Tag Archives: breast cancer

The First Decade of the Human Genome: What’s on the Horizon?

To mark the 10th anniversary of the sequencing of the human genome the BBC aired a documentary yesterday evening entitled “Miracle cure: a decade of the human genome” that can be viewed on the BBC iPlayer.  It was an enjoyable look at what has been accomplished since the famous announcement at the White House in June 2000, and while I think the program could have done with exploring some of the science in more depth, it gave a good overview and didn’t shrink from the sheer complexity of many of the questions that face scientists who are now attempting to understand the genome.

Sophie Longton holds a vial containing a gene therapy treatment that may one day cure her of cystic fibrosis. Image Courtesy of the BBC.

The program followed three individuals as they sought to understand what impact the knowledge gained from studying the genome could have on illnesses that have affected them, breast cancer, cystic fibrosis, and alcoholism, and what basic, applied, and clinical research is currently underway. The case of a woman whose breast cancer is linked to a defective BRCA1 gene turned to discussion of the potential for the development of personalized medicine – treatments that are tailored to the genetic makeup of an individual patient’s cancer cells. Animal research plays a very important role in the development of targeted therapies that can be used in personalized medicine, and an early example of this is the drug Herceptin, which is used to treat cancers that express the HER2 gene.

The cystic fibrosis thread focussed on the development of gene therapy and clinical trials now underway under the direction of Professor Eric Alton of the UK Cystic Fibrosis Gene Therapy Consortium. These gene therapy trials use lipid spheres to transport working copies of the CFTR gene – defective in cystic fibrosis – to the lungs of patients, and the particular lipid formulation used in these trials, known as  GL67A was selected after careful evaluation against other candidates, first in CF mice and then in sheep (1).  Mice models of cystic fibrosis have helped researchers to understand more about the disease and to assess therapies, but until very recently research has been hampered by the lack of a large animal model of cystic fibrosis that models the lung pathology of cystic fibrosis.  This situation finally changed in 2008 when scientists at the Universities of Iowa and Missouri produced genetically modified pigs that lack the CFTR gene and develop all the pathologies that are characteristic of cystic fibrosis in humans. This new animal model for cystic fibrosis will be very useful for evaluating the safety and efficiency of new gene therapy techniques as the science advances.

Finally the thread on the influence on genetics on alcoholism was a reminder of just how complex the interaction between an array of genetic variations and the environment can be, and that while it may be possible to identify factors that predispose an individual towards a particular condition it is often difficult, if not impossible, to identify a single cause that tips the balance. Considering the enormous damage caused to society by addiction, and the high failure rate of addiction treatment programs, there is no doubt that addiction research is a neglected area within biomedical science.  This is sad because research into the physiological underpinnings of addiction can aid the development of more effective treatment programs. Hopefully the identification of genes that predispose certain individuals to addiction will help society to realise that science can make an important contribution to solving this medical and social problem.

Paul Browne

1)       Griesenbach U, Alton EW; UK Cystic Fibrosis Gene Therapy Consortium. “Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy.” Adv Drug Deliv. Rev. Volume 61(2), Pages 128-39 (2009) DOI: 10.1016/j.addr.2008.09.010.

Herceptin: When personalized medicine and animal research meet.

Personalized medicine is very popular among medical researchers these days, and it’s not hard to see why. By tailoring treatment to fit an individual patient, for example by using information about their genetic makeup, scientists hope to make treatments more effective while at the same time avoiding or minimizing adverse effects.

Anti-vivisectionist Dr. Greek writes about personalized medicine as if one could do this work without relying on animal research at all.

For example, he writes:

When will personalized medicine become a reality?

We are already seeing it, with breast cancer being a prime example. Breast cancer treatment is now determined in part based on a patient’s genetic makeup. About 25-30 percent of breast cancer patients overexpress the HER2 oncogene, which is a gene involved in the development of cancer. The overexpression results in an increase in the replication of the cancer cells. Physicians are now able to identify which breast cancer patients overexpress HER2 and give them Herceptin, a monoclonal antibody that inhibits HER2

This is true…  but where did Herceptin come from?   Does he know?

