Category Archives: Diagnostics

Innovation with Innocentive…

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thinking red,green and black
Image by jmsmytaste via Flickr

Got ideas that could help produce the next drug,diagnostic test or process.Could you come up with the answer to a company’s research question?
Want to some earn money for solving these problems…then this is for you..

Become a solver:
http://www.nature.com/openinnovation?moreChallenges=true

http://www2.innocentive.com/

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US Judge Rules That Gene Patents Are Invaild

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BRCA1-Gene located on chromosome 17.

BRAC1 Gene on Chromosome 17,Image via Wikipedia

In a powerful ruling a district Judge  for the Southern District of New York in the  US has ruled that patents on genes are invalid.Approximately 20 per cent of the human genome is currently subject to a patent.The judge,Robert Sweet,has overturned the patents on two genes linked to breast and ovarian cancer on the grounds that they’re not man-made, but products of nature. A company Myriad Genetics had previously patented the BRCA1 and 2 genes which were the subject of the ruling.They were charging women more than $3000 for one test for genetic mutations and banned them from getting a second opinion.

BRAC1 and BRAC2

BRAC 1 and 2 are human tumor suppressor genes that produce proteins which combine with other tumor suppressors to repair damaged DNA and destroy the cell if the DNA is unrepairable. Some inherited mutations in these genes lead to uncontrolled cell division i.e. cancer and testing for these mutations can determine the risk of contracting ovarian or breast cancer.

Court Case

The case was taken to court by the American Civil Liberties Union (ANLU) and individual breast cancer patients who argued that the patent stifled medical research.This ruling  follows much earlier rulings in Europe by the European Patent Office in 2004 which revoked Myraid genetics European patents on the BRAC1 and 2 genes ,effectively locking them out of the European market.However those patents were revoked because the charity Cancer Research UK had filed its patent on the BRAC2 gene first and the patent on the BRAC1 was deemed not ‘inventive’.

Previous Fate of Myriad Genetics Patents in Europe

The European Patent Organisation (EPO) had originally granted 3 patents on the BRCA1 gene (EP-B-699754, EP-B-705903, EP-B-705902) to Myriad Genetics. The patents, and the option by the patent holder to strictly exert its monopoly right by requesting that all diagnostic testing be done at its laboratory in the United States,evoked strong reactions throughout Europe. Several opposition procedures had been started against these patents. After oral hearings at the EPO in Munich in May 2004, the first patent was revoked due to discrepancies of about 10 DNA letters between the BRCA1 gene sequence described in Myriad’s patent, issued in 2001, and the sequence in Myriad’s original patent application on the gene in 1994.By the time that Myriad had resubmitted the correct sequence it was found that the sequence had already been openly published elsewhere-this is known as ‘prior art‘.This deemed it automatically unpatentable as inventions have to be original/ inventive to be patented.At oral proceedings in January 2005, the other two patents were also severely limited in scope.

Current Law on Gene Patents

Patents cannot be granted on things found in nature and logically you would think that genes would fall into the

nature category since they are not man-made.However, patents can be granted on gene sequences as long as these sequences are claimed in the form of ‘isolated DNA’,that is DNA which has been purified from the body.This practice is based on the view that DNA should not be treated any differently to another chemical compound and that its isolation from the body renders it patentable as it has been transformed into a different character.Supporters of gene patents look at this as getting a patent on identifying the gene and not on the actual gene.However many scientists in the genomics and molecular biology field consider this to be a ‘lawyers trick’ as it gets around the problem of patenting DNA in the body which cannot be done since it constitutes a component of ‘nature’,but which in practical terms produces the same results as if we had patented DNA in the body

Breast cancer associated protein, BRCA1.

US Court ruling

DNA is essentially the physical form of biological information,and is distinct in its essential characteristics from other chemicals found in nature. It is concluded that DNA’s existence in an “isolated” form alters neither this fundamental quality of DNA as it exists in the body i.e. in nature  nor the information it encodes. Therefore, the patents at issue which were on  “isolated DNA” containing sequences found in nature are unsustainable as a matter of law and are deemed unpatentable subject matter under 35 USC 101.

