Synthetic Biology: Reaching Back 20 …Make that 50 Years

Recently I had the opportunity to meet emeritus professor Dr. Waclaw Szybalski from the University of Wisconsin- Madison, who has worked at the McArdle Laboratory for Cancer Research since 1960.  

During an interview we discussed Dr. Szybalski’s amazing exit from his native Poland in 1946 following the alternating German and Soviet occupations, his education in the early days of genetic engineering, and finally the foundational work he has done in both prokaryotic and eukaryotic genetic engineering.

Photo of award from Polish government for Szybalski's research contributions.

Doctor Honoris Causa awarded to Waclaw Szybalski. Szybalski, in his laboratory, background. Photo: Maciek Smuga-Otto.

At age 90 Szybalski continues to maintain a laboratory with postgraduate students. At the same time (and with Promega’s assistance) he continues to support research in Poland. In May 2011, Szybalski was honored by the President of Poland with the highest order, Grand Cross of Polonia Restituta, celebrating his many scientific contributions, including: 1) establishment of the genetic basis of antibiotic resistance in bacteria;
2) multidrug therapy for bacterial pathogens and leukemia; and 3) the ability to sensitize mammalian cells to radiation.

Synthetic Biology: The Early Years

Interestingly, the publication of an article in The Scientist coincided with our interview.  The article, Tinkering with Life  is about the early days of synthetic biology, in the 1990s.

Hold the phone.

The synthetic biology Wikipedia page quotes Dr. Szybalski using the term ‘synthetic biology’ in 1974 (1) :

Let me now comment on the question “what next”. Up to now we are working on the descriptive phase of molecular biology. … But the real challenge will start when we enter the synthetic biology phase of research in our field. We will then devise new control elements and add these new modules to the existing genomes or build up wholly new genomes. This would be a field with the unlimited expansion potential and hardly any limitations to building “new better control circuits” and ….. finally other “synthetic” organisms, like a “new better mouse”. … I am not concerned that we will run out of exciting and novel ideas, … in the synthetic biology, in general.

The Wikipedia page also notes a much earlier use of the term synthetic biology by Stéphane Leduc, in 1912 (2). However, Leduc did not know of DNA as the basis for life; his book concept was purely speculation and not on target.

Szybalski, on the other hand, was actively doing research in the 1950s and 1960s, tinkering with yeast genetics and the genetics of antibiotic resistance. In 1963, Szybalski and Litman showed that DNA synthesized enzymatically in the lab retained its biological transforming activity. This activity remained even when halogen atoms replaced the methyl groups of thymine  in DNA (3).

Engineering Meets Biology

In the same issue of The Scientist, George Church, Professor of Genetics at Harvard Medical School, noted in an opinion piece on synthetic biology entitled “Evolving Engineering”, “Much of the progress can be credited to engineers who have developed a deeper appreciation of life’s power.”

Indeed, Dr. Szybalski, the product of parents with degrees in chemistry and engineering, started out as a student of engineering, until a course in fermentation brought yeast genetics to his attention, this in 1943-44. When his fermentation professor, Adolf Joszt, lectured in Lwów, Poland, about a new field of “genetic engineering” and the contributions of Danish yeast geneticist, Ojvind Winge, Szybalski was excited to the point of changing his plans from study of chemical engineering to this newly proposed  field of “genetic engineering”.

When the opportunity presented itself to spend a summer of study in Denmark, Szybalski met  Dr. Winge and later worked in his laboratory. Details and remembrances of the ‘great yeast geneticist’ Winge can be found in a commentary written by Szybalski , published in “Genetics” in 2001 (4).

During our interview in Szybalski’s McArdle Laboratory office, he described how his engineering studies contributed to his research, stressing that he is a “methods person” and a “toolmaker”.

Coming to the U.S.

