case study Giving Birth to Someone else’s Children?
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Lesson9GivingBirth.pdf
25September/October 2007
Giving Birth to Someone Else’s Children? A Case of Disputed Maternity By Jessica Hutchison Most students have heard about situations in which the paternity of a child is ques- tioned; in a surprising reversal, in this case study, maternity is in question. Designed for an introductory biology course, the case in- volves concepts from genetics, inheritance, and the formation of pedigrees. Students develop hypotheses to explain how a mother might not be genetically related to two of her three sons, then reject these and form new hypotheses as additional data are revealed in a progressive-disclosure format.
The case Part I
“You know, Karen, something very unusual has happened here. We’ve tested your sons because they were possible donors. Your sons’ blood does not match your blood and that’s an impossibility, so they couldn’t be your children…these could not be your children.”
Karen’s hand shook as she listened to the nurse on the telephone tell her that two of her three sons could not pos- sibly be hers. She was a 52-year-old woman who was in need of a kidney transplant. She and her sons had un- dergone blood tests to determine if they were suitable donors.
The tests determined their human leukocyte antigen (HLA) genes, some of which encode cell surface recogni- tion proteins that the body uses to distinguish its own cells from foreign material. Because there are hundreds of different versions of the 200+ HLA genes, each person’s combination is almost unique. However, because these genes are located in a group on chromosome 6, they are often inher- ited together in a block known as a haplotype (see Figure 1).
Because a transplanted organ is seen as foreign tissue to a host’s im- mune system, it is important to try to
match as many of these genes as pos- sible to minimize the rejection of the new organ. The chance of matching is highest among related individuals.
The nurse told Karen that her lab report results indicated that her HLA haplotype was type 1 and 3 and that her three sons were types 2 and 5, 2 and 5, and 1 and 6, respectively.
Questions 1. H o w m a n y H L A h a p l o t y p e s
should this woman’s sons each share with her?
2. According to these data, which sons cannot be hers?
? Figure 1
Location of HLA genes.
26 The Journal of College Science Teaching
3. What are some hypotheses to explain this data? Write down as many explanations as you can, no matter how far-fetched.
4. What tests should be done next to evaluate your hypotheses?
Part II Karen sought help from Dr. Margot Krus- kall at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. Karen assured Dr. Kruskall that these were her children, conceived naturally, without the help of any reproductive technologies. Dr. Kruskall decided to rerun all the HLA tests on Karen and her sons’ blood. The tests yielded similar results. This time Karen’s husband was also tested. The tests indicated he had an HLA haplotype of 5 and 6. Dr. Kruskall also verified that Karen had a normal chromosome complement, 46 XX.
Questions 5. Make a pedigree of Karen’s fam-
ily, displaying their HLA haplotype combinations.
6. Draw a Punnett square using Karen and her husband’s haplotypes showing the possible haplotype combinations of their offspring. Determine the probability of each of their sons’ haplotype combinations and record it on your pedigree.
7. Which of your hypotheses from Part I are no longer likely, given this information, and why? Which of your hypotheses are still likely?
Part III Dr. Kruskall and her colleagues were stumped. They decided to test more of Karen’s family members. Her two brothers had haplotypes of 1 and 3 and 2 and 3, while her mother had a hap- lotype of 3 and 4. Karen’s father was deceased and could not be tested.
Questions 8. Add these data to your family tree. 9. Using what you know about genet-
ics, deduce the likely haplotype combination of this woman’s father and add it to the pedigree.
10. What do these data indicate about Karen’s relationship to her sons?
Part IV The data suggested that Karen’s three sons were related to her one brother, so they must, in theory, be related to her as well. Because the woman’s blood cells provided no match, the team of researchers decided to test some of her other tissues as well, including her hair and thyroid gland. The results are shown in Figure 2.
Questions 11. What HLA haplotypes does Karen
have in her blood? Her hair fol- licles? Thyroid?
12. What do these results indicate?
Part V Karen was a whole-body chimera, otherwise known as a tetragametic chimera, meaning she resulted from the fusion of four gametes—two eggs and two sperm (see Figure 3). Her mother released two eggs that were separately fertilized by two sperm. This usually results in fraternal twins, but in Karen’s case, these two zygotes fused into one organism. Therefore, one zygote went on to give rise to some of Karen’s cells, while the other zygote formed other cell types, giving Karen different genetic makeups depending on which cell was examined.
