邓林红论文当选《科学观察》快速突破论文

　　

    根据汤姆森科技信息集团(Thomson Scientific)出版的网络版《科学观察》（http://sciencewatch.com）发布的消息，重庆大学邓林红教授2006年发表在《Nature Materials (自然杂志•材料分刊)》上有关细胞骨架动力学的论文（www.nature.com/nmat/journal/v5/n8/abs/nmat1685.html ）于2008年2月当选材料科学领域的“快速突破论文”，《科学观察》为此与邓林红教授进行了书面访谈。

    《科学观察》是全球科技信息权威来源汤姆森科技信息集团(简称汤姆森科技，Thomson Scientific)旗下专门跟踪基础科学研究发展趋势与表现的信息提供者。汤姆森科技是目前全球科技创新、知识产权发展以及医药研发等领域最权威的信息服务解决方案供应商。所提供的信息资源与服务包括著名的: Science Citation Index (SCI收录), Current Contents, ISI Web of Knowledge等。汤姆森科技专家依据其独有的《基本科学指标， Essential Scientific Indicators, ESI》数据分析统计体系，对最近取得显著进展或具有特别影响的科研领域进行引用分析和评论，筛选出覆盖面很广的22个科学领域里引用率最高的论文。这些论文构成了各领域每年前1%的顶尖论文，并且每两个月更新一次入选论文。入选论文又被分成包括“快速突破论文，Fast Breaking Papers”在内的不同专题进行介绍。其认定的“快速突破论文”不仅引用率高，而且在每两个月更新期间的引用增长率最高，因此代表了正在日益得到科学界关注的最新的科学贡献，从而被冠以“快速突破论文”。

 

    细胞骨架的动力学特性很大程度上决定了活细胞的机械特性，而这种特性又影响一系列的重要的细胞行为如：细胞迁移，细胞增殖和细胞间通讯等。尽管已经有大量的研究，细胞骨架动力学的奥秘还没有完全解开，部分原因是由于缺少公认的物理模型来解释其复杂的本质和重要特性。由于近来在贴壁细胞培养的研究中，越来越多的证据表明细胞骨架行为表现很像胶体一类的材料；而这类材料都被归入不受热能驱动的“slow dynamics”－－非线性弹性力学中新发现的一种物理现象（生物通编者注）。

    然而长期以来人们熟知的体外细胞骨架蛋白重组纤丝系统－－这个模拟模型中的动力学是受由细胞骨架蛋白构成的半弹性纤维的热力波动来驱动的。新的发现和原来的模型之间的矛盾引发热烈的争论－－两种观察结果是否仅限于特定的研究材料，是否都不能代表真实活细胞的行为。邓教授的文章里采用了新鲜分离的平滑肌细胞和贴壁培养细胞。这种刚分离的细胞无论在结构上还是在生物学特性都朝着体内活细胞靠进了一大步。结果发现在低频条件下（<100Hz）下细胞骨架表现和培养细胞类似，如同软玻璃材料，不过更加有弹性柔软。但是在高频条件下这种软玻璃行为特征则表现为转向半弹性纤丝系统的弹性行为特征。这篇文章有助于理解重组纤丝系统的弹性模型和活细胞的玻璃态这两种不同的模型之间的关系，也是首次证实以往仅在体外实验中观察到的弹性模型确实存在。由于弹性体形式仅在高频（1kHz）态下出现，而细胞常态往往远低于这种高频，因此活细胞应被看作非弹性体为主。

    邓林红教授在与《科学观察》的访谈中称，此论文首次例证了活细胞行为表现既可以像软体玻璃材料一样，也可以像半弹性纤丝构成的网络系统一样，这取决于细胞改变其形状的速度。在高速变形的时候，细胞表现为单纯的弹性体, 其物理行为完全由平衡态热力学所决定。然而在生理变形速度范围内，细胞表现为一种所谓的软玻璃态。换句话说，细胞就像玻璃在受热时改变其性状一样是，可以在受到物理或者化学变化时转变其性状，在介于固态和液态之间发生形态游移。这个重要发现有可能个彻底改变我们对生命细胞行为规律及其调控机理的认识，帮助我们更好的理解细胞在正常和病态环境下的行为表现及其在疾病发生、发展过程中的所用机制。阅读访谈全文请登陆网址或者参考本文附件：http://sciencewatch.com/dr/fbp/2008/08febfbp/08febfbpDeng/#top
需要更详细资料可直接联系邓林红教授（[e-mail] )。

 