Also because the claimed comparisons of DNA sequences are abstract mental processes ,they also constitute unpatentable subject matter under Section 101

Comments

Myriad Genetics is likely to appeal this ruling so the story is far from over but its a nice step forward for research in this area.

References

Europe revokes controversial gene patent-New Scientist 2004

The European opposition against the BRCA gene patents.-Paper from Fam Cancer. 2006;5(1):95-102.

US Judge rules cancer gene patent invalid-abc.net.au

Court:Essentially All Gene Patents Are Invalid-patentlyO (patent law blog)

Human Genetics Commission

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Reveiw on Targeting of Drugs and Nanoparticles to Tumors

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Nice review in the Journal of Cell Biology on the targeting of drugs and nanoparticles to tumors.

Excerpt:

“The concept of targeted drug delivery is attractive because it recapitulates some of the advantages of topical application of drugs: high local concentration and low systemic exposure. In practice, this approach has met with some success but has not provided the hoped-for “silver bullets.” However, recent developments in the field have rekindled interest in the targeting approach. We call this mode of drug delivery “synaphic” targeting; it is also referred to as pathotropic or active targeting. Cancer stands out as a disease most likely to benefit from targeted drug delivery….”

To read the rest of the review click here.

More Information:

Video introducing  nanotechnology:

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Personalised Approach To Tackling Breast Cancer Studied

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Invasive ductal carcinoma of the breast. H&E s...

Invasive ductal carcinoma of the breast. H&E stain Image via Wikipedia

Introduction

Improving quality of life and potentially keeping the cancer under control for a longer period of time are goals of a new clinical trial at the cancer center’s TGen Clinical Research Services, a partnership of Scottsdale Healthcare and the Translational Genomics Research Institute (TGen).

“Many are living with refractory (cancer that has not responded to treatmnent), or advanced, breast cancer that has not responded or continues to grow despite standard treatments,” explains Nurse Practitioner Gayle Jameson, principal investigator.

The pilot study is supported by the Side-Out Foundation, a group founded by volleyball enthusiasts to help wage war on breast cancer.Women or men with advanced breast cancer that has progressed through three prior treatments are eligible for the trial, available in the western U.S. only.The new study, managed by TGen Drug Development (TD2), is open to a total of 25 patients at only two sites, the Virginia G. Piper Cancer Center at Scottsdale Healthcare and Fairfax Northern Virginia Hematology Oncology.

Approach

Biopsied tissue will be analyzed for unique characteristics and abnormal genes in cancer cells, which are then targeted for treatment with FDA-approved anticancer medications. “We may discover that a tumor has a gene mutation that responds to a drug not typically used in a ‘one-size-fits-all’ approach,” explains Jameson.

“What we are doing here is precisely matching a treatment to a specific type of cancer cell mutation and abnormal protein signaling pathways that may activate cancer cell growth. The patient would then be treated with one or more medications based on the information provided by the analyses.”

Researchers call the Side-Out study the “next generation of breast cancer treatment,” expanding on what was learned about molecular profiling in an earlier clinical trial at the Virginia G. Piper Cancer Center.

Results of the earlier trial, known as the Bisgrove Study, showed that molecular profiling can identify specific treatments that help keep cancer in check for significantly longer periods, and in some cases even shrinking tumors. Clinical trials at the cancer center are administered by the Scottsdale Healthcare Research Institute.

Disscussion

This is a great step forword in the whole area of personalised medicine which identifies charactertistiscs of disease that are specific to different people.These characteritics can then be targeted more accuratly using the correct medication.Although this is approach is used to some degree in many treatments e.g. identifying hormone receptive breat cancers from those that are not ,this takes that approach to a whole new level.

About TGen

The Translational Genomics Research Institute (TGen) is a non-profit 501(c)(3) organization focused on developing earlier diagnostics and smarter treatments.

