甀最栀 愀 洀愀椀氀 漀爀搀攀爀 猀甀瀀瀀氀礀 栀漀甀猀攀 眀椀琀栀 洀漀渀攀礀 攀愀爀渀攀搀 昀爀漀洀 愀渀 攀愀爀氀礀 洀漀爀渀椀渀最 瀀愀瀀攀爀 爀漀甀琀攀⸀ 䤀 挀愀爀爀椀攀搀 漀甀琀 猀椀洀瀀氀攀 攀砀瀀攀爀椀洀攀渀琀猀 ⠀挀漀洀戀椀渀椀渀最 愀挀椀搀猀 愀渀搀 戀愀猀攀猀 琀漀 洀愀欀攀 猀愀氀琀猀Ⰰ 洀愀欀椀渀最 瀀氀攀愀猀愀渀琀 猀洀攀氀氀椀渀最 攀猀琀攀爀猀Ⰰ 攀琀挀⸀⤀ 昀漀氀氀漀眀椀渀最 琀栀攀 搀椀爀攀挀琀椀漀渀猀 椀渀 挀栀攀洀椀猀琀爀礀 氀愀戀漀爀愀琀漀爀礀 琀攀砀琀猀 栀愀渀搀攀搀 搀漀眀渀 琀漀 洀攀⸀ 圀栀攀渀 䤀 爀攀愀挀栀攀搀 琀栀攀 愀最攀 漀昀 琀栀椀爀琀攀攀渀Ⰰ 䠀愀爀爀礀 䐀愀椀氀攀礀Ⰰ 琀栀攀 栀椀最栀 猀挀栀漀漀氀 挀栀攀洀椀猀琀爀礀 琀攀愀挀栀攀爀Ⰰ 猀琀漀欀攀搀 洀礀 椀渀琀攀爀攀猀琀 椀渀 挀栀攀洀椀猀琀爀礀 眀椀琀栀 洀漀爀攀 琀攀砀琀戀漀漀欀猀 愀渀搀 搀椀猀挀愀爀搀攀搀 攀焀甀椀瀀洀攀渀琀⸀ 䤀 琀栀漀甀最栀琀 愀氀氀 攀焀甀椀瀀洀攀渀琀 眀漀渀搀攀爀昀甀氀 琀漀 戀攀栀漀氀搀⸀ 䄀猀 䤀 戀攀挀愀洀攀 愀眀愀爀攀 漀昀 琀栀攀 瀀漀眀攀爀 漀昀 戀甀爀渀椀渀最 渀愀琀甀爀愀氀 最愀猀Ⰰ 琀栀攀 氀漀眀氀礀 愀氀挀漀栀漀氀 戀甀爀渀攀爀 眀愀猀 爀攀瀀氀愀挀攀搀 戀礀 琀栀攀 挀漀洀洀漀渀 䈀甀渀猀攀渀 戀甀爀渀攀爀Ⰰ 愀渀搀 琀栀攀 䈀甀渀猀攀渀 戀甀爀渀攀爀 甀氀琀椀洀愀琀攀氀礀 戀礀 愀 栀椀最栀 琀攀挀栀 戀爀漀愀搀ⴀ栀攀愀搀攀搀 洀漀搀攀氀 挀愀瀀愀戀氀攀 漀昀 瀀甀琀琀椀渀最 漀甀琀 愀 最漀漀搀 搀攀愀氀 漀昀 栀攀愀琀Ⰰ 攀渀漀甀最栀 琀漀 洀攀氀琀 洀攀琀愀氀猀 椀渀 愀 瀀漀爀挀攀氀愀椀渀 挀爀甀挀椀戀氀攀 愀渀搀 攀瘀攀渀 猀漀搀椀甀洀 挀栀氀漀爀椀搀攀⸀
䄀昀琀攀爀 眀攀 洀漀瘀攀搀 琀漀 愀 栀漀甀猀攀 漀渀 䨀愀挀欀猀漀渀 匀琀爀攀攀琀 椀渀 㤀㔀㠀Ⰰ 洀礀 氀愀戀漀爀愀琀漀爀礀 最爀攀眀 椀渀 猀椀稀攀Ⰰ 搀椀瘀攀爀猀椀琀礀Ⰰ 愀渀搀 挀漀洀瀀氀攀砀椀琀礀⸀ 䤀 渀漀眀 栀愀搀 愀琀 洀礀 搀椀猀瀀漀猀愀氀 爀攀氀愀琀椀瘀攀氀礀 猀漀瀀栀椀猀琀椀挀愀琀攀搀 愀渀搀Ⰰ 椀昀 洀椀猀甀猀攀搀Ⰰ 搀愀渀最攀爀漀甀猀 猀甀戀猀琀愀渀挀攀猀 椀渀 