Culture Collections

Memoirs of ECACC 

Chris Morris

 

Chris Morris was a longstanding member of the ECACC team who retired in 2017. This is a thorough account of his memories of ECACC, the path of his career and the people he has worked with along the way. 

 

Recollections of the career of Christopher Morris - written by Christopher Morris

 

My association with Porton Down, the current location of the European Collection of Animal Cell Cultures (ECACC), started at an earlier date than the inception of ECACC, and was when the site was known as the Microbiological Research Establishment (MRE), part of the Ministry of Defence. I joined MRE in 1966 after being selected for a post as a scientific officer in the Aerobiology division. So my first job in the world of science involved working with some of the most dangerous microbes known to man, at a time when there was mutual mistrust between the nations of west and east; leaving the possibility of biological weapons being used as a potential threat, if relationships broke down.

I had planned to have a career in biological sciences, so although microbiology was not a subject on my original list of possibilities, it subsequently proved an extremely valuable training when I later entered the world of cell culture, because it not only taught me aseptic technique and how to manipulate organisms in carefully controlled environments, without releasing them into the laboratory, but also because it helped me appreciate later on that they were a cell culturists greatest enemy!

After three years, I decided to undertake a joint honours degree in Zoology and Microbiology, with the intention of pursuing a career in marine biology, which had been an earlier ambition of mine; inspired by the forerunners to David Attenborough Blue Planet, namely Hans and Lotte Hass. They produced some the best television marine documentaries of the time, inspiring others to work in marine biology, and were early pioneers encouraging people to be aware of contemporary environmental issues threatening the planet. However by the completion of my degree, I had become aware of several things a) the skills I had learned at Porton, proved invaluable in modules of the course covering cell biology, and cell culture practicals, b) the emergence of exciting molecular biology techniques to understand health issues and advance medical treatments , and the subsequent use of cell lines in their study, and c) that after taking several trips on the departments oceanographic boat to collect marine samples, I didn’t have sea legs! A chance contact with my colleagues at Porton led to the offer of a new job in the new Cell Biology Unit, under Bryan Griffiths. (1972).

At the time, development of human viral vaccines was a major goal for health researchers, which included polio, rabies, Hepatitis and Rubella. In this instance, cells in culture were becoming the main substrate to grow both the virulent and attenuated strains of pathogenic viruses. Although a wide range of cell lines from species other than human could often produce satisfactory yields, the majority of countries had decided that for safety and ethical reasons to focus their development in human cell lines where possible. Unfortunately the vast majority of available human lines were either derived from cancerous tissue or considered transformed from normal healthy cells i.e. exhibiting infinite growth, even when not inducing metastases after injecting into animals. This left a very limited number of suitable characterised cell lines. The most well-known at the time were MRC-5 and WI-38; both derived from human foetal tissue. Growth was measured in population doublings (pd’s), rather than passages. This gave an accurate measure of culture capacity, and was considered to be about a maximum of 50-60 pd’s before cells entered the senescence phase. As virus yields i.e. viruses/cell, tended to be lower in these cells, and because they only grow in monolayers, (as opposed to transformed cells), maximising their numbers was critical. So the main obstacles were scale up and avoiding contamination. If you started with a seed of 2-3 million cells and all the cells undergo 30-35 pd’s, their number could reach in excess of 1x1015 cells; estimated to be enough to cover a football pitch, or equivalent to the cell mass of around 30 humans! Consequently the value of the seed ampoules was considerable as there was only a finite supply.

Many laboratories were still using glass vessels, including roller bottles for large scale culture. These were heavy, fragile and required rigorous sterilisation procedures. However plastic alternatives were being developed and could be manufactured aseptically, were much lighter (and safer) to handle and disposable.  At the same time novel designs for increasing the surface area to volume ratio were appearing e.g. thin plastic sheets rolled into a spiral and inserted into a roller bottle, microbeads in a continuously perfused culture vessel. The use of plastics over glass dramatically reduced microbial contamination and the need for antibiotics. During the period I worked in the Cell Biology Unit, I found that the aseptic techniques learned in my first job invaluable and utilising major improvements in culture media and growth factors, we succeeded in optimising the cell environment to improve cell yields. I worked with ostensibly with MRC-5 cells, testing ideas for scale up systems to increase the yield to volume ratio. We had some success, but a major constraint was maintaining a sufficient nutrient and oxygen supply in high density culture. However the burgeoning techniques of cell culture in the 1970’s were leading to new discoveries in cell genetics and molecular biology and these exciting developments were to open a new door for me.