Translational genomics research is a relatively new field employing innovative advances arising from the Human Genome Project and applying them to the development of diagnostics, prognostics and therapies for cancer, neurological disorders, diabetes and other complex diseases.

References:

http://www.tgen.org/index.cfm

Retrieved March 14, 2010, from http://www.sciencedaily.com­ /releases/2010/03/100311151722.htm

Other Interesting Articles:

A look at the treatment benefits of differentiating between characteristics of recurrent breat cancer from those of the original cancer :http://www.sciencedaily.com/releases/2009/03/090318211238.htm

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C-Reactive Protein (CRP) Gene Variants Not Assscoiated With An Increased Risk of Cancer

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A picture of CRP from 1B09.

A picture of CRP from 1B09.pdb made using pymol;Image via Wikipedia

Introduction

Gene variants associated with increased circulating levels of C-reactive protein, a marker of inflammation, are not associated with an increased risk of cancer, according to a brief new communication published online on January the 7th in the Journal of the National Cancer Institute.(1)

Research

The scientists,Stig E. Bojesen, M.D., Ph.D., of the Department of Clinical Biochemistry, Herlev Hospital, and Copenhagen University Hospital in Denmark, and their colleagues used a Mendelian randomization design (for more information on this see my blog post on Mendelian Randomization) to test whether four common C-reactive protein (CRP) polymorphisms were associated with increased circulating plasma CRP levels and to determine whether this increase was associated with cancer. The study population consisted of 10,215 participants in a prospective study and 36,403 participants in a cross-sectional study of the adult general population of Denmark, all of whom where genotyped for CRP single-nucleotide polymorphisms (SNPs).(1)

C-Reactive Protein

Human C-reactive protein (CRP) (a) is the classical acute phase reactant, the circulating concentration of which rises rapidly and extensively in a cytokine-mediated response to tissue injury, infection and inflammation. CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae was the first acute-phase protein to be described.(b)The protein resembles an antibody and performs several functions associated with host defence: it promotes agglutination, bacterial capsular swelling and phagocytosis, and activates the classical complement pathway through its calcium-dependent binding to phosphocholine which is expressed on the surface of dead or dying cells (and some bacteria). It is a member of the pentraxin family of proteins.(c)

Research Results

It was found that variants in the CRP gene  were associated with altered plasma levels of CRP but did not find an association between these gene variants and an increased risk of cancer. The authors write that “…although we may be able to exclude CRP per se as a cause of cancer, we cannot exclude the possibility that inflammation could lead to cancer. Also, our results do not invalidate the potential clinical use of slightly increased plasma CRP levels to predict the risk of certain cancer subtypes.”(1)

Research on C-Reactive Protein and Diabetes

Previously Eric Brunner of the Royal Free and University College London Medical School, London, and colleagues, examined the association between levels of C-reactive protein and the risk of type 2 diabetes in a paper published online in PLOS medicine in 2008.(1)

Results

Previous research had suggested that raised levels of this marker are linked with an increased risk of diabetes but it was not clear whether C-reactive protein actually caused the condition.Brunner and colleagues used Mendelian randomization to account for the effect of other variables (such as obesity, blood pressure, and socio-economic position) which might play a role in the development of diabetes.The researchers showed that levels of C-reactive protein in the blood are not likely to cause diabetes but noted that inflammation may play a causal role via upstream effectors rather than the downstream CRP.(2)

Sources:

1. Allin KH, Nordestgaard BG, Zacho J, Tybjærg-Hansen A, Bojesen SE.(2010)

‘C-Reactive Protein and the Risk of Cancer:A Mendelian Randomization Study’,available: http://jnci.oxfordjournals.org/cgi/content/abstract/djp459v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=snps+in+c+reactive+protein&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

2. Brunner EJ, Kivimäki M, Witte DR, Lawlor DA, Smith GD, et al. (2008) Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream. PLoS Med 5(8): e155. doi:10.1371/journal.pmed.0050155

3. Keavney B (2008) More Evidence Against a Causal Association between C-Reactive Protein and Diabetes. PLoS Med 5(8): e174. doi:10.1371/journal.pmed.0050174

References:

a. HUMAN C-REACTIVE PROTEIN COMPLEXED WITH PHOSPHOCHOLINE http://www.rcsb.org/pdb/explore/explore.do?structureId=1B09

b.Mark B. Pepys and Gideon M. Hirschfield (2003) C-Reactive protein:a critical update ,J. Clin. Invest. 111(12): 1805-1812 (2003). doi:10.1172/JCI18921.