     邓林红教授是重庆大学从哈佛大学引进的杰出人才，目前担任重庆大学“国家985工程”科技创新平台－重庆大学生物流变学与基因调控新技术研究院院长、生物医学工程国家一级重点学科的学科带头人，重庆市首批科技创新团队负责人，2008年3月当选为教育部“****”特聘教授。邓林红教授是当前国际上活跃的细胞生物力学和流变学专家，在气道平滑肌细胞的结构与功能，特别是力学功能及其在哮喘病机制方面的研究做出了杰出的贡献。除以上论文外，还在《Nature》、《Am J Physiology: Cell Physiology》等权威杂志上发表了一系列重要论文，并两次参加国际专家组撰写平滑肌力学特邀报告。

Article Title: Fast and slow dynamics of the cytoskeleton Authors: Deng, LH;Trepat, X;Butler, JP;Millet, E;Morgan, KG;Weitz, DA;Fredberg, JJ Journal: NAT MATER Volume: 5 Issue: 8 Page: 636-640 Year: AUG 2006 * Harvard Univ, Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Boston, MA 02115 USA. * Harvard Univ, Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Boston, MA 02115 USA. (addresses have been truncated)

Why do you think your paper is highly cited?

Dynamics of the cytoskeleton largely determine the mechanical properties of the living cell that influence a variety of important cellular behaviors such as migration, proliferation, and intercellular communication. Despite extensive studies, however, the dynamics of the cytoskeleton have not been fully understood, due in part to lack of a generally agreed upon physical model that can explain its complex nature and underlying mechanisms.

Recently, increasing evidence from studies on adherent cells in culture demonstrates that the cytoskeleton behaves much like soft glassy materials such as foam, slurry, and colloids. Although the physics underlying the behaviors of such materials remains largely elusive, they are generally regarded as slow dynamics not driven by thermal energy. (Ben Fabry et al., "Scaling the Microrheology of Living Cells," Physical Review Letters 87, [148102]: 2001; Predrag Bursac et al. "Cytoskeletal remodelling and slow dynamics in the living cell" Nature Materials 4: 557-61, 2005).

Figure 1: +enlarge Figure 2: Figure 3:

These findings seem to contradict what has long been known in filamentous systems formed by reconstituted cytoskeletal protein polymers in vitro—that is, that the dynamics of such cytoskeleton-mimicking systems is driven by the thermal fluctuation of semiflexible filaments made of the cytoskeletal protein (Frederick C. MacKintosh et al., "Elasticity of Semiflexible Biopolymer Networks," Physical Review Letters 75: 4425-28, 1995; Margaret L. Gardel et al., "Elastic Behavior of Cross-Linked and Bundled Actin Networks," Science 304 [5675]: 1301-05, 28 May 2004). This contradiction has been a hot debate with regard to whether each type of the observed dynamics is only true to the specific subject under study, and neither represents the behavior of real cells in vivo.

In this paper, we examined the material properties of the cytoskeleton of freshly isolated airway smooth muscle cells, using the same approach as with cultured adherent cells. These freshly isolated cells are one step closer to cells in vivo in terms of their structure and biological properties. But, how would they behave mechanically? As we characterized the material moduli of theses cells as we did with the adherent cells in culture, we found that at low (strain) frequencies (<100 Hz) the cytoskeleton still behaves like a soft glass material as those cultured cells, although softer and more elastic.

However, at high frequencies (>100 Hz), we observed a deviation from glassy behavior towards the elastic behavior associated with a semiflexible filament network. This finding was quite a surprise, and demonstrated for the first time the existence of the semiflexible filament dynamics commonly observed in vitro. Thus, our work has the potential to reconcile observations made in reconstituted cytoskeletal protein filament networks (which are usually characterized as elastic bodies) and in living cells (which behave non-elastically).

Furthermore, the finding that the elastic behavior of the cytoskeleton is observed only at high frequencies (near 1 kHz) suggests that cells may be more appropriately characterized as non-elastic bodies because physiological functions (which require deformation of the cytoskeleton) carried out by the cells normally occur at frequencies much lower than 1 kHz. This is an important conclusion. Taken together, this paper may have provided a more appropriate perspective when we treat the living cell as a complex material. I think this is why our paper is highly cited.

Does it describe a new discovery, methodology, or synthesis of knowledge?

This paper does describe a new finding that the response of the cell to oscillatory strain (0.1-1k Hz) is characterized by two distinct power-law regimes: from 0.1 to 100 Hz a very weak dependence (power-law exponent alpha = 0.05) and from 100-1000 Hz a stronger dependence (power-law exponent beta = 0.75). These are novel findings; in previous rheological studies of cells only one power-law regime had been observed over a very wide range of frequencies/times, with a power-law exponent of 0.1-0.3, and the other power-law regime with a constant power-law exponent of 0.75 had only been observed in reconstituted actin gels. Consequently, these results unify, within a single cell, two rheological models which had been used independently in the past to describe and interpret data from rheological measurements on cells.

