cell culture forensics. s. o’brien pnas july 3, 2001 vol. 98 no. 14 7656-7658 henrietta lacks...
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Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks
Cancer: Detection and Treatment
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Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks: the source of HeLa cells
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Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks: the source of HeLa cells“During the 1970s and 1980s, as many as one in three cell lines deposited in cell culture repositories were imposters, one cell line overtaking or masquerading as another. The most notorious culprit was a cervical carcinoma line, HeLa, established by George Gey at the Johns Hopkins Medical School in 1951”
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Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks: the source of HeLa cells
An estimated $10 million of research was discredited.
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Cancer:
• is the loss of control over cell division.
• Tumors are normal cells that are dividing inappropriately.
– They stop performing their “normal” function, and are dividing repeatedly.
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A cell becomes cancerous when there are incorrect positive AND negative
signals.
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Multiple mutations are required for cancer to occur
Fig22.17
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Fig. 3 TRENDS in Ecology and Evolution Vol 21 pg 47
Balance between Longevity and Health
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Causes of mutations:
• Replication errors– Exacerbated by poor DNA repair– Limited by telomere length
• Other biological agents– Viruses– Transposons
• Environmental factors– Ultraviolet light– Mutagenic chemicals
• smoking, industrial waste, natural toxins
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Environment plays a large role in the chance of contracting cancer…
The multiethnic cohort study: exploring genes, lifestyle and cancer risk. L Kolonel, D Altshuler, B Henderson (July 2004) Nature Reviews Cancer 4, 519-527 Fig 1
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Chernobyl fireApril 26, 1986
http://video.google.com/videoplay?docid=1108163171078608385
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The Chernobyl accident was by far the largest unintentional release of radioactive material into the environment and caused widespread contamination in Europe.
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After the accident on April 26, 1986, ~116,000 people were evacuated, most from a zone of 30-km radius. That included about 45,000 people from the town of Pripyat.
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The most heavily exposed emergency workers received doses that were sufficiently high to kill them in the weeks and months after the accident.
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Chernobyl April 26, 1986
Cancer consequences of the Chernobyl accident: 20 years on J. Radiological Protection26 (2006) 127–140Elisabeth Cardis et al.
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The rapidity of increased childhood thyroid cancer in the heavily contaminated areas of Belarus, Ukraine and Russia was surprising.
4 years
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The issue of the effects on health of the Chernobyl accident has become part of the political debate over the future role of nuclear energy, which has inevitably led to dispute over the level of effects either observed or anticipated.
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After the accident on April 26, 1986, ~116,000 people were evacuated, most from a zone of 30-km radius. That included about 45,000 people from the town of Pripyat.
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For more pictures: http://www.nikongear.com/Chernobyl/Chernobyl_1.htm
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Source: US Mortality Public Use Data Tape 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.
1. Heart Diseases 710,760 29.6
2. Cancer 553,091 23.0
3. Cerebrovascular diseases 167,661 7.0
4. Chronic lower respiratory diseases 122,009 5.1
5. Accidents (Unintentional injuries) 97,900 4.1
6. Diabetes mellitus 69,301 2.9
7. Influenza and Pneumonia 65,313 2.7
8. Alzheimer’s disease 49,558 2.1
1. Nephritis 37,251 1.5
10. Septicemia 31,224 1.3
Rank Cause of Death # of deaths
% of all deaths
US Mortality, 2000
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Change in the US Death Rates* by Cause, 1950 & 2000
* Age-adjusted to the 2000 US standard population.Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.
586.8
180.5
48.160.923.7
200.9193.7
258.2
0
100
200
300
400
500
600
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
1950
2000
Rate Per 100,000
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2003 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2003.
Men675,300
Women658,800
32% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Ovary
4% Non-Hodgkin lymphoma
3% Melanomaof skin
3% Thyroid
2% Pancreas
2% Urinary bladder
20% All Other Sites
Prostate 33%
Lung & bronchus 14%
Colon & rectum 11%
Urinary bladder 6%
Melanoma of skin 4%
Non-Hodgkin lymphoma 4%
Kidney 3%
Oral Cavity 3%
Leukemia 3%
Pancreas 2%
All Other Sites 17%
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2003 Estimated US Cancer Deaths*
ONS=Other nervous system.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2003.
Men285,900
Women270,600
25% Lung & bronchus
15% Breast
11% Colon & rectum
6% Pancreas
5% Ovary
4% Non-Hodgkin lymphoma
4% Leukemia
3% Uterine corpus
2% Brain/ONS
2% Multiple myeloma
23% All other sites
Lung & bronchus 31%
Prostate 10%
Colon & rectum 10%
Pancreas 5%
Non-Hodgkin 4%lymphoma
Leukemia 4%
Esophagus 4%
Liver/intrahepatic 3%bile duct
Urinary bladder 3%
Kidney 3%
All other sites 22%
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Cancer Death Rates*, for Men, US, 1930-1999
*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.
0
20
40
60
80
100
1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995
Lung
Colon and rectum
Prostate
Pancreas
Stomach
Liver
Rate Per 100,000
Leukemia
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Cancer Death Rates*, for Women, US, 1930-1999
*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.
0
20
40
60
80
100
1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995
Lung
Colon and rectum
Uterus
Stomach
Breast
Ovary
Pancreas
Rate Per 100,000
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Tobacco Use in the US, 1900-1999
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
190019051910191519201925193019351940194519501955196019651970197519801985199019952000Year
Per Capita Cigarette Consumption
0
10
20
30
40
50
60
70
80
90
100
Age-Adjusted Lung Cancer Death
Rates*
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.
