Scientists from the UK and Australia have seen the human immune system's assassin – a protein called perforin（穿孔素） – in action for the first time. The UK team, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust, is based at Birkbeck College where they used powerful electron microscopes to study the mechanism¹ that perforin uses to punch holes in rogue²（劣种，流氓） cells. The research is published today (1800hrs, 31 October) in Nature. Professor Helen Saibil, who leads the UK team at Birkbeck College, said "Perforin is a powerful bullet in the arsenal³（兵工厂，军械库） of our immune system – without it we could not deal with the thousands of rogue cells that turn up in our bodies through our lives."

"Perforin is our body's weapon of cleansing⁴ and death," said project leader Professor James Whisstock from Monash University, Melbourne, Australia.

Perforin works by punching holes in cells that have become cancerous or have been invaded by viruses. The holes let toxic⁵ enzymes⁶（酶） into the cells, which then destroy them.

If perforin isn't working properly the body can't fight infected cells. And there is evidence from mouse studies that defective⁷ perforin leads to an upsurge in malignancy（恶性肿瘤） , particularly leukaemia（白血病） , so says Professor Joe Trapani, head of the Cancer Immunology Program at the Peter MacCallum Cancer Centre in Melbourne, Australia.

The first observations that the human immune system could punch holes in target cells was made by the Nobel Laureate Jules Bordet over 110 years ago, but we have had to wait for the latest advances in structural⁸ molecular⁹ biology to find out how exactly this happens.

Professor Saibil continued "From our previous work we already knew that bacterial¹⁰ toxins¹¹, such as the one involved in pneumonia¹², dramatically change shape to punch holes in membranes¹⁴. We were fascinated by perforin and wanted to know its structure and how that might change in order for it to act as a hole-punching machine."

The structure was revealed by combining information about a single perforin molecule¹⁵ – visualised using the Australian Synchrotron – with Professor Saibil's electron microscope images, (taken in London), of a ring of perforin molecules¹⁶ clustered together to form a hole in a cell membrane¹³.

Professor Whisstock added "Now we know how it works, we can start to fine tune¹⁷ it to fight cancer, malaria¹⁸（疟疾） and diabetes¹⁹."

Another interesting finding is that the important parts of the perforin molecule are quite similar to those toxins deployed²⁰ by bacteria such as anthrax（炭疽） , listeria（李斯特菌属） and streptococcus（链球菌） , showing that this method of making holes in cell membranes is quite ancient in evolution. "The molecular structure has survived for close to two billion years, we think," said Professor Trapani.

Perforin is also the culprit（犯人，罪犯） when the wrong cells are marked for elimination²¹, either in autoimmune disease conditions, such as early onset²² diabetes, or in tissue rejection²³ following bone marrow²⁴ transplantation. So the researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute diseases such as cerebral²⁵ malaria. And with the help of a £600K grant from the Wellcome Trust they are working on potential inhibitors to suppress perforin and counter tissue rejection.

Professor Douglas Kell, BBSRC Chief Executive said "New technologies in microscopy and synchrotron experiments have opened up tremendous opportunities for molecular biologists. This is a great example where the knowledge we gain about the normal structure and function of a molecule has the potential to underpin²⁶ important developments in our health and well being."