The results were hard for Karen to cope with. Breaking the news to her sons was the hardest part for her. “I felt that part of me hadn’t passed on to them,” she explained.
Karen ended up accepting a kidney transplant from her husband and she is now a mixture of three genotypes.
Question 13. What are the implications of the
discovery of Karen’s condition?
Teaching notes In this case study, based on a true story (Ainsworth 2003; BBC News 2003), a 52-year-old mother of three sons needs a kidney transplant. She and her sons get blood tests to determine if any of them are suitable donors. But a few days later, the woman receives a distressing phone call. The nurse informs her that based on the blood- test results she cannot be the mother of two of her three sons.
Most students have heard about situations in which the paternity of a child is questioned. Therefore, the present case study, in which maternity is questioned, should be of interest to students. The case asks students to develop hypotheses to explain how “Karen,” as she is called in this case, cannot be genetically related to two of her three sons. Through an inter- rupted, progressive-disclosure format, students develop hypotheses, then reject or revise these, and formulate new hypotheses as additional data are revealed. At the conclusion of the case, students are asked to consider the moral, ethical, and legal implica- tions of Karen’s condition.
The case was originally written to be used in an introductory biology course, but could be adapted for a course in genetics or reproductive physiology. Students should have prior knowledge of formulating test- able hypotheses, genetics, inheritance, formation of pedigrees, and basic hu- man reproduction.
Objectives Upon completing this case study, students should be able to
• formulate testable hypotheses given preliminary data,
• suggest tests to evaluate current hypotheses,
Figure 2
HLA haplotype testing of Karen’s blood, hair, and thyroid tissue.
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• interpret data to evaluate and revise hypotheses,
• draw a pedigree, given genetic information,
• use a Punnett square to predict the likelihood of a genetic combina- tion, and
• discuss the condition of the protag- onist of the case story and describe its implications.
Classroom management This case was developed to be com- pleted in two 50-minute class periods, as described below, but it could easily be done in one 90-minute class period. With some modification, it is also pos- sible teach this case in one 50-minute class period. For this case, it is helpful to have plenty of board space or flip charts for students to share their ideas with the rest of the class.
Part I (25 minutes) I have tried giving this section out on the day of the case discussion, but it significantly lengthens the time needed to teach the case and it seems to negatively affect the number of cre- ative hypotheses that are generated by student groups. Therefore, I suggest giving this section to students ahead of time and assigning them the task of reading over Part I of the case and answering the four questions on their own. You may even want to offer an
incentive to the group that generates the most hypotheses, which you can collect at the beginning of class the day of the discussion.
The day of the case, I start out by placing students in groups of three or four to share their responses to the questions, especially questions 3 and 4 (this takes approximately five min- utes). During this time, I walk around the room, listen to the different ideas in the groups, and try to draw out the quieter students to encourage them to share their ideas. I try to refrain from supporting or discrediting any hypotheses.
I then follow up the small-group discussions with a whole-class dis- cussion of the basic facts in the case (five minutes) in which I ask students the following questions: Who is this case about? What is Karen’s problem? Why were blood tests done? What were the test results?
Students have trouble with the concept of a haplotype and HLA genes. In my introductory classes, I try to emphasize that this is not the main focus of the case and that they will not be expected to understand all the concepts related to HLA genes and transplantation. This is a topic that other instructors may want to expand on more depending on the course.
I then jump into the list of ques- tions in Part I. Questions 1 and 2 are
straightforward and serve as a review of basic genetic principles (answers to the questions in this case are on the website of the National Center for Case Study Teaching in Science at www.sciencecases.org/chimera/ chimera_notes.asp). I spend more time on question 3, the students’ hy- potheses to explain the test results. As students or groups present these, I write each one on the board. I invite other students to think about each hypothesis presented, but I try not to discount any ideas (no matter how far fetched) and give them all the same weight (10 minutes).
I then go down through the list of hypotheses written on the board and ask students what could be done to evaluate each hypothesis (question 4). I write their ideas (usually consist- ing of more tests or the gathering of additional information) next to the hypotheses that they correspond to (five minutes).
