Henk Buck
Encyclopedia
Henk Buck is an organic chemist
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

. He studied at the University of Leiden where he received his PhD
PHD
PHD may refer to:*Ph.D., a doctorate of philosophy*Ph.D. , a 1980s British group*PHD finger, a protein sequence*PHD Mountain Software, an outdoor clothing and equipment company*PhD Docbook renderer, an XML renderer...

 in 1959. He got a lector
Lector
Lector is a Latin term for one who reads, whether aloud or not. In modern languages the word has come to take various forms, as either a development or a loan, such as , , and . It has various specialized uses:...

ship at the University in Theoretical Organic Chemistry in 1964. For his research he received the Golden Medal of the Royal Netherlands Chemical Society
Royal Netherlands Chemical Society
The Royal Netherlands Chemical Society is the professional association for chemists and chemical engineers in the Netherlands...

 in 1967. In 1970 he was appointed to professor of Physical Organic Chemistry and Organic Chemistry at the University of Technology in Eindhoven
Eindhoven University of Technology
The ' is a university of technology located in Eindhoven, Netherlands. The motto of the university is: Mens agitat molem . The university was the second of its kind in the Netherlands, only Delft University of Technology existed previously. Until mid-1980 it was known as the...

. Because there was no Chair for Theoretical Chemistry and Biochemistry he gave lectures in organic chemistry, physical organic chemistry, theoretical organic chemistry, biochemistry and biotechnology. From 1988-1991 he was Dean of the Chemical Faculty. For his scientific contributions he became member of the Royal Netherlands Academy of Arts and Sciences
Royal Netherlands Academy of Arts and Sciences
The Royal Netherlands Academy of Arts and Sciences is an organisation dedicated to the advancement of science and literature in the Netherlands...

 in 1979. During his scientific career he published more than 300 scientific papers spread over a large area of the chemical field. Under his supervision 43 chemical engineers obtained their PhD. The end of his career came prematurely because of a publication in Science in 1990 that had to be retracted because of flawed research.

Research

His research in Leiden and later in Eindhoven was focused on organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 as the homogeneous catalysis of the oxidation of hydrocarbons with stable carbenium ion
Carbenium ion
A carbenium ion is a carbocation of the trivalent and classical type R3C+. It is one of two types of carbocation, the other being a carbonium ion. In older literature a carbocation of the type R3C+ may still be referred to as a carbonium ion, a term that is used now for five-coordinate carbon...

s as the pentamethylbenzyl cation and the chiral induction with the redox couple NADH-NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 in the nearly 100% stereospecific hydride transfer to ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

s and imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

s.ref>Vekemans, J.A.J.M. et al. (1991) "NADH model mediated reduction of C=N substrates: enantio-selective synthesis of D-and L-phenylglycinates",Thetrahedron: A symmetry, Vol.2, pp. 949–952. The latter process is controlled by the out-of-plane orientation of the carboxamide group. In the field of physical chemistry his work was directed on electron spin resonance
Electron paramagnetic resonance
Electron paramagnetic resonance or electron spin resonance spectroscopyis a technique for studying chemical species that have one or more unpaired electrons, such as organic and inorganic free radicals or inorganic complexes possessing a transition metal ion...

 measurements of phosphoranyl radicals with phosphorus in different geometries as the tetrahedral and the trigonal bipyramidal configuration with the unpaired electron in an equatorial or axial orientation. His contribution to the theoretical organic chemistry was based on Ab initio
Ab initio
ab initio is a Latin term used in English, meaning from the beginning.ab initio may also refer to:* Ab Initio , a leading ETL Tool Software Company in the field of Data Warehousing.* ab initio quantum chemistry methods...

 calculations of the radiationless transition of formaldehyde
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

 and ab initio calculations of single vibronic level fluorescence
Fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...

 emission spectra and absolute radiative lifetimes of formaldehyde. Further he investigated deviations of the Woodward-Hoffmann rules as the photochemical [1,3]-OH shift in 2-propen-1-ol. Here the stereochemical outcome is determined by relaxation of the excited double bond. A thermal study of the cis-[1,5]-H shifts in 1,3-pentadiene showed the effect of vibrationally assisted tunneling
Tunneling
Tunneling may refer to:* Digging tunnels * Quantum tunneling, the quantum-mechanical effect where a particle crosses through a classically-forbidden potential energy barrier...

 in this geometric orientation.

A special topic in his research was the organophosphorus chemistry. An important aspect of this project was based on the possibility of phosphorus
Phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...