"...this paper may help us better understand how cells behavior both in health and disease."

From a biological point of view, however, these findings suggest that the semi-flexible polymer dynamics are irrelevant for cellular functions since their influence becomes important at high frequencies (>100 Hz) which are outside of the normal physiological range. This, in turn, implies that the focus of the research in cellular rheology should be shifted from the dynamics of semi-flexible polymer networks, which had been a common approach in the past, to the soft glass rheology that is yet to be fully understood. An important by-product of this new finding is that the observed regime of entropic dynamics in the cell indirectly proved that the magnetic bead-twisting technique we used does probe the actin cytoskeleton.

Would you summarize the significance of your paper in layman’s terms?

This paper may be significant because it demonstrates, for the first time, that the living cell can behave either like a soft glassy material such as Ketchup and soft dough, or like a network system composed of semiflexible filaments, depending on how fast the cell is changing its shape. Although a filamentous network may look like the structure formed by cytoskeletal proteins both in vivo and in vitro, the mechanical behavior of such systems can be elegantly explained in terms of thermal dynamics, and only at a fast rate of shape change can the semiflexible filamentous network account for the mechanical behavior of the living cell.

Within the range of the physiological rate of shape change, the cell behaves, instead, rather like Ketchup or soft dough. In other words, the cell is neither a solid nor a fluid, but something between. What’s more important is that the cell can alter its property from solid-like to fluid-like or vice versa in response to both physical and chemical changes in its environment, much like what glass does when subjected to temperature change. All together, this paper may help us better understand how cells behave both in conditions of health and of disease.

How did you become involved in this research, and were there any problems along the way?

I become involved in this research when I joined the laboratory of Professor Jeffrey Fredberg at the Harvard School of Public Health. The group led by Dr. Fredberg had been studying the mechanical behavior of human airway smooth muscle cells in an attempt to understand its role in pathobiology of asthma. Over the years, the group gradually came to establish that adherent cells passaged in culture resemble soft glassy materials as far as the cell mechanics are concerned. Although soft glassy behavior of the cell has been replicated in other labs using other or similar techniques, the concept that cells are soft glassy materials seems contradictory to what has been learned from gel systems of reconstituted cytoskeletal protein filaments in vitro.

As usual suspects, the cultured cells were blamed for bringing about the peculiar soft glassy behavior that might not portray the true picture of cell mechanics in vivo. Such blame is reasonable due to the apparent structural difference between cultured cells and those observed in tissue or freshly isolated. In order to settle the discrepancy, Dr. Fredberg’s group decided to study the mechanics of the freshly isolated cells using the same technique as with the cultured cells.

The freshly isolated cells are the closest possible to those in vivo, and should more closely represent the cells in vivo with regard to the cell mechanics. However, it proved to be a major challenge to do such studies. The first problem was that it is extremely difficult to prepare freshly isolated cells in a state of attachment to the substrate in the culture dish in order to make mechanical measurement of these cells. There had been unsuccessful attempts to tackle this problem for about two years before I took up the task.

Then I spent about a year solving all aspects of this problem before the first good experiment was achieved. After the initial success in making the measurement, other problems soon followed, including complex issues of statistical analysis and interpretation of the experimental data.

Fortunately, I was surrounded by several geniuses to whom I could turn whenever I encountered a problem. Some of them are my coauthors on this paper. With the help of this resourceful team, all problems were eventually solved, one after another, with each of these individuals contributing an equal effort toward the solution.

Where do you see your research leading in the future?

There are still numerous unknowns regarding cell mechanics and rheology. For example, the physics underlying the soft glass rheology is not fully elucidated; the molecular pathways that regulate the cell’s physical state, whether it is more solid or more fluid, are not clear; how pathological factors affect the soft glassy rheology of the cells; whether there are more regimes of cytoskeleton dynamics, and whether the dynamic regimes are fixed or shiftable, etc. These are primarily the future topics which shall lead my research.

Do you foresee any social or political implications for your research?

My research involves basic sciences only. I don’t see that it has any social or political implications.

Dr. Linhong Deng
Professor and Director
Institute of National 985 Project on Biorheology and Gene Regulations
College of Bioengineering
Chongqing University
Chongqing, PRC
and
Visiting Scientist
Molecular and Integrative Physiological Sciences Program
Department of Environmental Health
Harvard School of Public Health
Boston, MA, USA