By the end of the 1970’s I realised my career horizon was becoming limited. A chance remark from a colleague, drew my attention to a post advertised at the recently build European Molecular Biology Laboratory in Heidelberg. Two weeks after applying I received a call from Kai Simons (my eventual departmental head) late on a Friday, asking me to be in Heidelberg on the Monday for an interview! In a pre-computer era, this meant visiting a travel agent the next day, and wait for them to telephone booking agents to see what flights were available. So, after discovering that there were technical problems with the phone lines, that every direct flight on Monday to Frankfurt was booked, plus everything was closed on Sundays, getting to the interview turned out to be a very stressful experience. However the agent did get me there, even though it meant taking a connection flight via Schiphol, and that my maiden flight from Southampton to Schiphol was in a turboprop that rattled from take-off. Watching the other passengers gripping their seat rests, I learnt what ‘taking a white knuckle ride’ really meant!

I was offered a post at the EMBO laboratory (EMBL) in Heidelberg to start in January 1979, and departed from Porton for the second time. It was one of the worst winters experienced for years. Our village was snowbound for three day, delaying my start. It took another six weeks for my family to join me, due to the weather. As head of the cell culture facilities, I was now responsible for supporting researchers needing the use of the culture suites, plus lead a programme for producing QC’d cell banks for use by the research groups. The most exciting and challenging part of my post was the additional responsibility for developing techniques to optimise fusion of myelomas with antibody producing cells i.e. hybridomas technology, which had recently won Kohler and Milstein a Nobel prize for their discovery. Working in a multinational laboratory was a marvellous experience, and at a time when molecular cell biology discoveries were on the hyperbolic part of the curve, were only capped by being invited to attend a training course on the production of monoclonal antibodies, run by George Kohler in Basel (which has some great bars), and then later succeeding in producing the first monoclonal against clathrin, the conservative protein unit forming coated vesicles in eukaryotic cells. In between work I took the opportunity to see as much as possible of Europe, having developed a passion for travel when frequently visiting France, at an earlier time in my life. Heidelberg has the remains of a fabulous, somewhat gothic castle perched on the side of a hill, overlooking the river Neckar. Reminiscent of the one in the Gormanghast novel by Mervyn Peake (1950), it provided the backdrop for one of life’s memorable experiences. Imagine sitting on a warm summers evening with hundreds of people in the inner courtyard, and watching a real coach and horses entering over the drawbridge, and through the portcullis, bringing the main character for the beginning of the Student Prince operetta (by Sigmund Romberg), which is set in Heidelberg in the 1800’s. It was a magical two hours listening to the music and songs, including the famous ‘Drinking Song’.

Unfortunately after five years, because of the non-contractual nature of employment in EMBL, it was necessary to seek a new post; fortunately after returning to England the door to Porton was about to open once more. (1984)

Bryan Griffiths (now a director at the recently renamed Centre for Applied Microbiology and Research), had been in discussions with various scientific bodies about the rise in the number of organisms being filed for patents. In the case of cell culture this was mainly due to the prolific creation of hybridomas to manufacture monoclonal antibodies. Britain did not have a depository location recognised by the International Depository Authority (IDA) for cell lines to be lodged, in order to apply for a patent to protect their unique line. The then Department of Trade and Industry (DTI), was concerned many laboratories in the UK would be forced to deposit their cell lines in other countries. An agreement was reached whereby the DTI would pay for the construction of a laboratory (depository) to handle and store cells in liquid nitrogen, and CAMR would provide the site. Thus ECACC was created.

