Fetal Cell Research

Background

• UNMC has invested more than $700,000 to provide for the infrastructure to develop alternative sources to the use of fetal cells in important research. An additional $100,000 was allocated in fiscal year 2003-04.
   
• In February 2002, UNMC hired a new coordinator, Betty Chin. Ms. Chin visited the Sun Health Research Institute rapid autopsy research group in Arizona in January 2003 to gain additional insight into organizing the RAP infrastructure. Since April 2002, Ms. Chin has responded to 155 potential donation calls and pre-enrolled 66 additional donors into the program.

All pre-enrolled donors have a thorough review of their medical history prior to completion of enrollment. On campus, the coordinator meets regularly with several academic disciplines and patient care programs, including Pathology/Microbiology, Neonatal Intensive Care Unit, Adult Intensive Care Unit, Pastoral Care and Acute Bereavement Team. In addition, the coordinator held preliminary discussions with a number of Omaha area hospitals and institutions.

• There are three teams of scientists and technicians involved in the UNMC Rapid Autopsy Program. Twenty members of UNMC’s Center for Neurovirology and Neurodegenerative Disorders are participating in some capacity in the Rapid Autopsy Program. These individuals have undergone extensive training.
   
• The rapid autopsy program at Duke University performed 51 autopsies over a 10-year period, or an average of five per year. Sun Health Research Institute in Arizona has the most active program, performing an average of 47 rapid autopsies annually. The high number of rapid autopsy cases at Sun Health Research Institute is due mostly to the large concentration of retirees living in Arizona.
   
• Because rapid autopsies must start within hours after death, they can take place at any time. Thus, it has been necessary to develop a 24-hour on-call schedule. When an individual dies and the family agrees to a rapid autopsy, the rapid autopsy research team needs to be on site within one hour. Each rapid autopsy procedure takes 5 to 7 hours to isolate the cells and make them viable for research.
   
• As one team member put it, "When you’re on call and a rapid autopsy opportunity becomes available, everything else in your life must be put on hold. It can be extremely disruptive." For example, this year, a rapid autopsy occurred on Halloween. In the past we performed rapid autopsy procedures on Thanksgiving and other holidays.
   
• Age is not a factor in performing a rapid (brain) autopsy.

Progress

• Since the beginning of 2004, we performed nine rapid autopsy cell isolation procedures. In addition to the rapid autopsies, three other brains were donated in 2004 by families, but for a variety of reasons were not used in the Rapid Autopsy Program. (The total provides an average of nearly two donations per month).
   
• These brains were archived in the UNMC Brain Bank and will be used for future brain research. In 2003 we were successful in performing rapid autopsies on all donations.
   
• UNMC has conducted a total of 78 rapid autopsy microglial isolation procedures since the program was first initiated in April 2000. That’s an average of nearly two per month over the last three and a half years. The breakdown by year is: 5 – 2000; 14 – 2001; 29 – 2002; 21 – 2003; and 9 – as of July 2004. Five rapid autopsies were done on newborn babies and children, the others on adults. Several potential rapid cell isolation procedures were instead converted to brain-bank donations for research due to medical issues.
   
• Of the nine rapid autopsies performed in 2004 (as of July 2004), six procedures were performed on individuals who were pre-enrolled, then transferred to UNMC from other institutions at the time of death.
   
• UNMC’s Rapid Autopsy Program will expand beyond just providing tissue for research into neurodegenerative disorders. The UNMC Institutional Review Board approved another Rapid Autopsy Program to provide cells for pancreatic cancer research. A pulmonary research group and researchers from the Ear/Nose/Throat section also obtained IRB approval for obtaining tissue for research. Unlike the neurodegenerative research program at UNMC, these research studies do not involve the use of fetal tissue.
   
• So far, UNMC’s Rapid Autopsy Program has been successful in obtaining two of the three cell types originally obtained from human fetal cells. The two cell types obtained are astrocytes and microglia. No functional neurons, the third cell type being studied at UNMC, have been obtained through the rapid autopsy procedure. Currently, no other medical center in the world has achieved this feat.
   
• Due to the success of the Rapid Autopsy Program, UNMC has been able to procure up to 95 percent of the microglia cells and 10 percent of the astrocytes required for its research.
   
• In September 2000, UNMC started obtaining its fetal cells from the Central Laboratory for Human Embryology at the University of Washington. Since then, UNMC has reduced its quantity of fetal cell specimens by approximately 40 percent. UNMC must still obtain a cell specimen from the University of Washington about every 2-3 weeks.
   
• UNMC was one of the first centers to perform a rapid autopsy on an HIV-dementia patient. This was an extremely complicated procedure involving five different regions of the donor’s brain. In essence, it was comparable to performing five different rapid autopsies. Since then, we have a performed a similar procedure on an age-matched, non-HIV individual. Several additional non-HIV-infected control donors from the hospital also donated to the program. A research paper is currently being compiled on the basis of information revealed from these comparative studies.
   
• The Rapid Autopsy Program has provided new research opportunities for UNMC scientists. It has allowed the scientists to conduct age-matched cell comparisons. In addition, it has allowed them to better study the disease process using a variety of controls and an established end-point.

Looking ahead

• UNMC Rapid Autopsy Program will continue to expand and include diverse ethnic backgrounds, HIV-1-infected subjects and younger controls as potential donors in addition to Alzheimer’s disease patients and controls.
   
• Recently, a research article from University of Texas described viable brain cell isolation up to 24 hours after death in younger donors. However, the numbers of cells were reduced. Currently, the UNMC Rapid Autopsy Program is evaluating whether this paradigm applies to elderly donors. The results of this will be confirmed after performing 6-8 donations.
   
• Two research papers are currently close to submission, one describing challenges and lessons learned from the infrastructure development of the Rapid Autopsy Program.  The second describes novel findings on the role of microglial activation in HIV-1-associated dementia. The titles of these research papers are the following:

1. Rapid Autopsy Recovery of Human Glia: Investigations of Brain Immunity and Program Development at the University of Nebraska Medical Center
2. Direct isolation of microglia from HIV-1-infected and seronegative subjects: Studies on neuroinflammatory mechanisms