Biotechnology: the second Cuban revolution

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Over the last 20 years, Cuba has invested heavily in biotechnology centres, which might make the island economically competitive despite the worst efforts of the US administration. Michael Gross investigates.

Cuba is well-known for its cigars, rum and revolutionaries, and as an increasingly popular tourist destination. Over the last 10 years, it has also become a major focus of research and development in biotechnology. While the leaders of the Cuban revolution have emphasised the importance of education and science from the beginning, there are two more recent developments that are generally credited with triggering the rise of Cuban biotech. In the early 1970s, the protein family of the interferons made headlines as a potential miracle cure both for cancer and viral diseases. Then, in 1981, Cuba suffered a severe outbreak of dengue fever, which infected over 300 000 people and killed more than 150.

Following these events, Fidel Castro visited research institutes in Moscow and swiftly decided to send Cuban scientists to the Soviet Union to learn the essential techniques of genetic engineering, so they would be able to set up interferon expression in recombinant bacteria. Interferon production was the nucleus from which an entire cluster of advanced biotech institutes, the so called Polo Cient?fico (scientific pole), grew.

Since then, the Cuban capital Havana has developed two very different faces. On one side, there is the city centre with the crumbling colonial style buildings and classic cars that have miraculously survived half a century, familiar to many as the picturesque backdrop of movies like Buena Vista Social Club. Just a couple of kilometres west of the Buena Vista district, however, there are dramatically different sights to be seen: a whole cluster of state-of-the-art research centres in modern, purpose-built developments.

One of the research institutes is the Centro de Inmunolog?a Molecular (CIM), built 10 years ago. Its central control room could easily serve a nuclear power station. It reveals at first glance that the centre is involved in large-scale production as well as in research. It currently produces several kilograms of monoclonal antibodies per year, and is soon to step up to more than a kilogram per month. (Current market prices for monoclonals are around ?300 per milligram - do the maths on your own!) This is in addition to the growth factors, vaccines, and other drugs that are being produced. While the first consideration is always the supply of affordable drugs for the pioneering Cuban health system, some products are sold commercially, such that the centre is already funding its own research.

On the research front, collaborations with European and Canadian laboratories are bearing fruit. Earlier this year, the centre, in collaboration with researchers at the technical university of G?teborg, Sweden, has published a crystal structure of the mouse antibody 14F7, which has been proven to be efficient in the therapy of melanoma and breast cancer. The group of bioinformaticists at CIM, led by Ernesto Moreno, contributed a prediction of the molecular details of antigen binding to this study.

CIM is just one of around 20 high-level research centres in the neighbourhood of Playa. There is also the Centro de Ingenier?a Gen?tica y Biotecnolog?a (CIGB), which was founded in 1986 as the first of the ’new generation’ research centres. It employs around 400 research staff and has developed several new vaccines, both for human and animal use. One of the key research areas is the expression of drug proteins in plants such as tobacco. This production method promises very high yields, but for the production of glycosylated human proteins (eg antibodies) the plant has to be engineered to ensure that it can produce the human-like glycosylation pattern. The centre also has research groups in proteomics and bioinformatics and has incorporated the former Centro de Investigaciones Biol?gicos (CIB), which in the 1980s hosted the first interferon production mentioned earlier.

One of the smaller research centres in the Playa area is the Centro de Qu?mica Farmac?utica, which is housed in a picturesque former monastery. It has over 60 researchers, who are exploiting the rich biodiversity of the Cuban flora to identify new natural products and develop them into drugs, diagnostics, and nutriceuticals. Unlike some of the larger institutes, it does not include production facilities, but leaves the late stage development and commercialisation to the local biotech companies. The most widely used product originating from this institute is the antioxidant Vimang which is produced from mango trees and is available in various formulations including creams and food supplements.

There are a number of other research institutes in Havana. These include the Centro Nacional de Investigaciones Cient?ficas (CENIC), which was founded in 1965. Since the foundation of the newer biotech centres, CENIC is more focused on education and training of researchers, along with providing analytical services. It has divisions covering biomedicine, chemistry, bioengineering, and electronics.

The Instituto Nacional de Medicina Tropical Pedro Kouri is another of these institutes. Originally a part of the university’s medical school, this institute moved to modern facilities in the western suburb of Marinao in 1993, and restructured its research in tropical medicine to include medical microbiology and epidemiology.