 (IV) to accommodate a fifth ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 under formation of a trigonal bipyramid which shows a number of unique properties. The significance of this geometrical change has been demonstrated in the conformational transmission in DNA for the B-Z transition with alternating CpG units under selective phosphate shielding. This change in geometry of phosphorus was also applicable on the biochemical dynamics of cAMP. Because of the importance of shielding, the OCH3 group was introduced as substitute for O in the study of intermediates for conformational transmission. This also resulted in the synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 of phosphate-methylated DNAs and RNAs. Methylphosphotriester DNAs were synthesized with 2-12 bases. Neutralization of the charge of the phosphate linkages by (specific) methylation resulted in methylphosphotriester DNAs with very exclusive (bio)chemical properties. The introduction of chirality at phosphorus appeared of importance for intra- and intermolecular dynamics. These modified DNAs mimicked the behavior of natural DNA in the absence of stabilizing factors as salts, proteins, and medium factors. In fact a high site-specific hybridization affinity was obtained with complementary natural DNA. In dependence of the bases, parallel DNA could be synthesized for pyrimidine bases in which the chirality of phosphorus was decisive. Phosphate methylation also gave the possibility to synthesize a self-complementary left-handed Z-DNA mini duplex.

After a publication in Science about the inhibition of HIV-1 replication had to be retracted, because it was based on flawed research, he accepted early retirement in 1990. (see The Buck-Goudsmit controversy)

At home without any academic support he wrote several articles based on quantum chemical calculations focused on the dynamics of organic reactions, electron spin resonance of organophosphorus radicals and the hybridization affinity of methylphosphotriester DNA and RNA. The latter subject is published as review articles in Nucleosides, Nucleotides & Nucleic Acids
Nucleosides, Nucleotides & Nucleic Acids
Nucleosides, Nucleotides & Nucleic Acids is a monthly academic journal published by Taylor & Francis since 2000, continuing the earlier Nucleosides and Nucleotides in series. It discusses topics relating to the biochemisty of molecules in these classes....

. In these reviews he gives also a description and explanation of the chemical and corresponding biochemical results of the methylphosphotriester DNA, RNA and related systems. This contribution that is mainly based on the work at Eindhoven also consists of new insights in solid-phase synthesis, B-Z transition, and methyl transfer reactions connected with replicational and transcriptional silencing. Special attention is given to the effect of phosphate shielding on duplex stability. Models based on molecular mechanics
Molecular mechanics
Molecular mechanics uses Newtonian mechanics to model molecular systems. The potential energy of all systems in molecular mechanics is calculated using force fields...

 calculations and recent density functional ab initio calculations support the impact of phosphate shielding at the various levels of stability of the DNA duplex.

The Buck-Goudsmit controversy

In the mid-80s Henk Buck focused his research on the use of antisense
Antisense therapy
Antisense therapy is a form of treatment for genetic disorders or infections.When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nuc acid that will bind to the messenger RNA produced by that gene and inactivate...

 DNA as an inhibitor of virus replication. Paul C. Zamecnik is generally regarded as the founder of this technique, but already in 1971 Paul S. Miller created short phosphate methylated DNA-fragments, and considered the possibility of using this as a means of influencing DNA-replication. Bucks research group focused on the use of this phosphate methylated DNA, in particular because of its neutral electrical properties. In several publications the selectivity and duplex forming were reported.

The strong growth of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

-infections in those days, commercial interests and patent rights led to the decision to cooperate with the virologist Jaap Goudsmit
Jaap Goudsmit
Jaap Goudsmit is Dutch scientist, known for his research in the field of AIDS.In 1978 Jaap Goudsmit received his MD degree with honor at the Faculty of Medicine of the University of Amsterdam. He was awarded a Fogarty fellowship, and joined the research on kuru with Nobel Prize winner Daniel...

 of the Academic Medical Center
Academic Medical Center
The Academic Medical Center , or AMC, is the university hospital affiliated with the Universiteit van Amsterdam ....

 of Amsterdam University. Jaap Goudsmit required longer DNA-strands, though, than the ones Buck was testing so far, so a new synthesis route was developed. Jaap Goudsmit tested the new strands on samples of HIV and reported the inhibition of the virus replication.

The results were published in Science
Science (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....

 on April 13, 1990.

On the eve of the publication, the University of Eindhoven made the news public. It resulted in excited media attention in the Netherlands, and under the pressure Buck publicly stated that he assumed that AIDS would be of the past in a couple of years, although it was agreed not to make such claims. Afterwards he explained, he deliberately had said this to raise more funds for his research, although much later he defended himself by saying that he was provoked by the reporter.

