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Research Highlight

The research interest of Prof. Chang is very broad, encompassing foundation of quantum physics, bio-medical physics and biotechnology. The following is a summary of his contribution in different research areas:

 

1. Foundation of Quantum Physics

We know our physical world at the atomic level is governed by quantum mechanics. Many branches of physics, including atomic and molecular physics, electron micro-device, laser and photonics, all depend on it. Yet, after almost one century of studies, there are still many unanswered questions in quantum physics. First, what is the physical nature of a particle? How can particles be created in the vacuum or disappear into nowhere? Second, how can one explain the “wave behavior” of a free particle? How can a single electron be diffracted from a crystal following the Bragg’s diffraction law?

Apparently, a quantum object can behave both like a particle as well as a wave. This phenomenon is called “wave-particle duality”. So far, there has been no satisfactory explanation to this strange behavior. In most textbooks, the wave-particle duality is usually explained using the “Copenhagen interpretation”, which proposed that the particle itself is a pointed object, but its distribution is like a wave. Such a view, however, is not agreed by many well-known physicists, including Schrödinger, de Broglie and Einstein. Furthermore, the Copenhagen interpretation cannot explain how a single electron can pass through two slits simultaneously. Some physicists, like Richard Feynman, were so pessimistic that they claimed such quantum mysteries could be beyond human comprehension.

We would like to examine these fundamental questions in quantum physics using a new approach. We proposed a Wave Model by hypothesizing that: (1) Like the photon, a particle is an excitation wave of the quantum vacuum. (2) Different types of particles are different excitation modes of the same vacuum. Based on such thinking, we showed that quantum mechanics can be a natural extension of the classical theory of electrodynamics.

Thus, our work is aimed to address the following specific questions:

(1)  How to explain the phenomenon of wave-particle duality in quantum physics?

(2)  How to explain why particles can be created in the vacuum?

(3)  Can one derive from first principle the well-known quantum wave equations, including the Dirac equation and the Schrödinger equation?

(4)  Can one understand the physical meaning of the quantum wave function beyond the Copenhagen interpretation?

 

Reference:

1.    Chang, D.C. 2004, What is the physical meaning of mass in view of wave-particle duality? A proposed model. arXiv: physics/0404044. Link: https://arxiv.org/abs/physics/0404044

2.    Chang, DC. 2013. A classical approach to the modeling of quantum mass. J. Mod Phys, 4: 21-30.

3.    Chang, D.C. 2017, On the wave nature of matter: A transition from classical physics to quantum mechanics. arXiv: physics/0505010v2. Link: https://arxiv.org/abs/physics/0505010v2

4.    Chang D. C. 2017. Is there a resting frame in the universe? A proposed experimental test based on a precise measurement of particle mass. Euro. Phys. J. Plus, 132: 140. https://doi.org/10.1140/epjp/i2017-11402-4

5.    Chang D. C. 2017. Physical interpretation of the Planck’s constant based on the Maxwell theory. Chin. Phys. B, 26:040301

6.    Chang, D. C. 2018. A quantum mechanical interpretation of gravitational redshift of electromagnetic wave. Optik 174, 636-641. https://doi.org/10.1016/j.ijleo.2018.08.127

7.    Chang, D. C. 2020. A quantum interpretation of the physical basis of mass–energy equivalence. Modern Physics Letters B. 34(18) :203002 (Invited review)

8.    Chang, D. C. 2021. Review on the physical basis of wave-particle duality: Conceptual connection between quantum mechanics and the Maxwell theory. Modern Physics Letters B, 35(13) 2130004. https://doi.org/10.1142/S0217984921300040

9         Chang, D. C. 2022. A quantum view of photon gravity: The gravitational mass of photon and its implications on previous experimental tests of general relativity. Mod. Phys. Lett. B, 36, 2250179. https://doi.org/10.1142/S0217984922501792

 