I returned to England in 1984 as the final plans for the laboratory were being approved, and was contacted by Bryan Griffiths. He outlined the opportunity for new posts and offered me the chance to join a new venture, on the basis that we would have to build up a collection of cell lines in a similar fashion to the ATCC, in order to generate income, as the patent depository income was unpredictable. The laboratory was completed that year, and once open, we started with four staff under the new head Alan Doyle and an empty shop! Fortunately a lot of ground work had already been done in contacting labs with collections of lines, and who were willing to deposit samples for availability to research labs. Eventually the collection was separated into several categories i.e. general collection, hybridomas, customer safe deposits and patented lines. The early days were challenging as we had to set up rigorous quality control criteria, agree the terms of release with the depositor i.e. some insisted that their lines for the general collection were supplied only to non-profit laboratories and were also to be informed of all recipients. To encourage deposits we contacted other researchers offering them a fully QC’d bank of their cells, plus release from the burden of supplying other researchers, if they agreed to deposit their cells with ECACC. This was sometimes of a poisoned chalice, as one of the most critical QC tests was for the presence of mycoplasma. It was generally agreed that infected lines could not be included in the collection, although a small number of labs either denied their presence was detrimental, or even that they enhanced the cells! Informing a depositor that their lines were contaminated was always difficult, especially if it was a patent deposit  as it was almost akin to informing them that someone they knew had died. Essentially they had two choices. Either they redeposited after eradicating the mycoplasma, but lose their original deposit date, or let us eradicate the mycoplasma for a fee, and if successful keep the original date. The latter service proved very popular, and was largely successful as new antibiotics were available. QC services during the first 5-6 years proved very popular and contributed a major part of income. This was largely because Biotechnology companies were being formed in rapid succession, in the belief that the new technologies promised the dawn of the ‘magic bullet’, namely that monoclonal antibodies would eradicate many of the current diseases, including cancers, because of their ability to target a specific molecule. As a consequence many of these companies used both the patent and QC services, establishing ECACC as a major service provider in the scientific community.

It is worth mentioning that although we now take it as ‘de rigueur’ that research projects today face a competitive market, and so need to take a more commercial approach to obtaining enough funding, at its inception ECACC was still in a period of transition when publicly funded projects were not encouraged to accept funding from commercial sources, in case of a conflict of interest. In this respect ECACC was a pioneer of its time. After three years we had outgrown the facilities both in the need for laboratory space and to accommodate the number of staff. Plans to double the laboratory space and create a larger nitrogen storage room were approved, but full funding was not forthcoming. We were told half the money could be available, if we could find the other half. We approached three of our biggest customers with a radical proposal. In return for a substantial deposit, (the three deposits would amount to the half we needed), we would supply a guaranteed quantity of services for a period of time. All three companies accepted the offer. However the current department responsible for Porton was not in agreement with the funds coming from commercial sources. Subsequently we learnt that they had not expected us to find the money, and because the culture collection side was of lesser interest they did not have a committed interest in our expansion plans. Fortunately we had influential friends in the scientific community, who endorsed the need for a culture collection as an essential resource for scientific research, and ultimately the full amount was forthcoming; and so the extension was finally built.

The collection of cell lines steadily increased and we passed the one thousandth accession a few years later. Expansion continued in the intervening years, with the need for ever increasing nitrogen storage to accommodate the large cell banks for the collection cell lines, and the customer cell lines held as secondary backups (safe deposits) in the event of a nitrogen failure with their primary stock. A dedicated building with failsafe systems for the tanks and nitrogen supply was located near to the original building providing 24/7 secure storage.

During those first ten years a hitherto unknown virus hit the headlines in the form of the ‘aids epidemic’. As Porton had the appropriate handling facilities and commercial companies needed large amounts of HIV to produce detection kits and possibly a vaccine, we were contracted to produce the virus. This required experienced cell culturists, so many of the ECACC staff were involved. Very little was actually known about transmission risk and anecdotal stories were confusing to say the least! Handling quantities of HIV sufficient to infect millions of people was a nerve racking experience, even with all the safeguards of a Cat 3 lab. I was glad when the work was finally completed. Normally I find handling cells in the lab quiet a relaxing occupation, as do others I know, but in this case it felt more like defusing a bomb without a diagram!

