Dr David Brown works at the department of Biochemistry at the University of Cambridge. Dr Brown has researched the way in which metals bind to prions, and believes that the balance of copper and manganese in the environment can contribute to the onset of both BSE and CJD. He believes that metal balances can cause prions to 'flip' in cows and humans independently, and that BSE does not necessarily cause CJD.

Could you summarise the BSE/ vCJD story?
The discovery of the disease scrapie and its parallels with vCJD suggested that perhaps scrapie was transmitted to humans by a virus, and so there was a lot of work to try and find a virus that could transmit a disease between sheep and humans. However, after many years of research nobody was able to find a virus and it was hypothesised by numerous people that perhaps there was no virus and there was no DNA associated with the transmissible agent. And so Stanley Prousner suggested that it could be in fact the protein that transmits the disease, and so much work was spent looking to see how a protein could cause these diseases. And it all boiled down to conversion of a normal protein into an abnormal protein, and this abnormal protein then could then lead to the disease.

Do you believe vCJD is caused by BSE? If not, why not?
I don't believe that vCJD is caused by BSE. There is good evidence that these diseases are very similar, but it is based on research involving infecting mice with extracts carrying the BSE agent or the vCJD agent and then looking at pathology in the mice. And this evidence suggests that the diseases are very similar, but doesn't actually prove one caused the other. One example of evidence of transmission is that of kuru in Papua New Guinea where humans ate the brains of other humans and then developed a disease from that. But that seems to be the exception and there's no proof that BSE or vCJD occur that way. Any evidence is based on a lot of circumstantial statements, such as that the outbreak of BSE preceded vCJD by some period of ten years, which although is true is a bit misleading because the incubation period - the time at which a person has the disease but doesn't show any symptoms - is much, much longer in humans than it is in cows. This implies that probably the first people with vCJD were developing the disease at the same time the first cows had BSE.

Are there experiments that would prove the link?
Unfortunately it's a very difficult thing to prove that BSE caused vCJD because you basically have to infect humans. Even if you could do that it wouldn't necessarily prove it, it would simply prove that you can infect humans with BSE. We would have to see once we had eradicated BSE that vCJD disappeared, and that's going to take 40 or 50 years, even if we eradicated BSE now.

Could you explain your theory that transition metals cause the diseases?
Our work has focused on the ability of metals to bind to the prion protein. The prion protein exists in 2 forms - it exists in the form that occurs normally in the brain and is therefore good and a healthy thing to have, and the abnormal form which is associated with the disease. We've been investigating the differences between these forms and we've found that the normal form binds copper that appears to be necessary for its normal function. However, we know the abnormal protein isn't broken down as readily as the normal protein, and builds up to high levels. So studying the brains of animals with the diesease we have high levels of the abnormal protein but low levels of copper, implying that it doesn't bind copper. What we've done in the lab is to investigate this further by looking for other metals which bind to the prion protein.

We've found that manganese can also bind and it will cause the normal protein to flip into a different structure which is more like that of the full found disease. So we are hypothesising that manganese can substitute for copper and this will lead to conversion of the protein into the abnormal form found in the disease.

It's uncertain yet as to whether the metals directly cause the disease or whether it's the imbalance of the metals. What is important is that anything which will increase the base levels of prion protein expression will make you more susceptible to the disease, because the central event in the disease is conversion of the normal prion protein to the abnormal form, so if you add more normal protein then there's a higher chance you'll generate the abnormal form. And if you have more protein you would also be more likely to incorporate manganese, possibly there would be insufficient copper to occupy all the sites on the high levels of prion protein that you have. So, it could be that another factor somehow is also necessary for the manganese to lead to disease.

Does this mean there is not necessarily a link between the animal and human forms of the disease?
The implication of this is that our hypothesis provides a model by which both BSE and vCJD would be caused by exposure to manganese, and something else possibly, that would lead to the change in humans and cows. Therefore there would not need to be a link between the two. One other thing about this is that if there's a common cause to both diseases then they would have a common pathology, which is what is found. It's theoretically possible that if you eat infected meat then if you have a disbalance in metals that this could lead to disease. However, the problem remains that we still have no evidence that meat will carry the infectious agent or that people when they eat infected meant or BSE-carrying meat that they will develop the disease from this.

So the advice to stop eating beef was a mistake?
I think the government's actions in regards meat and bringing in restrictions was a sensible move at the time because we had no evidence one way or the other what was causing the diseases, and it was far better to be safe than to be sorry. So if it really turns out to be that beef if the cause - which I greatly doubt at the moment, but certainly the possibility remains - I think it's appropriate that the government did make efforts to improve the standard of meat that people eat. Regardless of whether it's infected or not you don't want to eat beef from sick animals.

What evidence is there for this transmission metal hypothesis?
The work of Mark Purdy is of great interest because he's gone to various places in the world to look at regions where where there is high incidence of sporadic prion diseases such as scrapie or sporadic CJD. In these regions he has looked at the soil and he has found that there is a decrease in the levels of copper and very high levels of manganese. This is important because it can influence metals in foliage and food derived in these regions and when animals graze in these regions they would have an intake of high manganese and low copper.

Could you explain why there is confusion over what causes the diseases, whether it's virus or prion-only?
The problem is that when we think about a disease we have to find where it comes from, and in most diseases which are infectious it comes from somewhere like a bacterial virus that's carried by some other animal. However, most prion diseases - or Transmissible Spongiform Encephalopathies, as they have been called - actually occur sporadically with no known infectious event occurring: something just happens in the animal's brain and the protein flips into this abnormal form and then you have disease. And most animals there is no transmission to another animal, that animal becomes sick and dies and that's the end of the story.

Do you believe vCJD to be a new disease?
My hypothesis suggests that vCJD is also a form of sporadic CJD, but whatever is the cause of this disease is new. In other words that possibly there is a slow form of disease, which is what we call the sporadic form of CJD, but there's also a new form which for some reason the disease process is accelerated and people come down with the disease at a much younger age.

  < previous   next > Page 4 of 6