2. NMR detection of cancer

Prof. Chang was a pioneer in using the spin-echo NMR (nuclear magnetic resonance) technique to study the physical properties of water in biological tissues. He reported the first such study in Nature (1972) and then in Proc. Nat. Acad. Sci. (USA) (1972),  J. Nat.Cancer Inst. (1975, 1977 and 1980) and Science (1977 and 1980). His contributions included: (1) The nuclear magnetic relaxation times of water inside biological cells were found to be much shorter than those of free water. (2) The shortening of the relaxation times was not due to restriction in diffusion. Instead, the cellular water appears to be more structurally stable in comparison to bulk water. (3) Most importantly, the physical properties of cellular water changed with the morphological state of the tissue. For example, in studying a biological model of breast cancer, it was found that the relaxation times of cellular water increase progressively when the mammary tissue changes from normal to pre-neoplastic and then the tumor state. These findings suggest that it is possible to detect early development of cancer using the mangnetic resonance technique. (See News released by AIP 1972).

 

This work was started while he was a postdoctoral fellow in the Physics Department of Rice University. One year after he reported his findings in Nature and PNAS, Dr. P. Lauterbur published another paper in Nature (1973) suggesting that one can use a magnetic field gradient to differentiate water molecules in different location of a sample. This idea triggered the development of the MRI (magnetic resonance imaging) technology. The visualization of tumor from normal tissues by MRI, however, relies mainly on detecting the difference of water relaxation times in the patient. Thus, Prof. Chang’s findings were an important basis for the use of the MRI technology for cancer detection. (Dr. Lauterbur was awarded the Nobel Prize in 2003 for his MRI work).

 

Reference:

1.           Chang, D.C., Hazlewood, C.F., Nichols, B.L., and Rorschach, H.E. 1972. Spin-echo studies on cellular water. Nature 235:170-171.

2.           Chang, D. C., Rorschach, H. E., and Hazlewood, C. F.1972. Pulsed NMR Studied on Water in Biological Tissues. Bulletin of the American Physical Society 17, 328.

3.           Hazlewood, C.F., Chang, D.C., Medina, D., Cleveland, G., and Nichols, B.L. 1972. Distinction between the preneoplastic and neoplastic state of murine mammary glands. Proc. Natl. Acad. Sci. USA 69:1478-1480.

4.           Hazlewood, C.F., Chang, D.C., Nichols, B.L., and Woessner, D.E. 1974. NMR Transverse relaxation times of water protons in skeletal muscle. Biophys. J. 14:583-606.

5.           Medina, D., Hazlewood, C.F., Cleveland, G.G., Chang, D.C., Spjut, H.J., and Moyers, R. 1975. Nuclear magnetic resonance studies on human breast dysplasias and neoplasms. J. Nat. Cancer Inst. 54:813-818.

6.           Beall, P.T., Medina, D., Chang, D.C., Seitz, P.K., and Hazlewood, C.F. 1977. Systemic effect of benign and malignant mammary tumors on the spin-lattice relaxation time of water protons in mouse serum. J. Nat. Cancer Inst. 59(5):1431 1433.

7.           Chang, D.C. and Woessner, D.E. 1977. "Bound water" in barnacle muscle as indicated in NMR studies. Science 198:1180-1181.

8.           Chang, D.C. and Woessner, D.E. 1978. Spin echo study of Na23 relaxation in skeletal muscle: Evidence of sodium ion binding inside a biological cell. J. Mag. Res. 30:185‑191.

9.           Beall, P.T., Asch, B.B., Chang, D.C., Medina, D., and Hazlewood, C.F. 1980. Distinction of normal, preneoplastic and neoplastic mouse mammary primary cell cultures by water NMR relaxation times. J. Nat. Cancer Inst. 64(2):335-338.

10.        Michael, L., Seitz, P., Wood, J.M., Chang, D.C., Hazlewood, C.F., and Entman, M. 1980. Mitochondrial water in myocardial ischemia: Investigation with nuclear magnetic resonance. Science 208:1267-1269.

