Are biochemical reactions affected by weak magnetic fields?

T he scientific literature is replete with studies of the influence of weak magnetic fields on biological systems. Often motivated by alleged health hazards of the stray electromagnetic fields that accompany the distribution and use of electrical power, the majority of these articles report definite effects. However, in the relatively few cases in which independent replication has been attempted, the original results have usually proved irreproducible (1, 2). The situation is not helped by the scarcity of (bio)physical mechanisms by which weak magnetic fields might interact with biology. With no hypothetical mechanism to guide experimental design, the majority of these investigations have been, to varying degrees, unsatisfactory. A striking exception is a series of articles by Anatoly Buchachenko and Dmitry Kouznetsov (BK) and their associates (3–6). In more than 10 papers dating back to 2005, including one in PNAS (3), BK have reported effects of magnetic interactions on the rate of enzymatic synthesis of ATP in vitro. These studies are conspicuous in that the reported changes are large, the interaction mechanism is physically credible, an explicit reaction scheme is proposed, and the process itself is of considerable biological importance. If genuine and applicable in vivo, these results could have significant therapeutic (if not health) implications. In PNAS, the work by Crotty et al. (7) describes attempts to replicate BK’s findings. The conversion of ADP into ATP is catalyzed by a number of magnesium-dependent enzymes. The works by BK report that the rate of ATP production by four kinases—ATP synthase, phosphoglycerate kinase, pyruvate kinase, and creatine kinase—exhibits an unusual and substantial magnesium isotope effect (3, 4). Magnesium has three stable isotopes: Mg (79%), Mg (10%), and Mg (11%). Rather than a monotonic dependence of the reaction rate on the isotope mass number, which would be expected for the conventional kinetic isotope effect, it was found that ATP was formed more than twice as fast in the presence of Mg than in the presence of either Mg or Mg. This finding was taken as the signature of the radical pair mechanism (RPM) (8) in which magnetic isotope effects (MIEs) arise not from the mass but from the magnetic moment of the atomic nucleus (9). Of the three isotopes, only Mg is magnetic as a result of the number and disposition of its protons and neutrons. Although much less common than the kinetic isotope effect, the MIE is a wellcharacterized feature of chemical transformations that have radical pairs as transient reaction intermediates. Since its discovery by Buchachenko in 1976, it has been exploited as a probe of free radical reaction pathways. A somewhat more common manifestation of the RPM is the sensitivity of radical pair reactions to external magnetic fields (8, 10). Acknowledged for more than 30 y to be responsible for a multitude of magnetic effects on chemical reaction rates and yields, the RPM has been implicated in several experimental observations of biomolecular magnetic field effects (MFEs). Although there is little competition for the title, the RPM is arguably the most plausible mechanism by which weak magnetic interactions might affect biochemical reactions. Supporting their interpretation of the ATP data, BK found that the difference in phosphorylation rates for the magnetic and nonmagnetic isotopes of Mg increased from twofold to more than fourfold when an 80-mT magnetic field was applied (5). To put this finding in context, 80 mT is about 1,000 times stronger than the Earth’s magnetic field and about 100 times weaker than the strongest fields used for clinical MRI. The novel reaction pathway put forward by BK (3) to account for both MIE and MFE is shown in Fig. 1. As outlined, the hyperfine interaction of the magnetic Mg isotope in a radical pair comprised of a Mg ion and an ADP radical is thought to flip the electron spin of the former, opening up a reaction pathway that would otherwise be insignificant and favoring the catalytic reaction over the unproductive back reaction. Although there seems to have been no previous suggestion that the +1 oxidation state of Mg can mediate ATP production and scant evidence that Mg has any biologically relevant redox chemistry, the general idea that magnetic nuclei and applied magnetic fields can alter the coherent spin dynamics of radical pairs and therefore affect reaction rates and product yields is beyond doubt (8). The replication study by Crotty et al. (7) focuses on creatine kinase (CK), which converts phosphocreatine and ADP to creatine and ATP (7). Measurements of reaction yields and rates were performed independently in Dublin and Colchester using different techniques to study the same enzyme (MM1-type CK) from either + − 2 2 Mg + ADP