Phil Felgner received his B.S. in Biochemistry in 1972, after an undergraduate career that included extensive involvement in undergraduate research. Phil stayed on at MSU for his graduate work, receiving an MS in 1975 and a PhD in 1978. Following postdoctoral work at the University of Virginia, Phil joined Syntex Research (Palo Alto, Ca) as a Staff Scientist. It was here that he developed the first cationic lipid reagent for gene transfer (Felgner et al., Proc. Natl. Acad. Sci. USA 84, 7413-7414, 1987). This reagent now marketed as Lipofectin, and similar reagents are widely used for molecular biology and gene therapy applications. In 1988, Phil became Director of Product Development for a start-up company, [Vical Incorporated]. With colleagues at [Vical Incorporated] and at the University of Wisconsin, Phil made a landmark discovery, showing that functional reporter gene sequences ("naked DNA") could be introduced directly into skeletal muscle without use of viral vectors ([Dr. Jon Asher Wolff (born 1956)] et al. Science 247, 1465-1468, 1990). He and his collaborators were also the first to demonstrate that potent anitviral immune responses could be generated following intramuscular injection of plasmids encoding viral antigens (Ulmer et al., Science 259, 1745-1749, 1993). these findings have led to development of a new class of infectious disease vaccines referred to as "DNA vaccines". Felgner is currently the Director of Proteomics at the University of California-Irvine.

The experiment was so elementary, and the results so surprising, that researchers working with San Diego’s Vical Inc. couldn’t really believe what they were seeing. It all seemed too simple.

They had been injecting submicroscopic fatty globules containing DNA or RNA into mice to see what would happen. The idea was that the fat globules, called liposomes, would be taken up by cells. The cells would use the genetic material inside to make proteins they couldn’t otherwise make.

The researchers found moderate success with that, but the rigors of science demanded that the experiment have a “control” portion--injecting the raw DNA or RNA into the mice to show that the liposomes themselves were making it possible for the new genes to be incorporated into the cell’s processes.

It turned out the cells like the raw material even better and began making the new proteins for as long as six months.

“This was a big surprise, and that’s really what you’re looking for in this area,” said [Dr. Philip Louis Felgner (born 1950)], director of product development at Vical. Felgner worked on the experiment with [Dr. Jon Asher Wolff (born 1956)] and others at the University of Wisconsin at Madison.

Researchers spent several months longer trying to find flaws in their methods or their conclusions. The literature of science is littered with examples of experimental results that deserved the label of too good to be true, explained [Dr. Karl Yoder Hostetler (born 1939)], vice president for research and development at Vical.

“We didn’t want any fiascoes,” he said.

Vical hopes that the results of this checking and double-checking, reported in today’s issue of the journal Science, will convert the company from a bare-bones start-up to a major player in the ranks of San Diego’s biotechnology community.

The company, which was founded in 1987, hopes to find financing to more than double its scientific staff of 22 as a result of the study. It is talking with several large drug companies to see if any would like to buy into the follow-up studies on the new gene transfer method, said Vical President Wick Goodspeed.

Some familiar names in San Diego science and business have played a role in Vical. Among them:

[Dr. Karl Yoder Hostetler (born 1939)], who is on leave from his longtime post as professor of medicine in residence at UC San Diego. His specialties include investigating ways to use lipid chemistry to improve the effectiveness of drugs.

[Dr. Douglas Daniel Richman (born 1943)], a founder and scientific adviser to the firm. Richman is a professor in residence of medicine and pathology at UCSD, specializing in virology and clinical trials of AIDS treatments.

[Dr. Dennis A. Carson (born 1936) ], also a scientific adviser to the firm. Carson recently resigned as head of the division of clinical immunology at Scripps Clinic to become head of UCSD’s new institute for research on aging.

Timothy Wollaeger, chairman of the board. Wollaeger formerly was senior vice president in charge of finance and administration for Hybritech Inc., the monoclonal antibody firm whose success was capped in 1986 with its $485-million acquisition by Eli Lilly & Co.