Szybalski emigrated to the United States in 1950, and at the recommendation of Winge, was offered a position at Cold Spring Harbor Laboratories (CSHL). He described the atmosphere there in the 1950s/60s as congenial and like a ‘big family’. Everyone knew each other and research results were shared amongst researchers at that facility and outside of it. Recent discoveries were more often reported in talks given at conferences and discussed with collaborators, than reported in publications. Since the community was small, sharing of results could be done on a local, personal basis (5).

Early Days of Phage and Microbial Genetics

Szybalski tells in a 1992 BioEssays article that discoveries came fast and furious during the 1950s in those ‘wonderful early years of phage and microbial genetics’(5).

At CSHL, Szybalski worked on the genetics of antibiotic resistance, supported by the CSHL Director and the Office of the U.S. Navy. According to Szybalski, “We encountered the first antibiotic-resistance-carrying plasmids, developed systems to study chemical spot-mutagenesis and observed genetic transformation in Bacilli.” His contributions thus laid the groundwork for the genetics of drug resistance. The results made Szybalski the first advocate of the use of multiple chemotherapeutic agents for tuberculosis (5), now the standard of care in TB patients.

The Move to Eukaryotic Cells

Due to rapid progress in bacterial and phage genetics in the 1950s and looking for new challenges, scientific pioneers like Max Delbruck and Renato Dulbecco made a jump to research in eukaryotic systems such as fungi and human cells.

In the mid 1950s Szybalski also made the move to eukaryotes, but with a different motivation. Earlier research had shown that incorporation of halogenated thymidine analogs into their DNA made bacterial cells sensitive to radiation. Szybalski wanted to repeat these studies with human cells as a potential model for a new type of cancer radiotherapy.

You will find the well-described details of this work and further studies with mammalian cells in Szybalski’s 1992 BioEssays article (5).

A Nobel Contribution

It bears mentioning here that with his engineer’s thoroughness and discipline, Szybalski, along with his wife-collaborator, developed a novel method (HAT medium) for  selection of HPRT-defective mutants in mammalian (human) cells. This research, in 1962 called a ‘first step toward gene therapy’ led to the development of cell fusion techniques, monoclonal antibodies and genetic transformation of mammalian cells with cloned genes (5).

Milstein, Jerne and Kohler were awarded the Nobel prize in 1984 for development of monoclonal antibodies, a technique made possible by Szybalski’s development of  HAT selection.

There is much to tell about Dr. Szybalski, which might be expected for a researcher actively writing and communicating research results in his 9th decade. You can find further information in Szybalski’s curriculum vitae on his McArdle Laboratory page. Additional information about Szybalski can be found in Wikipedia  and on the synthetic biology Wikipedia page.

On his Wikipedia page Szybalski is pictured with James Watson, who’s name came up during our interview—Szybalski calls him “Jim”–they have been friends since 1950. Watson recently dedicated a Library Annex at CSHL to Waclaw Szybalski;  Szybalski’s portrait hangs there.

At our meeting in October Szybalski was wearing a DNA tie signed by James Watson.

A tie signed by James Watson.

Dr. Szybalski sporting his James Watson signed tie. Photo: Maciek Smuga-Otto.

How Funding has Changed Since the 1950s

In the presence of one with so much history in scientific research, and as a former graduate student and research assistant, I couldn’t help but ask Dr. Szybalski a few general questions about how things were done in research back in the 1950s and 60s. I was curious how funding differed from today.

As an example, Szybalski told of being contacted by the head of the National Science Foundation (NSF) circa the late 50s-early-60s. Szybalski commented that Director Alan Waterman often called to see if Szybalski or his colleagues could use some additional funding, because the US Congress was too generous.

A call from the director of the NSF looking to give away money might induce a coronary in a principal investigator today. Szybalski told me that at one particular occasion he and Waterman settled on a sum of several tens of thousands of dollars, for which the director then issued a check made out to “Waclaw Szybalski”, with only this stipulation:  “Waclaw, send me a short note on what is the objective of this project”. The money was of course signed over to the University of Wisconsin. This was not uncommon in the early days of the NSF, but this ‘efficient’ practice was soon discontinued (personal communication).