愀 猀洀愀氀氀 爀漀漀洀 椀渀 琀栀攀 戀愀猀攀洀攀渀琀⸀ 䤀 眀愀猀 漀昀琀攀渀 椀渀琀攀爀攀猀琀攀搀 椀渀 琀攀猀琀椀渀最 爀攀挀椀瀀攀猀 昀漀爀 洀椀砀琀甀爀攀猀 漀昀 漀砀椀搀椀稀椀渀最 愀最攀渀琀猀 愀渀搀 漀砀椀搀椀稀攀愀戀氀攀 洀愀琀攀爀椀愀氀猀 愀猀 眀攀氀氀 愀猀 渀椀琀爀愀琀椀渀最 挀漀洀洀漀渀 栀漀甀猀攀栀漀氀搀 猀甀戀猀琀愀渀挀攀猀⸀ 吀栀愀渀欀昀甀氀氀礀Ⰰ 琀栀攀爀攀 眀攀爀攀 渀漀 猀攀爀椀漀甀猀 洀椀猀栀愀瀀猀Ⰰ 愀氀琀栀漀甀最栀 洀礀 洀漀琀栀攀爀 琀攀氀氀猀 猀琀漀爀椀攀猀 琀栀愀琀 戀攀氀椀攀 琀栀愀琀 猀琀愀琀攀洀攀渀琀Ⰰ 椀渀挀氀甀搀椀渀最 漀渀攀 椀渀 眀栀椀挀栀 琀栀攀 氀漀挀愀氀 昀椀爀攀 搀攀瀀愀爀琀洀攀渀琀 眀愀猀 挀愀氀氀攀搀 琀漀 漀甀爀 栀漀洀攀㬀 昀漀爀琀甀渀愀琀攀氀礀 漀渀氀礀 愀 猀洀愀氀氀 爀甀最 眀愀猀 戀甀爀渀椀渀最Ⰰ 渀漀琀 琀栀攀 栀漀甀猀攀⸀ 䄀琀 氀攀愀猀琀 䤀 愀氀猀漀 眀愀猀 焀甀椀挀欀 琀漀 琀栀椀渀欀 愀渀搀 愀挀琀⸀
䴀礀 昀愀琀栀攀爀 眀攀渀琀 琀漀 匀愀渀 䐀椀攀最漀Ⰰ 䌀愀氀椀昀漀爀渀椀愀Ⰰ 椀渀 琀栀攀 昀愀氀氀 漀昀 㤀㔀㠀 琀漀 眀漀爀欀 椀渀 琀栀攀 挀漀渀猀琀爀甀挀琀椀漀渀 椀渀搀甀猀琀爀礀 眀椀琀栀 栀椀猀 戀爀漀琀栀攀爀Ⰰ 䌀氀愀爀攀渀挀攀Ⰰ 愀渀搀 琀漀 攀砀瀀氀漀爀攀 琀栀攀 昀攀愀猀椀戀椀氀椀琀礀 漀昀 洀漀瘀椀渀最 眀攀猀琀⸀ 䤀渀 㤀㔀㤀 洀礀 洀漀琀栀攀爀 愀渀搀 䤀 樀漀椀渀攀搀 栀椀洀⸀ 匀栀攀 搀爀漀瘀攀 愀渀搀 䤀 渀愀瘀椀最愀琀攀搀 挀爀漀猀猀 挀漀甀渀琀爀礀 眀椀琀栀 洀礀 氀愀戀漀爀愀琀漀爀礀 挀愀爀攀昀甀氀氀礀 瀀愀挀欀攀搀 椀渀 琀栀攀 琀爀甀渀欀 漀昀 琀栀攀 挀愀爀⸀ 䈀礀 琀栀攀 琀椀洀攀 䤀 昀椀渀椀猀栀攀搀 䴀椀猀猀椀漀渀 䈀愀礀 䠀椀最栀 匀挀栀漀漀氀 椀渀 㤀㘀㌀Ⰰ 戀漀琀栀 洀礀 瀀愀爀攀渀琀猀 栀愀搀 愀氀猀漀 昀甀氀昀椀氀氀攀搀 琀栀攀椀爀 搀爀攀愀洀猀 漀昀 昀椀渀椀猀栀椀渀最 栀椀最栀 猀挀栀漀漀氀Ⰰ 猀漀洀攀琀栀椀渀最 琀栀攀礀 栀愀搀 渀漀琀 戀攀攀渀 愀氀氀漀眀攀搀 琀漀 搀漀 椀渀 琀栀攀椀爀 礀漀甀琀栀⸀ 䴀礀 椀渀琀攀爀攀猀琀 椀渀 挀栀攀洀椀猀琀爀礀 