Digestive organs at 3 days development

Winning essays 2006

First prize of £100 went to Ania Kowalski of Dartford Grammar School for the essay 'Herceptin is a triumph of gene technology and perhaps a major advance in treatment of breast cancer'. This was the almost unanimous choice of the judges who were impressed with the variety of sources and the clarity and balance of the writing.

The runners up who received £50 each, were Francesca Rothkell and Nicholas Gower of the Latymer School for their essays on 'Is umbilical cord blood the answer to all our stem cell needs?'

The judges considered that two others deserved special commendation as they were almost as good as the runners up. These were:

As part of their prize the three winners also spent a day at NIMR, and saw some of the most interesting aspects of a research institute. Every entrant received a certificate recording their participation in the competition, and a copy of the latest Mill Hill Essays.

Read the winning essay

Herceptin is a triumph of gene technology and perhaps a major advance in treatment of breast cancer, by Ania Kowalski of Dartford Grammar School

We know what the media think about Herceptin: a 'miracle cure' for breast cancer; but how far is this true? In order to answer this question, it is necessary to examine Herceptin's development using new recombinant DNA technology. This can be described as a triumph, because of the triple effect of Herceptin but particularly because of its specialised targeting of cells with abnormal levels of HER2 receptors, leaving other cells untouched. The current situation also needs to be examined - the introduction of the drug's use in cancer treatment, limited to one type of breast cancer has been welcomed by doctors. However, the detrimental side effects and relatively few clinical trials prevent it from being regarded as a major advancement. Finally, we need to look to the future - into what is necessary to make Herceptin and its successors a major advancement in treatment of breast cancer.

Herceptin is the first attempt to exploit the underlying molecular causes of cancer and was developed using new genetic engineering techniques which produced a highly specific antibody (a substance produced in response to surface proteins on foreign cells in the body). In the 1980's a mouse gene increasing the likelihood of mice developing a type of breast cancer was discovered. Human epidermal growth factor receptor 2 (HER2), the human equivalent oncogene (a dominant, mutant form of the normal gene-proto-oncogene) involved in the control of cell growth and division (1) , was found to be responsible for expressing a receptor on the surface of the cell. If, for unknown reasons, multiple copies of the oncogene were produced, the receptor became "over expressed" (2) - instead of having 20,000 HER2 receptors, a breast cancer cell could have 1.5 million (3) , allowing for uncontrolled proliferation, which could cause fast growing, aggressive tumours (4) . The search was now on to develop an anti-HER2 antibody. A 'humanised monoclonal antibody' (5) called trastuzumab (Herceptin commercially), was developed using new biotechnological techniques. Earlier genetic engineering allowed transfer of a gene from one species to another and let the transformed cells produce the gene-coded protein, such as insulin production using bacteria. However, for more complex proteins, cultured animal cell hosts are needed, as bacteria are unable to process the proteins so they can function. The standard antibody procedure to produce antibodies directed against molecules within our bodies ('therapeutic antibodies') used immunised mice. To eliminate the body's immune response to reject the mouse antibody (because it is seen as a foreign agent), scientists had to develop a new technique to humanise it (modify it to make it contain over 90% human DNA sequences). The immune system produces structurally different (polyclonal) antibodies to bind to different parts of the foreign cell but Herceptin is monoclonal. This means that a large amount of identical, highly specific antibody is produced, only attaching to the HER2 receptors in cells that have dramatically more receptor proteins than normal ones (6) . This high specificity makes Herceptin particularly effective. Herceptin works in three ways. Firstly, it blocks tumour cell growth by binding to the tumour's HER2 receptors, preventing the signal for the cell to proliferate. Secondly, the drug creates a signal for the immune system using the natural killer (NK) cells, which attach to tumour-bound Herceptin and upon detection of abnormality, destroy the tumour. Thirdly, Herceptin works in conjunction with chemotherapy: when used together the drugs form a partnership (synergy) which destroys the tumour more effectively than single use of either (2) .

Currently, Herceptin has been welcomed by physicians but is not yet a major advancement: statistics are often unconvincing, based on small numbers of trials; the treatment is suitable only for one can cancer type and there are consistent negative side effects, but these are often ignored by the media. The use of Herceptin is currently approved for breast cancer which has spread (metastasised), an aggressive form accounting for 20-25% of all breast cancers - it has strong HER2 expression (HER2+) (2) . Tests exist for HER2+ cancer: immunohistochemistry(IHC) testing detects high levels of HER2 receptors while fluorescence in situ hybridisation (FISH) detects multiple copies of the HER2 oncogene (7) . However, doctors are still cautious. Herceptin has been prematurely proclaimed as a "cure for breast cancer" despite there being only three clinical trials, in total involving 6,500 women, only 20% of the women diagnosed with breast cancer each year in the UK (8) . The results, that for early-stage HER2-positive breast cancer, Herceptin with chemotherapy could decrease the rate of cancer recurrence by '50% compared to chemotherapy alone' (3) was exaggerated, which headlines of ' "Breast Cancer Deaths Cut in Half by a Drug" ' (9) demonstrate. The findings were wrongly interpreted as relating to reduction of breast-cancer related deaths, the true figures for which are only 0.5% (9) . In the only trial of absolute survival rates, the control group had 2.2% mortalities contrasted to 1.7% in the Herceptin group (9) . These differences are relatively small compared to the detrimental side effects: heart damage in 4.1% of patients and 40% of patients experiencing symptoms such as vomiting, pain and diarrhoea (1) .

Before Herceptin can be heralded a major advance in the treatment of breast cancer, it is necessary to look to the future to decide what further research is needed to make this judgement. So far, there have been no formal drug interaction studies done for trastuzumab (5) , which would enable physicians to gauge long term impact. Further clinical trials are necessary to increase reliability of statistics used in the media. Further research is also planned into combining Herceptin with other cancer treatments such as radiation (1) - this could increase Herceptin's suitability for other forms of breast cancers. Research has discovered that HER2 forms part of a complex signalling pathway that involves four 'HER' family members, but future studies are needed to discover the relationship between these receptors, especially HER3 and HER4 which are suspected to play a role in breast cancer and other cancers.

It is evident that Herceptin is a triumph of gene technology - its production has developed new techniques, such as humanising, which is used in other drug development. As a first attempt at exploiting the underlying molecular causes of cancer, a path for future research has been laid and could yield exciting results. Doctors have welcome Herceptin as a new treatment but the initial research from clinical trials has often been grossly misinterpreted in the media. In reality, there is still concern: the detrimental side effects reported with the drug's use, especially heart damage. The drug's long term future and impact on advancing cancer treatment is dependent on further research: the possibility of related HERs being closely linked by a signalling pathway has founded new research, which bodes well for future development of cancer treatment.

References:
  1. www.herceptin.com/herceptin/patient (March 2006)
  2. www.cancernet.co.uk/herceptin.htm (March 2006)
  3. www.aacr.org/page5566.aspx (March 2006)
  4. www.envirocancer.cornell.edu/Glossary/GL.index.cfm (March 2006)
  5. www.gene.com/gene/products/education/oncology/herpathway.jsp (March 2006)
  6. Paterson , A (April 2006) Biological Sciences Review, Volume 18 Number 4
  7. www.advanced.org/publicdocs/casestudy_her.htm (April 2006)
  8. www.statistics.gov.uk/cci/nugget.asp?id=575 (April 2006)
  9. Moss, R ( 4 March 2006 ) NewScientist, Number 2541

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