Part II (15 minutes) Students are handed Part II and asked to read the short paragraph and then answer three questions with their group members. I usually allow five minutes for this. I then appoint some of the first groups done to draw their pedigrees and Punnett squares on the board. I follow this with a brief dis- cussion of questions 5 and 6 (this is a good review of basic genetics: pedi- grees, Punnett squares, probability). This is also a good time to address any student misconceptions or defi- ciencies in basic genetics knowledge (five minutes).
I then go back to the section of the board containing the hypotheses and ask students to give me their feedback on question 7—which hypotheses are still likely given the new data and which are not (five minutes). I then cross out hypotheses when the class agrees that they should be eliminated. I also add any new hypotheses that students may think of at this point.
Part III (10 minutes) Students are given Part III of the case and asked to read the short paragraph
A Case of Disputed Maternity
Figure 3
Karen is the fusion of two zygotes, each resulting from the separate fertiliza- tion of two eggs by two sperm. If this fusion had not occurred, fraternal twins would have resulted. Therefore, different parts of Karen’s body carry different sets of genetic information.
28 The Journal of College Science Teaching
and answer questions with their group members. After five minutes, I ask members of some groups (different ones this time) to add the new data to the existing pedigree on the board. I follow this with a short discussion of their additions to the board (two minutes). Some groups may not have had time to answer question 10, but I like to discuss this question as a class by crossing out hypotheses that are no longer valid (three minutes).
Most students (depending on whether they have had exposure to this topic previously) will have ex- hausted all their possible hypotheses and only have a vague idea of what is happening but have no way to explain it. It is very important in this step to assure students that they are not expected to know the answer. In the past, my students have become frus- trated at this point because we have eliminated all their hypotheses. If you are using this case in a 50-minute period, you can stop at this point and continue with Part IV the following class period.
Part IV (10 minutes) Students are handed Part IV and asked to evaluate Figure 2 with their group members (five minutes). I then discuss the data as a class, projecting Figure 2 on an overhead (five minutes). Some students may have heard of this con- dition before; I ask them to explain their ideas thoroughly, and ask other students for comment.
The test results in Figure 2 are taken from Yu et al. (2002), which outlines the analysis (polymerase chain reaction [PCR] and sequence- specific oligonucleotide-probe hybrid- ization) that was performed on Karen to determine her haplotypes. Figure 2 is not an immunoblot, but shows the results of an HLA Quick-Type kit from Lifecodes (see References).
This method uses PCR and se- quence-specific primers to amplify the segments of DNA containing the HLA genes in such a way that single-stranded DNA is produced (uses unequal amounts of forward and reverse primers). Probes on mi-
crospheres that are complementary to this single-stranded DNA are then added. If a certain HLA allele is pres- ent in the DNA and was amplified during PCR, the probe will bind to the single-stranded DNA. These probes become fluorescent when hybridized to complementary DNA and this property is used for the detection of certain alleles in the DNA of interest. Figure 2 displays these results.
Part V—Conclusion (30–40 minutes) Students are handed Part V and asked to read the text and evaluate Figure 3. This section gives an explanation of Karen’s condition and how the test results can be explained. I run this as a class discussion, making sure all students understand Karen’s condition and how it explains the test results.
I use the remaining time to exam- ine some of the philosophical, moral, ethical, and legal implications of Kar- en’s situation and ask students how they would feel if they were found to have this condition. I leave the remainder of the class period for this type of discussion, using such lead- ing questions as the following: How would you feel if you found out you had this condition? What is Karen’s genetic and familial relationship to her sons? What medical implications does this have for Karen? Does the existence of people such as Karen have any legal implications (e.g., pa- ternity tests, criminal investigations)? Instead of two female twins converg- ing, what if it had been a male and a female (see Strain et al. 1998)? What are some moral and ethical implica- tions for this case? What do you think scientists should investigate about people with this condition?
Depending on how talkative your students are, you may or may not have trouble filling the entire 40 minutes with this discussion. You may want to have information from other resources (e.g., Drexler et al. 2005; Sudik et al. 2001) ready to present to students on topics related to this case. Related topics such as polyploidy and mechanisms that prevent polyspermy may also be brought up for discussion
if students have had an appropriate level of background knowledge (see Kenyon College website; Heiter and Griffiths 1999). You may also assign a follow-up activity that students can start working on in class.
Follow-up/extensions The activities below may be used to supplement the case study:
• Students role-play by writing a letter from Karen to her sons explaining her condition and how she feels about it. This would give students practice describing what they have learned in their own terms and gaining perspective on a unique viewpoint. They could begin this letter in class if there is any leftover time.