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‘Junk DNA’ -Not Actually Junk?

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Animation of the structure of a section of DNA...
Animation of the structure of DNA;Image via Wikipedia

Cancer Research UK funded scientists at the University of Nottingham, led by Dr Cristina Tufarelli, in the School of Graduate Entry Medicine and Health Sciences, have found that a group of genetic rogue elements, produced by DNA sequences commonly known as ‘junk DNA‘, could help diagnose breast and bowel cancer.Their research is published in the journal genomics.


‘Junk DNA‘

‘Junk DNA‘ (or non-coding DNA) is a name given to sections of a DNA sequence for which no function has been identified,.However some ‘Junk DNA’ could function in ways that are not currently understood or be an evolutionary artifact that serves no current purpose.About 95% of the human genome has at one time been designated as “junk” .

Discovery

The researchers discovered that seven of these faulty genetic elements -known as chimeric transcripts -are more common in breast cancer cells. Five were only found in breast cancer cells while two were present in both normal and breast cancer cells.

LINE-1 Genetic Elements

These rogue genetic elements  are produced by DNA sequences named LINE-1 (L1). About 17% of our DNA is made up of recurrent sequences called L1 elements that have colonised the genome by making copies of themselves and inserting these into new locations (are capable of retrotransposition). Many scientists simply dismissed them as molecular parasites whose main focus was to further their own survival and despite often being labelled as ‘Junk DNA’  it is clear that some of these sequences have important roles in the genome, such as influencing the switching on of genes.

L1s and Cancer

L1s have a switch that can randomly turn on nearby genes.Normal cells are generally able to silence L1s with a chemicial ‘off’ switch, preventing them turning on nearby genes and thus preventing the production of rogue genetic elements.However,cancer cells seem to lack the ability to do this (they are missing the chemical ‘off switch” needed) which leads to rogue genetic elements being produced.Expression of the cancer-specific chimeric transcripts can be induced in non-malignant breast epithelial cells by the demethylating drug 5-azacytidine.

L1s-Cancer Driver or Innocent Bystander?

The next step is to confirm whether L1 elements are driving cancer, or whether the L1 transcripts found in tumours are the result of the cancer. If they are driving it, it could be possible to develop drugs t target certain L1 elements and even if they are not thye could be useful as biomarkers to diagnose and monitor cancer.

L1s and Bowel Cancer

The researchers extended their studies to look at two bowel cancer cell lines. Two of the genetic rogue elements were found in invasive bowel cancer cell lines, but not in the pre-invasive cells, suggesting that these sequences could play a role in cancer progression.

Conclusion

This research has very interesting implications as it has succeeded in learning more about cancer and the often overlooked ‘Junk DNA’ sequences.

Source:

Hazel A. Cruickshanks and Cristina Tufarel (2009),

[accessed 09 Jan 2010]

References:

Eyre-Walker A, Keightley PD (2007). “The distribution of fitness effects of new mutations“. Nat Rev Genet 8: 610–618.