Right in the charming though crumbling centre of the capital, in the Vedado quarter, there is the campus of the University of Havana, which was founded by Dominican monks in 1728 and is thus one of the oldest universities in Latin America. Today, it teaches around 30 000 students covering the full range of university subjects.

For researchers at the universities, cash flow is more restricted than for those at the top-notch research centres. The key survival skill for any university researcher, therefore, is to find research fields that can yield maximum amounts of useful results at a minimal cost. Chemist Roberto Cao, a bioinorganic chemistry professor at Havana University, admits that he chose cyclodextrins (a kind of sugar made up of small rings of six, seven or eight glucose units, enclosing a hydrophobic cavity under one nanometer in diameter) for his research mainly because they are affordable. But that doesn’t stop them from being versatile and useful. Together with his colleague, Reynaldo Villalonga at the University of Matanzas, Cao has developed a surprising range of different applications for molecular constructs based on cyclodextrins.

The researchers have already developed a range of electrochemical sensors based on the self-assembly of cyclodextrin monolayers on electrode surfaces. Due to the molecular recognition properties, such sensors can discriminate substances that would otherwise give similar electrochemical signals, eg dopamine from ascorbic acid, or different isomers of nitrophenol. Cao’s group is now hoping to build a sensor (and possibly a scavenger) for nitric oxide (NO), which would be extremely useful for treating septic shock, a dangerous condition in which NO overproduction ultimately leads to collapsing blood pressure.

Cao’s collaborator Villalonga has started from cyclodextrins and branched out into protein research and even nanotechnology. When he was appointed professor at the University of Matanzas, Villalonga had only one analytical instrument, namely a UV/VIS spectrometer. Wondering what research he might be able to do with this, he arrived at the conclusion that enzymology would be the best option, so he went on to study enzymes modified with cyclodextrins.

Now he employs a dozen researchers in six different research projects, including the stabilisation of enzymes by attachment of non-natural sugar chains (neoglycoenzymes) or artificial metal binding sites. Supramolecular chemistry has shown that cyclodextrins are suitable host molecules for adamantanes. Villalonga has used this principle to couple proteins to each other, forming three-dimensional nano architectures.

Given the country’s economic difficulties, every researcher in Cuba starts from the question: which resources are available at a reasonable price, and how can I use them in an optimal way to benefit society? For example, Carlos Mart?n at the university of Matanzas investigates the production of bioalcohol (as a fuel) from bagasse, which is a waste product resulting from the production of sugar from cane. Meanwhile, Gerardo Gonz?les Oramas is trying to trick the agave plant, from which sisal fibres are made, into shorter reproduction cycles, which would allow biotechnologists to breed mutants and use the plant in many other applications.

Everybody seems to have a clear sense of purpose with their research. At the Centro de Biomateriales, an interdisciplinary research centre at the University of Havana, the focus is on developing new materials that are compatible with human tissues and can be used in surgery or implants. Under the trademark BIOMAT, the centre currently has five different commercial products, including hydroxyapatite beads for bone restoration and tissue adhesives for human and veterinary use. The pipeline of products in advanced development contains another five products. Some of the products are also earmarked for export to developing countries. In the long term, the centre will also introduce some of them in the European market, but, as Rub?n Alvarez points out, ’the application involves 170 steps and can take up to five years until it is approved’.

The University of Havana campus also boasts an interdisciplinary research centre for materials sciences. It was originally set up in 1985 with the aim of developing materials for electronics, but as it became clear that Cuba could not compete with the explosive growth of the computer industries in the US, the centre shifted its focus to laser-based technologies mainly used for medical applications, explains deputy director Ernesto Estevez. For example, it has developed a device that can take blood samples without touching the patient. Staff members in the university’s physics and chemistry departments, and the centre’s own staff each contribute about one third to the centre’s research, which also covers areas like zeolite-based systems for the controlled release of drugs or vitamin formulations and biostimulators, which are designed to improve nutrient uptake in plants in a catalytic fashion.