Per capita cigarette consumption
Male lung cancer death rate
Female lung cancer death rate
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Tobacco Use in the US, 1900-1999
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
190019051910191519201925193019351940194519501955196019651970197519801985199019952000Year
Per Capita Cigarette Consumption
0
10
20
30
40
50
60
70
80
90
100
Age-Adjusted Lung Cancer Death
Rates*
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.
Per capita cigarette consumption
Male lung cancer death rate
Female lung cancer death rate
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Treating cancer:• Avoid it
– Avoid mutagens– DNA repair gets less efficient as we age
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T-cells recognize and eliminate abnormal cells; such as cells with many mutations
Our immune system protects us from cancer
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P53 is activated by DNA damage
Fig 22.15
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p53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial
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Treating cancer:• Avoid it
– Avoid mutagens– DNA repair gets less efficient as we age
• Surgery– Must remove all cancer cells– Non-invasive
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Treating cancer:• Avoid it
– Avoid mutagens– DNA repair gets less efficient as we age
• Surgery– Must remove all cancer cells– Non-invasive
• Radiation– Directed at tumor; causes DNA damage
-> cellular self-destruction– Mutagenic, side effects
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Treating cancer:• Avoid it
– Avoid mutagens– DNA repair gets less efficient as we age
• Surgery– Must remove all cancer cells– Non-invasive
• Radiation– Directed at tumor – Mutagenic, side effects
• Chemotherapy– Toxins directed at rapidly dividing cells– Mutagenic, many side effects
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Chemotherapy
a rapidly dividing cell
Toxin
X X
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Normal Multi-Drug Resistance protein
MDR
MD
RMDR
MD
Rtoxin/hormone/etc
toxin/hormone/etc
toxin/h
ormon
e/etctoxi
n/h
orm
one/
etc
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Some cancers over-express MDR
Toxin
MDR
MD
R
MDRMDRMDR
MD
RMDRMDRMDRMDR
MD
RM
DR
toxin toxin
toxin toxin toxin toxin
toxintoxinto
xin
toxi
n
toxin toxin
I’m a cancer cell with over-expressing MDR. I laugh at your toxins.
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The Epigenetic Progenitor Origin of Human Cancer (2007) A P Feinberg, R Ohlsson, S Henikoff Nature Reviews Genetics 7: 21-31
Mutations continue after cancer develops
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OO
OOOO
OOO
OOCancer cell with mutation causing MDR over-production
Evolution: changes in DNA as information transmitted
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OO
OOOO
OOO
OO
OO
OOOO
OOO
OO
Applychemo-therapy
XXX
XX X XX
XX
Kills most cells.Except if some have mutation that allow them to be resistant.
Evolution: changes in DNA as information transmitted
Cancer cell with mutation causing MDR over-production
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OO
OOOO
OOO
OO
OO
OOOO
OOO
OO
O
XXX
XX X XX
XX
Kills most cells.Except if some have mutation that allow them to be resistant.
Continues to replicate
Evolution: changes in DNA as information transmitted
Applychemo-therapy
Cancer cell with mutation causing MDR over-production
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OO
OOOO
OOO
OO
OO
OOOO
OOO
OO
OO
OOOO
OOO
OO
O
XXX
XX X XX
XX
Kills most cells.Except if some have mutation that allow them to be resistant.
Continues to replicate
Tumor with cells expressing MDR
Evolution: changes in DNA as information transmitted
Applychemo-therapy
Cancer cell with mutation causing MDR over-production
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Some cancers over-express MDR
Toxin
MDR
MD
R
MDRMDRMDR
MD
RMDRMDRMDRMDR
MD
RM
DR
toxin toxin
toxin toxin toxin toxin
toxintoxinto
xin
toxi
n
toxin toxin
I’m a cancer cell with over-expressing MDR. I laugh at your toxins.
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Detecting Cancer or Types of Cancer
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Cancer Cells
Normal Cells
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A Microarray is a chip with DNA sequences (genes) bound to the surface at known locations.
It can be used to track or monitor expression of many genes.
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Tracking changes in gene expression using a Microarray
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Making cDNA from RNA
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Tracking changes in gene expression using a Microarray
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Tracking changes in gene expression using a Microarray
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Use of microarray to estimate genes likely present in malignant cancers
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Patients cancer free for 5+ years
Patients cancer spread in 5 years
Use of microarray to estimate genes likely present in malignant cancers
similar to Fig 22.19
different genes
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Fig 22.19 Microarrays can be used to get information about types of cancers
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Young (>55) Breast cancer patients
More accurate profiling of tumors results in more accurate choices of treatments. Patients with benign tumors can avoid chemotherapy (adjuvant).
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Effect of active smoking on the human bronchial epithelium transcriptome (2007)R Chari, K M Lonergan, R T Ng, C MacAulay, W L Lam, and S LamBMC Genomics, 8:297
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Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297CS=current smoker, FS=former smoker, NS=never smoked
Table 1: Subject Demographics
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Overlapping and unique genes expression
Fig 1B
Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
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Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Table 3: Reversible gene expression upon smoking cessation related to mucus secretion (genes in bold have not been previously associated with smoking)
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CABYR ENTPD8 TFF3
Fig 4AEffect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Some changes in gene expression induced by smoking are reversible
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MUC5AC GSK3B
Fig 4BEffect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Smoking can induce irreversible changes in gene expression
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Treating cancer:• Avoid it
– Avoid mutagens– DNA repair gets less efficient as we age
• Surgery– Must remove all cancer cells– Non-invasive
• Radiation– Directed at tumor – Mutagenic, side effects
• Chemotherapy– Toxins directed at rapidly dividing cells– Mutagenic, many side effects
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Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks
Cancer: Detection and Treatment