Many human L1 elements are capable of retrotransposition (1997)

http://www.ncbi.nlm.nih.gov/pubmed/9140393http://www.ncbi.nlm.nih.gov/pubmed/9140393

Jumping Gense can knock Out DNA;Alter Human Genome

http://www.sciencedaily.com/releases/2002/08/020809071852.htm

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Overview of some laboratory tests used in the detection of breast cancer

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1.0. Introduction to Cancer

Cancer is a genetic disease of the cell. A normal cell transforms to a cancer cell by acquiring an estimated four to seven chromosome mutations which cause the cell to become undifferentiated and undergo tumourigenesis if the alterations confer a selective advantage to the cell. These alterations or mutations can occur spontaneously in the cell due to errors during DNA replication and/or cellular repair mechanisms. They can also be induced by mutagenic agents such as UV light and in most cases these alterations only occur in tumour cells or cells on the verge of becoming cancerous and so are somatic mutations.(1)

Alterations in three types of genes are responsible for tumorigenesis: oncogenes, tumour-suppressor genes and stability genes. Oncogenes can become mutated in ways that render the gene constitutively active or active under conditions in which the wild-type gene is not. Tumour-suppressor genes are targeted in the opposite way by genetic alterations in that mutations reduce the activity of the gene product. The third class of cancer genes called stability or caretaker genes operate in a different way when mutated. Since stability genes keep genetic alterations to a minimum, mutations in other genes occur at higher rates when they are inactivated.(5)

1.1. General Characteristic of Cancer Cells

Cancer cells differ from normal cells in a number of ways. They can operate independently of growth factors thus the cell can proliferate uncontrollably, have unlimited cell division capabilities, can acquire their own blood supply (angiogenesis), can spread via diffusion and metastasis and can avoid apoptotic cell death.(2) The metastatic process is a complex cascade of events in which tumour cells in the primary site must erode the basement membrane, penetrate a blood vessel and spread to distant sites (13)

2.0. Brief introduction to Breast Cancer

Breast cancer is the most common malignancy in women and the second-most common cause of cancer related mortality. (2)It is nearly twice as common in the first-degree relatives of women with the disease, as in the general population.(3) The breast consists of fatty tissue and lobules that are connected to the nipples by ducts. Breast cancer usually begins in a cell lining a duct or a lobule (an epithelial cell).(6)

3.0. Current Diagnostic tests for breast cancer

The goals of breast cancer testing are to identify genetic risk in people with a familial risk, to detect and diagnose breast cancer in its earliest stages, to determine the degree of metastasis if any, to evaluate the cancer characteristics in order to guide treatment and to monitor the effectiveness of treatment or detect cancer recurrences.

Table 1: Some  Laboratory Tests Used in the Detection of Breast Cancer

Test Name Principal Use: Test Sample
BRCA-1 or BRCA-2 gene mutation (7) A mutation in either gene indicates that the patient has a significantly higher risk of breast cancer (up to 80%) Used in women who could be at high risk due to a strong personal or family history of ovarian or early onset breast cancer.(However only about 5-10% of familial breast cancer cases are caused by mutations in these genes.) Blood
Estrogen Receptor/Progesterone Receptor (7,8) Estrogen and/or receptor positivity indicates sensitivity to these hormones. Increased levels suggest that patient may be good candidate for anti-hormone therapy Tissue
CA 15.3 and CA 27.29 (7,11,12) CA 15-3 and CA 27.29 are well-characterized assays that allow the detection of circulatingMUC-1 antigen in peripheral blood.(12) Not used to screen for breast cancer but can be used to follow it in patients that have been diagnosed .However low sensitivity has limited its use.(11) (FDA approved).Recommended to use in conjunction with imaging techniques and physical exams i.e. not as a standalone test(12) Blood
MammaPrint (Agendia) (10,12) Evaluates gene activity patterns in 70 tumour genes Used to predict whether a breast cancer will recur or metastasize in women with early stage cancer, who are under 61 and who have cancer-negative lymph nodes.(1st breast cancer predicting tool to get FDA approval) Tissue
DNA Ploidy (7) Determines rate of tumour cell growth (S phase) To determine prognosis and treatment guidelines: Elevated rates of tumour cell growth suggest poorer prognosis. Often indicates need for chemotherapy. Tissue
Her 2/neu (7,8) Her2/neu is an oncogene.In about 20-30% of invasive breast cancers, this gene is amplified and its protein (a growth-factor receptor) is over-expressed. Patients that have this gene amplified respond well to Herceptin (Tastuzumab) that blocks the protein receptors, inhibiting continued replication and tumour growth. Blood
Tissue Biopsy(7) Malignant cells show changes in cell shape, size of cell nuclei and evidence of increased cell division. Tissue stained using immunohistochemical techniques. Screening tool. Also used to determine if cancer is early stage or invasive. Tissue
Cellsearch System (9) Detecting elevated numbers of CTC’s in peripheral blood of metastatic breast cancer patients is accompanied by a decreased disease free and overall survival. Enriches and enumerates circulating tumour cells (CTC’s) from peripheral blood. Blood
upA +PAI1 (12) uPA (Urokinase Plasminogen Activator)and PAI-1(Plasminogen Activator inhibitor) are part of the plasminogen activating system, which includes the receptor for uPA and other inhibitors (PAI-2 and PAI-3). This system has been shown experimentally to be associated with invasion, angiogenesis,and metastasis. Used for the determination of prognosis in patients with newly diagnosed, node-negative breast cancer.  Low levels of both markers are associated with a sufficiently low risk of recurrence (especially in hormone receptor–positive women who will receive adjuvant endocrine therapy). Tissue

