Text by Mara G. Haseltine
In 2006 I installed one of my largest sculptures to date, 12 meters in diameter, SARS Inhibited. The Sculpture is situated in a reflecting pool within the central plaza of Singapore’s Biotech Mecca ‘Biopolis’. The Biopolis campus was designed by the renowned architect Zaha Hadid.
SARS Inhibited celebrates and illustrates the groundbreaking discovery made in 2002-2003, by an international team of scientists, of a mechanism that could potentially lead to drug discovery- stopping the SARS virus from self-replicating. This mechanism of inhibition could stop the SARS-CoV in its tracks. Today mankind is faced with an offshoot of SARS-CoV; SARS-CoV-2 is the causative agent for COVID-19. These viruses share 82 per cent identical RNA sequence, which means they are Coronaviruses and function similarly. It could mean the mechanism portrayed in SARS Inhibited has the potential to apply to all Corona Viruses – including the virus responsible for COVID-19. In other words, these antiviral drugs apply to all Coronaviruses.
Almost immediately after finishing my SARS Inhibited installation, I had one of the most powerful moments of my life – art literally met science in the Biopolis plaza when I encountered Professor Rolf Hilgenfeld in front of my just completed sculpture. Rolf hails from the University of Lubeck in Germany and has 30 years of experience as a structural biologist under his belt. Rolf led a German team of structural biologists that played a pivotal role in the discovery that inspired SARS Inhibited as outlined in a 2003, May 14th New York Times Article, Experimental Drug May Fight SARS, Researchers Say.
At the time of our meeting, Rolf was visiting Singapore to give a talk on SARS-CoV and instantly recognised the structure of the sculpture from his research. This recognition deeply moved me, and I felt I had met my true collaborator for SARS Inhibited for the first time. Professor Rolf Hilgenfeld is currently busily working on an antiviral drug for novel Corona Virus SARS-CoV-2 or COVID-19.
Mara G. Haseltine: Rolf, we had the amazing luck of running into each other at Biopolis Epicenter in Singapore just as I finished installing SARS Inhibited ….as a scientist, how did it feel to see your discovery as an outsized 12-meter bronze sculpture emerging from a pool of water and flashing in the tropical sun for the for the first time?
Rolf Hilgenfeld: It was a great surprise. I had been invited to give a lecture on SARS-CoV in Singapore and afterwards, in the evening, my hosts took me to the little plaza where your sculpture was unveiled. I had not been informed about this event before and I was very happy to immediately recognize the structure of the coronavirus main protease from your sculpture.
Mara G. Haseltine: The public is being bombarded with images of Corona Viruses depicted as round ball with stick like protrusions because of the current COVID-19 pandemic . In addition, for most viewers, SARS Inhibited just looks like an abstract freeze frame of whirls of flashing movement. We both know this is not the case and the armature or shape for SARS Inhibited is in fact anatomically correct based on accurate sub-molecular data- gleaned directly from your research. To illuminate your discovery, I only used just a tiny piece of this SARS virus called the “active cleft”, I purposefully made it look like it was rising out of the reflecting pool to hint at the fact that it was part of a much larger structure. Rolf can you describe what this active cleft is anatomically both in SARS virus and in fact in all Corona Viruses? How it is important for drug discovery? In other words, what are we seeing in SARS Inhibited?
Rolf Hilgenfeld: Indeed, your sculpture illustrates the structure of a key enzyme, the main protease, which is only made from viral RNA after the virus has entered the human cell. So it is not a part of the virus particle that is transmitted between people, but it is encoded in the viral RNA and it is an essential player in the process of copying the viral genome once it has entered the human cell. When your sculpture was unveiled, I was very pleased to see six stepping-stones placed in the water, which you put there to symbolize the inhibitor consisting of six building blocks we had designed and synthesized in 2003. This compound binds to the active-site cleft of the protease and blocks its action.
Mara G. Haseltine: In viruses like so many natural forms, form follows function and function follows form. This equation is something that has always fascinated me as a science-based sculptor. For the SARS-CoV, you determined the structure of that key enzyme, the protease, by using X-rays generated by an electron accelerator, a so-called synchrotron. How did your X-ray crystallography work to elucidate the shape of the SARS-CoV protease? In addition, how did it subsequently lead to your discovery of the synthetic ‘man-made’ part of this sculpture, i.e. the very inhibitor which stops the protein from replicating- and is this the same process you are now utilizing for research on COVID-19 antiviral drugs?
Rolf Hilgenfeld: In X-ray crystallography, you first grow tiny crystals (less than half a millimeter in each dimension) of the protein the structure of which you wish to elucidate. Then you travel to the synchrotron with your crystals and shoot X-rays at them. The X-rays get diffracted into tens of thousands of little X-rays, the intensity of which you measure with an electronic detector. From this data, you calculate the three-dimensional structure of your protein. This process gave us the structure of the coronavirus main protease alone, atom by atom. Next, we identified the active-site cleft in this structure and designed the inhibitor. So the bronze “ribbons” in your sculpture symbolizes the chain of amino acids building this enzyme and the stepping-stones is the inhibitor. You have to use an abstraction for the amino-acid chain, because if you displayed all atoms of the enzyme, you would see nothing in the end.