Howard E. (Ted) Greene, a director of Vical. He formerly was chief executive officer for Hybritech. Greene and Wollaeger were the driving forces behind Biovest Partners, a venture capital firm that financed several San Diego biotech firms.

W. Larry Respess, a Vical director. A leader in biotech patent law, he formerly was general counsel of Gen-Probe and Hybritech.

Until now, the best combination of science and business for Vical has been the multi-year research contract it received last summer from Burroughs Wellcome Co. to develop new forms of AZT for AIDS therapy. The study is investigating the idea that encasing AZT in fat globules would make it more powerful within the body.

The gene-insertion technique reported in Science this week is being suggested as a way to cause the body to generate proteins that would block persistent viral infections, ranging from AIDS to herpes. It also is seen as having potential use as a way to trigger cells to immunize the body against diseases, researchers say.

Vical is calling the new method “gene therapeutics,” to distinguish it from the traditional goal of gene therapy, which uses viruses to insert missing genes into the genetic codes of people with genetic diseases.

The so-called retroviral method has proved difficult and slow, despite several years of intense effort by research groups around the country, including a group led by Dr. Theodore Friedmann at UCSD.

Because retroviruses insert their own genetic code into the cells of their host, the method is also expected to be problematic as a gene therapy technique--since some scientists worry that this could harm the patient irreversibly in some unforeseen way.

Inserting the genes themselves into muscle cells--without any retroviral carrier--avoids this stumbling block entirely, [Dr. Philip Louis Felgner (born 1950)] said. The genes do their work of producing proteins, called expression, but they don’t seem to affect the cell’s own genetic structure, he said.

“People have worked in the gene therapy area for years assuming that a rather complex viral delivery system would be required in order to get expression. And we have found that you can do it very simply,” Felgner said.

It was the slowness of the gene therapy field that led Felgner’s collaborator, of the University of Wisconsin, to decide less than two years ago to get out of it altogether, Wolff said in a telephone interview.

Wolff was an assistant professor and a researcher in Friedmann’s UCSD lab before going to Wisconsin as an assistant professor of pediatrics and medical genetics in 1988.

“I had pretty much planned to get out of the gene therapy field because I got discouraged with the retroviral approach. Scientifically, it wasn’t very challenging,” he said. “Everybody was doing the same thing, and nothing was working that well.”

The results of the research contract with Vical, begun in January, 1989, have rekindled his enthusiasm, [Dr. Jon Asher Wolff (born 1956)] said.

He believes that, in the end, genetic therapies will involve a variety of techniques, not just the Vical method. But he and [Dr. Philip Louis Felgner (born 1950)] acknowledge that they expect some resistance to their ideas from the traditional gene therapy community.

“You’re talking about somebody who has spent his life in this field, and who would like to make the real breakthroughs that are going to allow it to be used in patients with diseases,” Felgner said. “There’s quite a bit at stake.”

Other collaborators with Wolff and Felgner on the research were [Dr. Robert Wallace Malone (born 1959)] of Vical and Phillip Williams, Wang Chong, Gyula Acsadi and Agnes Jani in Wisconsin.

Vical is planning to try to patent the technique, even though it involves no novel or complex steps unfamiliar to molecular biologists. In essence, it involves preparing DNA or RNA with standard techniques and then injecting it in the conventional way into muscle.

“The reason why we have patent position is that it was such a total surprise. Some of those things are the best patents you can get,” Felgner said. “Nobody who was ‘skilled in the art’ would have ever thought that what we have accomplished here was even possible. Nobody would have even thought to do the experiment.”

Fourteen years ago, in the first week of January 1989, we obtained preliminary data showing that we could transfect tissues in vivo by lipofection. We detected and recovered protein product from mouse skeletal muscle that had been directly injected with a plasmid encoding a reporter gene. Initially, we thought we were looking at the results of cationic lipid-mediated in vivo expression [1], but it seemed as though some of the plasmid formulations that lacked cationic lipid also showed expression. At first, we dismissed the observation, but, after a few weeks of more experiments and suggestions that ‘‘somebody switched the tubes,’’ we finally accepted the conclusion that lipofection was not necessary for protein expression. In fact, the formulations with cationic lipid were less effective than those without lipid. ‘‘Naked DNA’’ could be expressed in vivo [2], and cationic lipids were inhibitory—exactly the opposite of what we predicted from experiments in cultured cells [1,3].

