Dr. Alan H. Goldstein

biomanThirty years of burning in the electron fire


My journey into the world of nanoscience began over thirty years ago from the distant but related world of plant breeding which, after all, is one of Homo sapien’s most ancient forms of bioengineering. My goal upon entering the university was to create more efficient crops to feed the hungry. But from the moment I arrived at New Mexico State University, the simple questions of ‘why?’ and ‘how?’ carried me inexorably deeper into the universe of the cell. Why did some plants grow faster than others? Why did the productivity of the some plant genotypes change dramatically with small variations in environmental conditions? How did leaves harvest the energy of the sun? How did roots absorb nutrients and water from the soil? Each answer was like a door to a stairway leading deeper into the reductionist realm of science. Photosynthetic efficiency was a function of leaf surface which, in turn, was a function of the light harvesting cells on that surface which, in turn, was a function of the chloroplasts in those cells which, in turn, was a function of the chloroplast’s energy transducing membrane. And so on. Before long, my academic focus had shifted to the physiology of the cell and then to the structure and function of the biomolecules from which the cell was built. I came to realize that biochemistry was one of the most powerful tools available to improve crop plants. In my youthful exuberance, I reasoned that once we understood the molecular mechanisms that created and controlled plant cells we would know exactly how to breed for essential crop traits: salt tolerance, photosynthetic efficiency, disease resistance. Although I didn’t realize it at first, I was morphing from an agronomist into a cell biologist.

But as I evolved into a cell biologist, cell biology itself was undergoing a radical paradigm shift. In the mid-1970s the molecular biology revolution was irrevocably transforming and unifying the fields of physiology, cell biology, and biochemistry. In 1976 I won an NSF Graduate Research Fellowship in Plant Biology with a personal narrative focused on the use of genetic engineering for plant breeding. In other words, I wrote an essay praising the potential of GM crops.
By the time I reached graduate school at the Univ. of Arizona biotechnology had taken the world by storm. I sat enthralled at seminars by Walter Gilbert on DNA sequencing and James Bonner on the discovery of introns. My major was genetics which, because of the era, meant molecular genetics. But at heart I remained a chemist. I still considered that it was the unique properties of biomolecules themselves that created the unique phenomenon called biology. As a result I minored in Physical Chemistry… a highly unusual but providential choice for a plant breeder turned molecular geneticist.

An NSF Fellowship followed by an International Harvester Dissertation Research Fellowship provided the privilege of almost complete academic freedom. I created my own curriculum; a (then) unusual fusion of life sciences, physical sciences, chemistry, and engineering. I did my Master’s thesis with Professor Robert McDaniel on mitochondrial respiration and then intentionally changed fields for my Ph.D. dissertation. By now I had come to understand that molecular metabolism was controlled by multiple, interrelated processes. Workers were beginning to apply nonlinear systems computer modeling to this and other complex biological problems. In order to learn these techniques first hand, I joined Professor William Gensler’s lab in the Department of Electrical Engineering. With funding from Cotton Inc., Professor Gensler had spent several years implanting Palladium microelectrodes (100 micron diameter) into the stems of cotton seedlings under field conditions. After wound healing he would collect real-time measurements of electropotential by remote telemetry and correlate these with standard analyses of tissue water content obtained from plant physiologists working on the same experimental field plot. The goal was to develop remote sensing-based control systems for high-efficiency irrigation to conserve the groundwater stored in aquifers beneath the Sonoran Desert of Southern Arizona.

My dissertation research focused on modeling and physically characterizing the interface between cells and the metal implant surface… a field now known as Biomaterials. To explore the frontier between living and nonliving materials with submicron resolution required an interdisciplinary toolkit that ranged from computer modeling to innovations such as the (then unheard of) technique of placing live samples in the scanning electron microscope (now called Environmental SEM). My committee was made up of an electrical engineer, two plant physiologists, a biochemist, and a physical chemist. I maintained my minor in Physical Chemistry and an active interest in molecular biology so that my coursework ranged from plant physiology to genetic engineering to digital systems design to quantum mechanics. At the time, my specific research area was considered Bioelectrochemistry. Now is would be called Biosurfaces. But in fact, I was inadvertently training for the most interdisciplinary field of all – Nanotechnology.