After ten years Porton’s administration was transferred to the Public Health Laboratory Service, and the budget was cut; resulting in redundancies, including my post as a Deputy Curator. Fate again proved that contacts and good friends are often more valuable in life than a string of qualifications. After a few months at Celltech, I was told about a possible vacancy in a new molecular biology laboratory in Oxford. Following some enquiries, an interview was offered. Within a week I was offered the post of Laboratory Manager at the Welcome Trust Laboratory for Human Genetics. Within the laboratory was a suite of cell culture rooms, similar to those I supervised in EMBL. The pace of my learning curve accelerated because not only had molecular biology technology moved on, so had the use of computing power to analyse data, and therefore the need to supply cell cultures for the labs.  During my time there, the speed of analysing sequencing data reduced from a months, to weeks, then a few days. I subsequently rubbed shoulders with some of the best programmers (and molecular biologists) in the world. Time moved on, and fate brought me back to Porton for one last time in 2003. Porton was about to change its department management again to become part of the newly created Health Protection Agency (HPA), and ECACC was eventually to become the focal point of a collection of Culture Collections!

ECACC had undergone a period of renaissance after my departure in 1994. The reduction of staff numbers and budgetary restrictions had put a severe strain the operating efficiency and morale. To survive it was necessary to return to the core values and focus on maintaining a sustainable income to cover running costs. By the time I returned in 2003 a new head had taken over ECACC. David Lewis had come from a commercial background and applied his experience to restoring the income generating services, whilst at the same time continuing to encourage new depositors to add their cell lines to the collections. Despite its trials and tribulations ECACC had not only survived, but was continuing to grow. It was good to reunite with some old faces, get to know some new ones and be able to contribute my experience and services once again. Some QC techniques had moved into the molecular biology age, but it was good to know that the original Hoechst staining technique to detect mycoplasma, which I had brought with me from EMBL, was still useful, especially when training staff who had never actually seen them under a fluorescent microscope.

Over the next fourteen years funding in the public sector continued to be squeezed, but fortunately the demand for ECACC’s services steadily increased, as the discoveries from cell culture research produced the eras of 3-D culture, stem (iPS) and pluripotent cells and CRISPR gene editing tools to study inherited diseases. As a result iPS cells have now become available through ECACC.

During this time a rational was forming in the HPA, that instead of some UK culture collections operating independently, they could cut costs if part of their administrative operations were undertaken at one location. It was proposed that three other collections, the National Collection of Type Cultures for bacteria (NCTC), National Collection of Pathogenic viruses (NCPV) and National Collection of Pathogenic Fungi (NCPF) should amalgamate their sales and marketing with ECACC and coordinate the operation at Porton. In 2012 Julie Russell took over as the third head of ECACC and the then HPA Culture Collections, having previously been in charge of a service department in the HPA’s Microbiology Services Division. Then a year later when the HPA became an executive agency under the Department of Health, and its name was changed to the current Public Health England (PHE), she guided the culture collections through a demanding transition period, as staff adjusted to another set of changes and the priorities and core values of the PHE. By the time I retired the collections had formed a distribution partnership with Sigma-Aldrich to market and supply cell lines, the family of five which had started ECACC in 1984 had grown into a family of around eighty, and through the years of the annual training courses provided by dedicated ECACC staff, and supported by Ian Freshney, the PHE Culture Collections have become known in the four corners of the earth!

Whilst futures are uncertain, I believe that the foundations on which ECACC was build, will survive well into the future, and although a move to another location is likely in the near future, I hope the future staff feel the same level of enthusiasm, motivation and dedication as their predecessors did. It is impossible to say how many people I have known through the fifty years of my working life, but I can honestly say they made those years both memorable and enjoyable and I thank them all for being part of my life.

 

Written by Christopher Morris

December 2017

 

 

 

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