 

3. Neural biophysics

Using the squid axon as a model and applying the voltage-clamp and internal perfusion techniques, Prof. Chang had conducted a series of studies on the mechanisms of electrical potential generation in neurons. He showed that divalent ions such as Ca2+ contribute significantly to the resting potential and proposed a modification of the Goldman-Hodgkin-Katz equation in relating the membrane potential with the ionic gradients. Most of these works were published in Biophys J. His edited book entitled “Structure and Function in Excitable Cells” (published by Plenum Press, 1983) also received favorable reviews in major journals including Science and Trends in Neuroscience.

 

Reference:

1.         Chang, D.C. 1983. Dependence of cellular potential on ionic concentrations:  Data supporting a modification of the constant field equation. Biophys. J. 43:149-156.

2.         Chang, D.C., Tasaki, I., Adelman, W.J., Jr., and Leuchtag, H.R. (Eds). 1983. Structure and Function in Excitable Cells, Plenum Publishing Co., New York. (499 pages).

3.         Chang, D.C. and Liu, J. 1985. A comparative study of the effects of tetrodotoxin and the removal of external Na+ on the resting potential:  Evidence of separate pathways for the resting and excitable Na currents in squid axon. Cell Molec. Neurobiol. 5:311-320.

4.         Chang, D.C. 1986. Axonal transport and the movement of 45Ca inside the giant axon of squid. Brain Res. 367:319-322.

5.         Chang, D.C. and Tasaki, I. 1986. Ultrastructure of the squid axon membrane as revealed by freeze-fracture electron microscopy. Cell Molec. Neurobiol. 6:43-53.

6.         Chang, D.C. 1986. Is the K permeability of the resting membrane controlled by the excitable K channel? Biophys J. 50:1095-1100.

7.         Fong, C.N. and Chang, D.C. 1987. K+-selective microelectrode study of internally dialysed squid giant axons. Biophys J. 53:893-897.

8.         Chang, D.C. 1988. Is the delayed rectifier the major pathway for resting K current?  Biophys J. 54:971-972.

 

4. Electroporation and electrofusion

Prof. Chang was actively involved in the early development of electroporation and electrofusion technology. He obtained 14 international patents in this field. It was discovered in the 1980s that cell membrane can be transiently permeabilized using an intense electric pulse. Various types of molecules, including DNA, RNA and proteins can be introduced into living cells using this method. Prof. Chang was an active investigator in this field. He invented a new type of electroporation and electrofusion technique by using a pulsed radio-frequency electric field to permeabilize the cell membrane. This method was shown to have a significantly higher efficiency in gene transfection and cell fusion in comparison to conventional methods. Furthermore, using rapid-freezing freeze-fracture electron microscopy, he revealed the dynamic structure of the membrane pores induced by electric field. This study provided the first structural evidence for the existence of the previously-hypothetical “electro-pores” and was reported as the cover story in the July 1990 issue of the Biophysical Journal. His book entitled “Guide to Electroporation and Electrofusion” remains to be the best known book in this field today. He also wrote a number of invited reviews for major research handbooks, including Methods in Molecular Biology (1997), Cell Biology: A Laboratory Manual (A three-volume treatise published by the Cold Spring Habor Laboratory Press, 1997) and Encyclopedia of Molecular Cell Biology and Molecular Medicine (2004). Electroporation is now the most efficient method for gene transfer in many biological systems.

 

Reference:

1.           Chang, D.C. 1989. Cell poration and cell fusion using an oscillating electric field. Biophys. J. 56:641-652.

2.           Chang, D.C. 1989. Cell fusion and cell poration by pulsed radio-frequency electric fields. In: Electroporation and Electrofusion in Cell Biology. (E. Neumann, A.E. Sowers, and C.A. Jordan, Eds), Plenum Press Co., New York.

3.           Chang, D.C. and Reese, T.S. 1990. Changes of membrane structure induced by electroporation as revealed by rapid-freezing electron microscopy. Biophys. J. 58:1-12.

4.           Zheng, Q. and Chang, D.C. 1990. Dynamic changes of microtubule and actin structures in CV-1 cells during electrofusion. Cell Motil. Cytoskel. 17:345-355.

5.           Zheng, Q. and Chang, D.C. 1991. High-efficiency gene transfection by in situ electroporation of cultured cell. Biophys. Biochim. Acta 1088:104-110.