By the time I graduated, it was obvious that elucidation of the molecular mechanisms of life would open the door to the integration of living and nonliving chemistries… now called Nanobiotechnology. I moved to the San Francisco Bay Area in 1980 to help build Chevron’s biotechnology group and found myself at the center of the nascent biotechnology industry. Because Chevron owned the second largest rock phosphate reserve in North America and produced phosphate fertilizers, I worked on the biophysical chemistry and molecular genetics of phosphate uptake by plant cells and the dissolution of mineral (rock) phosphates by bacterial cells. The ability of some Gram-negative soil bacteria to dissolve rock phosphates with high efficiency is, in fact, one of the oldest observations in microbiology. My goal was to elucidate the molecular genetic basis for this trait. To accomplish this, I also learned and applied the techniques of molecular biology: cloning, sequencing, transformation et al. In 1985 I moved back to Tucson and then to CSU Los Angeles. I continued to work on phosphate transport in plants using the methods of tissue and cell culture, and on the dissolution of mineral phosphates by bacteria. I began a collaboration with workers at the Scripps Research Institute that resulted in a series of papers showing that higher plants, like bacteria and fungi, had evolved genes to enhance nutrient uptake in phosphate limited environments, the so-called phosphate starvation inducible (PSI) regulon. I also began a collaboration with workers at the Idaho National Environmental Engineering Lab on the bacterial bioprocessing of rock phosphate ore. Phosphate is the world’s second largest bulk agricultural chemical; costly to extract in terms of energy, and a major source of environmental pollution from open-pit mining operations, processing via extraction with concentrated sulfuric acid, and its return to the environment in the form of soluble phosphates that enter ground and surface waters. By combining bacterial biotransformation of rock phosphate ore in the soil with selection for high efficiency PSI-regulon genes in plants, I was confident that we could create a sustainable P fertilizer technology. I retain that belief to this day. However, like many academics, I found that funding for basic research in the plant sciences was extremely difficult to obtain, especially for the ‘esoteric’ area of sustainable agriculture. So I gradually shifted my focus towards biomedical research.

I moved to Alfred University in 1995 to Chair the Division of Biology. Alfred offered a unique opportunity to make the transition into biomedical materials (a.k.a. biomaterials) because it is home to one of New York State’s four ‘statutory’ colleges… the New York State College of Ceramics. The Ceramic Engineering program at NYSCC had a long history of biomaterials research. My previous work on rock phosphates served me well during this transition. As a physical chemist, I had a studied calcium phosphate materials similar to those used in the bioengineering of hard tissues such as bones and teeth. Investigation of the mechanisms of biosolubilization of rock phosphate and the plant PSI regulon had taken me deeply into a number of fields (e.g. regulation of gene expression and biofilms) that have cognate systems in the world of medical implants. I began a series of collaborations with NYSCC faculty that eventually led to a Whitaker Special Opportunity Grant and the founding of the Biomedical Materials Science Program.

In 2003 I returned to the Bay Area for a research sabbatical. The goal was to develop a prototype for commercial bioprocessing of rock phosphate ore at the Genencor Research Facility in Palo Alto. The project was to be funded by International Minerals and Chemicals Corporation (IMC), the largest supplier of phosphate in the world. I could use my sabbatical to bring this twenty year old project to closure and simultaneously learn the latest techniques of bioinformatics-based metabolic engineering that had emerged from the nascent field of genomics. If successful, I might catalyze serious interest in the green technology of bioprocessing rock phosphates. If not, I could at least take these new skills back to Alfred and enhance my ongoing research in biomedical engineering. I tried to work out all the details in advance. But upon arrival, the lawyers had still not come to final agreement. For the first time in over 25 years, I had no lab to work in.