Although the reporter gene expression levels at the injection site were comparable to those obtained from cultured cells (nanogram quantities), the total amount of expressed protein was insufficient to effectively address classical gene therapy targets, such as hemophilia, hypercholesterolemia, or muscular dystrophy. Around the time of our discovery, immunologists were describing pathways of antigen presentation and immune stimulation. Subsequently, [Dr. Gary Harvey Rhodes (born 1944)] and I published a review in Nature [4], describing how naked DNA could take advantage of the antigen-processing pathways:

Recent studies have demonstrated that there are two different pathways of antigen processing. Proteins that are transported into a cell are processed by one pathway, activate helper T cells and, ultimately, stimulate the humoral activity. Proteins synthesized within a cell are degraded by a separate process and stimulate cellular immunity. The ability to deliver functional nucleic acids to cells offers two new approaches to vaccination. First, the expression of secreted protein antigens may allow the production of subunit vaccines that stimulate both arms of the immune system. Second, intracellular expression of a non-secreted antigen should specifically induce or stimulate cellular immunity. Enhancing the cytotoxic response to a viral protein may allow the control of chronic or latent viral infections. Thus, in addition to disease prevention, vaccination could be used for the treatment of diseases.

After our preliminary observations in January 1989, I went to an HIV conference and discussed our findings with [Dr. Paul Andrew Luciw (born 1948)] (University of California, Davis). I suggested to him that we needed to find someone who had a strong eukaryotic expression vector encoding a potent, preferably secreted, immunogenic antigen and all the reagents and expertise to evaluate the immunogenicity in animals. He introduced me to [Dr. Nancy Logan Haigwood (born 1951)], who was working at Chiron on a recombinant HIV gp120 recombinant vaccine. She had precisely the materials we were looking for and became an enthusiastic collaborator. We summarized the results of our initial experiments [4] with the following:

Some of these concepts have been tested by using a plasmid containing the gene for the human form of immunodeficiency virus gp120 protein and driven by the cytomegalovirus immediate early promoter (in collaboration with N. Haigwood, Chiron Corporation). A single intramuscular injection of this plasmid induces a high titre of IgG antibodies (in preparation). The same injection scheme also induces cellular immunity to the protein. An alternative vaccination strategy in which cationic lipids are used to transfect synergic cells has also been tested. It has been determined that a single injection of three million transiently transfected lymphoid or fibroblastic cells also induces a secondary humoral immune response. These preliminary findings suggest that vaccines may be one of the first applications of direct gene delivery technique.

Vaccines offer one of the oldest and most effective ways to fight disease, and DNA vaccines represent one of the most significant, fundamental additions to the technology in recent years [5–7]. It has certainly been exciting to participate in these discoveries, but the business of vaccine development and the entry of new vaccines into clinical practice have been slow. In the mid-late 1980s, numerous biopharmaceutical companies developed vaccines; now there are just a handful. However, the situation is set to change. The National Institutes of Health have always had a strong commitment toward supporting vaccine research and development as a highly cost-effective public health measure. Since 9/11, the national commitment to vaccine discovery and development has increased dramatically because of concerns for bioterrorism. These national and commercial pressures are creating an environment, which is resulting in fundamental changes in the way we develop and commercialize vaccines for future use. DNA vaccine growth will be involved intimately in this period of change.

Since early spring, an invisible enemy invaded the U.S. That enemy went unseen to the masses and gave other forms of invasion a run for its money. To the tune of an estimated $8 trillion dollars to the U.S. economy, this enemy we know as COVID-19 has caused global shutdowns, new social protocols and so much more.