Herceptin, a humanized mouse monoclonal antibody. Image courtesy of Andrey Ryzhkov.

The basic research that led to the development of Herceptin (Trastuzumab) goes back to work by Milstein and Kohler who discovered the potential for using antibodies to fight disease.    They developed the first methods to produce monoclonal antibodies using mice.   Both Milstein and Kohler went on to win the Nobel Prize partly for this work.

Harold Varmus (now back as Director of the National Cancer Institute) showed that disturbances in some gene families could turn the cells cancerous.  He also went on to win the Nobel Prize for this work.  Robert Weinberg subsequently discovered in rats that a mutant gene (named “neu”) encoding a tyrosine kinase promoted cancer features in cells, contributing to the development of neuroglioblastoma tumors.

Later, Axel Ullrich and collaborators at Genentech cloned the human HER2/neu gene.  Work at UCLA Dennis Slamon and colleagues showed HER2 over-expression in 25% of patients with aggressive breast cancer.

Through screening studies on monoclonal antibody candidates in vivo in mice implanted with HER-2 positive human tumors the group at Genentech then developed the mouse 4D5 (parent of Herceptin) and showed that 4D5 could suppress the growth of HER2 tumor cells as well as enhance the ability of the host immune system to kill them.   A collaboration between UCLA and Genentech then demonstrated that radio-labeled 4D5 localized to HER2-expressing tumors in both mice and human patients.

With the information obtained from animal experiments, Genentech created Herceptin by humanizing the 4D5 mouse antibody directed at HER2.   The ability of Herceptin to prevent tumor growth was then assessed in mice implanted with HER-2 positive human tumor xenografts, and the concentration of Herceptin required in the blood to achieve anti-tumor activity was determined before starting human clinical trials.

So, you see…  Herceptin was derived from a mouse antibody.

Let me repeat: a mouse antibody!

Clinical trials in humans subsequently showed the effectiveness of Herceptin to treat HER2 positive breast cancer.

Perhaps, Dr. Greek and other animal rights activists should carefully listen to the experts that were actually involved in the process of developing Herceptin (a drug he appears to thinks highly of) which, indeed, benefits so many women battling breast cancer.   A drug derived from mice, and developed in mice.

Here is what Robert Weinberg had to say about Dr. Greek’s views on research:

Dr. Greek says the silliest things, […] implying that people are not studying human tumors, and implying that the kinds of experiments that one can do in mice can be done as well in humans — truly mindless!

I couldn’t have said it better.

Dario Ringach

SR at SSR

SSR Heading

On Monday July 20th Tom Holder gave a presentation as part of the President’s Sympozium at the Society for the Study of Reproduction‘s 42nd Annual Meeting. The presentation was attended by around 500 members of the society, ranging from undergraduates up to well established professors. The talk provided suggestions on how to talk about science to those without a science background, as well the importance of speaking out. After the talk a number of members of SSR have been in contact to ask how they can get involved with Speaking of Research’s activities – a positive result all round.

SR at SSR

The rest of the conference provided an interesting overview of some of the research going on to tackle illness such as infertility, cancer and endometriosis. Animal models varied from fish and rodents, through to cattle, pigs and primates, with scientists careful to explain why their particular choice of animal was the most suitable for their particular research. GnRH (Gonadotropin-releasing hormone) agonists are a good example of the crucial role that animals have played in fighting disease in reproductive biology. After significant work with monkeys, mice and sheep scientists were able to come up with some of the leading treatments for prostate cancer, breast cancer and endometriosis – such as Leuprolide (Market Name: Viadur/Lupron) and Goserelin

You can read the abstract for Holder’s speech here.

Regards

Dave