Henk Buck (born
Dordrecht
Dordrecht (), historically known in English as Dordt (still colloquially used in Dutch, ) or Dort, is a city and municipality in the Western Netherlands, located in the province of South Holland. It is the province's fifth-largest city after R ...
, 1930) is an
organic chemist. He studied at the
University of Leiden where he received his
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in 1959. He got a
lectorship at the University in Theoretical Organic Chemistry in 1964. For his research he received the Golden Medal of the
Royal Netherlands Chemical Society in 1967. In 1970 he was appointed as professor of Physical Organic Chemistry and Organic Chemistry at the
University of Technology in Eindhoven. 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 a member of the
Royal Netherlands Academy of Arts and Sciences
The Royal Netherlands Academy of Arts and Sciences ( nl, Koninklijke Nederlandse Akademie van Wetenschappen, abbreviated: KNAW) is an organization dedicated to the advancement of science and literature in the Netherlands. The academy is housed ...
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 is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
as the homogeneous catalysis of the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of
hydrocarbons
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ex ...
with stable
carbenium ion
A carbenium ion is a positive ion with the structure RR′R″C+, that is, a chemical species with a trivalent carbon that bears a +1 formal charge.
In older literature the name carbonium ion was used for this class, but now it refers exclusivel ...
s as the pentamethylbenzyl cation and the chiral induction with the redox couple
NADH-NAD+ in the nearly 100% stereospecific hydride transfer to
ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
s and
imines. 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 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 calculations of the radiationless transition of
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
and ab initio calculations of single vibronic level
fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...
emission spectra and absolute radiative lifetimes of formaldehyde. Further he investigated deviations of the Woodward-Hoffmann rules as the photochemical
,3OH 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-
,5H shifts in 1,3-pentadiene showed the effect of vibrationally assisted
tunneling in this geometric orientation.
A special topic in his research was
organophosphorus chemistry. An important aspect of this project was based on the possibility of
phosphorus
Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...
(IV) to accommodate a fifth
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
under formation of a
trigonal bipyramid
In geometry, the triangular bipyramid (or dipyramid) is a type of hexahedron, being the first in the infinite set of face-transitive bipyramids. It is the dual of the triangular prism with 6 isosceles triangle faces.
As the name suggests, i ...
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 OCH
3 group was introduced as substitute for O
− in the study of intermediates for conformational transmission. This also resulted in the
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
*Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
** Organic synthesis, the chemical synthesis of organ ...
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.
[European Patent entitled Poly(deoxyribonucleotides), pharmaceutical compositions, use and preparation of the poly(deoxyribonucleotides) München 09-06-1993, Patent NO]
0358657
/ref> 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.[Buck, H.M. e.a. (1990) "Phosphate-Methylated DNA Aimed at HIV-1 RNA Loops and Integrated DNA Inhibits Viral Infectivity"]
''Science'', 13 April 1990: Vol. 248. no. 4952, pp. 208 - 212.
/ref>[Moody, H.M. e.a. (1990) "Inhibition of HIV-1 Infectivity by Phosphate-Methylated DNA: Retraction"]
''Science'', Vol. 250, pp. 125-126.
/ref> (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. 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 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 DNA as an inhibitor of virus replication. Paul C. Zamecnik
Paul Charles Zamecnik (November 22, 1912 – October 27, 2009) was an American scientist who played a central role in the early history of molecular biology. He was a professor of medicine at Harvard Medical School and a senior scientist at Mas ...
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
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
-infections in those days, commercial interests and patent rights led to the decision to cooperate with the virologist Jaap Goudsmit
Jaap Goudsmit (born 22 July 1951 in Amsterdam) is Dutch scientist, known for his research in the field of AIDS and influenza. He shifted his research interest to aging and neurodegenerative diseases, like Alzheimer's Disease. He is also a prolific ...
of the Academic Medical Center
An academic medical centre (AMC), variously also known as academic health science centre, academic health science system, or academic health science partnership, is an educational and healthcare institute formed by the grouping of a health profes ...
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 is a systematic endeavor that builds and organizes knowledge in the form of testable explanations and predictions about the universe.
Science may be as old as the human species, and some of the earliest archeological evidence for ...
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 (abbreviated as ''LEI''; nl, Universiteit Leiden) is a Public university, public research university in Leiden, Netherlands. The university was founded as a Protestant university in 1575 by William the Silent, William, Prince o ...
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 (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
equipment in the lab of Organon, 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 too 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 impermissibly 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'' [Buck, H.M. (2004) "The Chemical and Biochemical Properties of Methylphosphotriester DNA"]
''Nucleosides, Nucleotides and Nucleic Acids'', Vol. 23, pp. 1833 - 1847.
br>
Buck, H.M. (2007) "The Chemical and Biochemical Properties of Methylphosphotriester DNA and RNA in Comparison with their Corresponding Methylphosphonates. A Dynamic Model Description"
''Nucleosides, Nucleotides and Nucleic Acids'', Vol. 26, pp. 205-222.
/ref> 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: Fomivirsen
Fomivirsen (brand name Vitravene) is an antisense antiviral drug that was used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It was administered via intraocular injection.
It was d ...
.
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
References
{{DEFAULTSORT:Buck, Henk
1930 births
Living people
20th-century Dutch chemists
Eindhoven University of Technology faculty
Leiden University alumni
Leiden University faculty
Members of the Royal Netherlands Academy of Arts and Sciences
People from Dordrecht