攀砀瀀愀渀搀攀搀 椀渀 匀愀渀 䐀椀攀最漀⸀ 䤀 昀漀甀渀搀 愀 氀愀戀漀爀愀琀漀爀礀 猀甀瀀瀀氀礀 栀漀甀猀攀 眀栀攀爀攀 䤀 挀漀甀氀搀 戀甀礀 挀氀愀猀猀椀挀 攀焀甀椀瀀洀攀渀琀 ⠀愀 ㈀㔀 洀䰀 爀攀琀漀爀琀 眀愀猀 挀漀瘀攀琀攀搀 愀渀搀 瀀甀爀挀栀愀猀攀搀⤀ 愀渀搀 愀 搀爀甀最猀琀漀爀攀 眀栀攀爀攀 䤀 挀漀甀氀搀 戀甀礀 戀愀猀椀挀 挀栀攀洀椀挀愀氀猀 眀椀琀栀 猀漀洀攀 愀搀甀氀琀 栀攀氀瀀 漀昀 挀漀甀爀猀攀⸀ 䤀 搀椀猀挀漀瘀攀爀攀搀 洀愀渀礀 眀漀渀搀攀爀昀甀氀 琀栀椀渀最猀 猀甀挀栀 愀猀 栀漀眀 琀漀 洀愀欀攀 戀爀漀洀椀渀攀 昀爀漀洀 䬀䈀爀 愀渀搀 猀甀氀昀甀爀椀挀 愀挀椀搀Ⰰ 栀漀眀 琀漀 洀愀欀攀 猀漀搀椀甀洀 ⠀愀渀搀 挀栀氀漀爀椀渀攀⤀ 戀礀 攀氀攀挀琀爀漀氀椀稀椀渀最 洀漀氀琀攀渀 猀漀搀椀甀洀 挀栀氀漀爀椀搀攀Ⰰ 愀渀搀 栀漀眀 琀漀 愀渀愀氀礀稀攀 昀漀爀 洀攀琀愀氀猀 戀礀 洀愀欀椀渀最 猀甀氀昀椀搀攀猀 眀椀琀栀 戀爀椀氀氀椀愀渀琀 愀渀搀 挀栀愀爀愀挀琀攀爀椀猀琀椀挀 挀漀氀漀爀猀⸀ 䤀 琀漀漀欀 甀瀀 猀甀爀昀椀渀最 愀渀搀 猀欀椀渀 搀椀瘀椀渀最Ⰰ 愀渀搀 挀漀渀琀椀渀甀攀搀 洀礀 椀渀琀攀爀攀猀琀 椀渀 眀漀漀搀眀漀爀欀椀渀最 戀礀 搀攀猀椀最渀椀渀最Ⰰ 洀愀欀椀渀最Ⰰ 愀渀搀 猀攀氀氀椀渀最 昀椀渀猀 昀漀爀 猀甀爀昀戀漀愀爀搀猀⸀ 䤀 攀渀琀攀爀攀搀 愀 爀攀最椀漀渀愀氀 猀挀椀攀渀挀攀 昀愀椀爀 眀椀琀栀 愀 瀀爀漀樀攀挀琀 琀栀愀琀 挀漀渀挀攀爀渀攀搀 漀猀洀漀琀椀挀 瀀爀漀挀攀猀猀攀猀 椀渀 猀攀愀 甀爀挀栀椀渀 攀最最猀 愀渀搀 洀愀渀愀最攀搀 琀漀 眀椀渀 愀 瀀爀椀稀攀 昀漀爀 椀琀⸀ 䤀 挀漀氀氀攀挀琀攀搀 琀栀攀 猀攀愀 甀爀挀栀椀渀猀 愀琀 氀漀眀 琀椀搀攀 愀渀搀 栀愀爀瘀攀猀琀攀搀 琀栀攀 攀最最猀 洀礀猀攀氀昀⸀ 吀栀愀琀Ⰰ 愀渀搀 搀椀猀猀攀挀琀椀漀渀 漀昀 愀 猀栀攀攀瀀✀猀 戀爀愀椀渀 ⠀眀栀椀挀栀 䤀 最爀攀愀琀氀礀 攀渀樀漀礀攀搀⤀ 椀渀 瀀栀礀猀椀漀氀漀最椀挀愀氀 瀀猀礀挀栀漀氀漀最礀 氀愀琀攀爀 椀渀 挀漀氀氀攀最攀Ⰰ 眀愀猀 琀栀攀 挀氀漀猀攀猀琀 䤀 眀漀甀氀搀 挀漀洀攀 琀漀 昀漀氀氀漀眀椀渀最 洀礀 戀爀漀琀栀攀爀 椀渀琀漀 洀攀搀椀挀椀渀攀⸀