I also asked Szybalski about the amount of money taken out of each grant award, by universities. Today such “costs” can range upwards of 40% of a grant…moneies taken out of the grant dollars to cover building and equipment costs to the university. Back in the day, I was told, this was not done.

Of course research costs to universities were very different at that time. Szybalski told us that McArdle Laboratories on the University of Wisconsin campus, was built, in the 1950s at a cost of $25 per square foot, finished. To save money on construction costs, 60% of the building was initially left unfinished (at a cost of $8 per square foot).

These recollections of an earlier time in scientific research provide some wonderful subtext to the high costs of running a research laboratory in the 21st century. Thanks to Dr. Waclaw Szybalski for his amazing power of recollection, not to mention his early contributions to the field of synthetic biology, now going on 50 years of age.

References

  1. Szybalski, W. (1974) In Vivo and in Vitro Initiation of Transcription. In: Control of Gene Expression, A. Kohn and A. Shatkay eds., Plenum Press, New York. pp. 23–4, 404–5, 411–2, 415–7. 
  2. Leduc, Stéphane (1912). Poinat, A., ed. La biologie synthétique, étude de biophysique.
  3. Litman, R.M., Szybalski, W. (1963) Enzymatic synthesis of transforming DNABiochem. Biophys. Res. Comm. 10 473–81.
  4. Szybalski, W. (2001) My road to Øjvind Winge, the father of yeast genetics. Perspectives: Anecdotal, Historical and Critical Commentaries on Genetics. Crow, J.F. and Dove, W. F., ed. Genetics 158, 1–6.
  5. Szybalski, W.S. (1992) Use of HPRT Gene and the HAT Selection Technique in DNA-Mediated Transformation of Mammalian Cells: First Steps Toward Developing Hybridoma Techniques and Gene Therapy. BioEssays 14, 495–500.
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Kari Kenefick

Kari has been a science writer/editor for Promega since 1996. Prior to that she enjoyed working in veterinary microbiology/immunology, and has an M.S. in Bacteriology, U of WI-Madison. Favorite topics include infectious disease, inflammation, aging, exercise, nutrition and personality traits. When not writing, she enjoys training her dogs in agility and obedience. About the practice of writing, as we say in DNA purification, spin, rinse and repeat.

2 thoughts on “Synthetic Biology: Reaching Back 20 …Make that 50 Years

  1. Engineering Meets Biology… somone will say it’s good, that’ll help us to fight a cancer, ok, but what about GMOs, are there any relations between them and cancer?

  2. Thanks for your comment, Marcis. The following is a long, (and possibly non-) answer to your question.I find the term ‘synthetic biology’ intimidating, maybe even frightening. I enjoy nature, and plants, birds and animals as they are, not genetically modified. But I must say that Dr. Waclaw Szybalski’s work was in no way intimidating; on the contrary, the part of his research that I know of was done to answer basic biology questions. The way he used engineering was to take things apart, then rebuild them, to better understand how they work. And if you read The Scientist article by George Church, (linked in my blog) regarding recent medical advances driven by synthetic biology, you learn that synthetic biology is responsible for (miraculously) curing Tim Brown of both leukemia and HIV-AIDS. This was done by transplanting him with stem cells (to cure the leukemia) that happened to lack the CCR5 HIV receptor. What Tim received was taken from nature (human-derived stem cells). According to George Church, this success has led to a trial using a zinc finger-nuclease aimed at eliminating the CCR5 gene from HIV-infected persons.
    GMO foods can be altered by inserting a gene to make the plant resistant to glyphosphate, and yes, this insertion of this unnatural plant component sounds scary, however, I don’t have any data on the incidence of cancer, if any, related to GMO plants.

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