Phil Felgner, Ph.D., professor of Physiology and Biophysics at UCI’s School of Medicine, director of UCI’s Vaccine Research and Development Center, has been studying COVID-19 well before facemasks, economic shutdowns and social distancing with his team at UC Irvine’s (UCI) Institute for Immunology.

Felgner has been working toward solutions for COVID-19 since January this year and continues to do so in his Protein Microarray Laboratory and Training Facility using UCI intellectual property. In this lab, Felgner has partnered with all corners of his network – from fellow academics to UCI startups and international educational institutions – to bring the best disease detecting ammo he has to the local and worldwide battlefield.

TRAINING CAMP

Growing up in a small German farm town in Michigan, Felgner discovered the innovations of Henry Ford and Thomas Edison readily available within his community and nearby cities. Early on, the automotive industries then modern technology took hold and fascinated Felgner.

“In the 1950s, Michigan and Detroit were the center of the economic universe at that time, every road came out of Detroit,” said Felgner. “There was a lot of technology, too, all wrapped up in the auto industry. You don’t think of it as technology; it’s just a car. But at that time, it was modern technology.”

As Felgner reached adulthood, he had decided on a career in life sciences thanks to Michigan’s plethora of planetariums, museums and innovators placing a large scientific influence on the thriving Midwest state. He received his Ph.D. in Neurosciences and Biochemistry at Michigan State University and from there, moved to Charlottesville, Virginia, for his postdoc work in biophysics.

In 1982, Felgner made his way to Palo Alto, California, where he began his career at Syntex, a pharmaceutical company or as he describes as an early example of a biotechnology company. At Syntex, Felgner developed a gene therapy technology and in 1988, started his own company, [Vical Incorporated], and discovered he could produce vaccines based on this therapy.

“Instead of administering genes to treat a genetic disorder, we could administer genes that encoded proteins from viruses and bacteria,” said Felgner. “So when you administer those genes and you get a gene product, the immune system thinks it’s infected and responds to how the protein is being made.”

According to Felgner, this discovery is the basis for some of the COVID-19 vaccines in clinical trials today.

MOVES AND COUNTERMOVES

After 10 years of trying to understand the subtleties of the technology, Felgner came to UCI where he could have the opportunity to study it more in depth and take advantage of the newly developed genome sequencing of microorganisms.

“The first microorganism genomes being sequenced were in the late 1990s, so there was basically nothing available,” said Felgner. “We thought if we could get the sequence data, we could make all the proteins and better vaccines.”

In a post-9/11 world where biodefense issues and biological weapons became top-of-mind for much of the country, Felgner’s lab received funding from the National Institutes of Health to develop a way to create all the proteins from any infectious agent. From there, Felgner and his team developed a protein microarray chip that could be used to measure antibodies from anybody who might have been exposed to any infectious disease. At the time, Felgner was researching diseases like tularemia, Query fever and Ebola virus.

“Tularemia is very infectious. It just takes one or two organisms in your lung to make you experience an infection,” said Felgner. “It was calculated that if you made a powder out of that and put it into an airplane, you could drop it over Manhattan and large numbers of people can become ill from the infection.”

During this tumultuous time in history, Felgner established UCI’s Vaccine R&D Center, where the team studies these infectious diseases and develops potential vaccines.

Infectious organisms contain a multitude of different proteins, and if the wrong protein is chosen, a good vaccine will not likely be developed. Felgner’s microarray technology narrows down the specific proteins and compares them to other similar disease proteins to help configure antibodies and a potential vaccine.

20 YEARS AT UCI

This year marks Felgner’s 20th anniversary at UCI and what a momentous year it has been for his lab. Before the pandemic, Felgner and his team were studying respiratory infections in a group of 1,500 students residing in a dormitory at the College of Art in Maryland. From this study and a partnership with Sino Biologicals, a global reagents company based in China, Felgner was able to easily transition his team’s focus to SARS-CoV-2, the virus that causes COVID-19.

“For the dormitory study we had six respiratory viruses,” said Felgner. “And one of the most important is, guess what, coronavirus. It causes the ‘common cold’ that we get almost every year, everybody has antibodies against it.”