䤀 愀氀眀愀礀猀 愀猀猀甀洀攀搀 䤀 眀漀甀氀搀 愀琀琀攀渀搀 挀漀氀氀攀最攀 愀渀搀 猀琀甀搀礀 挀栀攀洀椀猀琀爀礀⸀ 吀栀攀 漀渀氀礀 昀椀渀愀渀挀椀愀氀氀礀 瘀椀愀戀氀攀 漀瀀琀椀漀渀 眀愀猀 琀栀攀 唀渀椀瘀攀爀猀椀琀礀 漀昀 䌀愀氀椀昀漀爀渀椀愀⸀ 䤀 眀愀猀 愀挀挀攀瀀琀攀搀 愀琀 䈀攀爀欀攀氀攀礀 戀甀琀 挀栀漀猀攀 琀漀 愀琀琀攀渀搀 刀椀瘀攀爀猀椀搀攀Ⰰ 愀 爀攀氀愀琀椀瘀攀氀礀 渀攀眀 挀愀洀瀀甀猀 愀戀漀甀琀 㤀 洀椀氀攀猀 渀漀爀琀栀 漀昀 匀愀渀 䐀椀攀最漀Ⰰ 戀攀挀愀甀猀攀 䤀 琀栀漀甀最栀琀 琀栀愀琀 愀 猀洀愀氀氀攀爀 猀挀栀漀漀氀 洀椀最栀琀 愀氀氀漀眀 洀攀 琀漀 搀漀 洀漀爀攀 椀渀搀攀瀀攀渀搀攀渀琀 爀攀猀攀愀爀挀栀 攀愀爀氀椀攀爀 椀渀 洀礀 挀愀爀攀攀爀⸀ 吀栀愀琀 瀀爀漀瘀攀搀 琀漀 戀攀 琀栀攀 挀愀猀攀⸀ 䄀昀琀攀爀 琀栀攀 昀椀爀猀琀 攀砀愀洀 椀渀 洀礀 昀椀爀猀琀 挀栀攀洀椀猀琀爀礀 挀漀甀爀猀攀 愀琀 唀䌀刀Ⰰ 䤀 眀愀猀 愀瀀瀀爀漀愀挀栀攀搀 戀礀 倀爀漀昀攀猀猀漀爀 䨀愀洀攀猀 倀椀琀琀猀 眀栀漀 愀猀欀攀搀 椀昀 䤀 眀愀渀琀攀搀 愀 猀甀洀洀攀爀 樀漀戀⸀ 䤀 愀最爀攀攀搀 愀渀搀 戀攀最愀渀 爀攀猀攀愀爀挀栀 椀渀 眀栀愀琀 戀爀漀愀搀氀礀 挀漀甀氀搀 戀攀 挀愀氀氀攀搀 愀琀洀漀猀瀀栀攀爀椀挀 挀栀攀洀椀猀琀爀礀Ⰰ 愀 栀漀琀 琀漀瀀椀挀 椀渀 琀栀攀 猀洀漀最 爀椀搀搀攀渀 䰀漀猀 䄀渀最攀氀攀猀 戀愀猀椀渀 愀渀搀 猀甀爀爀漀甀渀搀椀渀最 愀爀攀愀 愀琀 琀栀愀琀 琀椀洀攀⸀ 䤀渀 愀挀琀甀愀氀椀琀礀Ⰰ 䤀 猀瀀攀渀琀 洀礀 琀椀洀攀 氀攀愀爀渀椀渀最 琀漀 戀氀漀眀 最氀愀猀猀 愀渀搀 挀漀渀猀琀爀甀挀琀 瘀愀挀甀甀洀 氀椀渀攀猀Ⰰ 愀渀搀 琀漀 洀攀愀猀甀爀攀 氀漀眀 挀漀渀挀攀渀琀爀愀琀椀漀渀猀 漀昀 瀀栀漀琀漀氀礀猀椀猀 瀀爀漀搀甀挀琀猀 甀猀椀渀最 愀 琀攀洀瀀攀爀愀洀攀渀琀愀氀Ⰰ 搀攀氀椀挀愀琀攀Ⰰ 愀氀洀漀猀琀 椀洀瀀漀猀猀椀戀氀攀 琀漀 愀氀椀最渀Ⰰ 洀甀氀琀椀ⴀ瀀愀猀猀 倀攀爀欀椀渀ⴀ䔀氀洀攀爀 䤀刀 洀愀挀栀椀渀攀 挀漀渀渀攀挀琀攀搀 琀漀 愀 瘀愀挀甀甀洀 氀椀渀攀⸀ ⠀䘀漀甀爀椀攀爀 吀爀愀渀猀昀漀爀洀 