6.           Chang, D.C., Gao, P.Q. and Maxwell, B.L. 1991. High efficiency gene transfection by electroporation using a radio-frequency electric field. Biophys. Biochim. Acta 1992:153-160.

7.           Zheng, Q. and Chang, D.C. 1991. Reorganization of Cytoplasmic Structures During Cell Fusion. J. Cell Sci. 100:431-442.

8.           Chang, D.C., Chassy, B.M., Saunders, J.A., and Sowers, A.E. (Eds). 1992. Guide to Electroporation and Electrofusion, Academic Press, San Diego. (581 pages).

9.           Chang, D.C. 1992. Structure and dynamics of electric field-induced membrane pores as revealed by rapid-freezing electron microscopy. In: Guide to Electroporation and Electrofusion, ed. by Chang, D.C., Sowers, A.E., Chassy, B. and Saunders, J.A., Academic Press, San Diego. (pp. 9-28).

10.        Chang, D.C. 1996. Electroporation and electrofusion. In: The Encyclopedia of Molecular Biology and Molecular Medicine, ed. by R.A. Meyers, VCH Publishers, Weinheim, Germany. Vol. 2, pp 198-206.

11.        Chang, D.C. 1997. Experimental strategies in efficient transfection of mammalian cells: Electroporation. In: Methods in Molecular Biology. Vol. 62: Recombinant Gene Expression Protocols, ed. by Rocky S. Tuan, Humana Press. pp 307-318.

12.        Chang, D.C. 1997. Chapter 88: Electroporation and electrofusion, In: Cell Biology: A Laboratory Manual, ed. by D. Spector, R.Goldman and L. Leinwand, Cold Spring Harbor Laboratory Press, New York.  pp. 88.1-88.11.

13.        Chang, D.C. 2004. Electroporation and electrofusion. In: Encyclopedia of Molecular Cell Biology and Molecular Medicine. Ed. by R.A. Meyers, Wiley-VCH Publishers, Weinheim, Germany. Vol. 4, pp.135-157.

 

5. Studying molecular signaling within a single living cell using biophotonic techniques

One important problem in life science is to understand the control mechanisms of cell cycle and programmed cell death (also called “apoptosis”). Prof. Chang’s laboratory had actively investigated such signaling mechanisms in a single living cell using novel biophysical techniques. These techniques included laser confocal microscopy, GFP (green fluorescent protein), fluorescent probes and FRET (fluorescence resonance energy transfer). The followings were some major findings from his lab:

 

Ca2+ signaling in controlling cell division and apoptosis

Ca2+ ion is a major regulator of cell function. Using a fluorescent Ca2+ probe and confocal microscopy, Prof. Chang’s lab was the first to provide conclusive evidence that a localized Ca2+ signal is associated with cell division. This work was done on zebrafish embryo and was published in the J. Cell Biol. (1995). It was discovered later that three distinct types of Ca2+ signals were actually involved in the process of cytokinesis in zebrafish embryos.

 

He also showed that the mechanism of Ca2+ signaling in cell division was different between embryonic cells and somatic cells. In mammalian cultured cells, no localized Ca2+ ion elevation was found to associate with cell division. Instead, the localized Ca2+ signal was mediated by a temporal- and spatial-specific distribution of the Ca2+ ion receptor, calmodulin. This work was a collaboration with Dr. Roger Y. Tsien (UCSD) and it was an early demonstration that one can use the GFP-fusion technology to monitor the dynamic redistribution of signaling molecules in an intact living cell. (Dr. Tsien was awarded the Nobel Prize in 2008 for his work in GFP).

 

Besides cell division, his lab also showed that an early Ca2+ signal is involved in the upstream signalling pathway of cell death. This finding is useful for future development of stroke treatment.

 

Reference:

1.     Chang, D.C. and Meng, C. 1995. A localized elevation of cytosolic free calcium is associated with cytokinesis in zebrafish embryo.  J. Cell Biol. 131:1539-1545.