Doubts raised immediately after the article appeared in Science. The next day, the Leiden University
Leiden University
Leiden University , located in the city of Leiden, is the oldest university in the Netherlands. The university was founded in 1575 by William, Prince of Orange, leader of the Dutch Revolt in the Eighty Years' War. The royal Dutch House of Orange-Nassau and Leiden University still have a close...

 professor Van Boom, expert in the field of DNA synthesis, said in a leading Dutch newspaper, that pure phosphate methylated DNA is very difficult to produce, and easily contaminated. Six days after the publication internal criticism came to the surface. Buck colleague, professor Van Boeckel, also an expert in this field, had already criticized Bucks research a year before, and resigned because his warnings were not taken seriously. Van Boeckel had also been working on synthesis of phosphate methylated DNA, and knew how difficult it was to make such DNA-strands. A year before Bucks downfall, he came to the conclusion that Bucks longer strands could not be pure, because Van Boeckels research-assistant Kuijpers noticed that even a short phosphate methylated DNA wasn't stable. In May 1989 he invited one of Bucks research assistants to test their material on HPLC
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...

 equipment in the lab of Organon
Organon International
Organon is a human pharmaceutical company headquartered in Oss, Netherlands. In November 2007 the company became a part of Schering-Plough Corporation, acquired Organon, active pharmaceutical ingredient producer Diosynth , and its veterinary pharmaceutical sister company Intervet from Akzo Nobel. ...

, a Dutch pharmaceutical company. The measurement showed that the test material was not at all pure, but Buck refused to accept this fact. When Van Boeckel showed Buck a draft of the publication of his own research at the end of 1989, it resulted in a confrontation in which the University chose Bucks side. Van Boeckel and Kuijpers were ordered to stop their research, because "it was to expensive and not productive".

The doubts and criticism following the publication in Science led to a heated public debate in several Dutch newspapers and science magazines, and the University eventually acknowledged that the purity of the phosphate methylated DNA was still to be investigated. A committee was formed to investigate the proceedings and their conclusion (30 August 1990) was, that no phosphate methylated DNA could be traced. Also the committee reproached Buck for not paying attention to criticism from within his faculty. As a result Buck was dismissed as dean of the faculty. Goudsmit was requested to test the antisense material once again, but his enthusiasm had cooled, and Buck could not produce the pure phosphate methylated DNA in time.

The publication in Science therefore had to be retracted.

A second investigating committee reported at the end of the year that the presentation of the results in Science bordered on fraud. The report also said that Bucks behaviour in his group was impermissably harsh at times. The committee concluded that it disqualified him as a research leader. As a result, Buck accepted early retirement.

Although Jaap Goudsmit generally was regarded as a victim in the affair, half a year later a journalist of a leading newspaper questioned his role in the débâcle. Goudsmit had reported the inhibition of HIV-replication, which was questionable, given the fact that the phosphate methylated DNA was not pure enough. Therefore a third committee investigated the work of Goudsmit and his group as well. The committee concluded that Goudsmit had not checked the quality of Bucks material. Also they saw shortcomings in the interpretation and presentation of the results. The committee concluded that Goudsmits research had been scientifically inadequate. Goudsmit did not go in appeal and could continue his work.

Henk Buck never accepted the outcome of this controversy. Up to this day he persists in his opinion that he could produce sufficiently pure phosphate methylated DNA. In several interviews he said that he feels that he has been pilloried for making a sincere mistake. He published two articles in the scientific magazine Nucleosides, Nucleotides and Nucleic Acids in which he tries to retrace what happened, and he goes as far as to claim that the investigating committees were wrong.

To this day, however, nobody produced pure phosphate methylated DNA strands in the quality Goudsmit required. All the efforts from Miller, Van Boeckel and Buck resulted in short instable fragments. Recent researches in this field are based on methyl phosphonate or phosphorothioate DNA. At present (2008) only one antisense medication exists, based on phosphorothioate oligonucleotide
Oligonucleotide
An oligonucleotide is a short nucleic acid polymer, typically with fifty or fewer bases. Although they can be formed by bond cleavage of longer segments, they are now more commonly synthesized, in a sequence-specific manner, from individual nucleoside phosphoramidites...

: Fomivirsen
Fomivirsen
Fomivirsen is an antiviral drug. It is used in the treatment of cytomegalovirus retinitis in immunocompromised patients, including those with AIDS...

.

Sources

  • Hagendijk, R. en Meeus, J. (1993) "Blind faith: fact, fiction and fraud in public controversy over science". Public Understanding of Science, Vol. 2, No. 4, pp. 391-415.
  • Rozendaal, S. (1992) "Barbertje wil weer werken. Waarom AIDS-onderzoeker Henk Buck moest hangen". Elsevier 21-10-1992, pp. 96–100
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