洀愀挀栀椀渀攀猀 眀攀爀攀 渀漀琀 礀攀琀 欀渀漀眀渀⸀⤀ 䄀 瀀愀瀀攀爀 攀渀琀椀琀氀攀搀 ∀吀栀攀 䐀攀琀攀挀琀椀漀渀 漀昀 䔀琀栀礀氀欀攀琀攀渀 愀渀搀 攀渀漀氀ⴀ䌀爀漀琀漀渀愀氀搀攀栀礀搀攀 椀渀 琀栀攀 嘀愀瀀漀甀爀ⴀ瀀栀愀猀攀 倀栀漀琀漀氀礀猀椀猀 漀昀 琀爀愀渀猀ⴀ䌀爀漀琀漀渀愀氀搀攀栀礀搀攀∀ 爀攀瀀漀爀琀攀搀 猀漀洀攀 漀昀 洀礀 眀漀爀欀 椀渀 㤀㘀㠀 愀昀琀攀爀 䤀 栀愀搀 洀漀瘀攀搀 漀渀 琀漀 最爀愀搀甀愀琀攀 猀挀栀漀漀氀⸀ 䤀 愀氀猀漀 眀漀爀欀攀搀 ∀甀瀀 琀栀攀 栀椀氀氀∀ 眀椀琀栀 䐀爀⸀ 䔀⸀䄀⸀ ⠀䔀搀⤀ 匀挀栀甀挀欀 愀渀搀 椀渀 㤀㘀㘀 昀漀甀渀搀 洀礀 渀愀洀攀 漀渀 愀 瀀愀瀀攀爀 攀渀琀椀琀氀攀搀 ∀刀愀琀攀 䌀漀渀猀琀愀渀琀 刀愀琀椀漀猀 䐀甀爀椀渀最 一椀琀爀漀最攀渀 䐀椀漀砀椀搀攀 倀栀漀琀漀氀礀猀椀猀⸀∀ 䤀 氀攀愀爀渀攀搀 洀愀渀礀 琀栀椀渀最猀Ⰰ 猀挀椀攀渀琀椀昀椀挀 愀渀搀 漀琀栀攀爀眀椀猀攀Ⰰ 琀栀愀琀 渀攀攀搀 渀漀琀 戀攀 搀攀琀愀椀氀攀搀 栀攀爀攀⸀ 伀渀攀 琀栀愀琀 䤀 洀椀最栀琀 洀攀渀琀椀漀渀 眀愀猀 琀栀攀 樀漀礀 ⠀愀渀搀 猀漀洀攀琀椀洀攀猀 搀椀猀挀漀洀昀漀爀琀⤀ 漀昀 栀椀欀椀渀最 椀渀 琀栀攀 匀椀攀爀爀愀 一攀瘀愀搀愀 䴀漀甀渀琀愀椀渀猀⸀ 䤀 猀琀椀氀氀 攀渀樀漀礀 洀漀甀渀琀愀椀渀 栀椀欀椀渀最Ⰰ 愀氀琀栀漀甀最栀 琀栀攀 昀爀攀焀甀攀渀挀礀 栀愀猀 搀攀挀爀攀愀猀攀搀 挀漀渀猀椀搀攀爀愀戀氀礀⸀ 䤀 挀愀瀀椀琀愀氀椀稀攀搀 漀渀 洀礀 欀渀漀眀氀攀搀最攀 漀昀 䤀刀 猀瀀攀挀琀爀漀猀挀漀瀀礀 搀甀爀椀渀最 愀 猀甀洀洀攀爀 漀昀 爀攀猀攀愀爀挀栀 愀琀 䐀漀眀 椀渀 䴀椀搀氀愀渀搀Ⰰ 䴀椀挀栀椀最愀渀Ⰰ 眀栀攀爀攀 洀礀 漀氀搀攀猀琀 戀爀漀琀栀攀爀 䰀甀琀栀攀爀 眀愀猀 愀渀 攀渀最椀渀攀攀爀⸀
Research as an undergraduate at the University of California at Riverside in the group of James N. Pitts in the mid sixties. 㰀⼀瀀㸀㰀瀀㸀 At Riverside I was influenced by a talented and enthusiastic teacher in physical chemistry named Jerry Bell. Jerry decided that I had enough ability to attend Harvard University for graduate study where he had received his Ph.D. I liked the idea, applied, and was accepted. I celebrated by listening to Rachmaninoff's second piano concerto played by Byron Janis, loudly, through a Fischer amplifier and large home built speakers, each with a volume approaching 12 cubic feet; an arts in western civilization course at UCR had boosted my interest in music that I had acquired in high school. During the last semester at UCR I took an inorganic chemistry course taught by Fred Hawthorne who appropriately spent a good deal of time discussing boron compounds. Although I enjoyed organic chemistry, the possibility of exploring the chemistry of all elements in the periodic table was fascinating to me. Yet for some reason I still regarded myself as a physical chemist.
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