Mara G. Haseltine: The current COVID-19 pandemic — and one could argue all pandemics — put humanity’s relationship with nature into sharp focus. My goal with SARS Inhibited was to create a narrative around your discovery, not in a book or on the internet, but for the viewer to experience this discovery for themselves. I placed steppingstones between the “active cleft’ in the shape of the inhibitor, to show in a visual way how a physical object could stop viral replication. When the viewer walks on these stones in the shape of the “Inhibitor”, they are engulfed in the outsized active cleft of the virus thus the viewer metaphorically becomes the “cure’ for SARS by stopping the corona virus from replicating. In all of my work, I strive to depict the “link between our cultural and biological evolution”. Rolf, my question for you is, from a structural biologist’s point of view, is the battle depicted in SARS Inhibited, between human ingenuity and the microscopic viral world, in fact, evolution?
Rolf Hilgenfeld: Yes, it is part of evolution. These viruses are clever. When we attack them with inhibitors, they try to defend themselves. They create mutations that make them partly or fully resistant against the inhibitor. This is what happens at large scale with HIV, where treatment with a single inhibitor becomes inefficient after a few months because of the emergence of resistance mutations. Fortunately, one has learnt over the past 20 years how to counteract this drug resistance by combining several anti-HIV drugs. Coronaviruses also react with mutations against antiviral treatment, but they are less efficient in doing so compared to HIV, so one can in most cases still use the original inhibitor, even though it may have lost some of it potency because of mutation.
Mara G. Haseltine: In every epoch, humans have illustrated our own anatomy and that of the natural world. With technological invention and scientific discovery, the depiction of the natural world metamorphoses to reflect the science of and technology of the times. In addition, scientific depictions are subjectively seen through the lens of the artist’s eye. They reflect the particular interpretation, inspiration, and methodology of the artist that created them, in the fashion and ideology of the times. Two famous examples engrained in popular culture are: the sepia-toned the 15th century sketchbooks with flowing cursive of the artist, anatomist, engineer, inventor Leonardo Da Vinci; and the vastly different works of the turn of the century artist, marine biologist, philosopher and botanist Ernst Haeckel – his style meticulously draws whimsical microscopic renditions of uni-cellular Protista. Both accurately depict the natural world and its anatomy, and both are unique recognizable artistic styles.
SARS Inhibited is no exception to this rule it is both an accurate anatomical depiction and has its own unique artistic style. SARS Inhibited could not have been made without breakthroughs in modern science. I added sharp edges to the outline of the armature contrasting them with rounded compound curves and claw-like tips to depict the danger and the dynamism that this SARS-CoV poised. Proteins have no colour and are in a constant state of motion or vibration, yet I made “SARS Inhibited” is cast bronze with a brilliant red patina so it appeared in the plaza like a freeze frame of motion inspired by Chinese Ribbon dancing. My question for you Rolf: how do you think artists will depict scientific discovery that is influenced by breakthroughs in science one hundred years from now?
Rolf Hilgenfeld: Oh, that is a difficult one. It is almost impossible to predict. However, your way of illustrating it will remain valid: Your sculpture is as up-to-date now as it was in 2006 when you made it. In fact, nobody would be able to distinguish the protease of SARS-CoV that you show with your sculpture from the corresponding enzyme of the new coronavirus.
Mara G. Haseltine: As we both know because my 12-meter sculpture is based on your discovery of the active cleft in the SARS CoV, which you made in 2003, this means we had the potential to develop antiviral drugs for viruses in the Corona family nearly twenty years ago. Humanity is currently suffering greatly from a worldwide pandemic – which might have been avoided if we had developed your research earlier. I have read your interviews where you say developing a vaccine for COVID-19 could take 18 months or more. Coronaviruses could be like influenza, which though it mutates into different strains every year, we are prepared with a “tool-box” at hand to create new vaccines yearly for each strain. In addition, scientists all over the world agree future pandemics could be much worse, with death tolls in the billions, not millions like COVID-19.
On the upside, scientists are currently using the RNA sequence of SARS-CoV-2 globally, pooling this shared knowledge, to find vaccines and drugs, to fight COVID-19. Yet the fact remains we are not prepared with a vaccine or even drugs to treat COVID-19 when we could have been. The COVID-19 pandemic has captured the attention of the world many are craving change -both an end to our current pandemic and a solution to prepare ourselves for future pandemics. For this change to happen, it could be argued humanity needs a global cultural paradigm shift, so the world’s population IS protected against future pandemics. How do you envision this shift and what role will art play in the new paradigm?
Rolf Hilgenfeld: It is true that there was enough time to develop an anti-coronavirus drug between the SARS outbreak of 2003 and the COVID-19 pandemic. But that costs a lot of money and you need a pharmaceutical company to step in and perform clinical trials with the best inhibitors. We have developed our inhibitor of 2003 much further, now we have a great compound consisting of only three building blocks (three stepping-stones in your sculpture) and our collaborators have already shown that it is safe in mice (We published this work in “Science Magazine”, just last month on March 20th Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors We also showed that the compound would work against bat coronaviruses (should they spill over into the human population again) and against all kinds of other coronaviruses. But this is about how far I can go when working in academia. We are looking for a pharmaceutical company to take over now and run the long-term animal studies and the clinical trials.
The problem throughout all these years was that modern pharmaceutical industry has little interest in infectious diseases unless they are chronic such as HIV or Hepatitis C. Developing drugs against newly emerging viruses will not be profitable and our pharmaceutical industry is operating in such a way that they are responsible to their shareholders, so they must be profitable. Therefore, I think we need not-for-profit antiviral research institutes run by the state, not by private industry, to get prepared against future pandemics.
This would be a major paradigm shift, as you mentioned. Art can certainly play a role in supporting this shift. For me, it is difficult to imagine how, but I think of some Chinese illustrations, for instance, in the logo for the railways which also includes the symbol for the people, meaning that the railways belong to the people. But you are the artist, not me…