A Talk by Professor Stephen J O'Brien, molecular biologist

by Stephen Hewitt

On Friday 14 February 2014 the Darwin college annual public lecture series continued with Professor Stephen J O'Brien speaking under the title "Plagues, populations and survival".

Professor Stephen J O'Brien

O'Brien was introduced by the Master of Darwin as a molecular biologist whose team identified the first restriction gene that imparts immunity to HIV, founder of the genome 10k project which is assembling the genomes of 10,000 vertebrate species, and someone with a 40 years career at the National Cancer Institute, including 25 years as the founder and chief of the genomic diversity lab. She also said that he uses genome sequencing to understand diseases, "as well as to inform the conservation of endangered species." She said, "He has worked on the genomes of many species including cheetahs and red pandas and, and on and on."

Two years ago he moved to St Petersburg state university in Russia where he is chief scientific officer at the centre for genome bioinformatics.

Plagues, populations and survival

Video and audio of the whole talk are available from http://sms.cam.ac.uk/media/1659105

During the introductory part of his talk, O'Brien said, "In fact, one observer mentioned to me that world pandemics seem to occur about once a generation, every thirty years or so, as is illustrated by the slide here Spanish flu 1918, polio 1950, HIV AIDS 1982, SARS 2003. There are others, but none as horrific as these."

Soon he was saying, "I'm going to tell you three stories here today to illustrate how scientists, including members of our team, have learned from taking a population, evolutionary and molecular approach to understanding diseases".

It seemed to me that O'Brien told more than three stories, and his talk was packed full of interesting information. He talked about genetic homogeneity in the cheetah immune system, corona virus and SARS, FIV, lions in Africa, HIV and a human genetic mutation called CCR5 delta 32 which can confer immunity to HIV but increased vulnerability to West Nile disease, and then about the Black Death and Yersinia pestis and smallpox in connection with CCR5 delta 32.

He started by talking about SARS and a disease afflicting cheetahs in an American wildlife park during the 1980s and how the genetic homogeneity of the cheetah immune system made it vulnerable.

He said, "I'm going to start about twelve years ago when a severe flu-like outbreak began to appear in the emergency rooms of hospitals all around er Guangdong, Nanning and Hong Kong, a devastating syndrome that defied any and all treatments. It was new to medicine, to science to people and it was called severe acute respiratory syndrome or SARS. Within nine months it traversed 29 countries and infected over 8,000 people and killed almost 800. The alarming speed and virulence of transmission was dazzling."

It stopped in May 2003 and has not surfaced much since "except for a small outbreak in the, in the, in the Middle East which is going on right now."

He said that in March 2003 several groups were working independently to establish the cause of this disease. It was identified as a virus in a group called corona viruses.

"And I remembered when I began reading about this, an an an effect that very few other people did which was an epidemic of a similar cor corona virus which took place back in the early 1980s. And it occurred in a wildlife park in Oregon and it afflicted this species the African cheetah."

He went on to say that the cheetah had been noted as exceptional among the cat species for its lack of genetic diversity, which has been measured in different ways in different studies. The cheetah was hard to breed in captivity whereas lions and tigers are easy. "One correlate of in-breeding in this particular cheetah population was that its sperm morphology had a lot of problems."

He said that the lack of genetic diversity of the African cheetah could be traced back to the late Pleistocine about 10,000 years ago when the glaciers retreated for the last time. At this time about 40 species of large mammals became extinct, including the American cheetah. "We don't know really why but they all went away and pumas even went away from North America to be re-founded by migration from South America". This meant, he said, "that endangered species which have dropped to low numbers can contain a hidden hidden curse or axe hanging over their head and the cheetah was a good example."

"But one of the things that was kind of interesting was that the immune system was also homogenised and this lead us to worry and speculate that perhaps the cheetah's genetic situation would make it er sort of more vulnerable for any infectious disease that might drop into the species. Because genetic diversity itself among the immune system is basically something that is adaptive and keeps individual populations alive when pathogens overcome the defences of the first individual. That's sort of the traditional wisdom as it were. Well no sooner had we speculated it when we saw a realisation of this horrific prediction at a wildlife park which up at that time in the early 1980s was perhaps the most successful cheetah breeding organisation in North America."

He then told the story of how two cheetahs called Tamu and Saba were brought from Sacramento to the wildlife park and started an epidemic. They were quarantined but "they had a fever and they had little twitches and they were looking a little bit jaundiced and eventually in spite of aggressive symptomatic therapy by the veterinary clinicians on site at the place the animals would collapse dehydrated and pass away. At the necropsy which is a veterinary term for autopsy their bellies were opened up and it was filled with this milky proteinaceous fluid. And this was something that the clinicians recognised because they had seen it before in other cats, particularly domestic cats as a symptom of a disease called feline infectious peritonitis Feline infectious peritonitis is caused by a corona virus, the first cousin of the of the SARS virus but distant enough and what it does is it generates a hyper-immune reaction which accumulates immunoglobulin complexes in the peritoneum this milky fluid and strangulates the tissues and the animals die."

CCR5 delta 32

Towards the end of his talk, O'Brien said, "Now a few years ago there was a paper published from a group which hasn't been repeated but uh it was an interesting result. These workers were wondering whether our hypothesis was full or wet or true so they took mice which are hyper susceptible to Yersinia and they made knockouts that is they eliminate CCR5 so they had the equivalent of a delta 32 homozygote mouse strain and a wild type strain and they infected it with Yersinia pestis. And they quantified how much infection they got with or without CCR5 and the answer was that Yersinia pestis requires CCR5 to get into these cells. That's what they reported. Photograph is taken right out of the Nature letter.

"Monty Slatkin a good friend of mine from Berkeley did some mathematical calculations and modelling and says it can't be Yersinia there wasn't enough mortality. I said are you kidding? Course there was enough mortality. He said I think it was smallpox. Smallpox how are we going to test that? This was back at the time where smallpox was being extirpated completely - completely - by the world health organisations Then along came 911. That time there were biological anthrax mailers that killed several people in the United States and all of a sudden people became a little bit more worried about bio-terrorism and deadly diseases. The two places in the world where smallpox was housed was in Russia at our centre and at CDC in Atlanta Georgia. I was working at the NIH, was housed on Fort Detrick which is has a history of being a centre of excellence for biological warfare well that's stopped but some of those guys are still there. So I found them and I says you know can we test smallpox to see whether or not it requires CCR5. If I get you blood samples from people with alternative genotypes can we infect them? He says we couldn't do this before he says but I think I can get permission. So we did. So we did the experiment and we exposed human cells to Yersinia Pes er to smallpox and here's what we found. Basically we found that the difference between the wild type, the heterozygous and the homozygous was indistinguishable. Smallpox gets into cells it doesn't care what the delta 32 genotype is.

After recapitulating some facts about CCR5 he continued: "So...we need to do the same experiment with Yersinia on human cells. We're trying to arrange it. We found some guys in Russia who worked in these spooky things and they are willing to do the experiment so we'll see what happens. Stay tuned."