But this corporate ‘snafu’ turned into a life-changing opportunity. As I walked the hills of San Francisco waiting for permission to re-enter the world of biotechnology, I had time to consider a different spin on the ‘fundamental’ nature of my research. For the past two years I had been working to create enzymes stabilized in nanoporous silica glasses formed by a biocompatible ‘sol-gel’ process. I was, in effect, attempting to bring these enzymes out of the cell and keep them alive in an artificial, nonliving environment. More specifically, I was trying to create biomolecular-materials composites a state of matter where where both the living and nonliving materials retained their original properties. But if successful, the whole of this composite would clearly be greater than the sum of its molecular parts. Now I had time to consider my work from a radically different perspective. What were the ethical implications of fusing living and nonliving materials at the molecular level? What if I were to succeed in my further plan to create individual molecules that were part enzyme and part silica polymer; hybrid molecules (as opposed to hybrid materials) capable of ‘living’ either inside or outside the cell? Any scientist or engineer who has ever worked on a difficult problem knows that it takes everything one has just to get to the next experiment. Suddenly, and for the first time, I was on the outside looking in. I saw that I was part of a worldwide bioengineering initiative to build molecular devices that operated via the integration of living and nonliving materials at the atomic and molecular level. The biomedical rationales driving this initiative were certainly reasonable, even noble: to attenuate, cure, and ultimately eliminate disease and suffering. But were there other, perhaps equally compelling issues at stake? Clearly this was so. Was there another worldwide initiative to examine the ethical implications of molecular bioengineering and other applications of nanobiotechnology? Clearly there was not. It was a revelation.

As a result, in 2003 I began to write about the future of nanotechnology and, more specifically about the implications of the fusion of biotechnology and nanotechnology. My first effort, “Nature vs. Nanoengineering” won a Shell-Economist Prize. Since that time I have continued to chronicle these issues in a manner that, so far as I can tell, is unique. As a member of the National Research Council’s Committee to review the National Nanotechnology Initiative (NNI), I have received an unprecedented tutorial on the state of nanotechnology today. I was a prime organizer of a workshop on ‘Responsible Development of Nanotechnology’. But the more I listened and read, the more it became clear that the hard ethical questions were not and are not being asked. As a biomaterials engineer I remain committed to the technical goals of nanobiotechnology. But as a concerned citizen, I am also committed to examining the full range of possibilities that will open to humanity when the tools of nanobiotechnology become mature and widely available. Regenerative medicine and bioengineering represent the bright side of this endeavor, but there is a very dark side as well. By the time this application reaches the Committee, the NRC review of the NNI will have been published. I invite you to examine the section on ‘Responsible Development’. I am confident that you will agree that the hard questions were not asked. Nor did we find others in the community who were willing to speak plainly about areas such as performance enhancement, or nanobio-enabled weaponry. Most importantly, it became clear that there is no community of scholars dedicated to consideration of the most fundamental and profound concepts that emerge from direct molecular integration of living and nonliving materials. It is for this reason that “The Race To Break The Carbon Barrier” must be written and published. The original announcement of the National Nanotechnology Initiative correctly states that nanotechnology will revolutionize every aspect of human endeavor. That statement is, in and of itself, the most compelling argument I can think of for supporting my effort to write a book that makes the full range nanotechnology’s scientific applications and ethical implications accessible to the public.

Appointments to Federal Advisory Boards:

Committee To Review the National Nanotechnology Initiative (NNI), National
Research Council: 2004 - 2006 http://www4.nas.edu
Biomedical Engineering Materials Applications (BEMA) Roundtable, National Research Council): 2002-2006 www.nationalacademies.org/nmab/BEMA_History.html
Committee on Technologies to Deter Currency Counterfeiting National Research
Council 2005- ongoinghttp://www4.nas.edu

Awards:

1999 Fierer Endowed Chair in Biomedical Materials Engineering
1998 P.I. Whitaker Foundation Special Opportunity Award
1995 CSU Biotechnology Faculty Research Award
1979 International Harvester Dissertation Research Fellowship.
1977 National Science Foundation Graduate Research
Fellowship in Plant Biology.

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