  1. Li, C.J., Heim, R., Lu, P., Pu, Y.M., Tsien, R.Y. and Chang, D.C. 1999. Dynamic redistribution of calmodulin in HeLa cells during cell division as revealed by a GFP-calmodulin fusion protein technique. J Cell Sci. 112 (10):1567-1577.
  2. Li, C.J., Lu, P. and Chang, D.C. 1999. Using a GFP-labeling technique to study cell cycle-dependent distribution of calmodulin in living cells. Science in China, 42: 517-528.

4.     Pu, Y.M. and Chang, D.C. 2001. Cytosolic Ca2+ Signal is involved in regulating UV-induced apoptosis in HeLa cells. Biochem. Biophys. Res. Comm. 282(1):84-89.

5.     Pu, Y.M., Luo, K.Q. and Chang, D.C. 2002. A Ca2+ signal is found upstream of cytochrome c release during apoptosis in HeLa cells. Biochem Biophys Res Comm. 299:762-769

6.     Guo, J., Pu, Y.M., Chang, D.C. 2005. Calcium signalling and apoptosis. Acta Biophys. Sinica. 21:1-18. (Invited review)

7.     Lao Y, Chang D. C. 2008. Mobilization of Ca2+ from endoplasmic reticulum to mitochondria plays a positive role in the early stage of UV- or TNFalpha-induced apoptosis. Biochem Biophys Res Commun. 373(1):42-7.

 

Signaling mechanism in programmed cell death

Using the intact living cell research approach, his lab obtained important insights on the signalling mechanisms of programmed cell death. For example, they found that the mechanism of cytochrome c release from mitochondria during apoptosis was very different from the model suggested in previous literature. This finding was the cover story of the August 2001 issue of Journal of Cell Science.

 

Two apoptotic signalling proteins, Bax and Bak, are known to play a central role in facilitating the release of mitochondrial intermembrane proteins during apoptosis. The detailed mechanism, however, was not well known. Since this is a key step in the controlling of programmed cell death, his lab used a single living cell analysis to directly measure the dynamic changes of Bax distribution. They found that Bax underwent four distinct stages of dynamic redistribution during UV-induced apoptosis. Based on this finding, one can determine the detailed structure of Bax/Bak complex responsible for releasing mitochondrial proteins.

 

Reference:

1.       Gao, W.H., Pu Y.M., Luo, K.Q. and Chang D.C. 2001.Temporal relationship between cytochrome c release and mitochondrial swelling during UV-induced apoptosis in living HeLa cells.  J. Cell Sci. 114:2855-2862.

2.       Luo, K.Q., Yu, V.C., Pu Y.M. and Chang D.C. 2001. Application of the fluorescence resonance energy transfer method for studying the dynamics of caspase-3 activation during UV-induced apoptosis in living HeLa cells. Biochem Biophys Res Comm. 283(5):1054-1060.

3.       Luo, K.Q., Yu, V.C., Pu Y.M. and Chang D.C. 2003. Measuring dynamics of caspase-8 activation in a single living HeLa cell during TNFa-induced apoptosis. Biochem Biophys Res Comm. 304:217-222.

4.       Chang, D.C, Zhou, L.Y. and Luo, K.Q. 2005. Using GFP and FRET technologies for studying signaling mechanisms of apoptosis in a single living cell. In: Biophotoncs-Optical Science & Engineering for 21st Century. Roeland Van Wijk and Xun Shen (Eds), Springer, New York, pp. 25-38.

5.       Zhou, L.L., Zhou, L.Y., Luo, K.Q. and Chang D.C. 2005. Smac/DIABLO and Cytochrome c are released from mitochondria through a similar mechanism during UV-induced apoptosis. Apoptosis 10:289-299.

6.       Zhou L.Y. and Chang D.C. 2008. The dynamic process of Bax/Bak aggregation responsible for releasing mitochondrial proteins during apoptosis. J. Cell Science 121(13):2186-96.

7.       Zhou L, Chan WK, Xu N, Xiao K, Luo H, Luo KQ, Chang DC. 2008. Tanshinone IIA, an isolated compound from Salvia miltiorrhiza Bunge, induces apoptosis in HeLa cells through mitotic arrest. Life Sci. 83(11-12):394-403.