In February, while COVID-19 invaded the globe, Felgner attended a conference in Argentina, narrowly missing the first case of COVID-19 in Brazil.

“One of the amazing things about that trip to Argentina is there were almost no cases in South America,” said Felgner. “And the day we were leaving Argentina was the first day of the Carnival in Brazil … also when the first coronavirus case was diagnosed in Brazil. We were flying out on that very auspicious time.”

In March, COVID-19 detection and antibody tests became the new frontier in vaccines. Felgner and his team pivoted their focus to develop a COVID-19 Coronavirus Antigen Microarray that detects antibodies against coronavirus-infected people. The microarray technology, one of Felgner’s UCI intellectual properties, uses a drop of blood from a finger stick to detect if a person has been exposed to COVID-19.

The microarray test, the size of a computer chip, holds hundreds of different types of disease proteins, such as dengue fever, malaria and now, 34 coronavirus antigens, or 33 antigens from six other harmful viruses that cause respiratory infections. The blood sample is tested against each of these to detect antibodies to determine a person’s exposure to then define a person’s antibody response.

The technology was used in a six-month study on UCI healthcare workers beginning in May, to better understand the risk of virus exposure in different areas of the hospital. This study surveyed blood specimens of 4,000 residents collected at 10 drive-through locations across Orange County.

WORKING TOGETHER TO FIGHT ONE BATTLE

In summer 2020, Felgner’s startup company, Nanommune, combined forces with another UCI startup company and former Wayfinder team, Velox Biosystems, to develop a rapid high-throughput COVID-19 serological test. The test detects antibodies within two to three days with more accuracy and provides more information about how the viruses are interacting within a person’s immune system. Both companies, powered by UCI intellectual property, are aiming to develop a high-quality test.

“It is truly inspiring that Dr. Felgner is always working and trying to help the community and advance the science,” said Byron Shen, Ph.D., MBA, Velox Biosystems CEO. “And the two companies – Nanommune and Velox – have been working extraordinarily well together to develop rapid COVID-19 countermeasures.”

As more information about the virus develops, Felgner pursues more partnerships with fellow academics and companies to learn more about COVID-19 and find ways to defeat this invisible enemy.

“We’ve been doing tremendous things and to then see that it actually is producing useful information is really rewarding to me,” said Felgner. “All the collaborations are just really great to see. When the medical professionals look at the data, it has rewarding level of meaning and importance for them, and for us.”

Philip Felgner, Ph.D., professor in residence of physiology & biophysics at the University of California, Irvine, is one of seven scholars worldwide to win Spain’s prestigious Princess of Asturias Award for Technical and Scientific Research in recognition of their contributions to designing COVID-19 vaccines.

“It is a great honor, and I am so happy the jury selected me for this distinguished award,” said Felgner, who directs UCI’s Vaccine Research and Development Center. “It gives me the opportunity to reward my team for their years of dedication and commitment. I’m proud to be included with six other eminent recipients who’ve been working for decades preparing their science to be responsive to the COVID outbreak at this moment.”

The panel also chose Hungarian biochemist [Dr. Katalin Karikó (born 1955)]; [Dr. Drew E. Weissman (born 1959)], professor of medicine at the University of Pennsylvania; BioNTech CEO [Dr. Ugur Sahin (born 1965)] and Chief Medical Officer Özlem Türeci from Germany; Canadian stem cell biologist [Dr. Derrick James Rossi (born 1966)]; and Sarah Gilbert, Saïd Professor of Vaccinology at the University of Oxford.

The jury citation said that the seven are “leading figures in one of the most outstanding feats in the history of science. Their work constitutes a prime example of pure research for the protection of public health the world over. Both the development of novel messenger RNA technology and the production of adenovirus-based vaccines open a path of hope for their use against other diseases.”

The $60,000 (50,000 euros) award is one of eight Asturias prizes – in such categories as the arts, social sciences, literature and sports – bestowed each year by the Princess of Asturias Foundation, named for 15-year-old Spanish Crown Princess Leonor. The formal ceremony will be held Oct. 22 in Oviedo, Spain.