One of Cuban science’s most sensational recent success stories comes from the university’s laboratory for synthetic antigens, where a team led by Vicente Verez has succeeded in creating the first fully synthetic vaccine that is fully effective (see Chemistry World September 2004, p19). This research is typical for Cuban science in that it arose from a very specific domestic need. Since the late 1980s, a vaccine against the meningitis pathogen Haemophilus influenzae B (HiB) has existed, but, as Verez explains, ’it is only a vaccine for the rich countries’. With a cost of well over $10 (?5) per child, the established vaccine is out of reach for most of the world’s children. According to UNICEF, only two per cent get immunised, and half a million children under five die from HiB infection every year.

Verez’s lab set out in 1989 to develop a vaccine that would be affordable for Cuba. After the clinical trials conducted in collaboration with Canadian researchers showed the vaccine to be fully effective, the Cubans now have a developing world blockbuster drug on their hands. The global demand is estimated at around 500 million doses. The Cuban biotech industry has started production and is planning to make 50 million doses by the end of this year. Global coverage will however require additional production sites on other continents, such as in India.

This example illustrates the paradoxical advantage of having advanced biotechnology centres in a poor country. Whatever Cuban scientists develop for their domestic market is at the same time likely to benefit the over five billion people in the world who simply cannot afford most drugs sold by the pharma companies of the rich countries. Even if these customers cannot pay very much, they still represent a huge export market for a small country like Cuba.

For the first time in its history, the cash cows of tourism and biotechnology offer Cuba the prospect of becoming independently viable and economically competitive. Now this is exactly the kind of outcome that the US administration wants to avoid at all costs. Earlier this year, it tried to stop scientific journals from publishing papers by Cuban researchers. With the indomitable spirit of Asterix’s fight against the overwhelming power of the Romans, many researchers in Cuba laughed at the foolishness of such mean tricks. Eventually, it became clear that such a measure would breach the US constitution and the government quietly backed down. More surprisingly, it even approved a licensing deal between the Californian company CancerVax and the Cuban CIMAB (CIM’s commercial branch), under which the US company will carry out clinical tests for several Cuban vaccine candidate substances (Chemistry World, September 2004, p7).

A continuing and serious threat to Cuban research, however, are the impediments to buying vital equipment. Everybody has such a story to tell. Typically, a Cuban scientist would have ordered a scientific instrument from a European supplier, and it all went well until one day the contacts went cold and the shipment never arrived. Only after prolonged pestering would the researcher be able to get in touch with a highly embarrassed executive who would say something along the lines of: ’We are very sorry but it has turned out that a US company holds a patent on the design of the fuse used in this instrument, so if we sell you one of them, they will withdraw our licence to use that fuse.’ Cuban scientists still find channels to buy the equipment they need, but it is often a time-consuming and frustrating experience.

The second significant worry for the otherwise infectiously cheerful scientists on the island is internet access. As a tourist paying in hard dollars, you can comfortably access the internet from your hotel via satellite. Most university researchers, however, have to rely on what little bandwidth there is in the terrestrial connection to the rest of the world. The internet consortium insists that Cuba’s connection must go via Florida, US, ruling out politically less troublesome alternatives like Mexico. ’There is a cable to Florida, but it is thinner than my little finger, more like a hair,’ explains Sergio Pastrana, the foreign secretary of the Cuban Academy of Sciences, ’so the necessary bandwidth just isn’t there’. And that results in extremely slow and unreliable connections - an ordinary web page without heavy graphics may take five minutes to load or may in fact never arrive. Thus, there is a serious bottleneck in the information flow (books and journals are also scarce for currency reasons), which could be easily fixed with a bit of fibreglass cable, if the blockade were to be abandoned.

President Bush, if he achieves a second term is, of course, not going to make things better. In May, his government further restricted the amount of cash that Cuban Americans can send to their families back home. This summer, the US government has installed further measures aimed at reducing the cash flow from tourism, reducing the visits of expats to one week every three years, and threatening severe punishments to US citizens caught travelling to Cuba. His opponent, John Kerry, has criticised these measures and argued for a softer kind of pressure to be applied by the international community in order to encourage gradual democratic change.

The country’s success in biotech may help to defuse the conflict. In a few years from now, the whole world - minus US citizens - will be able to buy innovative and cheap pharmaceuticals made in Cuba. Future US presidents may find that reason enough to reconsider their country’s policy.

Acknowledgements

Michael Gross is science writer in residence at the school of crystallography, Birkbeck College, University of London. He can be contacted via "the prose and the passion" website.