 

Signalling mechanism in controlling cell division

Prof. Chang had made significant contribution in studying the signalling mechanisms of cell cycle.  First, he discovered evidence that degradation of cyclin B is required for the onset of anaphase during cell division. This was not expected in the standard model. Furthermore, he proposed a new paradigm for controlling the timing of different events during cell division. He suggested that the decreasing activity of Cdk1/cyclin B acts as a master signal, which utilizes different thresholds of enzyme activity to control the initiation of different mitotic events. This work provided a new understanding of the control mechanism of cell cycle.

 

Reference:

1.       Chang, D.C. and Meng, C. 1995. A localized elevation of cytosolic free calcium is associated with cytokinesis in zebrafish embryo.  J. Cell Biol. 131:1539-1545.

2.       Li, C.J., Heim, R., Lu, P., Pu, Y.M., Tsien, R.Y. and Chang, D.C. 1999. Dynamic redistribution of calmodulin in HeLa cells during cell division as revealed by a GFP-calmodulin fusion protein technique. J Cell Sci. 112 (10):1567-1577.

3.       Chang, D.C, Xu, N.H. and Luo, K.Q. 2003. Degradation of cyclin B is required for the onset of anaphase in mammalian cells. J. Biol. Chem. 278:37865-37873.

4.       Xu, N.H. and Chang, D.C. 2007. Different thresholds of MPF inactivation are responsible for controlling different mitotic events in mammalian cell division. Cell Cycle, 6(13):1639-1645.

5.       Yin, Y., Yu, V., Zhu, G. and Chang, D.C. 2008. SET8 plays a role in controlling G1/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail. Cell Cycle, 7(10):1423-32.

 

6. Development of new methods in biotechnology

Besides his earlier work on electroporation and electro-fusion, Prof. Chang had also involved in a number of other biotechnology projects, some of which are listed below:

 

Development of FRET bio-sensors for drug-screening

Prof. Chang’s lab developed a new class of molecular biosensors that can detect enzyme (caspase) activation in a single living cell. His biosensor is based on the FRET method and is very sensitive. It achieved a higher energy transfer ratio (about 4.5 fold) than most FRET probes reported in the literature (the typical ratio is about 2 fold or less). His sensor was highly sensitive to the target enzyme; it can detect caspase-3 activity in the range of 1 nano Molar concentration and thus is ideally suited to measure enzyme activity in a single cell. Furthermore, this sensor is a powerful tool for rapid-screening of new drugs. (This biosensor had obtained patents in USA and China).

 

Reference:

1.     Luo, K.Q., Yu, V.C., Pu Y.M. and Chang D.C. 2001. Application of the fluorescence resonance energy transfer method for studying the dynamics of caspase-3 activation during UV-induced apoptosis in living HeLa cells. Biochem Biophys Res Comm. 283(5):1054-1060.

2.     Luo, K.Q., Yu, V.C., Pu Y.M. and Chang D.C. 2003. Measuring dynamics of caspase-8 activation in a single living HeLa cell during TNFa-induced apoptosis. Biochem Biophys Res Comm. 304:217-222.

3.     Tian, H., Ip, L., Luo, H., Chang, D.C. and Luo, K.Q. 2007. A high throughput drug screen based on fluorescence resonance energy transfer (FRET) for anti-cancer activity of compounds from herbal medicine. British J. Pharm. 150:321-334.

 

Method to optimise the design of siRNA

He developed a new method to optimise the design of siRNA. RNAi (RNA interference) is a new technology for selectively suppressing a gene function. He showed that the gene-silencing effect of a given siRNA could vary strongly due to the secondary structure of the mRNA at the target site. He proposed that this structural factor can be characterized by a single parameter called “the hydrogen bond (H-b) index”. He demonstrated that this H-b index is closely associated with the gene-silencing effect. Thus, the H-b index has become a useful guideline for optimising the design of siRNA.

 

Reference:

Luo, K.Q. and Chang D.C. 2004. The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. Biochem Biophys Res Comm. 318:303-310.

 

The more detailed Reference list:

See Publications.

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