Philip Serwer, PhD

JAD profile

Affiliation(s): 

UT Health San Antonio

Areas of Interest: 

Bacteriophage Assembly, Bacteriophage-Based Biomedicine, Bacteriophage Structure, Biochemistry of Neurodegenerative Disease

Biography & Research: 

I have a multidisciplinary background that began with theoretical physics (AB degree, Physics, University of Rochester; 1963) and continued with microbiology (MS degree, Microbiology, New York Medical College; advisor, Richard A. Hartman; 1968) and biophysics (PhD degree, Harvard University; advisor, Charles A. Thomas, Jr.; 1973) and biochemistry. I currently have a primary appointment as Professor of Biochemistry and Structural Biology, UT Health, San Antonio, Texas. My primary initial research interest was mechanisms of phage assembly, including a four-year postdoctoral stay in the phage assembly-laboratory of Dr. William B. Wood, Jr. at Caltech (1972-1976). Work on phage assembly was my primary interest in early years as a faculty member at UT Health, where I have been assistant professor (1976-1981), associate professor (1981-1985) and full professor (1985-present). My basic strategy for studying phage assembly resembles the strategy implied by the following statement (that I recently discovered) by the professional physicist, amateur biologist, Richard Feynman. “It is very easy to answer many of these fundamental biological questions; you just look at the thing!” From the beginning, I was involved in electron microscopy, including, in temporal order: (1) assisting in the first ion-pumping of an electron microscope, (2) documenting and quantifying flattening and shrinkage of viruses during specimen preparation by negative staining, (3) developing improvements in specimen preparation for viruses and DNA, (4) stereo-electron microscopy of phage capsids and (5) collaborating in ~16 leading-edge studies of phages and their packaged DNA by cryo-electron microscopy. My way of “looking at the thing” in phage assembly (The “thing” is capsid assembly and DNA packaging in my case) included ultracentrifugation and native agarose gel electrophoresis (AGE). I developed new procedures for both these disciplines, including (1) hydration-based buoyant density centrifugation, (2) several combinations of buoyant density centrifugation and rate zonal centrifugation and (3) combined ultracentrifugation-AGE. In the area of constant field AGE, my laboratory generated a major fraction of both the world’s innovations and the world’s detailed characterizations of the gels used. My laboratory also introduced several innovations in pulsed field gel electrophoresis. I was a member of the scientific advisory board of the world’s leading biological gel manufacturer, FMC Bioproducts (now part of Lonza). My laboratory also produced the first high-efficiency in vitro DNA packaging systems for packaging that occurs via DNA concatemers. We did this for phages P22, T7 and T3. We used the T7 system to perform the first single-molecule studies of the process of DNA packaging (in 1997 and 1999), which triggered a subsequent burst of single-molecule studies from other laboratories. To assist studies of this type, we did a quantitative study of the excluded volume effect, a study that produced innovations that have been broadly used in biochemistry, although often without knowledge of the source of the innovation involved. By use of these innovations, our analysis of phage DNA packaging produced the finding that phage T3 (and probably other phages) undergo DNA packaging that is associated with hyper-expansion of the phage capsid, presumably to assist DNA packaging. While investigating possible conformations of the hyper-expansion-generating major outer shell protein, I began to sense a connection with a sheet-like protein conformation, discussed below, that others were suspecting of generating the toxicity that causes neurodegenerative diseases, with focus on Alzheimer’s disease (AD). Further investigation resulted in a chain of my publications that has ended with a publication in the Journal of Alzheimer’s Disease in which I did electron microscopy that “looked at the thing” in a human AD-brain (The “thing” is human AD-lipofuscin in this case). I saw damage to lysosomes apparently being caused by lipofuscin protein in a toxic, sheet-like conformation that appears to be the Pauling/Corey discovered conformation (called alpha-sheet) that I have proposed for the hyper-expanded phage capsids. I further proposed this to be the key pathological event of AD. Of course, more needs to be done. The above work on phages, in vitro/single-molecule analysis, ultracentrifugation and AGE led me into work on two other biomedical problems: (1) curing multi-drug resistant bacterial disease by use of phages (phage therapy) and (2) curing metastatic cancer. Our first advance for work on both problems was high-throughput environmental phage isolation. “High” means over 50 new phages per week isolated per person, which is close to 2 orders of magnitude higher than what is achieved in other laboratories. The second advance is solving the problems of rapid, high amount-preparative propagation and purification, followed by characterization, of the phages isolated. These are now solved problems in my laboratory, but apparently not in any other laboratory. The solutions include the elimination of liquid cultures. Phages are isolated and propagated only in-gel, with transfer by platinum needle only. The second advance includes finding that the persistence of phages in mouse blood is highly variable (< 10 minutes to ~ 6 hours), even among related phages, such as T3 and T7. Rapid screening for high persistence phages is the key problem to solve for improving phage therapy enough so that phage therapy is routinely useful, which is especially important for therapy of multi-drug resistant bacterial infections. Rapid screening for high persistence phages is also one of three key problems to solve in the field of phage-based drug delivery vehicles (DDVs) to be used as therapy for metastatic cancer. The others are (1) developing and testing gating for phage-DDVs used to deliver drugs selectively to tumors, which is designed to raise the tumor-drug dose to the point that tumor cells do not have the opportunity to evolve drug resistance, and (2) modifying phage-DDVs to increase the tumor-selectivity of drug release.