New and Exciting Information From Basic Science

Mitsuo Ochi, M.D.
Izumo, Japan

We have recently had striking news of advanced cell technology, where the telomeres of cloned cells from calves were longer than normal (Lanza et al., 2000; Vogel, 2000).

When Dolly was cloned from an adult sheep, one of the most serious concerns was that her cell age was that of an adult, i.e., her cellular clock had not been reset to zero (Wilmut et al., 1997). Dolly's age was demonstrated not to be that of a newborn but of a more mature animal by the fact that her telomeres, the "caps" at the ends of her chromosomes, were shorter than normal. Since telomeres become shorter with cell division, and the telomeres of a newborn are the longest, Dolly's cellular clock had obviously not been reset to zero.

Our hope is that this cloning technique can be applied to the production of autogenous tissue or organs, and there is a possibility that an autogenous new heart can be produced by this technique for transplantation. However, if the cloning technique is unable to reset the telomere clock to zero, an autogenous new heart will be too old for transplantation.

Tissue engineering such as the transplantation of cultured chondrocytes has been employed in the orthopaedic field since the clinical reports of Brittberg and Peterson published in the New England Journal of Medicine (Brittberg et al., 1994). Their method and results has served as an academic stimulus to orthopaedic surgeons; however, there are aspects of their method which concern us:

1. Leakage of grafted chondrocytes from the grafted site after ROM exercise, since cells in suspension are injected beneath the periosteal flap over the cartilage defect.
2. Unequal distribution of grafted chondrocytes in the three-dimensional space of the cartilage defect, since there is a possibility that graviry causes all chondrocytes to go down to the base of the defect or the same portion of the defect.

We have introduced the use of an atelocollagen gel, which has been used widely for the treatment of facial wrinkles (Ochi et al., 1998). Cultured chondrocytes embedded in atelocollagen were transplanted into a cartilage defect. Since 1996, 50 osteochondral defect cases have been treated with this procedure in our department. Apart from our and Britteberg's procedures, the most effective treatment requires the amount of cartilage resected from a non-weight-bearing site for cultivation to be as small as possible but the number of graft chondocytes to be as large as possible. This means that the promotion of the cell division during cultivation is regarded as an ideal method.

Despite the development of this excellent way of increasing the original number of chondrocytes to, for example, one million times during two weeks of cultivation, we still have one major concern: The chondrocytes cultured by this method and then grafted may function in the grafted site as hyaline cartilage for a certain period, but the telomeres of the grafted chondrocytes are shorter than those of the original and normal chondrocytes, indicating that the grafted chondrocytes are older than the original cells. Thus, there is a possibility that the hyaline cartilage formed by the grafted chondrocytes will at some point in time suddenly degenerate or break.

Lanza and his colleagues demonstrated that cells from the calves they cloned have telomeres that are longer than normal. This indicates the use of cloned cells may enable us to produce new autogenous organs or tissue, the cells of which are younger than those of the original cells, although ethical problems remain to be solved. This can be applied to new chondrocytes or new hyaline cartilage.

The future of orthopaedic treatment is deeply related to the advancement of basic research. We orthopaedic surgeons should have an astute awareness of information provided by other fields and carefully select relevant information that will lead to new avenues of ideal orthopaedic treatment.

References:

1. Lanza RP, Cibelli JB, Blackwell C, Cristofalo VJ, Francis MK, Baerlocher GM, Mak J, Schertzer M, Chavez EA, Sawyer N, Lansdorp PM, West MD. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science. 2000; 288:665-669.
2. Vogel G. In contrast to Dolly, cloning resets telomere clock in cattle. Science, 2000; 288:586-587.
3. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Canbell KHS. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997; 385:810-812.
4. Brittberg M, Lindahl A, Nilsson A, Ohisson CC, Isakson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New England J of Med. 1994; 331:899-895.
5. Ochi M, Uchio Y, Matsusaki M, Wakitani S, Sumen Y. Cartilage repair. A new surgical produce of cultured chondrocyte transplantation. Chan KM, Fu F, Maffulli N, Rolf C, Kurosaka M, Liu S, eds. Controversies in Orthopaedic Sports Medicine. Baltimore, MD: Williams & Wilkins. 1998; 549-563.