• Students write a response paper to the issues brought up in the case. They can comment on how they would feel if they were diagnosed with chimerism.
• Students write a paper on other aspects brought up with this case. Some possible paper topics in- clude: the various forms of chi- merism (twins, blood, whole body, mosaicism, and so on); other spe- cific cases of this condition; the oc- currence of the condition between mothers and children (exchange of cells during pregnancy); and the incidence of chimerism with in vitro fertilization (IVF) technolo- gies (see, e.g., Bonthron 2004 and Strain et al. 1998). Tell students to pretend they are researchers and come up with questions that could be investigated related to this phenomenon. What studies could be conducted?
• For an upper-division course, stu- dents could be asked about the pos- sible mechanisms for this condition (Chen et al. 2005; Niu et al. 2002). Did it occur through the fusion of two independent embryos or the fertilization of an ovum and its first polar body by two separate sperm?
29September/October 2007
Suggestions for shortening the case To shorten the case for use in a single 50-minute class period, instructors can give Part I to students ahead of time. Collect the answers to ques- tions 1–4 at the start of class and then jump into a class discussion of the answers without allowing group discussion first. Give Part V as a take-home reading assignment and assign students one of the follow-up assignments. n
Acknowledgment This case was developed with support from the National Science Foundation under CCLI Award #0341279. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.
References Ainsworth, C. 2003. The stranger
within. New Scientist 180 (2421): 34–37.
BBC News. 2003. When two be- came one in the womb. Novem- ber 13. http://news.bbc.co.uk/1/hi/ health/3264467.stm.
Bonthron, D.T. 2004. Letter to the editor. Prenatal Diagnosis 24 (7): 578.
Chen, C., S. Chern, J. Sheu, S. Lin, C. Hsu, T. Chang, C. Lee, W. Wang, and H. Chen. 2005. Prenatal diagnosis, sonographic findings and molecular genetic analysis of a 46,XX/XY true hermaphrodite chimera. Prenatal Diagnosis 25 (6): 502–06.
Drexler, C., B. Glock, M. Vadon, E. Staudacher, E.M. Dauber, S. Ul- rich, R.B. Reisacher, W.R. Mayr, G. Lanzer, and T. Wagner. 2005. Tetragametic chimerism detected in a healthy woman with mixed-field agglutination reactions in ABO blood grouping. Transfusion 45 (5): 698–703.
Heiter, P., and T. Griffiths. 1999. Poly- ploidy—More is more or less. Sci- ence 285 (5425): 210–11.
Kenyon College. BIOL 114: Animal fer- tilization and cleavage. www2.kenyon. edu/Depts/BioEllipse/courses/ biol114/Chap13/Chapter_13B.html.
Lifecodes: HLA Quick-Type kits, product insert. 2006. Tepnel Lifecodes Corporation. www. lifematchhla.com/downloads/docu- ments/PRODUCT%20INSERTS/ MASTERMIX/PI_HLAMM_RUO_ English.pdf.
Niu, D., C. Pan, C. Lin, B. Hwang, and M. Chung. 2002. Mosaic or chi- mera? Revisiting an old hypothesis about the cause of the 46,XX/46,XY hermaphrodite. Journal of Pediat- rics 140 (6): 732–35.
Strain, L., J.C.S. Dean, M.P.R. Ham- ilton, and D.T. Bonthron. 1998. A true hermaphrodite chimera result- ing from embryo amalgamation after in vitro fertilization. New England Journal of Medicine 338 (3): 166–69.
Sudik, R., S. Jakubiczka, F. Nawroth, E. Gilberg, and P.F. Wieacker. 2001. Chimerism in a fertile woman with 46,XY karyotype and female phe- notype. Human Reproduction 16 (1): 56–58.
Yu, N., M.S. Kruskall, J.J. Yunis, J.H.M. Knoll, L. Uhl, S. Alosco, M. Ohashi, O. Clavijo, Z. Husain, E.J. Yunis, J.J. Yunis, and E.J. Yunis. 2002. Disputed maternity leading to iden- tification of tetragametic chimerism. New England Journal of Medicine 346 (20): 1545–52.
Jessica Hutchison (jhutchison@cameron. edu) is an instructor of biological science at Cameron University in Lawton, Oklahoma.
A Case of Disputed Maternity
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