Bibliography:

1.Serre,J.L.,ed, (2006) ‘Diagnostic Techniques in Genetics’,Sussex: John Wiley and Sons Ltd,pgs 139-141

2.Zhong,L., et al, (2008) ‘Autoantibodies as potential biomarkers for breast cancer’ Breast Cancer Research,10(3), available: http://breast-cancer-research.com/content/10/3/R40 [accessed: 27 Feb 2009]

3. Easton, D.F., et al, (2007) ‘Genome-wide association study identifies novel breast cancer susceptibility loci’ Nature,447:1087 1095

4. Venkitaraman,A.R., (2009) ‘Linking the Cellular Functions of BRCA Genes to Cancer Pathogenesis and Treatment’ Annu. Rev. Pathol. Mech. Dis. 4:461–87

5. Vogelstein, B and K.W., Kinzler, (2004) ‘Cancer genes and the pathways they control’ Nature Medicine,10(4): 789-799

6. Breast Cancer Briefsheet,available: http://publications.cancerresearchuk.org/WebRoot/crukstoredb/CRUK_PDFs/CRBSBRC08.pdf [accessed:01 Feb 2009]

7. Lab Tests Online available: www.labtestonline.org/understanding/conditions/breast-3.html [accessed: 20 Feb 2009]

8. Ross,J.S. et al.(2007) ‘Standardizing Slide-Based Assays in Breast Cancer:Hormone Receptors, HER2, and Sentinel Lymph Nodes’ Clin.Cancer.Res., 13(10):2831-2835

9.Riethdorf,S. et al (2007) ‘Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer:A Validation Study of the CellSearch System’ Clin.Cancer.Res. 13(3):920-928

10.Ross,J.S. (2008) ‘Multigene predictors in early stage breast cancer: moving in or moving out?’ Expert.Rev.Mol.Diagn. 8(2):129-135

11. Thorat,M.A. and S.Badve (2007)’Prognostic factors in invasive breast carcinoma: Do new molecular techniques/profiling add significantly to traditional histological factors?’ Curr.Diag.Path.13:116-125

12.Harris,L. Et al (2007) ‘American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumour Markers in Breast Cancer’ J.Clin.Oncol. 25(33):1-26

13. Liotta, L. A., and W. G. ,Stetler-Stevenson,(1992) ‘Cancer: Principles and Practice of

Oncology’ pgs. 98–115. Philadelphia: J. B. Lippincott Co.

Further reading on recent discoverys in breast cancer research and general diagnostic methods e.g mammograms

http://www.technologyreview.com/biomedicine/23621/

http://www.telegraph.co.uk/health/healthnews/6261309/Breast-cancer-gene-discovery-most-important-for-20-years.html

http://www.cancer.gov/cancertopics/factsheet/Detection/breast-cancer

http://blog.oup.com/2009/11/mammography/

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